Non-platinum Therapy Research Articles

Phase III multicenter web-based study demonstrating survival equivalents of nonplatinum-based chemotherapy for advanced non-small cell lung cancer (NSCLC): Subgroup analysis from D0112

8100 Background: Based on limited data, NSCLC guidelines from ASCO includes non-platinum (non-P) therapy. D0112 provided the highest evidence supporting this guideline. Survival for this non-P and a carboplatin combination were equivalent. Recently, treatment choices and duration are based on subgroups of NSCLC. This report addresses the outcomes for subgroups from this trial. Methods: Eligibility patients (pts) with IIIB/IV NSCLC, performance status (PS) 0–2, and no prior chemotherapy. Randomized pts were stratified by stage (IIIB vs IV) and PS (0–1 vs 2) to arm A: carboplatin + docetaxel or arm B: gemcitabine + docetaxel. Therapy duration following 6 cycles was at the discretion of the investigator. Gender, histology, stage, PS, prior radiation, and central nervous system (CNS) metastasis were identified as independent variables. Multivariable analysis was performed using a proportional hazards regression. Wald test was performed. Treatment effect for each subgroups was evaluated. Results: Median follow-up time for 930 pts was 25.3 mos with 754 deaths. Median survival time (MST) for both treatment groups was 7.9 mos. Non-P arm was non-inferior to the platinum arm, unadjusted hazard ratio of 1.03 (95% confidence interval: 0.89 to 1.18) p = 0.017. By Wald tests, female (p = 0.002), IIIB (p = 0.025), adenocarcinoma (p = 0.002), and PS 0 (p < 0.001) had longer MST. Relative risk for each subgroups was not different for either treatment arm. Pts with non- squamous, no CNS disease and PS 0–1 had a MST of 9.5 mos. 314 pts (34%) received 6 cycles of therapy. Beyond 6 cycles, 163 pts received additional therapy and 151 pts had chemotherapy discontinued without disease progression. MSTs were 15.2 mos (1-yr 66%) and 13.1 mos (1-yr 55%) (p = 0.13), respectively. SAEs were more common for pts with more than 6 cycles (24% of pts) compared to treatment discontinued (16% of pts). Conclusions: For the palliative care of advanced NSCLC, non-P-based chemotherapy provides equivalent survival to carboplatin-based therapy. Females, intrathoracic disease, adenocarcinoma, and good PS do better with either therapy. This trial like others raises questions about the appropriate duration of therapy for incurable NSCLC. No significant financial relationships to disclose.

Extending the Platinum-Free Interval with a Non-Platinum Therapy in Platinum-Sensitive Recurrent Ovarian Cancer

Background: It has been proposed that extending the platinum-free interval with intervening non-platinum therapy increases the efficacy of a later re-treatment with platinum in platinum-sensitive recurrent ovarian cancer. This hypothesis is based on data from small series and although it has not been validated prospectively, this strategy has entered general practice in Italy in the last years. The SOCRATES study retrospectively assessed the pattern of care of a cohort of patients with recurrent platinum-sensitive ovarian cancer observed in the years 2000–2002 in 37 Italian centres. Data were collected between April and September 2005. Methods: Patients with recurrent ovarian cancer with a platinum-free interval >6 months were eligible. 493 patient files were collected and 428 were eligible and analyzed. Results: The interval from the end of the 1st line to relapse was 6–12 months in 164 patients (39.5%) and >12 months in 251 cases (60.5%). Patients received a 2nd (100%), 3rd (80.1%), 4th (50.2%), 5th (28.3%), and 6th (11.9%) line of chemotherapy. At 2nd line 282 (65.9%) received platinum (group A), while 146 (34.1%) received non-platinum chemotherapy (group B). In the latter group, 67 patients received platinum at later progression (group B1), while 79 never received platinum (group B2). Median time to platinum re-treatment was 20 and 23.1 months in patients of groups A and B1, respectively. The response rate to the first platinum received was 74.4 and 57.4% in groups A and B1, respectively (p = 0.02). Group B2 was characterized by the worst response rate and survival. At multivariate analysis time of first platinum re-treatment (2nd line vs. later; p = 0.0132; OR = 2.34) and age (p = 0.0029; OR = 2.41) was independently associated with a higher possibility of response to platinum. Conclusions: With the limits of a retrospective study, our data question the hypothesis that extending the platinum-free interval with an intervening non-platinum therapy in patients with recurrent platinum-sensitive ovarian cancer improves the response rate of a further platinum re-treatment.

