L. Maiorino

Randomized Trial Comparing Cisplatin, Gemcitabine, and Vinorelbine With Either Cisplatin and Gemcitabine or Cisplatin and Vinorelbine in Advanced Non–Small-Cell Lung Cancer: Interim Analysis of a Phase III Trial of the Southern Italy Cooperative Oncology Group

PURPOSE In our previous phase II study, the cisplatin, gemcitabine, and vinorelbine (PGV) regimen produced a median survival time (MST) of approximately 1 year in advanced non-small-cell lung cancer (NSCLC) patients. The present study was aimed at comparing the MST of patients treated with this triplet regimen with the MSTs of patients receiving cisplatin and vinorelbine (PV) or cisplatin and gemcitabine (PG). PATIENTS AND METHODS From April 1997, patients with locally advanced or metastatic NSCLC, an age of < or = 70 years, and an Eastern Cooperative Oncology Group performance status < or = 1 were randomized to receive one of the following regimens: cisplatin 50 mg/m(2), gemcitabine 1,000 mg/m(2), and vinorelbine 25 mg/m(2) on days 1 and 8 every 3 weeks (arm A); cisplatin 100 mg/m(2) on day 1 and gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks (arm B); or cisplatin 120 mg/m(2) on days 1 and 29 and vinorelbine 30 mg/m(2)/wk (arm C). According to the two-stage design for phase III trials, an interim analysis was planned when the first 60 patients per arm were assessable for survival. RESULTS The survival data of 180 NSCLC patients (stage IIIB, 76 patients; stage IV, 104 patients) were analyzed in April 1999. Overall, 128 patients had died (PGV, n = 33; PG, n = 42; and PV, n = 53). The MST of patients in the PGV, PG, and PV arms was 51, 42, and 35 weeks, respectively, and the corresponding 1-year projected survival rates were 45%, 40%, and 34%, respectively. When only patients with stage IV disease were considered, an even stronger difference was seen between PGV (MST = 47 weeks) and both PG (34 weeks) and PV (27 weeks). At multivariate Cox analysis, the estimate hazard of death for patients receiving PGV compared with those receiving PV was 0.35 (95% confidence interval, 0.16 to 0.77; P <.01). The response rates were 47% in the PGV arm, 30% in the PG arm, 25% in the PV arm. Both hematologic and nonhematologic toxicities were not substantially worse in patients who received the PGV regimen. CONCLUSION The PGV regimen is associated with a substantial survival gain (MST > 3 months longer) when compared with the PV combination. Because this difference in survival met one of the early stopping rules, the accrual in the PV arm has been stopped (null hypothesis rejected). Enrollment still continues in the PGV and PG arm to ascertain whether the PGV regimen can also produce a significantly longer survival than that obtained with the PG regimen.

Randomized Phase III Study of Surgery Alone or Surgery Plus Preoperative Cisplatin and Gemcitabine in Stages IB to IIIA Non–Small-Cell Lung Cancer

PURPOSE This study aimed to determine whether three preoperative cycles of gemcitabine plus cisplatin followed by radical surgery provides a reduction in the risk of progression compared with surgery alone in patients with stages IB to IIIA non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with chemotherapy-naive NSCLC (stages IB, II, or IIIA) were randomly assigned to receive either three cycles of gemcitabine 1,250 mg/m(2) days 1 and 8 every 3 weeks plus cisplatin 75 mg/m(2) day 1 every 3 weeks followed by surgery, or surgery alone. Randomization was stratified by center and disease stage (IB/IIA v IIB/IIIA). The primary end point was progression-free survival (PFS). Results The study was prematurely closed after the random assignment of 270 patients: 129 to chemotherapy plus surgery and 141 to surgery alone. Median age was 61.8 years and 83.3% were male. Slightly more patients in the surgery alone arm had disease stage IB/IIA (55.3% v 48.8%). The chemotherapy response rate was 35.4%. The hazard ratios for PFS and overall survival were 0.70 (95% CI, 0.50 to 0.97; P = .003) and 0.63 (95% CI, 0.43 to 0.92; P = .02), respectively, both in favor of chemotherapy plus surgery. A statistically significant impact of preoperative chemotherapy on outcomes was observed in the stage IIB/IIIA subgroup (3-year PFS rate: 36.1% v 55.4%; P = .002). The most common grade 3 or 4 chemotherapy-related adverse events were neutropenia and thrombocytopenia. No treatment-by-histology interaction effect was apparent. CONCLUSION Although the study was terminated early, preoperative gemcitabine plus cisplatin followed by radical surgery improved survival in patients with clinical stage IIB/IIIA NSCLC.

