A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer. GOIM (Gruppo Oncologico Italia Meridionale) 9902 study

BackgroundThe Gruppo Oncologico Italia Meridionale 9902 trial compared four cycles of high-dose epirubicin plus cyclophosphamide (EC) with four cycles of docetaxel (Taxotere, D) followed by four cycles of EC as adjuvant treatment of node-positive breast cancer.Patients and methodsPatients were randomly assigned to EC (E 120 mg/m², C 600 mg/m², arm A) for four cycles or four cycles of D (100 mg/m²) followed by four cycles of EC (arm B), both regimens every 21 days. Hormone receptor-positive patients were given hormonal therapy for 5 years. Primary end point was 5-year disease-free survival (DFS). Secondary objectives were overall survival (OS) and safety.ResultsThere were 750 patients enrolled. With a median follow-up of 64 months, 5-year DFS was 73.4% in both arms, and 5-year OS was 89.5% versus 90.7% in arm A and B [hazard ratio was 0.99 (95% confidence interval for DFS 0.75–1.31; P = 0.95)], respectively. Grade 3–4 toxicity was more common in arm B.ConclusionsThis study did not show advantages from the addition of docetaxel to high-dose EC as adjuvant chemotherapy in node-positive breast cancer. The small sample size and low number of DFS events may have limited the ability to observe statistically significant difference between the two arms.     

Weekly etoposide, epirubicin, cisplatin, 5-fluorouracil and leucovorin: an effective chemotherapy in advanced gastric cancer.

In order to optimize the therapeutic index of combining etoposide, epirubicin, cisplatin, 5-fluorouracil (5-FU), leucovorin (EEPFL) chemotherapy in the treatment of advanced gastric cancer, a trial of a novel schedule of weekly administration was conducted. Weekly EEPFL treatment consisted of a concomitant boost of etoposide 40 mg m(-2) i.v. over 30 min, epirubicin 10 mg m(-2) i.v. over 5 min to a backbone regimen, weekly PFL chemotherapy with cisplatin 25 mg m(-2), 5-FU 2200 mg m(-2), leucovorin 120 mg m(-2) given simultaneously by 24-h i.v. infusion. Response, survival and toxicity were evaluated. Forty-two patients were studied. Median age was 69 (range 31-84) years. Twenty-six per cent of patients showed complete response and 45% partial response. The overall response rate was 71% (95% confidence interval 58-84%). For a total of 507 weekly EEPFL cycles delivered, the incidence of grade 4 leucopenia was 1% of cycles. One patient died of neutropenia septicaemia. There was no other grade 4 toxicity. Grade 3 and 2 leucopenia occurred in 7% and 14% of cycles. The incidence of grade 3 and 2 mucositis was 1% and 3% of cycles. Grade 3 and 2 diarrhoea occurred in 0.4% and 1.6% of cycles. Overall median survival was 10 months (range 3-41+ months). Weekly EEPFL chemotherapy is an effective regimen with tolerable toxicities in the treatment of advanced gastric cancer. A randomized controlled clinical trial to formally assess the efficacy and benefit of EEPFL chemotherapy is under way.     

Epirubicin,taxotere and fluorouracil modulated by folinic acid in the treatment of advanced gastric cancer: A phase II study of the Gruppo Oncologico dell’ Italia Meridionale (GOIM)