Long-term survival in a randomized study of nonplatinum therapy versus platinum in advanced epithelial ovarian cancer

The purpose of this study was to compare long-term survival in first-line chemotherapy with and without platinum in advanced-stage ovarian cancer. From July 1987 to November 1992, 161 untreated patients with FIGO stage III-IV epithelial ovarian cancer were randomized: 81 patients received no platinum and 80 received platinum combination. Residual disease after surgery was <2 cm in 61 patients without platinum, 59 with platinum. Median age was 58 years in nonplatinum arm and 55 years in platinum arm (range: 15-73). Complete and partial responses were 51% and 10% for nonplatinum arm and 51% and 8% for platinum arm, respectively (P= 0.7960). Stable disease was observed in 18% of patients in nonplatinum arm and 15% of patients in platinum arm and progression in 20% of nonplatinum- and 21% of platinum-treated cases. Ten-year disease-free survival was 37% for therapy without platinum and 31% for platinum combination (P= 0.5679); 10-year overall survival was 23% without platinum and 31% with platinum combination (P= 0.2545). Fifteen-year overall survival showed a trend of short duration in favor of platinum (P= 0.0678). Relapses occurred after 60 months in ten patients (seven with and three without platinum). The overall and disease-free survivals at 5, 10, and 15 years show no statistically significant long-term advantage from the addition of cisplatin; however, there is a slight trend in its favor.

Phase II trial of vinflunine in patients with relapsed small cell lung cancer

18091 Background: Vinflunine (VFL) is a novel microtubule inhibitor of the vinca alkaloid class which has demonstrated significant preclinical activity in a small cell lung cancer (SCLC) model and antitumor activity in several other tumor types. This multicenter community- based trial was designed to examine the role of VFL in patients (pts) with relapsed SCLC. Methods: The primary endpoint is objective response rate (ORR). Eligibility criteria: previously treated SCLC (sensitive or refractory relapsed pts; limited to 1 prior platinum or non-platinum therapy for limited- or extensive-stage disease), ECOG PS 0–2, measurable disease, and informed consent. Treatment: VFL 320 mg/m2 IV over 20 minutes day 1 every 21 days for up to 6 cycles. Pts were restaged every 6 weeks. This 2-stage trial was designed to achieve a 20% ORR in platinum-sensitive pts (per RECIST criteria). Results: 29 pts were enrolled from 3/06 to 12/06 (trial ongoing, n=41 planned). Data are available for 16 pts in this analysis. Baseline characteristics: median age 64 years; male/female, 63%/37%; ECOG PS 0/1/2, 25%/50%/25%; and sensitive relapse, 50%. 3 partial response have been observed (ORR 19%, 95% CI 4%-46%). 3 pts (19%) had stable disease and 7 pts (44%) had progressive disease. 3 pts were not evaluable due to: treatment-related toxicity (sepsis; constipation); declining PS, 1 pt each. With a median follow-up of 5 months, the median progression-free survival and overall survival are 1.7 months and 3.6 months, respectively. Grade (G) 3/4 non-hematologic toxicity occurring in more than 1 pt: constipation, dyspnea, fatigue, and hyponatremia (13% each). G3/4 hematologic toxicity: leukopenia (44%), neutropenia (38%), and thrombocytopenia (6%). There have been no treatment-related deaths. Conclusions: VFL appears active as second-line treatment for SCLC. Additional assessment of myelosuppression is needed to better assess VFL’s role. Completion of accrual is anticipated by 4/07. No significant financial relationships to disclose.