Cisplatin, Gemcitabine, and Vinorelbine Combination Therapy in Advanced Non–Small-Cell Lung Cancer: A Phase II Randomized Study of the Southern Italy Cooperative Oncology Group

PURPOSE In a previous phase I study cisplatin (CDDP), gemcitabine (GEM), and vinorelbine (VNR) combination therapy was safe and very active in patients with non-small-cell lung cancer (NSCLC). This study was aimed at better defining the activity and toxicity of this regimen. PATIENTS AND METHODS One hundred eleven chemotherapy-naive patients, age < or = 70 years, with stage IIIB or IV NSCLC and a performance status of 0 or 1 (Eastern Cooperative Oncology Group scale) were randomized to two treatment arms. Patients on arm A received CDDP 50 mg/m2, GEM 1,000 mg/m2, and VNR 25 mg/m2 on days 1 and 8 of an every-3-weeks cycle (57 patients). Patients on arm B received CDDP 80 mg/m2, epirubicin 80 mg/m2, and vindesine 3 mg/m2, all delivered on day 1 every 4 weeks, plus lonidamine orally 150 mg three times daily (54 patients). In December 1996, randomization was stopped early, and an additional 30 patients were treated with the experimental regimen to obtain a more accurate estimation of its activity rate. RESULTS Among 87 patients who received the CDDP-GEM-VNR combination, four complete responses (CRs) and 46 partial responses (PRs) were observed, for an overall response rate of 57% (95% confidence interval [CI], 46% to 68%). Two CRs and 18 PRs were recorded among 54 patients on arm B, giving a 37% activity rate (95% CI , 24% to 51%). After a median follow-up duration of 19 months, the median progression-free and overall survival durations were 32 and 50 weeks in arm A, and 18 and 33 weeks in arm B, respectively. World Health Organization grade 3 to 4 neutropenia and thrombocytopenia occurred in 46% and 14% of patients in arm A and in 22% and 11% of those in arm B, respectively. Severe nonhematologic toxicity was uncommon in both arms. CONCLUSION The CDDP-GEM-VNR combination is a highly effective treatment for patients with advanced NSCLC and has a manageable toxicity. A phase III trial comparing this new combination with both CDDP-VNR and CDDP-GEM regimens is underway.

Gemcitabine with either paclitaxel or vinorelbine vs paclitaxel or gemcitabine alone for elderly or unfit advanced non-small-cell lung cancer patients

The aim of this study was to assess whether a combination of gemcitabine (GEM) with either paclitaxel (PTX) or vinorelbine (VNR) could be more effective than GEM or PTX alone in elderly or unfit advanced non-small-cell lung cancer (NSCLC) patients. A total of 264 NSCLC patients aged >70 years with ECOG performance status (PS)⩽2, or younger with PS=2, were randomly treated with: GEM 1200 mg m−2 on days 1, 8 and 15 every 28 days; PTX 100 mg m−2 on days 1, 8 and 15 every 28 days; GEM 1000 mg m−2 plus PTX 80 mg m−2 (GT) on days 1 and 8 every 21 days; GEM 1000 mg m−2 plus VNR 25 mg m−2 (GV) on days 1 and 8 every 21 days. In all arms, an intra-patients dose escalation was applied over the first three courses, provided that no toxicity of WHO grade ⩾2 had previously occurred. At present time, 217 (82%) patients had died. The median (months) and 1-year survival probability were 5.1 and 29% for GEM, 6.4 and 25% for PTX, 9.2 and 44% for GT, and 9.7 and 32% for GV. Multivariate analysis showed that PS⩽1 (hazard ratio (HR)=0.67; 95% CI 0.51–0.90), and doublet treatments (HR=0.76; 95% CI 0.59–0.99) were significantly associated with longer survival. Doublets produced no more toxicity than single agents. GT should be considered a reference regimen for elderly NSCLC patients with PS⩽1.