IntroductionDespite the large number of drugs active in AGC, no combination can be considered as the gold standard treatment. Modest increase have been obtained in overall survival with the most widely employed regimens such as CF or ECF, often obtained at expense of increased toxicity. So there is a strong need to develop new active drugs to improve the clinical outcome. Taxotere showed to be effective in preclinical studies and some phase II trials confirmed its clinical efficacy. Recently, the addition of TXT to CDDP + FU (TCF regimen), obtained, in a large randomised phase III trial, better survival than CF alone. However the toxicity of this combination was relevant and mainly due to the association with CDDP. Considering these data the GOIM started a phase II study aiming to evaluate efficacy and safety of a three drugs combination, employing EPI instead of CDDP.Materials and methodsForty-one histologically proven untreated gastric cancer patients, with advanced measurable disease, age between 18 and 75 years, performance status ⩾ 70 (Kfsky scale) and available to sign written informed consent, were enrolled. They received the following treatment: Epirubicin at 60 mg/m² on day 1, Taxotere at 50 mg/m² on day 1, Folinic Acid at 100 mg/m² on days 1–2, Fluorouracil bolus at 400 mg/m² on days 1–2 and Fluorouracil 22 h continuous infusion on days 1–2 every three weeks.ResultsAmongst the 38 evaluable patients we observed 5 CR (13%), 9 PR (24%), 9 SD (24%) and 15 PD (39%) for an ORR of 37% (95% CI: 22–52) and a tumor growth control rate of 61%. The median time to progression was 4 months and the median survival was 9 months.The treatment was well tolerated. The main grade III–IV haematologic toxicities were leucopenia 7%, neutropenia 5% and anemia 5% while non-haematologics were diarrhoea 2%, alopecia 2% and cardiac 2%.ConclusionThe three drugs combination of Taxotere, Epirubicin and Fluorouracil is active and well tolerated first-line treatment in advanced gastric cancer patients.     

Cisplatin, fotemustine and whole-brain radiotherapy in non-small cell lung cancer patients with asymptomatic brain metastases: A multicenter phase II study of the Gruppo Oncologico Italia Meridionale (GOIM 2603)

Background

More than 50% of brain metastases (BMs) occur in advanced non-small cell lung cancer (NSCLC) patients. Untreated patients with BMs have a poor prognosis with a median survival of 2 months. In most cases BMs are multiple and their optimal therapy is whole-brain radiation therapy (WBRT). The role of systemic therapies for these patients is still a matter for investigation due to concerns about the ability of these drugs to cross the blood-brain barrier (BBB). Cisplatin (CDDP) remains the backbone for medical treatment of NSCLC and fotemustine (FTM) is a nitrosurea able to cross the BBB.

Methods

Patients with advanced NSCLC, ECOG performance status (PS) 0-1 and multiple BMs not amenable to surgery or stereotactic radiotherapy were treated with 2 cycles of FTM 80 mg/m² days 1, 8 and CDDP 80 mg/m² day 1, every 3 weeks followed by WBRT 30 Gy (3 Gy daily in 10 fractions). Radiological restaging was performed before WBRT to assess the role of chemotherapy both for cranial and extracranial disease. Patients with disease control (DC: complete response plus partial response) received 4 more cycles. To assess the basic activities of daily living (ADL), the Barthel ADL Index was used to score patients’ performance every 2 cycles. The trial design provides a two-step evaluation according to the optimal two-stage design of Simon. In the first phase 29 patients were enrolled in order to verify if this schedule showed more than 25% response rate both for cranial and extracranial disease. If so, enrolment added up to a total of 81 patients.

Results

After the first evaluation 4 out of 29 patients were excluded from the study (3 untreated/1 not included for administrative reasons). At the time of the planned interim analysis patient's characteristics were the following: median age 61 years (range 44-70), M/F = 16/9, adenocarcinoma 11, squamous 5, large cell 2, undefined NSCLC 7; PS 0/1 in 11/14 cases, median Barthel Index score was 20 [13], [14], [15], [16], [17], [18], [19] and [20]. Three (12%) partial responses were observed, 9 subjects (36%) with stable disease and 13 (52%) showing disease progression. These data did not satisfy the pre-planned hypothesis and the study was stopped. At the time of the first evaluation before WBRT 12/25 (48%) patients had a systemic DC in contrast with 15/25 (60%) patients with BMs DC. Chemotherapy was relatively well tolerated with a prevalence of asthenia as the most relevant specific toxicity while the haematological toxicity was mild.

Conclusion

CDDP and FTM combined with WBRT do not represent a therapeutic option for patients with NSCLC. Therefore further studies to evaluate the combination of systemic treatments with WBRT are warranted.     

