Information

Why is cisplatin a very potent antineoplastic for testicular cancer, but not necessarily for other cancers?


Cisplatin (structure below) is a platinum-based chemotherapeutic agent which is very effective in the treatment of some cancers. Its introduction was responsible for improving the cure rate for testicular cancer from 10% to 85% according to the wikipedia page on cisplatin.

However, it is not very effective for other types of cancers; interestingly, ovarian cancer does not respond well to it (Siddick, 2003).

Does someone know why cisplatin is so specific to testicular cancer? I haven't found any sources explaining this.


From the dedicated cisplatin website and Drugbank it appears its use is quite diverse and not confined to testicular cancers. Further, your linked (Siddick, 2003) paper mentions on the first line of its abstract that cisplatin hasclinical activity against a wide variety of solid tumors.

Cisplatin.org mentions that cisplatin finds use as chemotherapy against a range of cancers:

Cisplatin is a chemotherapy drug which is used to treat cancers including: sarcoma, small cell lung cancer, germ cell tumors, lymphoma, and ovarian cancer. [I]t can be a valuable part of a combination chemotherapy regimen. Look at the regimens given to patients and you will often see cisplatin as one of the drugs.

Moreover, cisplatin is explicitly used to treat ovarian cancer:

Treatment of ovarian cancer involves putting the cisplatin into the peritoneal cavity rather than a blood vessel. The type and extent of a cancer determines the exact dose and schedule of administering the drug.

As to your comment that cisplatin has "magical powers" I can say that it does not. The article that your linked cisplatin wikipedia page refers to (Einhorn, 1990) is a review paper that describes the efficacy of combination therapies with cisplatin. The high cure rate of 75% was reached when cisplatin was used in combination with etoposide plus bleomycin. The last 10% was theorized to be achievable with 'salvage chemotherapy'. Hence, it is not cisplatin on its own.

In general, it is common practice to use various chemotherapeutic agents in consort, preferably with differing modes of action to reduce the dose of each and hence lessening the side effects.

References
- Einhorn, JCO (1990); 8(11): 1777-81
- Siddick, Oncogene (2003); 22: 7265-79


Any apparently "magical" powers of cisplatin in testicular cancer have more to do with the disease than the drug.

Unlike the similarly male-specific prostate cancer, testicular cancer is generally seen in young men in their 20s or 30s (click on "number of new cases and deaths"). This paper suggests, as is generally thought to be the case for earlier-onset types of cancer, that the affected individuals thus had some predisposing mutation or change in gene regulation prior to 10 years of age. As a result, it takes fewer sporadic acquired mutations to lead to this early-onset cancer versus a late-onset type like prostate.

This difference in incidence pattern is important because a late-onset tumor has had more opportunity to develop a broad range of cancer cells having different mutations within the tumor. Such intra-tumor heterogeneity has been recognized for over 30 years as a reason for resistance of tumors to cell-killing therapy like chemotherapy. For example, a heterogeneous tumor might be more likely to have cells that have mutated in a way that happens to make them resistant to cisplatin.

Also, testicular cancers develop in an accessible part of the anatomy that typically receives a lot of attention from men of the ages of peak incidence, so they are much more likely to be caught at an early stage than are prostate, ovarian, or colon cancers within the abdomen.


Emerging role of long non-coding RNAs in cisplatin resistance

1 Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, People&rsquos Republic of China 2 Institute of Clinical Pharmacology, Central South University, Hunan Key Laboratory of Pharmacogenetics, Changsha, Hunan, People&rsquos Republic of China 3 Department of Medicine, Weill Cornell Medicine, New York, NY, USA

Abstract: Cisplatin (CDDP) is one of the most commonly used chemotherapy drugs for the treatment of various cancers. Although platinum-based therapies are highly efficacious against rapidly proliferating malignant tumors, the development of CDDP resistance results in significant relapse as well as decreased overall survival rates, which is a significant obstacle in CDDP-based cancer therapy. Long non-coding RNAs (lncRNAs) are involved in cancer development and progression by the regulation of processes related to chromatin remodeling, transcription, and posttranscriptional processing. Emerging evidence has recently highlighted the roles of lncRNAs in the development of CDDP resistance. In this review, we discuss the roles and mechanisms of lncRNAs in CDDP chemoresistance, including changes in cellular uptake or efflux of a drug, intracellular detoxification, DNA repair, apoptosis, autophagy, cell stemness, and the related signaling pathways, aiming to provide potential lncRNA-targeted strategies for overcoming drug resistance in cancer therapy.

Keywords: cisplatin, lncRNAs, chemoresistance, cancer

Cancer significantly affects the quality of life and is a leading cause of death worldwide. It has been reported that about 14.1 million new cancer cases and 8.2 million deaths occurred in 2012 worldwide. 1 In 2018, 1,735,350 new cancer cases and 609,640 cancer deaths are projected to occur in the USA. 2 Increasing national investment in cancer research contributes to accelerating progress in the prevention and treatment of cancer. Currently, the gold standard for antitumor therapeutic strategies is a combination of chemotherapy and surgery. However, chemotherapeutic anticancer agents are the standard treatment regimen for patients in whom surgery is not a viable option. 3 Cisplatin is one of the most widely used and successful cytotoxic drugs for the treatment of a broad variety of tumors such as ovarian, testicular, bladder, lung, esophageal, and nasopharyngeal carcinoma (NPC). Since the discovery of the antitumor activity of cisplatin, novel platinum-based agents (carboplatin and oxaliplatin) have been developed with reduced side effects and increased efficacy. 4 However, as a prototype of platinum-based agent, cisplatin remains widely used as a chemotherapeutic agent. When cisplatin is used in platinum-based chemotherapy, nearly 85% of patients with metastatic testicular cancer can be cured 5 and the 5-year survival rate in patients with completely resected non-small-cell lung cancer (NSCLC) tumors is improved. 6

Nevertheless, there exist many patients intrinsically resistant to cisplatin-based therapies, especially with colorectal, lung, and prostate cancers. What is more, originally sensitive tumors eventually develop chemoresistance, which is frequently observed in ovarian cancer. 7 Chemoresistance allows the cancer cells to become increasingly antagonistic and improves the ability of cancer invasion and migration, leading to tumor relapse and poor prognosis. 8,9 Emerging studies have revealed that dysregulated expression of long non-coding RNAs (lncRNAs) plays an essential role in cisplatin resistance. 10 The lncRNAs, which are  nucleotides (nt) in length and which lack a significant open reading frame, may play major roles in a wide variety of biological pathways and cellular processes at the epigenetic, transcriptional, and posttranscriptional levels. 10,11 Here, we briefly review the functions and mechanisms of lncRNAs in the regulation of drug resistance in cancer cells, mainly focusing on cisplatin chemoresistance.

As an alkylating agent, cisplatin was first described by Michele Peyrone in 1845, and its antitumor activity was discovered in the 1970s. 12,13 Since its approval by the US Food and Drug Administration for the treatment of testicular and ovarian cancer in 1987, 12,14 cisplatin has gradually become a first-line chemotherapeutic agent. The platinum atom of cisplatin interacts with nucleophilic N 7 -sites of purine in DNA to form inter- and intra-strand DNA crosslinks, 8,14 which results in DNA damage, cell cycle arrest, and activation of multiple signal transduction pathways, leading to cell apoptosis. 8,15 Moreover, cisplatin-induced production of reactive oxygen species and activation of inflammatory pathways may also contribute to the induction of apoptosis. 16 The introduction of cisplatin for the treatment of testicular cancer has improved its cure rate from 10% to 85%. 17 Unfortunately, the development of cisplatin resistance limits its efficacy in cancer treatment. Studies over the years have revealed multiple potential mechanisms related to cisplatin resistance (Figure 1). Cisplatin resistance may occur through reduced intracellular platinum accumulation due to decreased drug uptake or increased drug export in cancer cells. Downregulation of copper transporter 1 (CTR1) has been associated with resistance to cisplatin by reducing cisplatin uptake. 18 On the other hand, the efflux of cisplatin is mediated by transporting P-type adenosine triphosphatases (ATP) 7A and ATP7B, or multidrug-resistance-associated proteins (MRPs) in the cell membrane, and an upregulation of these efflux transporters is one of the major mechanisms of cisplatin resistance. 19 Cisplatin scavenging by intracellular detoxification is another major mechanism of cisplatin resistance, in which glutathione (GSH) plays a key role in the overexpression of enzymes involved in GSH synthesis and GSH conjugation has been reported to be associated with cisplatin resistance. 20 In addition, activation of the DNA damage systems, such as the nucleotide excision repair system, can attenuate the apoptotic process, leading to cisplatin resistance. Increased expression of nucleotide excision repair proteins, including XPF–ERCC1 complex, is associated with reduced efficacy of platinum-based therapy. 21 Since the mismatch repair (MMR) system can detect cisplatin-induced DNA lesion and activate the apoptotic signal, downregulation or a mutation of MMR-related genes such as MLH1 and MSH2 has been reported to contribute to cisplatin resistance. 22 Homologous recombination is another mechanism to repair cisplatin-induced DNA damage, and hence, a deficiency of breast cancer susceptibility proteins 1 and 2 (BRCA1/2), two critical components in the homologous recombination system, promotes cell sensitivity to cisplatin in cancer cells. 23 The expression of tumor suppressor protein p53 and p53-related nuclear transcription factors in cancer cells has been shown to mediate the cytotoxic effect of cisplatin. 24,25 As the cytotoxic effect of cisplatin is associated with apoptotic signaling pathways, the expression levels of Bcl-2 proteins, caspases, and mitochondrial intermembrane proteins are crucial factors in influencing cell sensitivity to cisplatin. 26󈞈 Furthermore, accumulating evidence suggests that the alteration in cell autophagy and PI3K/AKT1 signaling pathway can modulate cell sensitivity to cisplatin through compensating for cisplatin-induced lethal signals. 29,30

Figure 1 Molecular mechanisms of cisplatin resistance.
Notes: Multiple cellular alterations in cancer cells, including cell cycle, apoptosis, autophagy, stemness, intracellular detoxification, and drug influx/efflux, contribute to cisplatin chemoresistance through genetic and/or epigenetic regulation of multiple signaling pathways. Some major genetic and epigenetic factors are illustrated in the figure (see text for detailed discussion).
Abbreviations: ALDH1, aldehyde dehydrogenase 1 family member A1 ATG7, autophagy associated gene BRCA2, breast cancer susceptibility proteins 2 CTR1, copper transporter 1 ERCC1, excision repair cross-complementing rodent repair deficiency, complementation group 1 GSH, glutathione GST, glutathione S-transferase HR, homologous recombination MMR, mismatch repair MRP, multidrug-resistant-associated protein NER, nucleotide excision repair γ-GCS, γ-glutamylcysteine synthetase.

With the rapid development of sequencing technologies, it has been determined that ɚ% of the human genome encodes proteins, while the remaining transcriptional products are ncRNAs, which are considered as non-functional and transcriptional noise. 31 The ncRNAs can be classified into two major groups based on their sizes: small ncRNAs for those with a length  nt and lncRNAs for those with a length  nt, which includes intronic lncRNAs, intergenic lncRNAs, bidirectional lncRNAs, enhancer lncRNAs, and sense or antisense lncRNAs. 32 The lncRNAs can modulate gene expression at epigenetic, transcriptional, and posttranscriptional levels. 10,33 In recent years, various studies have suggested that lncRNAs are involved in embryonic development and in the etiology of many human diseases, especially cancer. 34 Using advanced sequencing technology, numerous lncRNAs have been found to be dysregulated or aberrantly expressed in multiple types of cancers. The lncRNAs have been reported to act as critical factors in cancer development and progression by regulating cell proliferation, cell death, metastasis, and angiogenesis. 35 As lncRNAs play an important role in tumor cell survival and death, it is conceivable that lncRNAs may also alter cell sensitivity to chemotherapy, which is aimed at eradicating tumor cells by inhibiting cell growth and promoting cell apoptosis. It has been reported that lncRNA H19 contributes to doxorubicin resistance through regulating MDR1 expression. 36 Du et al have reported that lncRNA-XIST promoted temozolomide resistance in glioma cells through DNA MMR pathway. 37 Moreover, lncRNA UCA1 has been shown to promote 5-fluorouracil resistance in colorectal cancer cells by inhibiting miR-204-5p. 38 In sum, growing evidence has indicated that dysregulated expression of lncRNAs in cancer cells plays an important role in the development of chemoresistance through altering the mechanisms of drug export, drug metabolism, DNA repair, cell proliferation, apoptosis, and autophagy. 3,11

lncRNA and cisplatin resistance

As stated above, numerous studies over the years have demonstrated that lncRNAs play a significant role in chemoresistance. 11 Aiming to understand the roles and mechanisms of lncRNAs in cisplatin resistance, we searched PubMed for all articles associated with “lncRNA and cisplatin resistance” and found that 22 lncRNAs have been reported to play an important role in cisplatin resistance through various mechanisms in multiple cancers (Table 1 Figure 2).

Table 1 Predictive lncRNAs involved in response to cisplatin
Abbreviations: ABCB1, ATP-binding cassette subfamily B member 1 ABCC1, ATP-binding cassette subfamily C member 1 ABCG2, ATP-binding cassette subfamily G member 2 ceRNA, competing endogenous RNA CREB, cAMP response element-binding protein CTR1, copper transporter 1 lncRNAs, long non-coding RNAs LSCC, lung squamous cell carcinoma MDR1, multidrug-resistant protein MRP1, multidrug-resistant-associated protein 1 N/A, not available NEAT1, nuclear-enriched abundant transcript 1 NSCLC, non-small-cell lung cancer P-gp, P-glycoprotein R, resistance Ref, reference S, sensitivity.

Figure 2 Role of lncRNAs in cisplatin resistance.
Notes: lncRNAs that regulate drug efflux, drug uptake, apoptosis, DDR, cell cycle arrest, and autophagy of cancer cells are implicated in cisplatin resistance. Gray arrows indicate inhibition and black arrows indicate activation.
Abbreviations: DDR, DNA damage response lncRNAs, long non-coding RNAs MDR1, multidrug-resistant protein MRP1, multidrug-resistant-associated protein 1.

