Toxicity Of Platinum-based Chemotherapy Research Articles

Genetic variants of GADD45A, GADD45B and MAPK14 predict platinum-based chemotherapy-induced toxicities in Chinese patients with non-small cell lung cancer.

The JNK and P38α pathways play a crucial role in tissue homeostasis, apoptosis and autophagy under genotoxic stresses, but it is unclear whether single nucleotide polymorphisms (SNPs) of genes in these pathways play a role in platinum-based chemotherapy-induced toxicities in patients with advanced non-small cell lung cancer (NSCLC). We genotyped 11 selected, independent, potentially functional SNPs of nine genes in the JNK and P38α pathways in 689 patients with advanced NSCLC treated with platinum-combination chemotherapy regimens. Associations between these SNPs and chemotherapy toxicities were tested in a discovery group of 345 patients and then validated in a replication group of 344 patients. In both discovery and validation groups as well as their pooled analysis, carriers of GADD45B rs2024144T variant allele had a significantly higher risk for severe hematologic toxicity and carriers of MAPK14 rs3804451A variant allele had a significantly higher risk for both overall toxicity and gastrointestinal toxicity. In addition, carriers of GADD45A rs581000C had a lower risk of anemia, while carriers of GADD45B rs2024144T had a significantly higher risk for leukocytopenia or agranulocytosis. The present study provides evidence that genetic variants in genes involved in the JNK and P38α pathways may predict platinum-based chemotherapy toxicity outcomes in patients with advanced NSCLC. Larger studies of other patient populations are needed to validate our findings.

WISP1 polymorphisms contribute to platinum-based chemotherapy toxicity in lung cancer patients.

Platinum-based chemotherapy toxicity is always one of the serious problems from which lung cancer patients suffer. The genetic polymorphism of WISP1 was revealed to be associated with susceptibility and platinum-based chemotherapy response in our previous studies. In this study, we aimed to investigate the relationship of WISP1 genetic polymorphisms with platinum-based chemotherapy toxicity in lung cancer patients. A total of 412 lung cancer patients were enrolled in this study, and 28 polymorphisms of the WISP1 gene were genotyped by SequenomMassARRAY. We found that WISP1 polymorphisms (rs2929965, rs2929969, rs2929970, rs2929973 and rs754958) were related to the overall chemotherapy toxicity of lung cancer in subgroup analyses. Rs16904853, rs2929970, rs2977549 and rs2977551 (p = 0.021, 0.028, 0.024, 0.048, respectively) polymorphisms were significantly associated with hematologic toxicity. Rs2929946, rs2929970, rs2977519, rs2977536, rs3739262 and rs754958 (p = 0.031, 0.046, 0.029, 0.016, 0.042, 0.035, respectively) polymorphisms were significantly associated with the gastrointestinal toxicity of lung cancer. Genotypes of WISP1 may be novel and useful biomarkers for predicting platinum-based chemotherapy toxicity in lung cancer patients.

Association of CDC25 phosphatase family polymorphisms with the efficacy/toxicity of platinum-based chemotherapy in Chinese advanced NSCLC patients.

To explore relationships between single nucleotide polymorphisms (SNPs) of the CDC25 protein family and the survival and chemotherapy responses of patients with advanced non-small-cell lung cancer (NSCLC). We genotyped 14 SNPs of the CDC25 family in 663 Chinese patients with advanced NSCLC who were treated with first-line platinum-based chemotherapy and, in evaluable patients, analyzed relationships between the CDC25 family and the efficacy of platinum-based chemotherapy. CDC25A rs3731513 and rs1380053, CDC25C rs6861656, CDC25A haplotype T/A/A/A/C and CDC25C haplotype A/G/G/G/C were significantly associated with the patients' progression-free survival. In addition, CDC25B rs3761218 and haplotype G/T/G/G were associated with the occurrence of severe toxicity with platinum-based chemotherapy, especially gastrointestinal and hematological toxicity. These findings reveal a relationship between genetic variations of the CDC25 family and the efficacy and toxicity of platinum-based chemotherapy in patients with advanced NSCLC, especially in those with non-squamous-cell carcinoma.