0009: Extending the Platinum-Free Interval (PFI) with a Non-Platinum Therapy in Platinum (P)-Sensitive Recurrent Ovarian Cancer (Oc): Results From the Socrates Retrospective Study

0009: Extending the Platinum-Free Interval (PFI) with a Non-Platinum Therapy in Platinum (P)-Sensitive Recurrent Ovarian Cancer (Oc): Results From the Socrates Retrospective Study

Extending the platinum-free interval (PFI) with a non-platinum therapy in platinum (P)- sensitive recurrent ovarian cancer (OC): Results from the SOCRATES retrospective study

5093 Background: Chance of response to P is correlated to PFI (Markman, J Clin Oncol 1991). It has been proposed that extending PFI by interposing non-P therapy increase activity of delayed P retreatment in patients (pts) with P-sensitive recurrent OC, but this strategy is based on data from small series. The SOCRATES study retrospectively assessed the pattern of treatment of a cohort of pts with P-sensitive recurrent OC. Methods: Data of pts treated between 2000 and 2002 at 37 centers were collected in 2005. Pts with recurrent OC were eligible if P-sensitive [interval from end of first line to relapse (RFI) &gt; 6 months]. Results: Data on chemotherapy at relapse were available in 428 pts. RFI was 6–12 months in 40% and &gt;12 months in 60%. Pts received a 2nd (100%), 3rd (80%), 4th (50%), 5th (28%), 6th (12%) line of chemotherapy. 282 pts (65.9%) received P at first relapse (Group A) after a median RFI of 19 months, with a 74.4% response rate (RR) out of 246 evaluable pts. 67 pts (15.7%) received non-P at first relapse after a median RFI of 9.6 months, with a RR of 44.6% out of 56 evaluable pts, and then received P at later relapse after a median PFI of 23 months, with a 57.4% RR out of 47 evaluable pts (Group B). 79 pts (18.5%), with a median RFI of 8.4 months, had a on-P 2nd line with a RR of 28.8% out of 66 evaluable pts, and never received P later (Group C). The difference in RR to P given as 2nd line and delayed P is statistically significant (p = 0.02, Fisher exact test). Median overall survival was 27.2, 26.1 and 16.8 months for Group A, B and C, respectively. Conclusions: With the limits of a retrospective study, our data show that, although P was given in the group B after a similar PFI than in the group A, due to the interposition of a non-P therapy, activity of P was higher when given immediately after relapse than when postponed at subsequent lines. Overall, these data suggest that P-sensitive pts should receive P as soon as possible, and delaying it may preclude the chance of receiving the best treatment. (Study sponsored by GlaxoSmithKline). No significant financial relationships to disclose.

Nonplatinum therapy in advanced bladder cancer

Carcinoma of the bladder is the second most prevalent genitourinary malignancy and the fifth most common solid malignancy in the USA. Combination chemotherapy is used in most patients with advanced disease. Traditionally, on the basis of favorable response rates and survival data, cisplatin-based regimens have been the preferred chemotherapy for patients with metastatic bladder cancer. However, the toxicity profile of cisplatin precludes its use in a significant subset of patients with advanced bladder cancer. Conversely, noncisplatin-containing regimens have been shown to have a more favorable toxicity profile and to have activity in advanced bladder cancer. Here, various nonplatinum chemotherapy regimens for advanced disease are reviewed.