Successful initial treatment with weekly etoposide, epirubicin, cisplatin, 5-fluorouracil and leucovorin chemotherapy in advanced gastric cancer patients with disseminated intravascular coagulation

BACKGROUND: Acute disseminated intravascular coagulation (DIC) is a rare but severe complication of gastric adenocarcinoma. Conventional treatments, such as fresh frozen plasma, platelet replacement and heparin injections, are disappointing. The only way to correct this fatal condition is to control the underlying cancer promptly by effective chemotherapy. Here the successful initial control of acute DIC in gastric cancer patients with weekly EEPFL chemotherapy is reported. METHODS: Advanced gastric cancer patients complicated with acute DIC were eligible. Patients were treated with weekly EEPFL therapy (etoposide 40, epirubicin 10, cisplatin 25, 5-fluorouracil 2200 and leucovorin 120 mg/m2 ). Response, survival and toxicity were evaluated. RESULTS: From April 1997 to April 1999, six patients were included in this study. All patients received EEPFL chemotherapy. Clinical and laboratory evidence of acute DIC stabilized quickly after starting chemotherapy. Four patients showed a partial response, one stable disease and one progressive disease. The toxicity was mild and well tolerated. Median survival was 28 weeks (12, 14, 26, 30, 30 and 32 weeks). All patients suffered from a relapse of DIC after initial successful control and died within 30 days of clinical and laboratory evidence of acute DIC relapse. CONCLUSION: EEPFL therapy is an effective chemotherapy regimen for patients with advanced gastric cancer associated with acute DIC. The prognosis is poor if the DIC relapses after the initial successful control.     

Adjuvant chemotherapy in stage III colon cancer with 5-fluorouracil and levamisole versus 5-fluorouracil and leucovorin

BACKGROUND: Adjuvant chemotherapy for colon cancer has been established during the past decade. From 1990 until recently treatment with 5- fluorouracil (5-FU) and levamisole (LEV) lasting 12 months was recommended as standard treatment. At the initiation of this study in 1993 improvement of adjuvant therapy was expected by the modulation of 5-FU with folinic acid (FA). Therefore, we decided to perform a prospective randomized multicenter trial to compare standard 5-FU/LEV to 5-FU/FA for either 6 or 12 months. PATIENTS AND METHODS: Patients with stage III colon cancer after curative en bloc resection were randomized in 3 treatment groups: arm A (5-FU/LEV, weekly, 12 months), arm B (5-FU/FA, days 1-5, every 4 weeks, 12 months) and arm C (like B, 6 months). RESULTS: Between March 1993 and November 1997, 180 patients were randomized into the study, 155 were eligible for further evaluation. The interim analysis in November 2000 showed no significant difference for recurrence and disease-free survival in arm B and C, therefore the data from both 5-FU/FA treatment arms (B+C) were combined for comparison with 5-FU/LEV-treatment (A). Most pronounced toxicity in all treatment arms was mild nausea, loss of appetite and leukopenia. A tendency for more diarrhea and stomatitis was observed in arm B+C. After a median follow-up of 36.2 months no significant difference was seen for disease free survival (p = 0.9) and overall survival (p = 1.0). 3-year recurrence rates were 39.6% in arm A and 39.1% in arm B+C, 3-year survival rates amounted to 74.1% in arm A and 74.9% in arm B+C. CONCLUSION: Only a limited number of patients could be recruited in this study. The observed data support the results of other studies, which concluded that 6 months (or 12 months) treatment with 5-FU/FA is equivalent to 12 months treatment with 5-FU/LEV. Therefore the 6 months treatment with 5-FU/FA can be supported as standard for adjuvant therapy of stage III colon cancer.     