Effectiveness of Chemotherapy in Measurable Granulosa Cell Tumors: A Retrospective Study and Review of Literature

Patients with irresectable granulosa cell tumors (GCTs) often receive chemotherapy. The effectiveness of this approach, however, is uncertain. The aim of our study was to assess the response rate to chemotherapy for residual and recurrent inoperable GCT. All consecutive chemotherapy-naive patients in 3 referral hospitals who were treated with chemotherapy for residual or recurrent GCT between 1968 and 2011 were included. Main outcome was the response according to Response Evaluation Criteria in Solid Tumor criteria. A literature search in MEDLINE through PubMed was performed, from inception to August 19, 2013. Twenty-seven patients with a GCT who received chemotherapy were identified. Eighteen patients were not evaluable because they had either no measurable disease, or no imaging was performed before and after chemotherapy. One of the 9 evaluable patients (11%) had a complete response, and 1 patient (11%) had a partial response, resulting in a response rate of 22% (95% confidence interval, 0%-49%). Seven patients (78%) had stable disease (range, 2-50 months), and none had progressive disease. Fifteen studies that assessed response rates to chemotherapy on measurable disease in a total of 224 patients showed a response rate of 50% (95% confidence interval, 44%-57%). Strict criteria of response, however, were not uniformly applied in the majority of these published series. In the present study, we present only a moderate beneficial effect of chemotherapy in patients with irresectable GCT with measurable disease. Comparison with previous studies is hampered by a lack of standardized response evaluation in the majority of studies. Given the toxicity of platinum-based chemotherapy, administering this treatment should be a well-considered decision.

Platinum-based combinations as first-line chemotherapy in advanced, persistent, or recurrent cervical cancer.

e15543 Background: Platinum compounds are the most active agents in cervical carcinoma. The aim of this study was to evaluate the activity and toxicity of platinum-based chemotherapy as first line treatment in patients with advanced/recurrent cervical cancer. Methods: Since 2005 to 2011years 68 pts were include in the pilot study. Patients with histological proven primary carcinoma, measurable tumors, age ≥ 18, PS of 0-1, adequate bone marrow, renal and hepatic functions were eligible for this trial. Prior chemotherapy was allowed only in the context of radiosensitization. Treatment consisted of 2 modes: PC - paclitaxel 175 mg/m2 3-h I.v. + cisplatin 75 mg/m2 or carboplatin AUC-6 ( 6 pts)- d1x 21d; IC – irinotecan 65 ìg/m2 + cisplatin 40 mg/m2 on d 1 and 8 x 21 d. Responses were assessed using RESIST. Results: 68 pts were identified. There were no differences between the groups in terms prior radiation or radiochemotherapy. Group PC: 28 pts were included. Efficacy and toxicity was available for 27. Two pts continue treatment. Median age 43,5 years (range 28-69). The ORR was 55.5% (CR - 5(18.5%) and PR -10(37.0%)). 8 pts (29.6%) SD and 4 (14.8%) PD. The median TTP was 7 months. Overall, 148 cycles were administered with a median of 5 (range 2-8) cycles. Major toxicities were as follows: GIII and GIV neutropenia in 22.2% and 11.1% pts; GIII anemia - in 2 pts; GI-II neuropathy in 45.9% pts. G III nausea/vomiting were in 3 pts (11.1%). Group IC: 40 pts were included, 38 were available for efficacy. Median age 49,8 years (range 25-67). The ORR was 47.3% (5 CR(13.2%) and 13 PR (34.2%)). 13 (34.2%) pts had SD and 7 (18.4%) - PD. The median TTP was 6 months. All 40 pts receved 254 cycles ( median 6.3 (range 1-11) cycles. GIII and IV neutropenia were in 40% and 10% pts; GIII anemia in 20% pts. G I-II neuropathy and G I-II diarrhea in 15% pts and 30%pts. G IV of diarrhea observed in 1 pt. GIII-IV nausea and vomiting were in 20% and 15%pts. There were no statistical differences in clinical outcome (OR(p= 0,69) and TTP(p=0,65)) between these 2 platinum-based regimes. Conclusions: Our data indicate that both regimes had high efficacy and well tolerated as first line treatment in patients with advanced/recurrent cervical cancer. The randomized study is necessary.

Abstract LB-316: Association of Bcl2 family gene polymorphisms with response to and toxicity of platinum-based chemotherapy in non-small-cell lung cancer patients in a Chinese population