Influx/efflux of cisplatin

Previous studies have indicated that reduced drug uptake or increased drug efflux in cancer cells, which results in a reduced intracellular platinum accumulation, is an important biochemical and cytological mechanism of cisplatin resistance. 8 ATP-binding cassette transporters, including P-glycoprotein and MRPs, can increase the drug efflux. Hang et al 39 have reported that Notch 1 could promote cisplatin resistance in gastric cancer (GC) through upregulation of lncRNA AK022798 expression. When lncRNA AK022798 was knocked down, the expression of MRP1 and P-glycoprotein MDR1, two membrane drug efflux-porters, was significantly decreased, while cell apoptosis, caspase-3, and caspase-8 activities were significantly increased in SGC7901 and BGC823 cisplatin-resistant cancer cells. These results indicated that lncRNA AK022798 is a crucial mediator in Notch 1-induced cisplatin resistance in cancer cells. 39 In GC tissues and cells, high expression of lncRNA PVT1 was significantly associated with the development of cisplatin resistance. 40 PVT1 silencing could reverse the cisplatin resistance in cisplatin-resistant cell lines, while upregulation of PVT1 decreased the sensitivity of parental GC cells to cisplatin, which was mediated through upregulation of MDR1, MRP, mTOR, and HIF-1a expression. 40 The lncRNA ANRIL has also been reported to be highly expressed in cisplatin-resistant and 5-fluorouracil-resistant GC tissues and cells. 41 Further studies have revealed that ANRIL knockdown might inhibit cell proliferation and invasion, promote anticancer agent-induced apoptosis, and reverse drug resistance in cisplatin- and 5-fluorouracil-resistant GC cell lines by downregulating MDR-related gene expression, including MDR1 and MRP1. 41 CTR1, a copper influx transporter, plays a vital role in platinum drug uptake and the development of cisplatin resistance. 42 In lung cancer cells, lncRNA nuclear-enriched abundant transcript 1 (NEAT1) might enhance cisplatin sensitivity by upregulating (−)-epigallocatechin-3-gallate (EGCG)-induced CTR1 expression. 43 Furthermore, NEAT1 might act as a competing endogenous RNA (ceRNA) of hsa-mir-98-5p to regulate CTR1 expression. 43

GSH is a kind of metallothionein, which shows a much higher affinity to cisplatin than DNA. 44 Increased GSH synthesis was associated with cisplatin resistance, and GSH depletion increased sensitivity to cisplatin. 45 As such, overexpression of enzymes involved in GSH synthesis and metabolism participates in the process of cisplatin resistance. The lncRNA H19 was overexpressed in ovarian cancer tissues and correlated with cancer recurrence, whereas H19 knockdown in A2780-DR cells increased their sensitivity to cisplatin treatment with a lower GSH level. H19 contributed to cisplatin resistance by regulating NRF2 and its target proteins including NQO1, GSR, G6PD, GCLC, GCLM, and GSTP1, which are involved in the GSH metabolism pathway. 46

DNA repair and cell cycle

Nuclear factor-κB (NF-κB) signaling-mediated activation of DNA damage response plays a role in the development of cell resistance to cisplatin. 47 The lncRNA HOTAIR overexpression induced cisplatin resistance in ovarian cancer cells and resulted in sustained activation of DNA damage response after cisplatin treatment through NF-κB activation due to Iκ-Bα (NF-κB inhibitor) downregulation. Collectively, these data suggests that HOTAIR contributes to chemoresistance through DNA damage-induced NF-κB signaling pathways. 48 HOTAIR has also been reported to promote cisplatin resistance by regulating p21 WAF1 (p21), a cyclin-dependent kinase inhibitor which inhibits cell proliferation by inducing G0/G1 arrest, in lung adenocarcinoma (LAD) cells. 49 In nasopharyngeal carcinoma (NPC) cells, knockdown of lncRNA ANRIL inhibited cell proliferation, while it induced cell apoptosis and potentiated cisplatin-induced DNA damage by regulating microRNA let-7a expression. 50

As cisplatin-induced DNA damage causes cell apoptosis, inhibition of apoptosis may also be involved in the acquired cisplatin resistance. p53, a tumor suppressor gene, plays a critical role in the apoptosis pathway. Several studies have shown that lncRNAs were associated with the cisplatin chemoresistance by downregulating p53-induced cell apoptosis. The lncRNA p53-dependent apoptosis modulator (PDAM) silencing induced cisplatin resistance in glioma cells by harboring wild-type p53, while BCL2L1 knockdown in PDAM-suppressed cells abrogated the cisplatin-resistant phenotype. 51 These data indicate that PDAM regulated cisplatin resistance by regulation of p53-dependent antiapoptotic genes (OTs). 51 The long non-coding RNA regulator of reprogramming (lncRNA-ROR), which played a crucial role in cell proliferation, migration, and apoptosis of NPC, promoted cisplatin resistance in NPC by improving cell proliferation and reducing cell apoptosis mediated by p53 signaling pathways. 52 In A549 cisplatin-resistant cells, lncRNA MEG3 expression was significantly downregulated and overexpression of MEG3 restored cell sensitivity to cisplatin by suppressing cell proliferation and inducing apoptosis and cell cycle arrest. 53,54 Further studies elucidated that MEG3-mediated chemosensitivity was associated with the WNT/β-catenin signaling pathway by regulation of p53, as well as with the mitochondrial apoptosis pathway. 55 In addition, Ma et al have revealed that downregulation of lncRNA TRPM2-AS inhibited cisplatin resistance, induced cell apoptosis, and altered cell cycle distribution in NSCLC through activating the p53-p66 shc pathway. 56

The Bcl-2 family is a key member in mitochondrial apoptosis pathway, which consists of the antiapoptotic family (such as BCL-2 and BCL-XL), the proapoptotic family (BAX and BAK), and the proapoptotic BH3-only protein family (such as BAD, BIK). 57 The lncRNA H19 contributed to cisplatin resistance in LAD by promoting cell migration via vimentin and reducing apoptosis via FAS, BAK, and BAX. The clinical study has shown that in patients with LAD, a high tumor H19 expression was negatively correlated with cisplatin-based chemotherapy response and a significantly shorter median progression-free survival, which were consistent with the data in in vitro experiment. 58 The lncRNA ENST00000457645 could remarkably reverse cisplatin resistance by promoting apoptosis of cisplatin-resistant CP70 cells, which was associated with altered levels of apoptosis proteins such as Bax and cleaved caspase-3. 59

The lncRNA PVT1 was upregulated in ovarian cancer tissues from cisplatin-resistant patients and in cisplatin-resistant cells. PVT1 overexpression promoted cisplatin resistance through regulating the expression of TGF-⓵, p-Smad4, and caspase-3, molecules related to the apoptotic pathways. 60 The upregulation of UCA1 lncRNA contributed to cisplatin resistance by promoting cancer cell proliferation while inhibiting apoptosis in bladder cancer and cervical cancer cells. 61,62 In human bladder cancer cells, UCA1-mediated chemosensitivity was associated with the apoptosis pathway by upregulating miR-196a-5p targeting p27 Kip1 . 61 In cervical cancer cells, UCA1 suppressed cell apoptosis by downregulating caspase-3 and upregulating CDK2, whereas cell proliferation was enhanced through inducing survivin and decreasing p21 expression. 62 In ovarian cancer cells, curcumin-induced MEG3 lncRNA expression due to demethylation was directly associated with a decrease in miR-214 and extracellular vesicle-mediated transfer of miR-214, resulting in an elevation of cisplatin-induced cell apoptosis and cell sensitivity to cisplatin-based chemotherapy. 63 The lncRNA SFTA1P increased cisplatin chemosensitivity by enhancing cisplatin-induced apoptosis by increasing the expression of hnRNP-U and GADD45A in lung squamous cell carcinoma. 64

It has also been reported that lncRNAs CUDR, HOTAIR, and HULC modulated cisplatin resistance through alteration of cell apoptosis, but their exact molecular mechanisms remain to be elucidated. 65󈞯 Wang et al 65 have reported that lncRNA CUDR (UCA1a) played a pivotal role in bladder cancer progression, and promoted cell proliferation, migration, and invasion in UM-UC-2 cells. In addition, CUDR overexpression might contribute to cisplatin resistance by antagonizing apoptosis. 65 HOTAIR also promoted cisplatin resistance in ovarian carcinoma. The knockdown of HOTAIR suppressed cell proliferation and invasion, and notably increased chemosensitivity to cisplatin specifically by promoting cisplatin-induced apoptosis in SKOV-3 cisplatin-resistance cells. 66 Patients with a high expression of HULC lncRNA in GC showed a significantly worse prognosis, and HULC knockdown enhanced the sensitivity of GC cells to cisplatin by enhancing cisplatin-induced apoptosis. 67

Studies over the years have demonstrated that diverse signaling pathways are involved in the development of drug resistance. 68 Analysis of mRNA, lncRNA, and miRNA expression profiles by microarray in cisplatin-resistant A549 cells and parental A549 cells revealed that 1,471 mRNAs, 1,380 lncRNAs, and 25 miRNAs were differentially expressed. 69 Gene coexpression network analysis identified many genes including lncRNA AK126698 that potentially play a significant role in cisplatin resistance. 69 Pathway analysis showed that the Wnt pathway was targeted by both miRNAs and lncRNAs including lncRNA AK126698. Moreover, in vitro cell culture experiments confirmed that AK126698 lncRNA induced cisplatin resistance in NSCLC through activating Wnt/β-catenin pathway. 69 UCA1 lncRNA expression levels were significantly higher in T24-resistant cells and bladder cancer tissues from patients treated with cisplatin, and overexpression of UCA1 lncRNA promoted cisplatin resistance in bladder cancer cells through upregulating Wnt6 expression, which consequently activated Wnt signaling. 70 The lncRNA HOTTIP could promote cell proliferation, cell cycle progression, and induce cell resistance to cisplatin by activating the Wnt/β-catenin pathway in osteosarcoma and ovarian cancer cells. 71

Autophagy plays an important role in the maintenance of cell hemostasis, and LC3, Beclin-1, and Atg family members are important factors in autophagosome formation. 72 Recently, several studies have reported that autophagy could act as a protective mechanism against cisplatin treatment in cancer cells. 29 Like 3-MA, an autophagy inhibitor, lncRNA GAS5 was shown to inhibit autophagy and, therefore, enhance cell sensitivity to cisplatin in NSCLC cells. 73 In human endometrial cancer cells, HOTAIR lncRNA contributed to cisplatin resistance by regulating autophagy mediated through the regulation of Beclin-1 expression. 74 The lncRNA XIST was upregulated in NSCLC cells and promoted the progression of NSCLC through regulating autophagy. Knockdown of XIST enhanced the chemosensitivity to cisplatin in NSCLC cells, which was reversed by the administration of a miR-17 inhibitor and overexpression of ATG7, a key factor in autophagosome formation. These data suggest that lncRNA XIST enhanced the chemoresistance of NSCLC cells to cisplatin by regulating autophagy via the miR-17/ATG7 pathway. 75 In human glioblastoma cells, the upregulation of lncRNA AC023115.3 promoted chemosensitivity to cisplatin by decreasing autophagy. Further mechanism experiments showed that AC02115.3 acted as a miR-26a sponge and increased its target gene GSK3β expression. 76

CSCs are a small population of specialized cells that have the potential to self-renew and differentiate into other tumor cell subtypes and are involved in tumor initiation, progression, distant metastasis, and chemoresistance. Emerging evidence indicates that lncRNAs play an important role in the maintenance of CSCs, increasing tumor cells’ resistance to chemotherapy. 77 HOTAIR lncRNA could promote tumorigenesis and tumor metastasis by affecting the stemness of CSCs. Moreover, Liu et al have found that HOTAIR contributed to cisplatin resistance by regulating the biology of tumor stem cells. 78 HOTAIR was overexpressed in tumor tissues from NSCLC patients with drug resistance and in cisplatin-resistant A549 cells, and knockdown of HOTAIR expression increased the sensitivity of A549/cisplatin cells to cisplatin. Further mechanistic studies demonstrated that HOTAIR-induced cisplatin resistance might be associated with the promotion of tumor sphere cell growth through upregulating tumor stem cell-related Klf4 expression. 78

In recent years, accumulating evidence indicates that lncRNAs, such as ceRNAs, could regulate target mRNA levels by combining competitively with common miRNAs, which is a potential mechanism in the regulation of cisplatin resistance. The lncRNA NEAT1-enhanced cisplatin sensitivity was mediated through upregulating EGCG-induced CTR1 expression due to its sponging action on mir-98-5p in lung cancer cells. 43 The lncRNA LINC00161 promoted cisplatin-induced apoptosis and decreased cell resistance to cisplatin. Further studies revealed that the effect of LINC00161 was achieved through upregulation of IFIT2 protein expression mediated via competitively sponging miR-645 action on IFIT2 mRNA. 79 Moreover, other lncRNAs such as CASC, GAS5, and MEG3 have also been reported to function as ceRNAs of miR-21 and miR-21-5p and upregulate PTEN and SOX7 expression, respectively, in NSCLC 81,82 and cervical cancer cells, 80,83 resulting in an alteration of cell sensitivity to cisplatin. In glioma cell, lncRNA AC023115.3 acted as a ceRNA for miR-26a and attenuated the inhibitory effect of miR-26a on GSK3β, which impaired cisplatin resistance. 76

Cisplatin resistance, either intrinsic or acquired, is a significant burden for successful cancer treatment. Here, we have discussed the roles of lncRNAs in cisplatin chemoresistance (Table 1) through mechanisms such as alterations in cellular uptake or efflux of the drug, intracellular detoxification, cell apoptosis, autophagy, DNA repair, CSC, and ceRNA action (Figure 2). Although the study of lncRNAs on chemoresistance is still in its infancy, growing evidence suggests that lncRNAs may serve as biomarkers for cancer diagnosis and prognosis and molecular targets for cancer therapy, including chemoresistance. BC-819 (H19-DTA) is a DNA vector that carries the gene for diphtheria toxin-A under the control of the H19 promoter sequence, which therefore has the potential to treat various malignancies that overexpress H19 lncRNA. Current clinical trials indicate that BC-819 given locally in combination with systemic chemotherapy may provide an additional therapeutic benefit for the treatment of pancreatic, bladder, ovarian, or peritoneal cancer. 84󈟂

Of course, considerable work needs to be done for the lncRNA-based cancer therapy to be applied in clinical practice. First, chemoresistance is a complicated biologic process in which the roles and mechanisms of lncRNAs are still poorly understood. The majority of studies are in in vitro systems. Second, informative functional studies rely on animal experiments. However, establishing lncRNA function model in mice is difficult. Third, the sequence conservation of lncRNAs is much poorer than that of protein-coding genes. Thus, the lncRNAs which have been successfully verified in animal models may be not able to translate into clinical practice. Fourth, as a therapeutic strategy, the technology for either elimination or overexpression of a specific lncRNA at specific target cells in vivo is still in development. Finally, it is currently unclear whether interference of an endogenous lncRNA expression in the body will generate deleterious biologic consequence. Nevertheless, studies over the last decades have provided sufficient data to warrant further investigation of lncRNAs on tumorigenesis, tumor progression, and tumor chemoresistance.

This work was supported in part by the National Natural Science Foundation of China (number 81673516) and a Special Talents Fund from the Central South University of China. We are very grateful to Ms Jale Manzo (Department of Medicine, Weill Cornell Medicine, New York, NY, USA) for editing grammar and spelling of the article.

The authors report no conflicts of interest in this work.

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 201565(2):87�.