表柔比星、亚叶酸钙、氟尿嘧啶与顺铂联合化疗方案(ECF-L)治疗晚期胃癌的化疗与安全性临床研究

目的：评价表柔比星、氟尿嘧啶、亚叶酸钙以及顺铂(ECF—L)联合化疗方案对无法手术切除或术后复发的晚期胃癌的疗效与安全性。方法：本研究入选对象为经病理学证实的具有至少一个可测量病灶的原发性或转移至其他部位的无法手术切除的胃癌患者。所用化疗方案为：表柔比星50mg／m^2第一天，亚叶酸钙200mg／m^2第1—3天，氟尿嘧啶600mg／m^2第1—3天，以及顺铂20mg／m^2第1-3天静脉给药。3周为1周期，3个周期为一次疗程。治疗过程中允许必要的支持治疗。结果：2000年3月—2001年8月期间，各院共有79例患者入选并接受化疗(16例为Ⅲ期，63例为Ⅳ期；37例为初治患者，42例为复治患者；53例为术后复发患者)。最终66例患者可以评价疗效，其中CR4例、PR18例，总缓解率为33．3％(22／66)；初治患者缓解率为36．7％(11／30)，复治患者缓解率为30．6％(11／36)，具有淋巴软组织转移的患者其缓解率为50．0％(15／30)。除缓解病例外，NC患者25例，PD患者19例，以及治疗过程中出组患者13例(出组率16．4％，13／79)。化疗过程中发生的毒副反应(WH0标准)Ⅲ度-Ⅳ度主要为骨髓抑制20．1％、脱发5．1％和恶心、呕吐2．3％。结论：本研究提示ECF—L方案可以安全地用于治疗手术无法切除的晚期胃癌患者。     

A phase III randomized trial of 5-fluorouracil, doxorubicin, and mitomycin C versus 5-fluorouracil and mitomycin C versus 5-fluorouracil alone in curatively resected gastric cancer.

BACKGROUND: A phase III single-center randomized trial was performed in order to determine whether the addition of mitomycin C (MMC) and/or doxorubicin to 5-fluorouracil (5-FU) as adjuvant chemotherapy could influence survival in patients with curatively resected gastric cancer. PATIENTS AND METHODS: A total of 416 patients who had undergone curative resection for stage IB-IIIB gastric adenocarcinoma were stratified according to the stage and type of surgery, and then randomized to receive one of the three chemotherapy regimens, 5-FU alone (F) or 5-FU and MMC (FM) or 5-FU, doxorubicin and MMC (FAM) within 5 weeks after surgery. RESULTS: Of 416 patients registered, 395 (133 in F, 131 in FM and 131 in FAM) were assessable. Median follow-up duration was 91 months. Five-year overall survival rates were 67.2% for F, 67.0% for FM and 66.7% for FAM (P = 0.97). Five-year disease-free survival rates were 62.1% for F, 63.3% for FM and 62.5% for FAM (P = 0.83). Hematological toxicities were more frequent in the FM and FAM groups, whereas stomatitis was more common in the F group. CONCLUSIONS: Compared with adjuvant 5-FU alone, the addition of MMC and/or doxorubicin to 5-FU did not influence survival in patients with resected gastric cancer.     

Phase II study of the modified regimen of etoposide, leucovorin and 5-fluorouracil for patients with advanced gastric cancer

BACKGROUND: The efficacy of the treatment of advanced gastric cancer is not very good. The response rate to the original etoposide--leucovorin--5-fluorouracil (ELF) treatment is 53% with tolerable side effects. Whether increasing the dose intensity by prolonging the duration of infusion with 5-fluorouracil (5-FU) and leucovorin (LV) from 3 to 5 days for advanced or metastatic gastric cancer patients would enhance the efficacy but not increase side effects is still unknown. METHODS: Thirty-six advanced or metastatic gastric cancer and chemotherapy-naive patients with measurable or evaluable diseases were scheduled to receive intravenous etoposide 100 mg/m2/day on days 2-4, LV 300 mg/m2/day intravenously and 5-FU 500 mg/m2/day intravenously on days 1-5, every 4 weeks. All patients who received at least two courses of chemotherapy were evaluated for tumor response, survival and response duration and toxicity according to the WHO criteria. RESULTS: Thirteen patients showed a response, including five with complete response (CR). The overall response rate was 36% (95% confidence interval, CI, 20-52%) in the whole group and 46% (95% CI 28-66%) in the 28 patients with measurable disease. The median progression-free interval and overall median survival time were 5 and 7 months, respectively. The most frequent toxicity was alopecia (grade I/II 56.3%). The incidence of grade III or greater myelosuppression was 5.9%. No treatment-related death occurred. CONCLUSIONS: The efficacy of the modified ELF by increasing the dosages of 5-FU and LV is not superior to the results of the original regimen, yet it is a relatively safe and tolerable combination regimen for advanced gastric cancer.      