Cisplatin, Gemcitabine, and Paclitaxel in Locally Advanced or Metastatic Non–Small-Cell Lung Cancer: A Phase I-II Study

PURPOSE Because both cisplatin-paclitaxel and cisplatin-gemcitabine combinations are generally considered to be among the most active regimens in non-small-cell lung cancer (NSCLC) patients, this study aimed to determine the maximum-tolerated dose (MTD) of paclitaxel when combined with fixed doses of cisplatin and gemcitabine in advanced NSCLC patients and aimed to define the therapeutic activity of this new regimen. PATIENTS AND METHODS From October 1996 to September 1998, 75 patients with stage IIIB-IV NSCLC, who were either chemotherapy-naive (65 patients) or who had been pretreated (10 patients), received fixed doses of cisplatin (50 mg/m(2)) and gemcitabine (1,000 mg/m(2)) and escalating doses of paclitaxel in a 1-hour infusion, all on days 1 and 8, every 3 weeks. RESULTS Five different paclitaxel doses were tested, for a total of 275 cycles delivered. The escalation was stopped at the paclitaxel dose of 75 mg/m(2) in pretreated patients, whereas it continued to 150 mg/m(2) in chemotherapy-naive patients. A total of 65 chemotherapy-naive patients were treated. A paclitaxel dose of 125 mg/m(2) was recommended for phase II, and a total of 39 patients were treated at this level, for a total of 158 cycles delivered. No treatment-related deaths occurred. Five patients were hospitalized because of sepsis, and packed RBC transfusion was required in 13 patients. Grade 4 neutropenia and thrombocytopenia occurred in 23 (31%) and eight (11%) patients, respectively. Overall, 74 of the 75 patients were assessable for response. Four complete (CR) and 38 partial (PR) responses were recorded, for an overall response rate (ORR) of 57%. Three of the ten pretreated patients achieved a PR, compared with four CRs and 35 PRs in the 64 chemotherapy-naive patients (ORR, 61%). Thirty-eight of 39 patients included in phase II were assessable for response and quality of life (QOL) (one patients disease was not measurable). Two CRs and 24 PRs were recorded in this group, for an ORR of 68% (95% confidence interval, 51% to 82%). The QOL score improved in 27 of 38 (71%) patients. The median survival time was 15 months in the 65 chemotherapy-naive patients, but it had not yet been reached in the 39 patients included in phase II, for whom the 1-year projected survival was 70%. CONCLUSION The cisplatin-gemcitabine-paclitaxel combination is a feasible and well-tolerated approach in advanced NSCLC patients. Both a major response and a QOL improvement can be obtained in a high proportion of patients, with a median survival time exceeding 1 year. A phase III trial comparing this combination with other effective regimens is under way.

Irinotecan plus leucovorin-modulated 5-fluorouracil I.V. bolus every other week may be a suitable therapeutic option also for elderly patients with metastatic colorectal carcinoma

The aim of this study was to assess the safety and efficacy of biweekly irinotecan plus leucovorin-modulated 5-fluorouracil i.v. bolus in metastatic colorectal carcinoma according to the age of patients. For this purpose, we have analysed 108 patients randomly allocated to receive irinotecan 200 mg m−2 i.v. (1-h infusion) on day 1, and L-leucovorin 250 mg m−2 i.v. (1-h infusion) plus 5-fluorouracil 850 mg m−2 i.v. bolus on day 2 every 2 weeks (IRIFAFU) in our previous SICOG 9801 trial. According to age, patients were retrospectively divided into three groups: younger (⩽54 years, n=37), middle-aged (55–69 years, n=64), and elderly (⩾70 years, n=17). Apart from gender, pretreatment characteristics were well balanced across the three groups. WHO grade ⩾3 neutropenia and diarrhoea affected on the whole 46 and 16 patients, respectively, without any significant difference according to age-grouping. Patients aged ⩽54 years stayed on therapy for a longer time (median 24 vs 14–15 weeks), and received more cycles (median 9 vs 7), than the older ones. Only one patient in the young group withdrew consent to therapy as opposed to four patients each in the aged and elderly one. Response rate was 38% for younger patients, 34% for aged, and 35% for the elderly ones. Median time to progression was 7.4, 8.0, and 5.3 months, and median survival time was 13.4, 15.3, and 13.9 months, respectively. We conclude that IRIFAFU given every other week may represent a suitable therapeutic option also for elderly patients with metastatic colorectal carcinoma.