Abstract PURPOSE: The Bcl2 family members have dual functions in apoptosis. Platinum agents cause genetic lesions and cell death that may be modulated by the normal pathway of apoptosis regulated by the Bcl2 family genes. We hypothesized that genetic polymorphisms of these genes have an impact on the outcome of platinum-based chemotherapy. The aim of our research was to assess whether single nucleotide polymorphism (SNPs) of BAD, BAX, PUMA, BID, and BCL2 in a pathway of regulating apoptosis affect the response to and toxicity in patients with NSCLC treated with platinum-based chemotherapy. METHODS AND METERIALS: We genotyped 64 SNPS of 5 genes by Illumina Custom Designed Chip in 1004 patients with advanced NSCLC treated with platinum-based chemotherapy. We investigated the response and the toxicity of patients after platinum-based chemotherapy. The genotyping data were analyzed by the Sofeware of SPSS12.0, PHASE2.1 and Haploview. RESULTES: A SNP of BID (rs5746474) was significantly associated with the hematological toxicity. Compared with the wild-type GG genotype, the variant AA genotype was associated with significantly increased risk to hematological toxicity (adjusted OR: 2.4344, 95%CI=1.4084–4.2077, p=0.0014) in a recessive model (adjusted OR: 2.5241, 95% CI = 1.4839–4.2933, P=0.0006). In the allelic analysis, a SNP of BCL2 (rs8099575) showed an effect on gastrointestinal toxicity (adjusted OR: 0.3041, 95% CI=0.1524–0.6.68, P=0.0007). Several haplotypes of these genes were associated with the response and toxicity; however, after Bonfernoni correction, no association between haplotypes and clinical outcome remained. CONCLUSION: Genetic polymorphisms in the BID and BCL2 genes may have an impact on the response to and toxicity of platinum-based chemotherapy in patients with NSCLC, which may be prognostic biomarkers of chemotherapy in NSCLC patients, if validated in larger studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-316. doi:10.1158/1538-7445.AM2011-LB-316

Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX‐4 treatment in Asian patients with colorectal carcinoma

Glutathione S-transferase P1 (GSTP1) participates in detoxification of potentially genotoxic compounds that may alter the efficacy and toxicity of platinum-based chemotherapy. We analyzed the influence of I105V polymorphism of GSTP1 on clinico-pathological features and outcomes in 166 Chinese patients with metastatic colorectal carcinoma who had been treated with first-line FOLFOX-4. Combined analysis of GSTP1 I105V, ERCC1-118, and XPD-751 polymorphisms was also conducted. The results showed that, in comparison with Caucasian populations, a remarkably lower prevalence of Val105 allele variants was noted (24.7%). Patients with Val105 allele variants had a higher response to FOLFOX-4 (56.1%vs 37.6%, P = 0.04), and a longer progression-free (P < 0.01) as well as overall (P < 0.01) survival. By adjusted analysis, this polymorphism was identified as an independent prognostic factor (P = 0.01). In combined analysis, patients without any risk genotype, including GSTP1-105 Ile/Ile, ERCC1-118 C/T or T/T, and XPD-751 Lys/Gln, had significantly longer progression-free and overall survivals (P < 0.01). In addition, patients with Val105 allele variants had a higher incidence of grade 3/4 cumulative neuropathy after different cycles of treatment. These data suggest that Asian populations have a lower prevalence of I105V polymorphism in GSTP1. I105V polymorphism in GSTP1, by reducing its enzymatic activity and consequential detoxification to oxaliplatin, could be a key determinant for a better outcome, but more neurotoxicity, to FOLFOX-4 treatment.

Improved compliance with adjuvant vinorelbine and cisplatin in non-small cell lung cancer

Poor compliance has been a common feature in clinical trials of adjuvant chemotherapy for NSCLC with only 48% to 69% of patients completing all planned cycles. We retrospectively evaluated compliance and toxicity of platinum-based chemotherapy in the 2 years following recent reports of successful adjuvant chemotherapy trials for NSCLC. Patients who received adjuvant chemotherapy after complete resection of NSCLC between May 2003 and May 2005 were analyzed retrospectively. Patient demographics, ECOG status, stage, pathologic subtype and type of surgery were recorded. The number of chemotherapy cycles, delays, dose reductions and change of chemotherapy were reported. Fifty patients were identified. The median age was 62 years (38% stage I, 18% stage II, 30% stage III and 14% had multiple primary tumors of variable stages). Twenty percent were ECOG PS2; Only 12% had undergone pnemonectomy. Forty-one patients (82%) started cisplatin/vinorelbine (three switched to carboplatin because of nephrotoxicity, and one switched to carboplatin/paclitaxel because of fatigue and vomiting). Three patients received other cisplatin-based combinations; six received carboplatin-based treatment (one each because of advanced age and cardiac dysfunction and 4 because of preexisting neuropathy). Eighty percent completed all treatment; 40% required a dose reduction and 58% required delays in treatment. Six events of febrile neutropenia were reported in 5 patients and 5 patients required admission for toxicity. There were no toxic deaths. Multivariate analysis showed no effect of age, gender, extent of surgery or ECOG status on compliance, need for treatment modification or toxicity. Compared to historical trials, adjuvant platinum-based chemotherapy for resected NSCLC is now accepted by patients and physicians with a high degree of compliance.