Palonosetron for prevention of acute and delayed nausea and vomiting induced by moderately emetogenic adjuvant folfox-4 regimen in colorectal cancer (CRC) patients: A phase II study of the Gruppo Oncologico dell’ Italia Meridionale (GOIM)

IntroductionFolfox-4 is the standard adjuvant treatment in stage III colon cancer and is also recommended in high-risk stage II colon cancer. Oxaliplatin-based regimens are considered moderately emetogenic therapies. Palonosetron, a new selective inhibitor of 5-HT3 receptors, in combination with dexhametasone showed a high antiemetic activity in pivotal trials enrolling patients treated with moderately or high emetogenic regimens. Considering these data, the GOIM started a multicentre phase II trial aiming to evaluate the activity and safety of palonosetron plus dexhametasone in patients affected by radically resected colorectal cancer and treated with adjuvant folfox-4.Materials and methodsPatients with stage III or high-risk stage II colorectal cancer and receiving folfox-4 as adjuvant treatment entered into the trial. Informed written consent was required. A single pretreatment dose of palonosetron 0.25 mg (intravenous) i.v. followed by dexamethasone 8 mg i.v. was administered. Nausea and vomiting were evaluated on day 1 and over the following 4 d, with a patient diary including vomiting episodes, daily nausea and use of rescue medications. The main end-point of the study was the absence of vomiting in the entire period (5 d) at the first cycle. The absence of moderately or severe nausea and vomiting on days 1–5 was the secondary end-point. Adverse events were evaluated according to the NCI-CTC criteria.ResultsEighty-five patients entered into the study and were all evaluable for activity and safety. The absence of vomiting on the study period (days 1–5) was observed in 82 (96.5%) patients: one patient on the 1st and two on the 2nd day experienced mild vomiting. With respect to the secondary end-point, the complete control during the acute phase was 96.5% while during the late phase was 92%. The complete responses during the acute and delayed phases were 99% and 89.5%, respectively. The main side-effects (G1 grade) were: constipation 13%, headache 10%, vertigo and insomnia 2%.ConclusionsPalonosetron is a very active antiemetic drug for the prevention of nausea and vomiting induced by folfox-4 regimen.     

Adjuvant chemotherapy with 5-fluorouracil and cisplatin compared with surgery alone for gastric cancer: 7-year results of the FFCD randomized phase III trial (8801).

BACKGROUND: The aim of this study was to evaluate the efficacy of adjuvant chemotherapy after resection for gastric cancer in a randomized controlled trial. PATIENTS AND METHODS: After curative resection, stage II-III-IVM0 gastric cancer patients were randomly assigned to postoperative chemotherapy or surgery alone. 5-Fluorouracil (5-FU) 800 mg/m(2) daily (5-day continuous infusion) was initiated before day 14 after resection. One month later, four 5-day cycles of 5-FU (1 g/m(2) per day) plus cisplatin (100 mg/m(2) on day 2) were administered every 4 weeks. RESULTS: The study was closed prematurely after enrollment of 260 patients (79.7% N+), owing to poor accrual. At 97.8 months median follow-up, 5- and 7-year overall survival were 41.9% and 34.9% in the control group versus 46.6% and 44.6% in the chemotherapy group (P=0.22). Cox model hazard ratios were 0.74 [95% confidence interval (CI) 0.54-1.02; P=0.063] for death and 0.70 (95% CI 0.51-0.97; P=0.032) for recurrence. An invaded/removed lymph nodes ratio >0.3 was the main independent poor prognostic factor identified by multivariate analysis (P=0.0001). Because of toxicity, only 48.8% of patients received more than 80% of the planned dose. CONCLUSION: There was no statistically significant survival benefit with this toxic cisplatin-based adjuvant chemotherapy, but a risk reduction in recurrence was observed.     