Neuropathy in the Cancer Patient: Causes and Cures

Neuropathic pain is often defined as pain caused by a lesion or disease of the somatosensory nervous system. Peripheral neuropathies arise from disorders associated specifically outside the central nervous system (CNS) and within the peripheral nervous system. 1 Symptoms of peripheral neuropathy include numbness, tingling, paresthesia (pins and needles sensations), sensitivity to touch, or muscle weakness. In patients with extreme symptoms, they may present with burning pain, muscle wasting, paralysis, or organ dysfunction. 1

There are multiple causes of peripheral neuropathy, and in the cancer patient, identifying the culprit may be complicated by a plethora of etiologies. This review will focus on potential origins of neuropathic pain in the cancer patient, including both disease- and drug-induced peripheral neuropathy current treatment modalities of cancer-induced peripheral neuropathy (CIPN) and how to prevent the development of peripheral neuropathy in cancer patients. According to the American Cancer Society, about 11.9 million Americans suffer from cancer pain, but it remains unclear what portion of that pain is specifically neuropathic versus somatic, visceral, or a combination. It also is equally unclear what percentage of these cases is due to disease, treatments, or both. 2

Cancer-induced Peripheral Neuropathy

By virtue of the nature of the disease, cancer alone can cause neuropathy. Certain neuropathies can develop due to remote or paraneoplastic effect invasion of the cancer or compression of the nerves or as a side effect secondary to treatment. 3 The cancers commonly associated with neuropathies are listed in Table 1. This section focuses on the role of CIPN in the cancer patient.

PEN/SN
Paraneoplastic encephalomyelitis/sensory neuronopathy (PEN/SN) is a type of neuropathy most commonly associated with lung cancer, typically small-cell lung cancer. Unlike other types of pain syndromes, PEN/SN is not due to the effects of the tumor itself, metastasis, treatment, infection, or metabolic abnormalities. Rather, it is thought to be a result of "remote effects" of the cancer that lead to the production of antibodies or inflammatory cells against any neural antigens that the tumor may express. 4 The symptoms can be acute or progressive. Patients typically present with numbness and parasthesias in the distal extremities, usually unilaterally. Eventually, this type of neuropathy may result in loss of proprioception and sensory ataxia. Oftentimes, these patients develop confusion, memory loss, depression, hallucinations, seizures, and/or cerebellar ataxia. Treating the underlying cancer does not always affect the clinical course of PEN/SN. Some patients may occasionally improve after the tumor has been treated. Other treatments such as plasmapheresis, intravenous immunoglobulin, and immunosuppressive agents have not shown any greater benefit. 3,4

Tumor Infiltration
Peripheral neuropathy may develop secondary to tumor infiltration. Leukemia and lymphoma cells can infiltrate the cranial and peripheral nerves the result can be mononeuropathy, mononeuropathy multiplex, polyradiculopathy, or plexopathy as a complication. This neuropathy is generally painful and may be an indication of newly diagnosed cancer and/or disease progression. The symptoms can be managed by treating the underlying hematological malignancy or by initiating glucocorticoids if not contraindicated. 3

Lymphoma
Lymphoma most often causes neuropathy either by infiltration or direct compression of nerves, or by a paraneoplastic process. 3 Most peripheral complications are due to non-Hodgkin's lymphoma (NHL). 5 Hodgkin's lymphoma, on the other hand, rarely causes neuropathy it generally causes immunological disorders of the peripheral nervous system such as inflammatory plexopathy or Guillain-Barré syndrome. 5 Although the NHL neuropathy may manifest as a sensory or motor symptom, it is commonly seen as a sensorimotor neuropathy. The course of the neuropathy may be acute, gradually progressive, or relapsing and remitting. The neuropathy may respond to the treatment of the underlying lymphoma. 5

Multiple Myeloma
Multiple myeloma (MM) is a common hematologic malignancy associated with monoclonal gammapathy. About 40% of patients with MM develop some type of peripheral neuropathy. Patients may develop painful paresthesia and loss of differentiating between pinprick and temperature sensations. The mechanism of the neuropathy is primarily due to amyloidosis with infiltration of the nerves. It is also thought to be due to the metabolic or toxic effects of the systemic consequences of renal failure. 3,5

Waldenström's Macroglobulinemia
Waldenström's macroglobulinemia is a cancer of the B lymphocytes. It is caused by a malignant proliferation of lymphoplasmacytoid cells, which produces an overabundance of immunoglobulin M monoclonal proteins with a κ light chain—causing the blood to become hyperviscous. The mechanism of neuropathy is unknown, but it's thought to be related to myelin-associated glycoprotein antibodies. However, a causal relationship has not been confirmed. 6

Solid Tumors
The most common solid tumors associated with peripheral neuropathy include breast cancer and lung cancer as reported in case reports and in a prospective, multicenter study in radiotherapy oncology units. 7,8

Bone Marrow Transplantation
Although not a neoplasm, bone marrow transplantation (BMT) is a treatment for certain malignancies, which may cause neuropathy. Peripheral neuropathy associated with BMT usually occurs concurrently with chronic graft-versus-host disease (GVHD). Chronic GVHD is a clinical syndrome that occurs in approximately 60% to 80% of long-term survivors of allogeneic hematopoietic stem cell transplantation. 3 Chronic GVHD is defined as an autoimmune disorder that occurs 100 days after the allogeneic transplant. Symptoms of chronic GVHD usually include oral ulcerations keratoconjunctivitis xerophthalmia hepatic failure obstructive lung disease involvement of the skin and soft tissues and involvement of the neuromuscular system, CNS, and the gastrointestinal tract. 9 These features are shared with a variety of autoimmune disorders, and it is possible that the etiology of this peripheral neuropathy is an immune-mediated response directed against the peripheral nerves. Patients may develop cranial neuropathies, sensorimotor polyneuropathies, multiple mononeuropathies, and severe generalized neuropathies. Symptoms may improve when the intensity of the immunosuppressive therapy for GVHD is increased. 3

Non–cytotoxic-induced Peripheral Neuropathy

When identifying medication-induced peripheral neuropathy in a cancer patient, it is important to first identify which of the patient's non-cytotoxic medications could cause or contribute to their painful neuropathy. All iatrogenic causes must be considered in order to delineate the various possibilities and capitalize on opportunities for successful prevention and treatment. Table 2 outlines some of the common agents that cause peripheral neuropathy. It excludes the antiretrovirals that are well-known to cause peripheral neuropathy.

Antimicrobial Agents
Some antimicrobial agents have been shown to induce peripheral neuropathy. Among antituberculosis agents, isoniazid and ethambutol (Myambutol) are well known for inducing peripheral neuropathy. 10 Isoniazid induces a mixed sensorimotor peripheral neuropathy. This neuropathy can be prevented by administering vitamin B6 or pyridoxine. Long-term use of isoniazid can cause depletion of pyridoxine by two mechanisms. First, isoniazid metabolites can bind to and inactivate pyridoxine. Second, isoniazid inhibits the enzyme pyridoxine phosphokinase, which is necessary to activate pyridoxine to pyridoxal-5'-phosphate, the active cofactor in many reactions that involve pyridoxine. 11 Ethambutol can also cause peripheral neuropathy of the extremities, which is manifested by numbness and tingling, 12 but it is much less neurotoxic than isoniazid.

Nitrofurantoin, an antibacterial, has also been reported to cause mixed sensorimotor neuropathy. The symptoms may develop during or after treatment with nitrofurantoin. 13 It is more prevalent in patients with renal impairment however, it has also been reported in patients with normal renal function. 14

Peripheral neuropathy has also been reported in patients treated with the antibiotic metronidazole at conventional doses for 6 to 24 weeks. 15 Dapsone, used in the treatment of bacterial skin infections, has been linked to peripheral neuropathy. In a case reported by Koller et al, the patient experienced significant motor deficit and loss of vibration sense shortly after initiation of low-dose dapsone. This reaction was reversible after cessation of the therapy. This patient was a slow metabolizer of isoniazid (slow acetylator), thus also was most likely a slow acetylator of dapsone. 16

Cardiovascular Agents
For the cancer patient with cardiovascular comorbidities, it is important to properly evaluate all their medications, as some cardiovascular drugs can cause peripheral neuropathy. Propranolol is a commonly prescribed non-cardioselective ß blocker used in the treatment of hypertension, angina, secondary prevention of myocardial infarction, arrhythmia, migraine headaches, and tremor. It is also used in the management of hyperthyroidism and thyrotoxic crisis. There have been several documented episodes of peripheral neuropathy associated with the use of propranolol—for example, paresthesias of the hands, peripheral neuropathy, and myotonia have been reported with the use of propranolol. 17

Hydralazine, a vasodilator used in the treatment of hypertension and as an adjunct following heart failure, may cause a subclinical peripheral neuropathy in about 15% of patients. 18 The development of peripheral neuropathy is linked to an antipyridoxine effect, since hydralazine is structurally similar to isoniazid. Peripheral neuropathy has also been linked to the use of amiodarone and disopyramide (Norpace). 19-21 Studies have shown that long-term use of high-dose amiodarone therapy induces peripheral neuropathy. 22 The agent is thought to cause demyelinating neuropathy. 22

Other Agents
Chloroquine (Aralen) is a quinolone derivative with several indications such as malaria, sarcoidosis, systemic lupus erythematosus, scleroderma, and rheumatoid arthritis. Chloroquine is an amphiphilic drug with both hydrophilic and lipophilic properties thus, it interacts with the anionic phospholipids of cell membranes. The drug–lipid complexes are resistant to lysosomal destructions so the result is formation of vacuoles filled with myeloid debris. 6 Peripheral neuropathy ensues secondary to severe vacuolar myopathy, which has been supported by histological studies showing both axonal degeneration and damage to Schwann cells.

Hydroxychloroquine shares structural similarity with chloroquine and it also causes neuropathy. Patients taking hydroxychloroquine do not have severe abnormalities as they would with chloroquine-induced peripheral neuropathy. 6

Phenytoin is an anticonvulsant, which, when given long term, could cause predominantly sensory polyneuropathy. This type of neuropathy could be bothersome, but is usually mild and rarely symptomatic. 10

Colchicine (Colcrys) inhibits the polymerization of tubulin into microtubules. It is used to treat patients with gout. The proposed mechanism of neuropathy lies in the disruption of the microtubules that lead to defective intracellular movement or lysosomes, which accumulate in autophagic vacuoles in muscle and nerve fibers. 6 This mechanism of iatrogenic neuropathy correlates closely with that caused by the vinca alkaloids as outlined below.

Although rare, indomethacin has also been associated with the development of mostly motor peripheral neuropathy. 23

Chemotherapy-induced Peripheral Neuropathy (CIPN)

Peripheral neuropathy is a well-documented adverse reaction to several cancer chemotherapeutic agents (Table 3). These agents include the platinum-based salts (eg, cisplatin, carboplatin, oxaliplatin), vinca alkaloids (eg, vinblastine, vincristine), and the taxanes (eg, paclitaxel, docetaxel). The incidence of the neuropathy varies, and the incidence rates can increase to about 38% when agents are combined. 24 However, newer anti-cancer formulations have also proven to cause neuropathies.

Bortezomib (Velcade), a proteasome inhibitor, is one such agent. It is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells indicated for the treatment of MM, and as a second-line therapy in patients with mantle cell lymphoma. 25 It is increasingly being recognized that bortezomib-induced peripheral neuropathy may be a proteasome inhibitor class effect, producing primarily a small fiber and painful, axonal, sensory distal neuropathy. 26

The mechanism of bortezomib-induced peripheral neuropathy is currently unknown. When bortezomib is administered, metabolic changes are observed secondary to accumulation of the drug in the dorsal root ganglia cells mitochondrial-mediated dysregulation of calcium (Ca 2+ ) homeostasis and dysregulation of neurotrophins may be responsible for this adverse event. 26 There is no neuroprotective treatment effective to reduce bortezomib-induced peripheral neuropathy however, a dose modification algorithm is available as a guideline.

Cytosine arabinoside, also known as cytarabine or Ara-C (Cytosar-U), is an antimetabolite used in the management of leukemia and lymphoma. Peripheral neuropathy has been reported in patients at cumulative doses of 36 to 60 g/m 2 . 27 The mechanism of toxicity is not well understood. It has been hypothesized that the antimetabolite action of cytarabine inhibits proteins that are important in the production of myelin or in axonal transport. These neuropathies may start within hours or weeks after treatment. 28

Platinum-based Agents
Platinum-based agents exert their antineoplastic effects by forming covalent bonds and creating a crosslink with DNA, preferentially to guanine. Cisplatin is a platinum agent used widely in the treatment of a variety of malignancies such as ovarian, testicular, and bladder cancer. It produces mainly a sensory neuronopathy at cumulative does of 225 to 501 mg/m 2 . The proposed mechanism of this neuropathy is due to potential inhibition of transcription of important proteins and impairment of axonal transport secondary to cisplatin's binding to DNA. 3 Oxaliplatin administration also has been linked to the development of peripheral neuropathy. 29 The neuropathy is mostly sensory and it occurs in two forms—acute and chronic. Acute oxaliplatin-induced neuropathy is the most common form (>90%), develops shortly after infusion, and is transient. Patients will develop dysthesias that are exacerbated by cold and sometimes muscle contractions and weakness. For chronic oxaliplatin-induced peripheral neuropathy, dose intensity plays a significant role (cumulative doses ≥540 mg/m 2 ). 29 It is usually observed after a long treatment duration and resembles cisplatin-induced neuropathy. 30 This neuropathy can be mitigated by administering intravenous calcium and magnesium prior to and post-oxaliplatin infusions. 31

Taxanes
Taxanes are a class of medications that disrupt microtubule function. Paclitaxel is utilized in chemotherapy regimens for the treatment of ovarian cancer, breast cancer, lung cancer, bladder cancer, head and neck cancer, and lymphoma. It has shown to produce dose-dependent neuropathy, predominantly sensory neuropathy. 7 Up to 85% of patients exposed to paclitaxel after 3 to 7 cycles at a dose of 135 to 200 mg/m 2 develop mild, subclinical peripheral neuropathy. 32 For doses between 250 to 350 mg/m 2 , neuropathy can develop within the first or second cycle. 33-35 Docetaxel is a semisynthetic analog of paclitaxel that also produces a dose-dependent sensory neuropathy with an incidence rate of 17% to 50%. 36,37 The taxanes induce the peripheral neuropathy secondary to toxic effect to the neuronal cell body, axon, or both. 3

Vinca Alkaloids
Vinca alkaloids inhibit microtubule formation by binding to α- and β-tubulin. Vincristine produces a sensorimotor and autonomic neuropathy. The earliest symptoms presented include paresthesias and numbness that occur in the fingers prior to the toes. Symptoms can occur within 14 days of a single 2 mg/m 2 dose. 7,38 Vinorelbine, another vinca alkaloid, used in a variety of different cancers, has a much lower incidence of neurotoxicity compared to vincristine. 7,39 In a study of vinorelbine, dose-related peripheral neuropathy has been observed in 20% to 50% of exposed patients, with severe neuropathy reported only in 1% of patients. 40 Impairment of the microtubules interferes with axon transport, which subsequently causes cytoskeletal disarray and degeneration.