Compliance of adjuvant chemotherapy in non-small cell lung cancer (NSCLC); No longer an issue

7154 Background: Poor compliance has been a common feature in clinical trials of adjuvant chemotherapy for NSCLC with only 48%-69% of patients completing all planned cycles. This may have been due to lack of perceived benefit by patients and physicians and toxicity of the regimens employed. We retrospectively evaluated compliance and toxicity of platinum-based chemotherapy in the two years following the recent reports of successful adjuvant chemotherapy trials for NSCLC. Methods: Following institutional ethics approval, patients who received adjuvant chemotherapy after complete resection of NSCLC between May 2003 and May 2005 were analyzed retrospectively. Patients were identified using an institutional cancer registry. Patient demographics, ECOG status, stage, pathologic subtype and type of surgery were recorded. The number of chemotherapy cycles, delays, dose reductions and change of chemotherapy were all reported. Results: A total of 50 patients were identified. The median age was 62. 38% were stage I, 18% stage II, 30% stage III and 14% had multiple primary tumors of variable stages. 20% were ECOG PS2 and the rest ECOG 0–1. Only 12% had undergone pnemonectomy. 41 patients (82%) started cisplatin /vinorelbine (3 switched to carboplatin because of nephrotoxicity, and one switched to carboplatin/paclitaxel because of fatigue and vomiting). 3 patients received other cisplatin-based combinations. 6 received carboplatin-based treatment (one because of advanced age, one because of cardiac dysfunction and 4 because of preexisting neuropathy). 80% completed all treatment. 40% required dose reduction. 58% required delays in treatment. 6 events of febrile neutropenia were reported in 5 patients. 7 patients required admission. There were no toxic deaths. Multivariate analysis showed no effect of age, gender, extent of surgery or ECOG status on compliance, need for treatment modification or toxicity. Conclusions: Compared to historical trials, adjuvant platinum-based chemotherapy for resected NSCLC is well tolerated and is now accepted by patients and physicians with a high degree of compliance. No significant financial relationships to disclose.

Platinum-based Chemotherapy in Metastatic Breast Cancer: The Leicester (UK) Experience

After failure of anthracycline- and taxane-based chemotherapy in metastatic breast cancer, treatment options until recently were limited. Until the introduction of capecitabine and vinorelbine, no standard regimen was available. We conducted a retrospective study to determine the efficacy and toxicity of platinum-based chemotherapy in metastatic breast cancer. Forty-two women with metastatic breast cancer previously treated with anthracyclines (93%) and/or taxanes (36%) received mitomycin-vinblastine-cisplatin (MVP) (n=23), or cisplatin-etoposide (PE) (n=19), as first-, second- and third-line treatment at a tertiary referral centre between 1997 and 2002. Chemotherapy was given every 3 weeks as follows: mitomycin-C (8 mg/m2) (cycles 1, 2, 4, 6), vinblastine (6 mg/m2), and cisplatin (50 mg/m2) all on day 1; and cisplatin (75 mg/m2) and etoposide (100 mg/m ) on day 1 and (100 mg/m2) orally twice a day on days 2-3. The response rate for 40 evaluable patients (MVP: n=23; PE: n=17) was 18% (95% confidence interval [CI]: 9-32%). The response rate to MVP was 13% (95% CI: 5-32%, one complete and two partial responses) and to PE 24% (10-47%, four partial responses). Disease stabilised in 43% (26-63%) and 47% (26-69%) of women treated with MVP and PE, respectively. After a median follow-up of 18 months, 37 women (MVP: n=19; PE: n=18) died from their disease. Median (range) progression-free survival and overall survival were 6 months (0.4-18.7) and 9.9 months (1.3-40.8), respectively. Median progression-free survival for the MVP and PE groups was 5.5 and 6.2 months (Log-rank, P = 0.82), and median overall survival was 10.2 and 9.4 months (Log-rank, P = 0.46), respectively. The main toxicity was myelosuppression. Grades 3-4 neutropenia was more common in women treated with PE than in women treated with MVP (74% vs 30%; P = 0.012), but the incidence of neutropenic sepsis, relative to the number of chemotherapy cycles, was low (7% overall). The toxicity-related hospitalisation rate was 1.2 admissions per six cycles of chemotherapy. No treatment-related deaths occurred. MVP and PE chemotherapy have modest activity and are safe in women with metastatic breast cancer.