A prospective randomised phase III trial of adjuvant chemotherapy with 5-fluorouracil and leucovorin in patients with stage II colon cancer

The purpose of this trial was to investigate the efficacy of adjuvant chemotherapy with 5-fluorouracil (5-FU) and leucovorin (LV) in stage II colon cancer. Patients with stage II colon cancer were randomised to either adjuvant chemotherapy with 5-FU/LV (100 mg m(-2) LV+450 mg m(-2) 5-FU weekly, weeks 1-6, in 8 weeks cycles x 7) or surveillance only. Five hundred patients were evaluable for analyses. After a median follow-up of 95.6 months, 55 of 252 patients (21.8%) have died in the 5-FU/LV arm and 58 of 248 patients (23.4%) in the surveillance arm. There was no statistically significant difference in overall survival (OS) between the two treatment arms (hazard ratios, HR 0.88, 95% CI 0.61-1.27, P=0.49). The relative risk for tumour relapse was higher for patients on the surveillance arm than for those on the 5-FU/LV arm; however, this difference was not statistically significant (HR 0.69, 95% CI 0.45-1.06, P=0.09). Consequently, disease-free survival (DFS) was not significantly different between the two trial arms. In conclusion, results of this trial demonstrate a trend to a lower risk for relapse in patients treated with adjuvant 5-FU/LV for stage II colon cancer. However, in this study with limited power to detect small differences between the study arms, adjuvant chemotherapy failed to significantly improve DFS and OS.     

Adjuvant sequential methotrexate --> 5-fluorouracil vs 5-fluorouracil plus leucovorin in radically resected stage III and high-risk stage II colon cancer

The aim of the study was to determine whether modulation of 5-fluorouracil (FU) by methotrexate (MTX) improves survival compared to FU+6-s-leucovorin (LV) following potentially curative resection of stage II and III colon cancer. Within 8 weeks from surgery, 1945 patients with stage III (44%) or high-risk stage II (55%) colon cancer were randomly assigned to receive either 6 monthly cycles of FU 370 mg m(-2) i.v. bolus preceded by LV 100 mg m(-2) i.v. bolus on days 1-5, or 6 monthly cycles of sequential MTX 200 mg m(-2) i.v. days 1 and 15 and FU 600 mg m(-2) i.v. on days 2 and 16 followed by LV rescue (15 mg given p.o. q 6 h x 6 doses). Levamisole 50 mg p.o. t.i.d. on days 1-3, every 14 days for 6 months, was planned to be given in both arms. After a median follow-up of 4.2 years, 568 patients have relapsed and 403 have died. Survival was similar with MTX --> FU and FU+LV (77 vs 77% at 5 years; P = 0.90), as were 5-year disease-free survivals (67 vs 63%; P = 0.44). Efficacy results were similar for both stage III and II patients. There were two toxic deaths, two in the MTX --> FU arm (0.2%) and zero in the control arm. We conclude that biochemical modulation of FU with LV or with MTX produces similar results in the adjuvant setting of colon cancer.     

Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years' follow-up.

PURPOSE: To investigate whether chemotherapy with etoposide and cisplatin (EP) is superior to cyclophosphamide, epirubicin, and vincristine (CEV) in small-cell lung cancer (SCLC). PATIENTS AND METHODS: A total of 436 eligible patients were randomized to chemotherapy with EP (n = 218) or CEV (n = 218). Patients were stratified according to extent of disease (limited disease [LD], n = 214; extensive disease [ED], n = 222). The EP group received five courses of etoposide 100 mg/m(2) intravenously (IV) and cisplatin 75 mg/m(2) IV on day 1, followed by oral etoposide 200 mg/m(2) daily on days 2 to 4. The CEV group received five courses of epirubicin 50 mg/m(2), cyclophosphamide 1,000 mg/m(2), and vincristine 2 mg, all IV on day 1. In addition, LD patients received thoracic radiotherapy concurrent with chemotherapy cycle 3, and those achieving complete remission during the treatment period received prophylactic cranial irradiation. RESULTS: The treatment groups were well balanced with regard to age, sex, and prognostic factors such as weight loss, and performance status. The 2- and 5-year survival rates in the EP arm (14% and 5%, P =.0004) were significantly higher compared with those in the CEV arm (6% and 2%). Among LD patients, median survival time was 14.5 months versus 9.7 months in the EP and CEV arms, respectively (P =.001). The 2- and 5-year survival rates of 25% and 10% in the EP arm compared with 8% and 3% in the CEV arm (P =.0001). For ED patients, there was no significant survival difference between the treatment arms. Quality-of-life assessments revealed no major differences between the randomized groups. CONCLUSION: EP is superior to CEV in LD-SCLC patients. In ED-SCLC patients, the benefits of EP and CEV chemotherapy seem equivalent, with similar survival time and quality of life.