Other Agents
Etoposide is a semisynthetic derivative of podophyllotoxin used in lymphoma, leukemia, small cell lung cancer, and testicular cancer. Four percent of patients treated with etoposide develop moderate to severe distal, axonal, and mostly sensory polyneuropathy. The potential mechanism for this neurotoxicity is inhibition of microtubule function. 41

Ifosfamide is an analogue of cyclophosphamide with neuropathy as a side effect at a total dose of at least 14 g/m 2 . 42 Patients often experience numbness and painful paresthesias that begin in both hands and feet within 10 to 14 days after treatment. 42

Thalidomide (Thalomid) is an antiangiogenic drug used in patients with refractory MM. Greater than two-thirds of patients exposed to thalidomide for at least 6 months experience some form of peripheral neuropathy. Mostly motor, sensory, and autonomic dysfunctions are observed. 43

Management of Neuropathic Pain

The World Health Organization's analgesic ladder for cancer pain relief recommends a stepwise approach, starting with non-opioids then moving up the ladder to opioid therapy, as needed. 44 Several factors have been identified that impede appropriate pain control in cancer patients. 45 Often, when multiple agents are administered at the same time, it is difficult to assess which of the agents are efficacious and which cause adverse events. Proper management of neuropathic cancer pain (NCP) is complex because of the heterogeneity of etiologies, variable symptoms, and the underlying neurogenic pathophysiology. These properties contribute to patients' poor responses to conventional pain management therapy.

An additional consideration is that most of the agents used in the management of neuropathic pain are grouped according to their pharmacological class or original therapeutic category—such as antidepressants and anticonvulsants. Confusion occurs when healthcare professionals unfamiliar with neuropathic pain assume that all anticonvulsants or antidepressants may be efficacious in the management of neuropathic pain. A pain medication that was efficacious for a group of patients with similar mechanisms of neuropathic pain may not translate to equal response in a different patient population or varying neuropathy types. 45

Lastly, it has been noted that opioid therapy has limited utility in treating neuropathy. 46 However, it is important to note that certain opioids seem to have more usefulness than others for neuropathic pain disorders these include methadone, levorphanol, tapentadol (Nucynta), and
tramadol. 47 Often, higher doses of opioids are required to manage neuropathic pain. However, increased opioid doses usually translate into increased risk of toxicity, which often leads to discontinuation of the therapy. When managing patients with NCP, it is important to initiate pharmacotherapy one medication at a time, with a slow titration to match the patient's response and tolerability. 48 Thus, the recommendation is to tailor each patient's pain management therapy to suit the individual.

Table 4 highlights treatments for NCP. As noted, addition of adjuvant analgesics to schedule II and III opioids are the mainstay of neuropathy management in a cancer patient however, non-opioid analgesics that combine multiple mechanisms across two or more agents are often more useful than adding or continuing an opioid. A list of recommended adjuvants include antiepileptic drugs (AEDs), antidepressants (eg, tricyclic antidepressants, duloxetine [Cymbalta], and venlafaxine), corticosteroids, bisphosphonates, N-methyl-D-aspartate (NMDA) antagonists, and other substances. Selection of the right agent depends on side-effect profile, and the final choice should be based on identifying the type of painful neuropathy and perhaps comorbid non-neuropathic pain issues. If, for example, the patient does in fact require an opioid other than for neuropathy, it makes sense to select an agent that is particularly useful for both pain types.

Adjuvant Analgesics

Antidepressants
Tricyclic antidepressants (TCAs) inhibit norepinephrine and serotonin reuptake by blocking the serotonin and norepinephrine transporters. This action results in an increased synaptic concentration of serotonin and norepinephrine to enhance neurotransmission. TCAs also modulate peripheral sodium channels and antagonize NMDA to a small degree. As a result, they are known to enhance dorsal root inhibition and reduce peripheral sensitization. 49 Since it was first reported by Paoli et al in 1960, 50 TCAs have been shown to exhibit an effect in managing chronic pain. In addition, clinical reports have also demonstrated their effectiveness in treating neuropathic pain and HIV sensory neuropathy. The effectiveness of amitriptyline in relieving neuropathic pain following breast cancer was reported by Kalso et al in a randomized, placebo-controlled study with a 2-week washout period. 51 Fifteen patients participated in the study, and each started at a dose of 25 mg, which was escalated to 100 mg daily over 4 weeks. At the end of the study, 53% of the patients were classified as good responders (50% decrease in pain intensity) with a median dose of 50 mg amitriptyline. The patients who were poor responders reported more adverse effects with amitriptyline and placebo.

Despite efficacy in treating neuropathic pain related to breast cancer, the adverse effects prevent many patients from regularly using the medication. Tertiary amines such as amitriptyline, imipramine, and doxepin produce a greater anticholinergic activity than the secondary amines: nortriptyline and desipramine. Anticholinergic side effects include dry mouth, impaired diaphoresis, increased thirst, tachycardia and pupillary dilation. Patients may also experience urinary retention, agitation, cognitive impairment, seizures, cardiac arrhythmias, and heart block. The anticholinergic side effects all can add to problematic side effects that are common with opioids.

TCAs should be started at the lowest effective dose possible and should be given at bedtime. The dose can be titrated upward slowly every 3 to 7 days usually until 150 mg or until adverse events make them intolerable. 45

Serotonin norepinephrine reuptake inhibitors (SNRIs) have a different chemical structure compared to TCAs. They exert their antidepressant effects by inhibiting norepinephrine and serotonin reuptake. Venlafaxine is an SNRI with some efficacy for neuropathic pain. Data supporting its use in this patient population reported a number needed to treat (NNT) of 3.6. In a randomized, crossover trial of venlafaxine (220 mg/d) and imipramine (150 mg/d) in patients with polyneuropathy, both antidepressants provided superior relief compared to placebo. 52 However, there were no differences in efficacy between those two groups. Venlafaxine was effective at a dose >150 mg/day in diabetic neuropathy, whereas 75 mg daily was ineffective. The side effects of venlafaxine include hypertension, which limits its use in patients with pre-existing or uncontrolled hypertension. 53 The efficacy of venlafaxine in cancer patients was demonstrated in a study by Tasmuth et al. 54 In the randomized, double-blind, crossover study, patients given venlafaxine over a 10-week period showed superior pain relief for painful polyneuropathy and neuropathic pain following treatment with venlafaxine compared with placebo. 53

Duloxetine is an SNRI that is FDA approved for the treatment of diabetic neuropathy. Recently, it was reported in a randomized, placebo-controlled phase III trial to be effective in reducing painful chemotherapy-induced peripheral neuropathy. 55 The study showed that duloxetine 60 mg daily was efficacious and well tolerated for the treatment of either taxane- or platinum-related painful chemotherapy-induced peripheral neuropathy.

Milnicipran (Savella) is also an SNRI, which is FDA approved for the management of fibromyalgia, but not depression. 56 There have been no comprehensive studies involving milnacipran in cancer patients with peripheral neuropathy. However, since it has similar mechanisms as other medications in this class, it is probable that this drug may have utility in some patients.

Antiepileptics
Gabapentin is an analogue of the neurotransmitter γ-aminobutyric acid (GABA). The agent binds to the α xml:lang="ar-SA">2 δ subunit of calcium-dependent voltage-gated channels in the nervous system. Gabapentin is an anticonvulsant medication that currently has the broadest evidence for efficacy in the management of neuropathic pain. 57-59 It exerts its action on the brainstem via its glutamate-dependent mechanism. It has also been shown to have antimallodynic effects through alteration of the microglial cell function. In one study, 75 patients with CIPN and neuropathic pain were given a fixed low dose of gabapentin (800 mg/d). 60 These patients were compared to 35 patients in the control group (same symptoms and history of similar treatment who refused gabapentin) who were given fixed-dose naproxen (250 mg bid) and codeine/acetaminophen (30/500mg tid). The authors noted that outcomes were based on four stages of analgesic response: complete, partial, minor, and no response. In the gabapentin arm, the treatment led to 25.3% complete response, 44% partial response, 25.3% minor response, and 5.3% no response. In the control group, none of the patients experienced complete response percentages for partial, minor, and no response were 5.7%, 45.7%, and 48.6%, respectively. 60

In another study evaluating gabapentin in cancer patients previously treated with opioids with minimal analgesia response, 121 patients were given gabapentin at a dose of 600 to 1,800 mg daily. The study found a significant difference of average pain intensity between gabapentin (pain score, 4.6) and placebo group (pain score, 5.4 P=0.0250). Among secondary outcome measures, dysesthesia score showed a statistically significant difference (P=0.0077). This study demonstrated that patients who were unsuccessfully managed on opioids can transition to gabapentin and obtain pain relief. 61

In addition, gabapentin has been shown to be helpful in patients with burning pain, shooting pain, and allodynia when pain does not respond to opioids. Results from a study looking at a combination of gabapentin with morphine showed improvement in sleep, daily activity, mood, and quality of life in cancer-related pain conditions. 62 Gabapentin also is a useful medication for patients with malignancies of the upper abdomen such as pancreatic cancer for reducing pain associated with procedures in cancer and for decreasing myoclonic movements that are associated with high doses of opioids in cancer pain. 61,62

Effective doses of gabapentin for neuropathic pain in adults range from 1,800 to 3,600 mg daily, in divided doses, based on a meta-analysis of double-blind placebo-controlled, randomized trials in 2003. 63 Effective counseling points for patients include knowing that the drug can induce somnolence, dizziness, and some mild peripheral edema.

Pregabalin's (Lyrica) mechanism of action is similar to gabapentin: both bind to the α xml:lang="ar-SA">2 δ subunit of voltage-gated calcium channels of the nervous system. Pregabalin also minimizes the release of the neurotransmitters glutamate, norepinephrine, substance P, and calcitonin gene-related peptide. It does not bind directly to GABA receptors. Pregabalin has been approved for postherpetic neuropathy and peripheral diabetic neuropathy, but not NCP. The efficacy of pregabalin to provide significant pain relief and decrease the need for higher opioid doses in cancer patients battling neuropathic pain was assessed in a prospective, open-label study. 64 In the study, 66 cancer patients with neuropathic pain resistant to a combination of acetaminophen, codeine, non-steroidal anti-inflammatory drugs, and methylprednisolone were randomly divided into two groups. Group one received pregabalin added to their pain regimen. Pregabalin was titrated up to 600 mg daily until pain relief was observed or patients experienced intolerable side effects. The second group received fentanyl 25 mcg per hour, which was escalated by 25 mcg per hour every 72 hours—up to a maximum of 125 mcg per hour—until the patient experienced adequate pain relief or intolerable toxicities. The authors discovered that pregabalin was effective in providing significant pain relief (69% decrease in a visual analogue scale [VAS] pain score—from 7.8 to 2.4) and both minimized the use of opioids and opioid-induced side effects. Pregabalin was also found to be efficacious in an open-label study of pediatric cancer patients on a daily dose of 150 to 300 mg for 8 weeks. 65 The investigators reported significant and long-lasting pain relief in 86% of the children, and the median VAS score decreased by 59%. Adverse effects were infrequent and transient. According to pharmacokinetic studies, pregabalin is more potent than gabapentin because its binding affinity for the α2δ subunit is six times greater than that of gabapentin, it has faster absorption (does not bind to plasma proteins), and has greater bioavailability (>90%). 66

Other AEDs have shown efficacy in other types of neuropathic pain but not in neuropathic pain associated with cancer. For instance, lamotrigine is effective in treating HIV sensory neuropathy, painful diabetic neuropathy, central poststroke pain, and pain from spinal cord injury. 67-70 There has been wide application of anticonvulsants in neuropathic pain management however, only a few trials have shown efficacy in cancer patients. We must be especially cognizant that drugs such as lamotrigine may carry a higher risk of hepatotoxicity in patients receiving hepatotoxic antineoplastics. A huge advantage of gabapentin is that it's not metabolized in humans, has very limited effect on the liver, and has relatively no drug interactions for this reason. 71 It should be noted, however, that the dose of gabapentin must be adjusted for renal insufficiencies beginning with a creatinine clearance <60 mL per minute. Pregabalin presents less of an issue with reduced renal function. 66

Other Agents
Tramadol works by inhibiting norepinephrine and serotonin reuptake, and has indirect monoaminergic action similar to the TCAs. 72 The NNT with tramadol compared to placebo was 3.8, with at least 50% relief of the neuropathic pain alleviated. 72,73 In patients with musculoskeletal pain and NCP, the NNT for tramadol is 3.4. Tramadol has been shown to improve the quality of life in patients with neuropathic pain. There was no change in their level of anxiety, depression, and nervous system function despite obtaining adequate analgesic control. Generally, a common starting dose of immediate-release tramadol is 100 mg daily titrated up to 200 to 400 mg daily (in four divided doses). Efficacy for neuropathic pain can be observed at doses >250 mg daily. Due to its low abuse potential and minimal chance of developing tolerance and dependence during long-term use, tramadol serves as a good alternative for cancer patients with disease-induced neuropathic pain. The most common side effects associated with tramadol include dizziness, nausea, constipation, somnolence, and orthostatic hypotension. It is possible for patients to develop seizures when tramadol is used concomitantly with selective serotonin reuptake inhibitors or monoamine oxidase inhibitors.

Methadone is an opioid that blocks NMDA receptors and inhibits reuptake of norepinephrine—both activities contributing to its efficacy in the management of neuropathic pain and NCP. Cancer patients who might be ideal candidates for a trial of methadone include patients with poor pain control, those who have received an adequate trial of other schedule II or III opioids, patients with severe or multiple toxicities to other strong opioids, and those receiving opioids who have difficulty swallowing. 74 Methadone is associated with life-threatening adverse effects that are attributable to elevated serum levels from drug interactions. Drugs that inhibit P-glycoprotein and cytochrome P450 isoenzymes CYP2C19, CYP3A4, and CYP2B6 could significantly increase serum levels of methadone and induce methadone toxicity. 75

Ketamine is a general anesthetic that recently has been studied as a postoperative pain medication. Ketamine is an NMDA-receptor antagonist. The NMDA receptors within the spinal cord have been shown to play a significant role in the pathophysiology of chronic neuropathic pain. At subanesthetic doses, ketamine has been shown to reduce hypersensitivity in the dorsal horn. 76 There has been some suggestion that ketamine may reduce opioid-resistant NCP. When combined with morphine, ketamine provided superior pain relief and opioid-sparing ability. 76 There are multiple case reports of ketamine's use, either orally or intravenously, as an adjuvant for cancer-induced neuropathic pain management. What limits the use of ketamine are the potential developments of dissociative reactions and hallucinations after a patient is exposed to it. Ketamine has been used as a recreational drug due to its rapid onset, short duration of action, and psychotropic effects. 77

Topical Therapy
The only topical antineuralgic agent shown to have efficacy in NCP is the lidocaine 5% patch (Lidoderm). It is most effective with pain associated with allodynia, a pain due to stimulus that does not normally provoke pain. 78 It has also been used in central neuropathic pain syndrome in patients with metastatic lesions of the spinal cord. 79 Despite some stated efficacy, lidocaine patches did not significantly reduce pain intensity ratings or related secondary endpoints in cancer patients with persistent pain associated with incisions. 80

Thus far, no single pharmacotherapy has an FDA indication for CIPN. Only pregabalin, tapentadol, and duloxetine are approved for diabetic peripheral neuropathic pain, with pregabalin having an added indication for neuropathic pain associated with spinal cord injury. Carbamazepine has the indication for trigeminal neuralgia.

Preventing CIPN

Calcium and magnesium infusions have been shown to reduce the incidence of CIPN. Several studies have shown that calcium-magnesium infusions reduce the incidence of neurotoxicity and subsequent peripheral neuropathy in cancer patients undergoing chemotherapy. 81,82 The antitumor efficacy of these chemotherapy agents was not affected however, patients who received the infusions stayed on therapy longer than the control group.