Role of Non-Platinum-Based Chemotherapy in Advanced Non-Small Cell Lung Cancer

Platinum-based chemotherapy regimens have been the mainstay of systemic chemotherapy in advanced NSCLC. However, substantial toxicity impairs the survival and symptom control advantages of cisplatin- and even carboplatin-containing regimens. With the advent of newer active agents in the 1990s, investigators began conducting clinical studies with the aim of potentially eliminating platinum from initial therapy for patients with advanced NSCLC. Conceptually, three major hypotheses were tested in phase III trials: (i) single, non-platinum agents are equal in efficacy to platinum in combination with these agents; (ii) non-platinum combinations are potentially more effective than platinum-based therapy; and (iii) non-platinum combinations are at least equally efficacious, but less toxic than, platinum-based therapy. An overall analysis of phase III data indicates that combinations of these newer agents with platinum are superior to the single agent alone and that combinations of non-platinum agents are no more effective than platinum-based therapy. Non-platinum therapy has a different and perhaps marginally improved toxicity spectrum compared with platinum-based therapy. In the few studies utilizing a formal quality-of-life analysis, no differences have been detected. Therefore, while several non-platinum regimens have been validated in phase III trials as reasonable alternatives to platinum-based therapy, they have not been proven to be clearly superior.

Paclitaxel, carboplatin, and gemcitabine (PCG) versus gemcitabine and vinorelbine (GV) in chemotherapy naïve patients (pts) with advanced non-small cell lung cancer (NSCLC): A phase III trial of the Minnie Pearl Cancer Research Network (MPCRN)

7056 Background: The MPCRN phase III trial comparing the triplet PCG to the non-platinum doublet GV has been completed for pts with advanced NSCLC. Initially, a four-arm randomized trial was done and PCG and GV were associated with the best median survivals (Cancer 2002; 95:1279–85). GV was significantly less toxic than PCG, providing the rationale for extending the randomized comparison of PCG to GV as a phase III trial. Methods: The primary objective of this randomized phase III study was to compare survival of previously untreated pts with advanced NSCLC treated with PCG versus GV. PCG treatment consisted of P 200mg/m2 IV D1, C (AUC=5) IV D1, G 1000mg/m2 IV D1,8 q 21D. GV treatment was G 1000mg/m2 IV D1,8,15 q 28D and V 25mg/m2 IV D1,8,15 q 28D. Pts were re-evaluated q 2 cycles. Pts without evidence of progression or undue toxicity received a maximum of 6 cycles. Eligibility criteria included: stage IIIB/IV NSCLC, no prior chemotherapy, measurable disease, ECOG PS 0–2, adequate organ function, absence of brain metastases, and informed consent. Study was powered (0.80) to demonstrate an increase in expected 1-year survival from 30% with GV to 45% for PCG, requiring a total of 174 pts on each arm. P-values reported are two sided. Results: 349 pts were enrolled. Baseline pt characteristics were similar in the two groups. Objective response rates were similar for both regimens (PCG 25%; GV 26%). There was less grade 3/4 neutropenia, thrombocytopenia, anemia, alopecia, nausea/vomiting, myalgia/arthralgia and neuropathy (grade 2/3/4) with GV. One-year progression-free survival (PFS) and survival for PCG versus GV were 12% versus 15% (p=NS), and 39% versus 43% ((p=NS), respectively. Conclusions: In the first-line treatment of advanced NSCLC, PCG and GV are equivalent in terms of PFS and survival. Doublet non-platinum therapy with GV is associated with much less toxicity. Further study of GV in early stage NSCLC is warranted. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb

Platinum retreatment of platinum-resistant ovarian cancer after nonplatinum therapy

Objective The objective was to determine the response rate to platinum retreatment of “platinum-resistant” ovarian cancer after intervening nonplatinum therapy. Methods We retrospectively identified 30 patients with platinum-resistant ovarian cancer who received nonplatinum chemotherapy for recurrent epithelial ovarian cancer prior to additional platinum therapy. All patients were treated between July 1, 1997, and June 30, 2001. Platinum resistance was defined as less than a partial response to platinum therapy or progression within 6 months of the last platinum therapy. Results Overall, 7 of 30 patients experienced an objective response to platinum therapy (partial response, 23%; complete response, 0%) based on CT scan (2/21) and/or CA-125 (5/9) criteria. The median time to progression for the group was 17 weeks (range, 4–59 weeks). Several predictive factors were identified. The interval since the last platinum treatment did not appear to be predictive in this group. Only 1 of 16 patients who did not have an objective response to the most recent platinum-based therapy responded to platinum rechallenge. Similarly, no patient who received more than three intervening nonplatinum treatments responded to additional platinum therapy (0/10). Conclusions Our small retrospective series suggest that the platinum-resistant category is heterogenous and includes patients who may respond to retreatment with platinum-based agents. This group includes the patients with prior platinum responses and early progression. However, patients without an objective response to the last prior platinum therapy or more than three intervening treatments are unlikely to respond to subsequent platinum therapy.