Cisplatin–epirubicin–paclitaxel weekly administration with G-CSF support in advanced breast cancer. A Southern Italy Cooperative Oncology group (SICOG) phase II study

AbstractPurpose.It has been shown in vitro that both cisplatin and epirubicin increase the antitumor activity of paclitaxel. Weekly administration could give a substantial improvement in the therapeutic index of cisplatin and paclitaxel. This study was aimed at defining the antitumor activity of a weekly cisplatin–epirubicin–paclitaxel (PET) administration in locally advanced or metastatic breast cancer patients. Patients and methods.Sixty-eight breast cancer patients with advanced disease, who had not received prior chemotherapy (except adjuvant), received weekly cisplatin 30 mg/sqm, paclitaxel 120 mg/sqm and epirubicin 50 mg/sqm plus G-CSF (day 3–5), for a maximum of 12 cycles. Thirty-five patients had stage IIIB and 33 stage IV disease (14 with visceral metastases). Results.All patients were evaluable for response on an intent to treat basis. Overall, 21 complete and 38 partial responses have been recorded for an 87% ORR (95% CI = 76–94%). Fourteen CRs and 19 PRs have been registered in the 35 patients with locally advanced disease for a 94% ORR (95% CI = 81–99%) while 7 CRs and 19 PRs were observed in the 33 patients with metastatic disease for a 79% ORR (95% CI–61–91%). Surgery was performed in 33/35 women with locally advanced disease. Four of these patients (11%) showed no invasive cancer on pathologic examination, and in an additional 8 patients tumor < 1 cm was found in the breast. Only 4/33 patients who underwent surgery relapsed. The projected one-year RFS was greater than 80%. At an 11-month median follow-up (range, 3–19), 11 patients had progressed and 5 had died among the 33 patients with metastatic disease, the median progression-free survival in this group being 14 months. Severe hematologic toxicity was uncommon, grade 3–4 neutropenia and thrombocytopenia occurring in 32% and 4% of patients, respectively. Only 2 episodes of neutropenic sepsis were registered. Packed red blood cell transfusions were required in 7 patients. Vomiting, diarrhoea, mucositis and skin toxicity were severe in 6%, 9%, 10%, and 9% of patients, respectively. Peripheral neuropathy was observed in 47% of patients. Conclusions.The weekly PET administration is a well tolerated and very effective approach in advanced breast cancer patients. It can produce a 40% clinical complete response rate, with a more than 10% pCR rate in patients with T4 disease, and an about 80% ORR in those with distant metastases. A phase III trial comparing PET with a standard every 3 weeks epirubicin—taxol administration is underway.

Phase III randomized study of fotemustine and dacarbazine versus dacarbazine with or without interferon-α in advanced malignant melanoma

BackgroundThe effect of the addition of fotemustine and/or interferon (IFN) to standard therapy with dacarbazine alone in patients with advanced malignant melanoma was investigated in a multicenter, randomized 2x2 factorial design trial.MethodsA total of 260 patients were randomly assigned to one of four treatment groups: (A) fotemustine and dacarbazine repeated on 3-week cycle; (B) same treatment as (A) plus IFN-α2b three times per week; (C) dacarbazine alone repeated on 3-week cycle; (D) same treatment as (C) plus IFN-α2b three times per week. Two comparisons were planned to assess the efficacy of fotemustine (groups A+B vs. C+D) and IFN-α2b (groups A+C vs. B+D).ResultsAddition of fotemustine did not significantly improve overall survival (OS) (p=0.28) or progression-free survival (PFS) (p=0.55); Hazard ratio (HR) for OS was 0.93 (95% CI 0.71-1.21). Similarly, addition of IFN-α2b did not improve OS (p=0.68) or PFS (p=0.65); HR for OS was 0.92 (95% CI 0.70-1.20). Overall response rate was not improved by the addition of either fotemustine (p=0.87) or IFN-α2b (p=0.57). The combination of all three drugs resulted in the highest occurrence of adverse events.ConclusionsNo significant improvement in outcomes were observed with the addition of either fotemustine or IFN-α2b to dacarbazine.Trial registrationClinicalTrials.gov: NCT01359956