Glutamine was studied in an open-label trial in patients receiving oxaliplatin. There was significantly less grade 1-2 and grade 3-4 CIPN after 4 to 6 cycles in patients who were given glutamine compared to the control arm. 83 While there was a lower need for oxaliplatin dose reduction in the glutamine group, a larger randomized placebo-controlled trial is needed before this can be used in a larger practice.

Glutathione has been shown to prevent the accumulation of platinum agents in the dorsal root ganglia. Two small trials looked at the effectiveness of glutathione in preventing CIPN in patients receiving either cisplatin or oxaliplatin. There was significantly less peripheral neuropathy of any grade in patients receiving either 4 or 8 cycles of oxaliplatin in the glutathione-treated group, compared with the placebo-controlled group. 84 Moreover, there was no difference in chemotherapy response rates. A similar result was obtained in patients given glutathione while undergoing treatment with cisplatin. 85

N-acetylcysteine is an antioxidant that increases the body's concentration of glutathione. In a study where 14 patients were receiving oxaliplatin, oral N-acetylcysteine reduced the incidence of CIPN in these colon cancer patients. 86 Additional, larger studies are needed prior to recommendation for widespread use.

Vitamin E may have some role to play in decreasing the risk of CIPN. In an open-label study, patients were given vitamin E
300 mg daily during cisplatin therapy and for 3 months after treatment completion. CIPN was observed in 31% of patients who received vitamin E compared to 86% of the control arm (P<0.01). 87 Subsequent studies have shown that vitamin E reduced CIPN in patients undergoing treatment with cisplatin, paclitaxel, or a combination of cisplatin and paclitaxel. 88,89 The major concern with the use of vitamin E in patients receiving chemotherapy is that as an antioxidant, it might interfere with the oxidative breakdown of cellular DNA and cell membranes necessary for the chemotherapy agents to work.

Conclusion
Peripheral neuropathy treatment is a challenge in any setting, but requires unique skills and an even more comprehensive evaluation in the presence of cancer, especially with concurrent ongoing or previous antineoplastic therapy. While there has been much progress made in this area, identifying adjuvant analgesics that are safe and effective in the cancer patient requires careful diagnostic delineation, a keen knowledge of rational polypharmacy, and skillful assessment for success.


Conclusions

It is critical to target drugs to tumor cells in order to improve the clinical efficacy and avoid the adverse effects of anticancer drugs. The efficacy of chemotherapy may be largely dependent on the relative activity of transporters in normal and cancer tissues. In addition to already extensively investigated efflux transporters, multiple types of membrane influx transporters, in particular the SLC superfamily members play very important roles in conferring sensitivity and resistance to anticancer agents. These SLC transporters not only directly bring anticancer agents into cancer cells but also serve as the uptake mediators of essential nutrients for tumor growth and survival. The differential expression patterns of SLC transporters between normal and tumor tissues may be well utilized to achieve specific delivery of chemotherapeutic agents. The transporters may be also directly targeted in development of anticancer drugs to increase chemosensitivity, for example, via limiting nutrient supply to cancer cells and regulating their apoptosis and electrochemical gradients. The SLC transporters expressed in the intestine, liver and kidney are of particular importance as their activity may be critical to systemic exposure and disposition of various anticancer agents, serving as a common basis or determinant for drug-drug interaction, pharmacological effects, and side effects. The function of SLC transporters in anticancer drug disposition and action has been increasingly recognized. However, the major biological implication and pathophysiological function of these membrane proteins are far from clear and under extensive exploration. With advanced knowledge of SLC transporters, their role in the development, optimization, and personalization of anticancer medicine will be further underscored and merited.


Cancer Management in Patients With End-Stage Renal Disease

Significant improvements in the management of patients with endstagerenal disease (ESRD) who are on chronic renal replacementtherapy (CRRT), has led to an increased prevalence of this populationamong older Americans. Since cancer is also common in the elderly,oncologists are likely to be faced with patients who suffer from bothcancer and ESRD. There is a paucity of information regarding issuessurrounding the optimal management of such patients, especially thoseneeding chemotherapy. This review surveys the relevant problemsoncologists may encounter in such patients and summarizes the availableliterature on chemotherapeutic management of common cancers.The reader is strongly urged to consult the original references for detailsof chemotherapy administration prior to use in an individualpatient.

Significant improvements in the management of patients with endstage renal disease (ESRD) who are on chronic renal replacement therapy (CRRT), has led to an increased prevalence of this population among older Americans. Since cancer is also common in the elderly, oncologists are likely to be faced with patients who suffer from both cancer and ESRD. There is a paucity of information regarding issues surrounding the optimal management of such patients, especially those needing chemotherapy. This review surveys the relevant problems oncologists may encounter in such patients and summarizes the available literature on chemotherapeutic management of common cancers. The reader is strongly urged to consult the original references for details of chemotherapy administration prior to use in an individual patient.

Significant improvement in the management of end-stage renal disease (ESRD) has led to increased survival for patients receiving chronic renal replacement therapy (CRRT)-hemodialysis or continuous ambulatory peritoneal dialysis (CAPD)-over the past 2 decades. In the United States from 1980 to 2001, the overall mortality for patients with ESRD declined by 10% from roughly 275 to 250 deaths per 1,000 patientyears at risk.[1] Since 1985, the mortality rate for patients on dialysis for less than 2 years declined by 23%, from roughly 290 to 220 deaths per 1,000 patient-years at risk.[1] Much of this improvement can be attributed to advances in the dialysis vascular access, improvements in artificial dialyzers, availability of recombinant erythropoietic agents to treat anemia, and improvement in general supportive care.

From 1994 to 2001, however, the mortality of patients who had been on dialysis for more than 5 years increased by 12%, from 259 to 291 deaths per 1,000 patient-years at risk.[1] This suggests an increased need to address medical issues that arise later in the clinical course of patients with ESRD. While the majority of deaths in patients on CRRT are due to cardiovascular disease and infection, cancer is not infrequently observed in this population. Approximately 6% of patients currently initiating hemodialysis in the United States have cancer as a comorbidity.[1] Furthermore, several reports have linked chronic renal insufficiency with an increased incidence of cancer.[2-10]

About 300,000 patients were on hemodialysis in the United States in 2001.[1] By the year 2030, an estimated 2,240,000 people in the United States are expected to have ESRD and half these patients will be 65 years of age or older.[1] The life expectancy for patients on CRRT aged 50, 60, and 70 years is approximately 5, 4, and 3 years, respectively.[1] These life expectancies are only one-third to one-sixth that of the general US population, but they represent a significant period of potentially good quality life during which the treatment of cancer with chemotherapy may be appropriate.

Common Chemotherapeutic Agents Requiring Dose Modification and Monitoring for Renal Insufficiency

Although the population of patients requiring CRRT is increasing and ESRD is associated with an increased risk of cancer, there is a paucity of available information on the optimal management of ESRD patients with cancer. Because of uncertainty, general treatment goals may vary widely with clinician and patient preferences. This is even more relevant given that subspecialists such as nephrologists and oncologists increasingly serve as their patient's primary care providers.[11] Challenges facing nephrologists caring for patients with ESRD may include delays in cancer diagnosis, unclear utility of cancer screening, and dilemmas in diagnostic imaging.[12,13] Furthermore, in patients with advanced or refractory cancer, both nephrologists and oncologists may be called upon to help negotiate ethically complex palliative care issues including the withholding of dialysis treatment.[14-17]

This article will address the supportive, palliative, diagnostic, and prognostic dilemmas facing clinicians caring for cancer patients with ESRD. We review here the current reports available in the literature and provide an overview of chemotherapy use in ESRD. One recent review focused principally on the pharmacokinetic details for selected single agents.[18] Our review is broader in scope and oriented to guiding the practicing oncologist in clinical decision-making. The use of various chemotherapeutic agents for patients with lesser degrees of renal insufficiency and acute renal dysfunction has been extensively reviewed elsewhere, and the reader is referred to these available sources.[19-21] Table 1 provides a summary of chemotherapeutic agents requiring dose modification or monitoring in renal insufficiency.

The Comorbidity of Cancer and ESRD

The relationship between chronic renal failure and malignancy is complex. The increased incidence of cancer in ESRD patients may be explained through multiple mechanisms, which are detailed in Table 2 and two pertinent review articles.[22,23] Several of these pathways are speculative and warrant further study.

Medical Decision-Making

Interrelationships Between Cancer and End-Stage Renal Disease

As noted previously, elderly ESRD patients on CRRT can have several years of good-quality life. Oncologists should appreciate this when formulating a cancer-directed treatment plan for their patients with ESRD. Performance status can occasionally be difficult to assess in patients on dialysis because of time spent on dialysis and transient complications of CRRT. Given the paucity of information on quality of life in cancer patients with ESRD, decisions to initiate cancer treatment, especially with chemotherapy, are problematic.

Oncologists also can expect to face palliative care and ethical dilemmas among cancer patients with ESRD. Dialysis represents a proximate lifesustaining measure, and withdrawal of such support could hasten death far in advance of an incurable malignancy. Formulating a plan for hospice care could additionally include a discussion regarding the option of withdrawal of dialysis support. When considering cessation of dialysis, patients should have a full evaluation (including a psychiatric assessment) and counseling.[24] A discussion of withdrawing CRRT or withholding initiation of CRRT involving patients or their proxies should be documented, and appropriate orders should be written.[25]

A recent multicenter prospective cohort study of acute hemodialysis in hospitalized patients demonstrated that a diagnosis of cancer was more commonly associated with withholding (ie, not starting) hemodialysis than it was with withdrawing from ongoing hemodialysis.[15] This was particularly true among older patients, and patients viewed as having a poor overall prognosis. This study also demonstrated infrequent recording of decisions in the medical chart, with only 18% of decisions to withhold hemodialysis and 4% of decisions to withdraw hemodialysis documented.[ 15] Optimizing palliative care for this complex patient population and their families can prove to be a challenge that greatly benefits from a multidisciplinary approach.[14,16]

Diagnostic and Prognostic Issues

Several confounding factors associated with ESRD can affect the diagnosis and evaluation of a malignancy. These include the following: (1) delayed symptomatic presentation, (2) unclear utility of tumor markers in ESRD, (3) imaging dilemmas, and (4) lack of prognostic information.

ESRD and Cancer Presentation-There are several clinical scenarios in which the common clinical symptoms of malignancy may be missed in the setting of ESRD. For example, hypercalcemia may be associated with malignancy or the secondary hyperparathyroidism of ESRD.[26] An elevated serum phosphate level, however, may favor a renal etiology over malignancy. Oliguria and anuria may mask the symptoms of urinary retention secondary to obstructive uropathy from certain pelvic cancers such as prostate cancer.[27] Other symptoms, such as pruritis related to hyperphosphatemia or anemia from renal disease, may also mask similar initial presentations of malignancy.

ESRD and Tumor Markers-Serum cancer antigen 125 (CA-125) can serve as a useful tumor marker but can be increased by intraperitoneal volume such as ascites, even when nonmalignant. Indeed, CA-125 concentration in the dialysate of peritoneal dialysis patients is a marker of mesothelial mass and can help determine optimal dwell times for continuous ambulatory peritoneal dialysis.[ 28] Although prostate-specific antigen (PSA) in 63 men on hemodialysis was found to be lower than that of a comparison group of 729 healthy male subjects, the prevalence of abnormally elevated levels of total PSA was similar.[29] In another study of 41 Japanese patients (a population with a low incidence of prostate cancer) on hemodialysis, 4 patients required further diagnostic evaluation based on a cut-off point of 4 ng/mL for PSA, resulting in a biopsy diagnosis of prostate cancer in 2 patients (5%).[30] Although PSA is not dialyzed, fluctuations and increases in PSA levels may still occur secondary to hemoconcentration or alteration in binding proteins following dialysis.[31]

ESRD and Imaging-Imaging studies requiring contrast are frequently ordered for cancer diagnosis, staging, or monitoring. In ESRD patients, controversy surrounds the issue of whether and when to perform dialysis (hemodialysis or CAPD) around the time of intravenous contrast administration. Because of a lack of consensus among radiologists, guidelines were developed by the Contrast Media Safety Committee of the European Society of Urogenital Radiology (ESUR).[13]

It is important to distinguish the issues of contrast administration in patients with renal insufficiency from those of patients with ESRD and al- ready on CRRT. In the presence of renal insufficiency, water-soluble iodinated contrast agents that are predominantly cleared by the kidney can have a longer half-life and increased toxicity-in particular, additional renal toxicity. Recommendations for patients with renal insufficiency who are not receiving dialysis include judicious use of iodinated contrast media with prehydration, use of low or iso-osmolar contrast media, discontinuation of nephrotoxic drugs for at least 24 hours before contrast administration, and possible use of N-acetylcysteine or sodium bicarbonate.

Prophylactic hemodialysis prior to contrast administration has not demonstrated any benefit and could be harmful.[32] However, intravenous contrast administration for computed tomography scans is not usually contraindicated in patients already on CRRT, as preservation of residual renal function is of minimal value. While it is recommended that excessive volume load with intravenous contrast be avoided, the subsequent timing of dialysis is unimportant and additional dialysis treatments are not recommended.[13]

The use of gadolinium-based contrast agents has also been studied in renal failure because of their predominant renal clearance, and the frequent performance of magnetic resonance imaging examinations in patients with ESRD. No adverse events were reported in a prospective, randomized, double-blind, placebo-controlled study of patients with chronic renal insufficiency (not requiring CRRT) using gadolinium at a concentration of 0.2 mmol/kg vs saline.[33] However, in patients with renal insufficiency, doses greater than 0.3 mmol/kg should be avoided.[13]

The safety of gadolinium administration in ESRD patients undergoing dialysis has also been established. CAPD is very slow to clear gadolinium, with nearly one-third of administered gadolinium remaining after 20 days.[34] However, no adverse events have been observed with the use of 0.1 to 0.3 mmol/kg of gadoliniumbased contrast media. With hemodialysis, gadolinium-based contrast concentrations decline to 97% of initial levels after three dialysis sessions over 6 days.[34] Despite this, no adverse effects were seen in a case series report of 70 hemodialysis patients, even when dialysis was delayed for up to 3 days following contrast administration in 6 of the patients.[35]

As with iodinated contrast media, the ESUR does not recommend any specific timing for performance of hemodialysis following gadolinium administration. However, in selected situations, interpretation of gadolinium- enhanced images can be misleading in CRRT patients. For example, in two hemodialysis patients, retention of gadolinium was associated with its excretion into the cerebrospinal fluid, resulting in artifactual subarachnoid enhancement.[36]

ESRD Impact on Cancer Prognosis-The validity of conventional prognostic factors and outcome data for specific cancers in ESRD patients on CRRT is uncertain because of the absence of clinical trials in this population. Therefore, treatment recommendations are subject to clinical judgment and extrapolation from cancer clinical trials in patients with adequate renal function. We suggest that the prognosis from ESRD and the specific cancer condition should be judged independent of the other condition, and that known, powerful, and consistent prognostic factors are assumed to be generalizable to ESRD patients.