Chemotherapy for advanced ovarian cancer. Advanced Ovarian Cancer Trialists Group.

Ovarian carcinoma is the seventh most common cancer of women in the world and is responsible for the greatest number of deaths from gynaecological malignancy in Europe and North America. Although many studies have explored the use of chemotherapy in this disease, most individual trials have been too small to show clear benefit of one type of chemotherapy over another. The type and intensity of chemotherapy used routinely for women with advanced ovarian cancer has varied because of uncertainty about the effectiveness of the different regimens. The objective of this review was to compare single drugs versus combinations of drugs, platinum versus non-platinum, and carboplatin versus cisplatin-based chemotherapy in women with advanced ovarian cancer. Search strategy: We searched MEDLINE, and CancerLit bibliographic databases and the National Cancer Institute and the UK Co-ordinating Committee on Cancer Research registers of trials. We also handsearched the proceedings of meetings and contacted experts in the field and drug companies. Randomised trials of: (1) single non-platinum versus non-platinum combination chemotherapy (2) single non-platinum versus platinum combination chemotherapy (3) non-platinum regimen versus the same regimen plus cisplatin (4) single platinum versus platinum combination chemotherapy (5) cisplatin versus carboplatin-based chemotherapy in women with advanced ovarian cancer. Individual patient data were obtained from the trial investigators, checked by the reviewers and finally verified by the trial investigator. Main results: 49 trials involving 8763 women were included. The data were combined to calculate hazard ratios (HR) for survival on an intention-to-treat basis. For single non-platinum versus platinum combination chemotherapy the overall HR for survival was 0.93, 95% confidence interval (CI) 0.83-1.05 in favour of platinum-based combination chemotherapy. For non-platinum regimens compared with the same regimen plus cisplatin the survival HR was 0.88, 95% CI 0.79- 0.98 in favour of the addition of platinum to drug regimens. Single platinum compared with platinum combination therapy gave a HR of 0.91, 95% CI 0.79-1.05 in favour of combination chemotherapy. Cisplatin versus carboplatin gave a HR of 1.02, 95% CI 0.93-1.12. Sub-group analyses for age, stage, grade, histology, resection, bulk of residual tumour and performance status were undertaken for cisplatin versus carboplatin only. No difference in effect was found. The available evidence, although not conclusive, suggests that platinum-based chemotherapy is better than non-platinum therapy. There is some evidence that combination therapy improves survival compared with platinum alone. No difference in effect has been shown between cisplatin and carboplatin.

Chemotherapy in advanced ovarian cancer: four systematic meta-analyses of individual patient data from 37 randomized trials. Advanced Ovarian Cancer Trialists' Group.

The purpose of this systematic study was to provide an up to date and reliable quantitative summary of the relative benefits of various types of chemotherapy (non-platinum vs platinum, single-agent vs combination and carboplatin vs cisplatin) in the treatment of advanced ovarian cancer. Also, to investigate whether well-defined patient subgroups benefit more or less from cisplatin- or carboplatin-based therapy. Meta-analyses were based on updated individual patient data from all available randomized controlled trials (published and unpublished), including 37 trials, 5667 patients and 4664 deaths. The results suggest that platinum-based chemotherapy is better than non-platinum therapy, show a trend in favour of platinum combinations over single-agent platinum, and suggest that cisplatin and carboplatin are equally effective. There is no good evidence that cisplatin is more or less effective than carboplatin in any particular subgroup of patients.