Predictive Comprehensive Geriatric Assessment in elderly prostate cancer patients: the prospective observational scoop trial results

The Comprehensive Geriatric Assessment (CGA) represents the future of the geriatric oncology to reduce toxicities and treatment-related hospitalization in the elderly. Most patients receiving docetaxel for metastatic castration-resistant prostate cancer are in their seventies or older. We explored the efficacy of the CGA in predicting chemotherapy feasibility and response to docetaxel in a cohort of 24 patients aged at least 70. This was an observational, prospective study involving 24 patients who were 70 years of age or older and about to start chemotherapy with docetaxel for metastatic castration-resistant prostate cancer; we performed a CGA including five domains and divided our patients into ‘healthy’ and ‘frail’; the relations between general condition and (i) early chemotherapy discontinuation and (ii) response to docetaxel were explored. We found a statistically significant relationship between frailty assessed by CGA and early docetaxel discontinuation; we also found an association between frailty and response to chemotherapy, but this did not reach statistical significance. A geriatric assessment before starting chemotherapy may help clinicians to recognize frail patients, and hence to reduce toxicities and early treatment discontinuation. Further analyses are required to simplify the CGA tools and to facilitate its incorporation into routine clinical practice.

Irinotecan and mitomycin C in 5-fluorouracil-refractory colorectal cancer patients. A phase I/II study of the Southern Italy Cooperative Oncology Group.

Purpose: To define the maximum tolerated dose (MTD) of irinotecan (CPT-11) given on days 1 and 8 with mitomycin C (MMC) given on day 1 in a monthly cycle, and to assess the toxicity and activity of this regimen in patients with previously treated colorectal carcinoma. Methods: Fifty-two patients, all pretreated with adjuvant 5-fluorouracil (20 patients) and/or one (35 patients) or two (8 patients) lines of chemotherapy, were entered in this study. Escalating doses of CPT-11 (starting from 150 mg/m2) were administered on days 1 and 8, with escalating doses of MMC (starting from 8 mg/m2) given on day 1, recycling every 28 days. At least 3 patients were treated at each dose level. Escalation proceeded unless 2 out of 3 or 4 out of 6 patients experienced a dose-limiting toxicity (DLT) after the first cycle. Results: Twelve patients were entered in the phase I study, and 4 consecutive dose levels were tested. At the last dose level (CPT-11 200 mg/m2 plus MMC 10 mg/m2) 4 of 6 patients experienced a DLT (i.e., grade 4 neutropenia in 2 patients and grade 3 diarrhea in 2 patients). Therefore, this dose level was considered as the MTD. Forty patients were treated at the previous dose level (CPT-11, 175 mg/m2 plus MMC 10 mg/m2). One complete, 4 partial, 3 minor responses and 11 cases of stable disease were registered, giving a response rate of 12% [95% confidence interval (CI), 4–27%] and an overall control of tumor growth in 47% (95% CI, 31–64%) of patients. The median time to treatment failure was 6 months (range 1–19+). The median survival time was 14.5 months, and the 1-year and 2-year probability of survival were 56 and 43%. Neutropenia and diarrhea affected 62 and 58% of patients, grade 3 or 4 being registered in 26 and 23% of them, respectively. One episode of neutropenic fever was reported. Other acute toxicities were usually mild and manageable. Conclusions: CPT-11 175 mg/m2 on days 1 and 8 associated with MMC 10 mg/m2 on day 1, every 4 weeks, is a safe and moderately active regimen in heavily pretreated patients with advanced colorectal carcinoma. The role of MMC in this combination is doubtful, and further attempts with other new agents should be made to improve the outcome in these patients.