Treatment-Related Issues

Several aspects of chemotherapy administration and CRRT are important to consider in ESRD patients. These include (1) chemotherapeutic agent selection, (2) dosing adjustment, (3) timing of dialysis in relation to chemotherapy treatment, (4) method of dialysis, (5) vascular access for dialysis and chemotherapy, and (6) staff safety considerations.

The renal clearance of a chemotherapeutic agent is important in CRRT-dependent patients. However, clearance of a particular drug by dialysis is not necessarily predicted by its renal clearance in patients with normal renal function. ESRD and dialysis can affect drug clearance in more ways than simple first-order kinetics. The stepwise removal of a chemotherapeutic agent by dialysis is a strong determinant of drug exposure as measured by the effective area under the concentration-time curve (AUC). Alterations in the availability of binding proteins, fluid shifts, and acid-base changes can all influence chemotherapy pharmacokinetics. Furthermore, the pharmacodynamics of these drugs can be influenced by an increased exposure to a drug's active metabolites as well as to the agent itself. For these reasons, studies of the pharmacokinetics and pharmacodynamics of chemotherapeutic agents in dialysis patients should be empirically determined for each drug when possible.

A patient's exposure to a chemotherapeutic agent that is cleared by dialysis can be affected by the dose given as well as the timing and characteristics of the subsequent dialysis. Although dialysis dependence complicates the delivery of cancer therapy, it also offers a way to modulate a patient's chemotherapy drug exposure. The timing (immediate vs delayed) or method of CRRT (hemodialysis vs CAPD) can be adjusted to either generate high peak doses of chemotherapy or maintain low drug concentrations. Additionally, CAPD may facilitate intraperitoneal exposure to chemotherapy that may be of importance for tumors in this location. However, the literature is insufficient to determine the relative advantage of each of these CRRT strategies to optimize chemotherapy delivery.

The preservation of vascular access for dialysis is critical and especially challenging in a patient receiving chemotherapy. The development of the arteriovenous fistula was an important advance in the care of patients with ESRD. The use of such an access for chemotherapy administration must be carefully con- sidered because loss of vascular access due to vascular sclerosis, stenosis, or infection can profoundly impair the ability to provide CRRT. Additionally, while it may be more convenient, the effects of rapidly introducing cytotoxic agents through an arterialized vein have not been adequately studied.

Finally, the administration of chemotherapy in a dialysis unit has implications for the safety of staff and patients. It is therefore recommended that dialysis units institute a policy regarding the safe administration of cytotoxic therapy, including whether or not it may be administered during dialysis. If it is felt that the timing of dialysis in relation to chemotherapy administration is critical, then the appropriate availability of timely CRRT must be ensured.

Chemotherapy in Patients on CRRT

Reports of Chemotherapy Use in Patients on CRRT

We reviewed available reports in which chemotherapy was administered to patients on hemodialysis by performing a Medline search using the key words "cancer chemotherapy" and "hemodialysis." Additional reports were retrieved by cross-referencing the name of a specific chemotherapy or cancer type with "end-stage renal disease," "hemodialysis," or "peritoneal dialysis." Finally, article reference lists and abstracts from the Proceedings of the American Society of Clinical Oncology were also reviewed. Only articles with available English language abstracts or texts were included and are summarized in Table 3 by chemotherapeutic agent and cancer type.

The majority of the literature is limited to case reports and small case series. Some include data regarding the pharmacokinetics and pharmacodynamics of these agents in CRRT and/or information on toxicity and outcome. A variety of dialysis schedules and methods are described. Only a few reports refer to the use of newer chemotherapeutic agents. Although publication bias in favor of cases with a positive outcome is likely, these reports provide a basis for offering chemotherapy to dialysis-dependent patients.

Crooke et al published one of the earliest reports of cancer chemotherapy use in a patient receiving dialysis in 1977.[37] A 24-year-old male with recurrent testicular cancer required hemodialysis for acute tubular necrosis secondary to cisplatin. He was treated successfully with bleomycin and vinblastine on hemodialysis, eventually recovered renal function, and remained in complete remission 7 months later. This report suggested that giving weekly bleomycin to a patient receiving hemodialysis was safe and effective. Since then, a variety of malignancies treated with different chemotherapeutic agents have been reported. However, for some of the common cancers, there have been surprisingly few reports and only limited data presented.

This section provides a brief overview of chemotherapy by tumor type in ESRD patients. Tumor types described include those for which treatment has been addressed in multiple reports (testicular cancer, ovarian cancer, transitional cell cancer, multiple myeloma, leukemia, and lymphoma) as well as those that are common in the United States (breast cancer, prostate cancer, lung cancer, and colorectal cancer).

Testicular Cancer

Crooke's original report described above showed that serum bleomycin levels fell to extremely low values within 72 hours even though the drug is renally cleared and nondialyzable.[ 37] A year later, bleomycin, vinblastine, and cisplatin was used for the treatment of nonseminomatous testicular cancer in a 32-year-old patient on hemodialysis.[38] This patient developed diffuse pulmonary fibrosis suspected to be related to bleomycin (first cycle given at a standard dose of 30 units IV push weekly and "reduced" for the second cycle). Since then, there have been no reports of the complete BEP regimen (bleomycin, etoposide, cisplatin) being used in ESRD patients.

There are reports of single-agent etoposide,[39] carboplatin plus etoposide,[ 40] as well as cisplatin plus cyclophosphamide .[41] Two patients with nonseminomatous germ cell tu- mors were treated to complete remission with etoposide (100 mg/m 2 , days 1 to 3 or 4) and carboplatin (100 to 300 mg/m 2 , day 1) with hemodialysis performed on day 2.[40] Cisplatin plus etoposide, but without bleomycin, for the treatment of a patient with seminoma, was associated with severe myelosupression noted at higher doses.[ 42] This led to the use of lower doses of cisplatin (14 mg/m 2 , days 1, 3, and 5) and etoposide (35 mg/m 2 , days 1 to 5) with hemodialysis on days 1, 3, and 5, which was found to still be effective. The risk-benefit equation for the addition of bleomycin as a third agent in patients with testicular cancer on hemodialysis remains unresolved.

Ovarian Cancer

There are at least 10 reports of chemotherapy for ovarian cancer in ESRD patients. The first of these was reported in 1981.[43] Based on a pharmacokinetic profile derived after administration of a 12-mg tracer dose of cisplatin to an anuric patient, cisplatin was then given as a 50-mg infusion. In four subsequent cycles, doxorubicin (30 mg IV on day 1), teniposide (50 mg IV on day 2), and cyclophosphamide (300 mg IM on days 3 and 4) were given in combination with cisplatin, 50 mg IV on day 5. Less than 10% of cisplatin was removed by hemodialysis, which was performed immediately following the cisplatin infusion. A partial objective response was observed in peritoneal metastases with an associated decrease in ascites.

Subsequent reports in ovarian cancer patients have described the use of single-agent carboplatin,[44,45] cisplatin, or carboplatin combined with cyclophosphamide,[46,47] singleagent paclitaxel,[48,49] and cisplatin or carboplatin combined with paclitaxel.[ 50,51] Of particular interest, six cycles of standard-dose carboplatin (AUC of 5) given every 3 weeks in combination with paclitaxel (175 mg/m 2 over 3 hours) was safely delivered to a patient with surgically debulked advanced ovarian cancer.[51] Hemodialysis was performed 24 hours following the carboplatin dose, although the authors were aware that dialysis has only modest efficacy in clearing carboplatin. The details of their dose calculation, according to the Calvert formula, used a glomerular filtration rate of 0 to arrive at a carboplatin dose of 125 mg. The patient was disease-free 11 months after completion of treatment.

In another report, topotecan was used to treat advanced refractory ovarian cancer in a 58-year-old woman.[ 52] Infusing topotecan only on days 1 and 3 (rather than standard treatment on days 1 through 5) with hemodialysis on days 2 and 4, grade 3 thrombocytopenia and grade 4 neutropenia without fever, were observed. This toxicity was essentially unchanged by infusing topotecan on day 1 over 30 minutes, beginning at the initiation of hemodialysis, and with a second topotecan infusion on day 2 and subsequent hemodialysis on day 3. Pharmacokinetic sampling showed a fourfold increase in topotecan plasma clearance with hemodialysis, from 5.3 to 20.1 L/h/m 2 . The authors recommended consideration of hemodialysis in the event of topotecan overdose or in the presence of severe renal dysfunction while receiving topotecan.

Transitional Cell Cancer

MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) was among the earlier regimens administered for transitional cell cancer in patients on hemodialysis.[ 53-55] In 1993, Yokogi et al gave 20 mg of methotrexate intravenously on day 1 and 30 mg of cisplatin on day 2 followed 2 hours later by hemodialysis.[54] Since the serum methotrexate level of 0.27 μM at 72 hours after low-dose methotrexate administration was in a high-risk range, the authors recommended careful monitoring of methotrexate levels to facilitate leucovorin rescue.

Another patient with advanced recurrent transitional cell cancer previously treated with MVAC, was subsequently treated with a carboplatin- based regimen while on hemodialysis.[ 54] Hemodialysis was performed 24 hours after IV administration of carboplatin (100mg/m 2 ), vinblastine (3 mg/m 2 ), and doxorubicin (22.5 mg/m 2 ). Three cycles were given at approximately 5-week intervals, complicated by one episode of septicemia but with stable disease observed at 5 months.

Recently, a regimen of carboplatin (AUC = 5, calculated according to the Calvert formula) plus paclitaxel (175 mg/m 2 over 3 hours) given to a 69 year-old man with metastatic transitional cell cancer on hemodialysis, resulted in a 20% reduction in tumor size after 3 cycles.[56] Hemodialysis was performed 1 hour after carboplatin administration. Grade 1 thrombocytopenia and grade 3 neutropenia were the principal toxicities observed.

Multiple Myeloma

As listed in Table 3, several studies (including eight case series) have described the use of chemotherapy to treat patients with multiple myeloma and renal failure. Overall, these reports demonstrate the utility of most standard therapies for patients with ESRD and encourage aggressive treatment as indicated. Some include a discussion of the form of renal replacement.[ 57,58] For example, although CAPD may additionally remove myeloma proteins (more so than with hemodialysis), the increased risk of infection and peritonitis outweigh this advantage.

Standard vincristine, doxorubicin, and steroid regimens (VAD [with dexamethasone] and VAMP [with methylprednisolone]) as well as intravenous and oral melphalan plus steroid regimens have been successfully used in patients with renal failure.[ 59-63] Accumulating evidence supports the use of high-dose chemotherapy with autologous stem cell transplant, occasionally demonstrating a recovery of renal function even after a period of 6 months of dialysis dependence.[64-69] Finally, thalidomide (Thalomid), 100 mg daily, was used in a 64-year-old man on hemodialysis for ESRD associated with IgD lambda myeloma but required dose reduction for neuropathy and constipation.[70]

Leukemia

Several reports of chemotherapy in ESRD patients with leukemia have been published. These are evenly divided among chronic myelogenous leukemia (CML), acute myelogenous leukemia (AML), acute myelomonocytic leukemia (AMML), acute promyelocytic leukemia (APML), and acute lymphoblastic leukemia (ALL). Most involve reduced doses of chemotherapeutic agents or alternative schedules.

Consolidation therapy was given to a patient on CAPD for APML with a standard-dose "5 + 3" regimen employing cytarabine (200 mg/m 2 /d) for 5 days and daunorubicin (50 mg/m 2 /d) for 3 days.[71] Interestingly, while there were no additional toxicities beyond myelosupression lasting 10 days, plasma cytarabine levels were found to be significantly higher than in leukemia patients with normal renal function. Although the authors could not rule out random interindividual variation in cytarabine metabolism as an explanation, they recommended a dose reduction of the drug for CAPD patients until further studies became available.

Similarly elevated plasma levels of drug without excess toxicity was observed in a child receiving hemodialysis for acute renal failure, when a 5-day course of cladribine, 9 mg/m 2 /d, was given for AML.[72] The role of plasma drug level measurements in clinical practice remains unclear.

Lymphoma

Doxorubicin pharmacokinetics were studied in five patients on hemodialysis, including two patients with lymphoma who received CHOP (cyclophosphamide, doxorubicin [40- 60 mg over 30 minutes], vincristine, and prednisone) chemotherapy, and compared to eight patients not receiving hemodialysis.[73,74] Delayed clearance of doxorubicin and its active metabolite, doxorubicinol, resulted in an AUC 1.5 and 3 times higher, respectively, in hemodialysis patients, but no additional toxicity was reported.

Weekly rituximab (Rituxan) at a standard dose of 375 mg/m 2 was given to a 54-year-old man with low-grade lymphoma receiving hemodialysis.[75] Sustained therapeutic rituximab serum levels comparable to patients with normal renal function, were achieved after the infusion as well as after dialysis, without any rituximab clearance into the dialysate.

Standard-dose cytarabine (at a regimen of 100 mg/m 2 /d) for 7 days was given to an 8-year-old boy with Burkitt's lymphoma on daily concurrent hemodialysis for ESRD secondary to hemolytic-uremic syndrome.[76] Unlike another report of cytarabine use in an AML patient on CAPD,[71] this report found that cytarabine was cleared by hemodialysis, and that standard dosing yielded serum drug levels not likely to cause additional toxicity. This patient's leukemia progressed despite chemotherapy, and given cytarabine clearance by hemodialysis, the authors expressed a cautionary note regarding efficacy of the drug at this dose in hemodialysis patients.

Breast Cancer

Despite the high prevalence of breast cancer, we found only three reports of chemotherapy in patients with breast cancer and ESRD.[77-79] The dose of weekly vinorelbine given after hemodialysis to a patient with metastatic breast cancer had to be reduced by 50% (to 12.5mg/m 2 ) to eliminate repeated episodes of neutropenic fever.[77] Single-agent doxorubicin, 140 mg, was given intravenously as adjuvant therapy to a woman with breast cancer undergoing CAPD.[78] This was complicated 5 hours later by a clinical syndrome suggestive of chemical peritonitis and loss of peritoneal surface permeability, necessitating transition to hemodialysis. However the relationship of intravenous doxorubicin to peritonitis during CAPD remains conjectural. A male patient with metastatic breast cancer was treated with a combination of epirubicin (Ellence) and fluorouracil (5-FU), leading to an objective tumor response.[79]

We were unable to find reports of standard adjuvant therapy for breast cancer in patients with ESRD. However, doxorubicin and cyclophosphamide have been used successfully in combination with other chemotherapeutic agents (although at variable doses) for other malignancies (see Table 3). Delayed doxorubicin clearance should lead to caution when used in ESRD patients.[ 73,74] Successful use of endocrine therapy with tamoxifen for bone metastasis and associated hypercalcemia has also been described in a 50- year-old woman.[26] No published reports have described aromatase inhibitor use in ESRD.

Prostate Cancer

In three men with prostate cancer on CRRT, total androgen blockade with leuprolide (7.5 mg IM every 4 weeks) and flutamide (250 mg po tid) effectively lowered serum testosterone but exacerbated the patient's preceding anemia of chronic renal failure [80]. Goserelin (Zoladex) at 3.6 mg SC every 4 weeks) and flutamide at 250 mg po tid given to a patient on long-term hemodialysis resulted in a complete response in lung metastases from prostate cancer.

There have been no reports of cytotoxic therapy for the treatment of prostate cancer in ESRD patients. Several agents known to have activity in prostate cancer (with the notable exceptions of docetaxel and estramustine [Emcyt]) have been used to treat ESRD patients with other malignancies, including paclitaxel (see Table 3). The dose and schedule of administration of these agents may be judiciously extrapolated to patients with prostate cancer.

Lung Cancer

There have been 11 reports of lung cancer treated with chemotherapy in ESRD. Five reports involved patients with small-cell lung cancer, four involved non-small-cell lung cancer, and two did not provide details of histologic subtype. Platinum-containing regimens employed in the treatment of lung cancer in this setting have included single-agent cisplatin,[81] cisplatin with etoposide,[82, 83] carboplatin with etoposide,[84-86] and nedaplatin with etoposide.[87] A dose escalation study of cisplatin and etoposide was conducted in five hemodialysis patients, two with smallcell lung cancer and three with non- small-cell lung cancer.[83] Full-dose cisplatin (80 mg/m 2 on day 1) and etoposide (100 mg/m 2 on days 1, 3, and 5) with hemodialysis performed within 10 minutes of completing chemotherapy administration was found to be safe and effective. Toxicities included grade 3/4 anemia in all five patients (four patients required transfusion support), grade 3 neutropenia in three patients (one patient required a 1-week dose delay), grade 3 thrombocytopenia in two patients, and grade 3 nausea and vomiting in two patients (a single etoposide dose was missed in one patient due to prolonged nausea). All patients recovered completely from these toxicities. A partial response was obtained in four of the five patients.

In another recent report, carboplatin (300 mg/m 2 on day 1) and etoposide (50 mg/m 2 IV on days 1 and 3) was given to three patients with smallcell lung cancer and followed by hemodialysis within 1 hour of chemotherapy.[ 86] Two complete and one partial response were achieved. Myelosuppression was prominent in two patients who developed grade 3/4 neutropenia without fever, requiring blood product support for anemia and thrombocytopenia.

Agents with known activity in lung cancer have been used for the treatment of other cancers in ESRD patients such as single-agent gemcitabine (Gemzar) for pancreatic cancer,[88] vinorelbine for breast cancer,[77] and irinotecan (Camptosar) for colorectal cancer.[89] The combination of cisplatin or carboplatin with etoposide, as described above, appear to constitute the most reasonable, tested chemotherapy regimens for lung cancer patients with ESRD.[83,86] There are no reports of docetaxel use in ESRD patients.

Colorectal Cancer

Three reports have addressed the use of chemotherapy in patients with both ESRD and colorectal cancer, all of which used 5-FU-based adjuvant therapy.[89-91] Uracil/tegafur (300 mg/d tid) in four patients,[90] as well as 5-FU (425 mg/m 2 IV daily for 5 days) plus leucovorin (35 mg/m 2 ) in a single patient,[91] were safely administered. The pharmacokinetics of 5-FU were similar to what is seen in patients who have normal renal function.

A 45-year-old woman with stage III colorectal cancer received a single cycle of 5-FU and leucovorin that was complicated by gastrointestinal toxicity.[ 89] At the time of recurrence with liver metastasis, she went on to receive IV irinotecan, 80 mg/m 2 /wk, which was well tolerated. Further dose escalation to 100 mg/m 2 /wk resulted in grade 4 diarrhea. A partial remis- sion lasting 1 year was achieved. These reports are insufficient to make a treatment recommendation for either adjuvant or palliative chemotherapy in colorectal cancer.

Conclusions

General Recommendations for Chemotherapy Dose Adjustment in Patients With End-Stage Renal Disease

Cancer chemotherapy will be provided to an increasing number of patients with ESRD. However, data regarding the optimal use of chemotherapeutic agents in this patient population are sparse. For several drugs, case reports indicate that many ESRD patients can tolerate standard treatment. Table 4 summarizes our general chemotherapy dosing recommendations based on a review of available case reports.

The optimal timing of CRRT in relationship to chemotherapy dosing has not been determined for most treatments. A systematic approach to investigating antineoplastic therapy in the growing ESRD population is needed, particularly for the common cancers (such as lung, breast, colorectal, and prostate) for which the data are frequently underrepresented compared to certain rarer cancers (transitional cell, testicular, leukemia). Development of a National Cancer Institute-sponsored registry to capture key data on ESRD patients given chemotherapy in the United States would provide a broader resource for practicing physicians and clinical investigators to draw on, which in turn will advance the care of this group of patients.

Acknowledgments:We gratefully acknowledge Linda Norton for secretarial assistance and Hyman Muss, MD, for advice during preparation of this manuscript.

Financial Disclosure:The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


'Metal' drugs to fight cancer

What is the mechanism of action of metal-based chemotherapy drugs (the most widely used for treating common cancers like testicular or ovarian cancer)? How can we improve their effect and reduce their toxicity? A new study combining experiments and theory has broadened our knowledge of the molecular mechanisms of these active drugs to help experimentalists devising increasingly effective drugs with fewer side effects. The study, just published in the journal ChemMedChem, was conducted with the participation of International School for Advanced Studies (SISSA) of Trieste.

Pharmaceutical research can be difficult and frustrating. Often, one happens to synthesize a molecule without knowing exactly what kind of therapeutic effect it will have (if it ever will have any). "It is rare for someone to develop a new active drug already knowing what mechanism it will trigger in the body," explains Alessandra Magistrato, CNR-IOM/SISSA research scientist. "This also applies to the most widespread chemotherapeutic drugs, like cisplatin, or novel ones based on ruthenium." "Studies relying on modelling and simulations, like the ones we do here, may be very helpful in this sense, in that they increase our insights into the molecular mechanisms of action exerted by the drugs inside the body's cells," the scientist explains.

Magistrato is among the authors of a new study that reviews previously published experimental and computational reports visualized through the "lens" of computational microscope. "We produced models that enable us to rationalize the action of chemotherapeutic molecules on the body's cells," Magistrato explains. "For some types of drugs, we tried to understand which chemical form of the drug is most abundant when it enters the blood circulation and it reaches the cell ."

Scientists in fact use the term "prodrug" when referring to an injected chemotherapy agent this, because as soon as the agent enters the body, it quickly changes before the interactions with it biological target. That's why it is difficult to know precisely which molecule (and how much of it) is responsible for the therapeutic action, in other words the actual medication.

On the other hand for other drugs with a known active form, Giulia Palermo, first author and researcher at the Swiss Federal Institute of Technology in Lausanne (EPFL), described how the the drug binds to different targets inside the cell. "A molecule can act on three fronts: on free DNA, on chromatin (the most common form of packed DNA in the nucleus) and on other proteins found in the cell," explains Palermo. Depending on which target is involved, the action of the drug can vary widely, as well as its side effects. "In fact, it is believed that when the drug exhibits cytotoxic effects, it may bound preferentially to the DNA, whereas when it has anti-metastatic effects, it may act on the proteins involved in motility or on protein/DNA complexes affecting gene regulation, for example."

"With the help of studies like this, experimentalists can improve the rational design of the new therapeutic molecules so as to obtain drugs that are more effective and with fewer side effects, a very important aspect as we know very well how physically demanding chemotherapy is for patients," concludes Magistrato.

The study is the result of an international collaboration between CNR-IOM/SISSA and the research groups led by Ursula Roethlisberger (professor of computational chemistry and biochemistry at EPFL), Paul Dyson, expert in organometallic and medicinal chemistry at EPFL, and Curt Davey, leader in crystallography of protein/DNA complexes at Nanyang Technological University (NTU) in Singapore.


Half the amount of chemo prevents testicular cancer from coming back, new trial shows

Testicular cancer can be prevented from coming back using half the amount of chemotherapy that is currently used, a new clinical trial has shown.

In many men who have had surgery for an aggressive form of testicular cancer, the disease can come back elsewhere in their bodies and need intensive treatment, often within two years after initial diagnosis.

The new trial showed that giving men one cycle of chemotherapy was as effective at preventing men's testicular cancer from coming back as the two cycles used as standard.

Crucially, lowering the overall exposure to chemotherapy reduced the debilitating side effects which can have a lifelong impact on patients' health.

The 111 trial has already begun to change clinical practice, reducing the number of hospital admissions, and lowering the costs of treatment.

The trial, led by The Institute of Cancer Research, London, and University Hospitals Birmingham NHS Foundation Trust, involved nearly 250 men with early-stage testicular cancer at high risk of their cancer returning after surgery.

The research was published in the journal European Urology today (Thursday), and was funded by Cancer Research UK and the Queen Elizabeth Hospital Birmingham Charity.

Testicular cancer is the most common cancer affecting young men, with many patients being diagnosed in their twenties or thirties.

After surgery, patients are currently offered two cycles of chemotherapy to destroy any cancer cells that may have already spread, or a watch-and-wait approach -- where they receive no treatment unless their cancer comes back, at which point they are given three cycles of chemo.

Survival rates are very high, but as men are diagnosed young, if they choose to have chemotherapy they may have to live with long-term side effects for many decades.

In the new study, patients were given one three-week cycle of a chemotherapy known as BEP -- a combination of the drugs bleomycin, etoposide and the platinum agent cisplatin.

The researchers looked at the percentage of men whose testicular cancer returned within two years of being treated with one cycle of chemotherapy, and compared these relapse rates with established data from previous studies in patients who were given two cycles.

The researchers found that only three men -- 1.3 per cent -- saw their testicular cancer return after finishing treatment -- a nearly identical rate to previous studies using two cycles of BEP chemotherapy.

In the new study, 41 per cent of men receiving one cycle of chemotherapy experienced one or more serious side effects while receiving treatment, such as an increased risk of infection, sepsis or vomiting. But only a small number -- six patients, or 2.6 per cent -- experienced long-term side effects such as damage to their hearing.

It is well established that lower chemotherapy doses are related to reduced rates of side effects, and the researchers are confident that the rates found in this study are substantially lower than those currently seen in the clinic.

Professor Robert Huddart, Professor of Urological Cancer at The Institute of Cancer Research, London, and Consultant in Urological Oncology at The Royal Marsden NHS Foundation Trust, said:

"Men with testicular cancer who are at high risk of recurrence have generally been treated with two cycles of chemotherapy -- but our new study found that one cycle was enough to stop their tumour from coming back.

"Reducing the overall dose of chemotherapy could spare young men who have their whole lives ahead of them from long-term side effects, and also means they will need fewer hospital visits for their treatment.

"This new trial is already changing clinical practice on a global scale, and is set to improve patients' quality of life as well as reducing the cost of testicular cancer treatment.

"Reducing the number of cycles and the dosage of chemotherapy for testicular cancer could save the NHS money, and free up valuable hospital time and resources."

Kris Taylor, 35, from the West-Midlands, was treated as part of the 111 trial at the Queen Elizabeth Hospital Birmingham after having surgery for his testicular cancer. He said:

"I was playing football semi-professionally at the time I was diagnosed. Even though my prognosis was good, knowing that you have cancer is really scary, and the key thing for me was to get back to normality as soon as possible. I'd already had to have time off for surgery, so, when I was offered the chance to have less chemo but with no greater risk the cancer would return, I jumped at it.

"The side effects of the treatment were really difficult, but I was straight back on the pitch as soon as it finished -- five years on, and I'm still fighting fit. It's great to know that others may now be able to benefit from the trial's findings. Being able to reduce the amount of chemotherapy a person receives can make such a big difference to their quality of life in both the short-term and the long-term."

Professor Emma Hall, Deputy Director of the Clinical Trials and Statistics Unit at The Institute of Cancer Research, London, said:

"We tend to be focused on whether we can cure a cancer or not, but for a disease like testicular cancer which affects young people, it is also crucial to ensure treatment does not leave patients with a lifetime of adverse effects.

"There is an important balance to be struck in giving men enough chemotherapy to stop their testicular cancer from coming back, without giving them so much that they suffer unnecessary side effects.

"Our study has found strong evidence to suggest that testicular cancer chemotherapy can be safely reduced from two cycles to just one -- making their treatment shorter, kinder and cheaper."

Martin Ledwick, Cancer Research UK's head information nurse, said:

"Thanks to advances in treatments, survival for testicular cancer is very high, but the chemotherapy can cause unpleasant, sometimes lasting side effects. That's why it's such good news to see that we can cut down the amount of treatment we give.

"Providing men with a kinder treatment option linked to fewer side effects could make a huge difference to their quality of life. As more and more people survive cancer, it's essential to carry out studies like this, which look at how to improve things for people living with and after the disease."


Why is cisplatin a very potent antineoplastic for testicular cancer, but not necessarily for other cancers? - Biology

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Mutated Genes and Abnormal Protein Expression (69)

Clicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

GeneLocationAliasesNotesTopicPapers
MDM2 12q15 HDMX, hdm2, ACTFS -MDM2 and Testicular Cancer
23
DROSHA 5p13.3 RN3, ETOHI2, RNASEN, RANSE3L, RNASE3L, HSA242976 -DROSHA and Testicular Cancer
16
DICER1 14q32.13 DCR1, MNG1, Dicer, HERNA, RMSE2, Dicer1e, K12H4.8-LIKE -DICER1 and Testicular Cancer
16
SPRY4 5q31.3 HH17 -SPRY4 and Testicular Cancer
13
CYP19A1 15q21.2 ARO, ARO1, CPV1, CYAR, CYP19, CYPXIX, P-450AROM -CYP19A1 and Testicular Cancer
13
PTEN 10q23.31 BZS, DEC, CWS1, GLM2, MHAM, TEP1, MMAC1, PTEN1, 10q23del -PTEN and Testicular Cancer
12
TOP1 20q12 TOPI -TOP1 and Testicuar Cancer
10
DNMT3B 20q11.21 ICF, ICF1, M.HsaIIIB -DNMT3B and Testicular Cancer
9
XIST Xq13.2 SXI1, swd66, DXS1089, DXS399E, LINC00001, NCRNA00001 -XIST and Testicular Cancer
8
CDK4 12q14.1 CMM3, PSK-J3 -CDK4 and Testicular Cancer
7
PDGFRA 4q12 CD140A, PDGFR2, PDGFR-2 -PDGFRA and Testicular Cancer
7
CTAG1B Xq28 CTAG, ESO1, CT6.1, CTAG1, LAGE-2, LAGE2B, NY-ESO-1 -CTAG1B and Testicular Cancer
6
FGFR3 4p16.3 ACH, CEK2, JTK4, CD333, HSFGFR3EX -FGFR3 and Testicular Cancer
5
PDE11A 2q31.2 PPNAD2 -PDE11A and Testicular Cancer
5
TGCT1 Xq27 -TGCT1 and Testicular Cancer
5
FOXL2 3q22.3 BPES, PFRK, POF3, BPES1, PINTO -FOXL2 and Testicular Cancer
5
PTER 10p13 HPHRP, RPR-1 -PTER and Testicular Cancer
5
MAGEA4 Xq28 CT1.4, MAGE4, MAGE4A, MAGE4B, MAGE-41, MAGE-X2 -MAGEA4 and Testicular Cancer
4
CLU 8p21.1 CLI, AAG4, APOJ, CLU1, CLU2, KUB1, SGP2, APO-J, SGP-2, SP-40, TRPM2, TRPM-2, NA1/NA2 -Clusterin and Testicular Cancer
4
HLA-DRB1 6p21.32 SS1, DRB1, HLA-DRB, HLA-DR1B -HLA-DRB1 and Testicular Cancer
4
MYD88 3p22.2 MYD88D -MYD88 and Testicular Cancer
3
TERC 3q26.2 TR, hTR, TRC3, DKCA1, PFBMFT2, SCARNA19 -TERC and Testicular Cancer
3
NR5A1 9q33.3 ELP, SF1, FTZ1, POF7, SF-1, AD4BP, FTZF1, SPGF8, SRXY3, hSF-1 -NR5A1 and Testicular Cancer
3
MAGEA1 Xq28 CT1.1, MAGE1 -MAGEA1 and Testicular Cancer
3
MAGEA3 Xq28 HIP8, HYPD, CT1.3, MAGE3, MAGEA6 -MAGEA3 and Testicular Cancer
3
MIB1 18q11.2 MIB, DIP1, ZZZ6, DIP-1, LVNC7, ZZANK2 -MIB1 and Testicular Cancer
3
GPER1 7p22.3 mER, CEPR, GPER, DRY12, FEG-1, GPR30, LERGU, LyGPR, CMKRL2, LERGU2, GPCR-Br -GPER and Testicular Cancer
3
CTCF 16q22.1 MRD21 -CTCF and Testicular Cancer
3
BCL10 1p22.3 CLAP, mE10, CIPER, IMD37, c-E10, CARMEN -BCL10 and Testicular Cancer
3
SNRPN 15q11.2 SMN, PWCR, SM-D, sm-N, RT-LI, HCERN3, SNRNP-N, SNURF-SNRPN -SNRPN and Testicular Cancer
3
CDKN2D 19p13.2 p19, INK4D, p19-INK4D -CDKN2D and Testicular Cancer
3
SOX17 8q11.23 VUR3 -SOX17 and Testicular Cancer
3
CD79A 19q13.2 IGA, MB-1 -CD79A and Testicular Cancer
3
SLC5A5 19p13.11 NIS, TDH1 -SLC5A5 and Testicular Cancer
2
MCC 5q22.2 MCC1 -MCC and Testicular Cancer
2
GSTT1 22q11.23 -GSTT1 and Testicular Cancer
2
DCC 18q21.2 CRC18, CRCR1, MRMV1, IGDCC1, NTN1R1 -DCC and Testicular Cancer
2
CTCFL 20q13.31 CT27, BORIS, CTCF-T, HMGB1L1, dJ579F20.2 -CTCFL and Testicular Cancer
2
CKAP4 12q23.3 p63, CLIMP-63, ERGIC-63 -CKAP4 and Testicular Cancer
2
HLA-B 6p21.33 AS, HLAB, B-4901 -HLA-B and Testicular Cancer
2
SCGB3A1 5q35.3 HIN1, HIN-1, LU105, UGRP2, PnSP-2 -SCGB3A1 and Testicular Cancer
2
CYP3A4 7q22.1 HLP, CP33, CP34, CYP3A, NF-25, CYP3A3, P450C3, CYPIIIA3, CYPIIIA4, P450PCN1 -CYP3A4 and Testicular Cancer
2
ETV6 12p13.2 TEL, THC5, TEL/ABL -ETV6 and Testicular Cancer
2
HLA-DQB1 6p21.32 IDDM1, CELIAC1, HLA-DQB -HLA-DQB1 and Testicular Cancer
2
MAGEB2 Xp21.2 DAM6, CT3.2, MAGE-XP-2 -MAGEB2 and Testicular Cancer
2
MC2R 18p11.21 ACTHR -MC2R and Testicular Cancer
2
PATZ1 22q12.2 ZSG, MAZR, PATZ, RIAZ, ZBTB19, ZNF278, dJ400N23 -PATZ1 and Testicular Cancer
2
CYP1A2 15q24.1 CP12, P3-450, P450(PA) -CYP1A2 and Testicular Cancer
2
CYP1B1 2p22.2 CP1B, GLC3A, CYPIB1, P4501B1 -CYP1B1 and Testicular Cancer
2
CYP3A5 7q22.1 CP35, PCN3, CYPIIIA5, P450PCN3 -CYP3A5 and Testicular Cancer
2
APAF1 12q23.1 CED4, APAF-1 -APAF1 and Testicular Cancer
2
IMP3 15q24.2 BRMS2, MRPS4, C15orf12 -IMP3 and Testicular Cancer
1
FSHR 2p21-p16 LGR1, ODG1, FSHRO -FSHR and Testicular Cancer
1
SNX29 16p13.13-p13.12 RUNDC2A, A-388D4.1 -SNX29 and Testicular Cancer
1
CDH2 18q12.1 CDHN, NCAD, CD325, CDw325 -CDH2 and Testicular Cancer
1
CD79B 17q23.3 B29, IGB, AGM6 -CD79B and Testicular Cancer
1
CLP1 11q12.1 HEAB, hClp1 -CLP1 and Testicular Cancer
1
MCF2 Xq27.1 DBL, ARHGEF21 -MCF2 and Testicular Cancer
1
CTGF 6q23.2 CCN2, NOV2, HCS24, IGFBP8 -CTGF and Testicular Cancer
1
PITX1 5q31.1 BFT, CCF, POTX, PTX1, LBNBG -PITX1 and Testicular Cancer
1
KNL1 15q15.1 D40, CT29, Spc7, CASC5, MCPH4, hKNL-1, AF15Q14, PPP1R55, hSpc105 -CASC5 and Testicular Cancer
1
SOX1 13q34 -SOX1 and Testicular Cancer
1
FAS 10q23.31 APT1, CD95, FAS1, APO-1, FASTM, ALPS1A, TNFRSF6 -FAS and Testicular Cancer
1
MUM1 19p13.3 MUM-1, EXPAND1, HSPC211 -MUM1 and Testicular Cancer
1
PCDH10 4q28.3 PCDH19, OL-PCDH -PCDH10 and Testicular Cancer
1
PPP1R13L 19q13.32 RAI, RAI4, IASPP, NKIP1 -PPP1R13L and Testicular Cancer
1
HSD3B2 1p12 HSDB, HSD3B, SDR11E2 -HSD3B2 and Testicular Cancer
1
PTPRC 1q31.3-q32.1 LCA, LY5, B220, CD45, L-CA, T200, CD45R, GP180 -PTPRC and Testicular Cancer
SLC43A1 11q12.1 LAT3, PB39, POV1, R00504 -SLC43A1 and Testicular Cancer

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Recurring Structural Abnormalities

Selected list of common recurrent structural abnormalities

This is a highly selective list aiming to capture structural abnormalies which are frequesnt and/or significant in relation to diagnosis, prognosis, and/or characterising specific cancers. For a much more extensive list see the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer.


INTRODUCTION

Many therapeutics can be classified as “ototoxic,” that is, having side effects on the inner ear. More specifically, they can be “cochleotoxic” (affecting the hearing organ) or “vestibulotoxic” (affecting balance). Despite their potential ototoxicity, such drugs remain in current use, either because the risk of damage to the ear is small, or because there simply are no comparable alternatives. Historically, cochlear and vestibular complications have been experienced by patients and recorded by clinicians for centuries, but it was not until the 1940s that ototoxicity caught widespread awareness. At that time, the first aminoglycoside, streptomycin, was discovered by Selman Waksman and his graduate student, Albert Schatz (Schatz et al., 1944 ), and introduced as a highly successful drug against tuberculosis. Within a short time, it became obvious that many patients suffered vestibular and hearing deficits, as well as kidney problems (Hinshaw and Feldman, 1945 ). The ensuing years saw the introduction of further natural and semisynthetic compounds in search of improved aminoglycosides, but side effects remained associated with all of them. Today, aminoglycosides remain in widespread use as broad-spectrum antibiotics, including specific applications against life-threatening sepsis, Mycobacterium tuberculosis, and opportunistic pulmonary Pseudomonas infections in cystic fibrosis patients. Arguably, however, the largest market for aminoglycosides is in developing countries. The drugs offer the benefits of being extremely inexpensive to produce, having broad-spectrum efficacy against most infections, causing a relatively small incidence of allergic reactions, and being easily accessible, in many areas even without a prescription. The advent of aminoglycoside antibiotics was considered a crowning achievement in medicine and earned Waksman the Nobel Prize in 1952.

Unlike the immediate recognition of aminoglycoside antibiotics as efficacious antibacterial drugs, the discovery of cisplatin as an effective anticancer agent was an accidental one. Cisplatin was already synthesized in 1845 by Peyrone, earning it the common name of Peyrone's salt. Over 70 years later, Barnett Rosenberg discovered the biological application of cisplatin while studying the effects of electric fields on bacterial growth, deducing that the platinum compounds from his electrodes were inhibiting cell division (Rosenberg et al., 1965 ). He and his coworkers then demonstrated cisplatin as a successful antitumor agent in rats and mice, efficacious against advanced tumors and tumors resistant to other drugs (Rosenberg et al., 1969 ). Today, cisplatin is used singly or in combination therapy, especially in the treatment of head, neck, lung, bladder, cervical, ovarian, testicular, and gastrointestinal cancers, as well as malignant gliomas and metastatic cancers such as metastatic melanoma, mesothelioma, and those of the prostate and breast (Boulikas and Vougiouka, 2004 ). The later synthesized platinum-based antineoplastic agents carboplatin and oxaliplatin are indicated in limited applications: carboplatin against specific types of breast cancer and in combination therapy against lung cancer, oxaliplatin in combination therapy against colorectal cancer. Cisplatin is considered the most ototoxic in this class, but is up to 45 times more effective against certain neoplasms than carboplatin and oxaliplatin.

This review is dedicated to the detailed discussion of cisplatin and aminoglycosides but we should not neglect to mention other ototoxins. Salicylate (aspirin) has long been associated with elevated hearing threshold and tinnitus (ringing in the ear), two effects that disappear with cessation of drug intake. Loop diuretics such as furosemide, ethacrynic acid, and bumetanide have transient side effects on the inner ear given singly, but create disastrous repercussions in combination with aminoglycoside antibiotics. Recently, observational evidence has earned some phosphodiesterase inhibitors (such as Cialis, Viagra, Revatio, and Levitra) a safety warning that administration may be associated with sudden hearing loss and/or vestibular disturbances (Maddox et al., 2009 ). Other potentially ototoxic substances include organometals such as organotins and mercury preparations, as well as solvents such as toluene and styrene used in industrial settings, putting workers at risk for auditory side effects.


‘Less Is More’ When it Comes to Testicular Cancer Chemo, Study Suggests

Latest Cancer News By E.J. MundellHealthDay Reporters THURSDAY, Jan. 9, 2020 (HealthDay News) — Treatment with half the typical amount of chemotherapy can still prevent the return of one type of testicular cancer, a new study suggests. Giving patients with the “non-seminoma” form of testicular tumor just one cycle of chemotherapy was just as effective [&hellip]

Latest Cancer News

By E.J. Mundell
HealthDay Reporters

THURSDAY, Jan. 9, 2020 (HealthDay News) — Treatment with half the typical amount of chemotherapy can still prevent the return of one type of testicular cancer, a new study suggests.

Giving patients with the “non-seminoma” form of testicular tumor just one cycle of chemotherapy was just as effective at preventing the cancer from coming back as the standard two cycles, the study found.

Cutting the amount of chemotherapy in half also reduced serious side effects that can have a lifelong impact on a patient’s health, said the team of British researchers.

The findings might prove a boon for patients, most of whom are young.

“Reducing the overall dose of chemotherapy could spare young men who have their whole lives ahead of them from long-term side effects, and also means they will need fewer hospital visits for their treatment,” said lead researcher Robert Huddart.

He spoke in a news release from The Institute of Cancer Research in London, where he’s a professor of urological cancer.

One patient who’s been treated using the lower-dose strategy said he’s already benefiting.

“I was playing [soccer] semi-professionally at the time I was diagnosed,” noted 35-year-old Kris Taylor, from Britain’s West Midlands. “Even though my prognosis was good, knowing that you have cancer is really scary, and the key thing for me was to get back to normality as soon as possible.”

Speaking in the institute news release, Taylor said he’d “already had to have time off for surgery, so when I was offered the chance to have less chemo but with no greater risk the cancer would return, I jumped at it.”

Currently, testicular cancer patients first undergo surgical removal of the affected testicle. They then choose between two cycles of chemotherapy — to destroy any cancer that may have spread to other areas — or a watch-and-wait “surveillance” approach.

If the latter route is chosen, the patient receives no chemotherapy unless their cancer comes back, at which point they receive three cycles of chemo.

Survival rates for testicular cancer are very high, but many patients are diagnosed in their 20s and 30s, so having chemotherapy means they may have to live with long-term side effects, the researchers noted.

In the new study, Huddart’s group tracked outcomes for nearly 250 men with early-stage testicular cancer that was at high risk of returning after surgery. The men received one three-week cycle of a chemotherapy known as BEP — a combination of the drugs bleomycin, etoposide and the platinum agent cisplatin.

After two years, testicular cancer returned in just 1.3% of the patients. That was nearly identical to the rate found in prior studies of patients who had received two cycles of the chemotherapy, the researchers said.

About 41% of patients who received one cycle of chemotherapy had one or more serious side effects during treatment — such as an increased risk of infection, sepsis or vomiting — but only 2.6% had long-term side effects such as damage to their hearing.

For his part, Taylor acknowledged that “the side effects of the treatment were really difficult.”

But he said that he was still able to return to soccer quickly, and “five years on, and I’m still fighting fit.”

“It’s great to know that others may now be able to benefit from the trial’s findings,” he added. “Being able to reduce the amount of chemotherapy a person receives can make such a big difference to their quality of life in both the short-term and the long-term.”

Two U.S. experts in treating testicular cancer agreed that the study might change practice. But they also cautioned that treatment decisions are always made on a case-by-case basis.

“This is an important study emphasizing how ‘less is more’ in patients,” said Dr. Nikolaos Karanikolas, who directs urologic surgical oncology at Staten Island University Hospital in New York City.

But overall, “the need to provide effective care while preserving quality of life and reproductive success is paramount,” he said.

Dr. Michael Schwartz directs robotic and laparoscopic surgery at Northwell Health’s Arthur Smith Institute for Urology in Lake Success, N.Y. He said the results of the British study do look promising, but more research is needed.

“This study measured short-term toxicity, which appeared similar between the two groups,” Schwartz noted. “Long-term toxicities, and the effects of the different chemotherapy doses on fertility, were not reported in this study, but are expected with longer follow-up of the patients.”

SLIDESHOW

Also, not every man with non-seminoma testicular cancer will benefit equally from a reduced dose of chemo, he said.

“The results here have the potential to influence the treatment paradigm for testicular cancer, but it is important to remember that the results only apply to a highly selected patient population,” Schwartz said. “All patients with non-seminoma testicular cancer will not necessarily be candidates for this reduced chemotherapy regimen.”

The study was published Jan 2 in the journal European Urology.


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