Bevacizumab as adjuvant treatment of colon cancer: updated results from the S-AVANT phase III study by the GERCOR Group.

BACKGROUND: The bevacizumab-Avastin® adjuVANT (AVANT) study did not meet its primary end point of improving disease-free survival (DFS) with the addition of bevacizumab to oxaliplatin-based chemotherapy in stage III colon cancer (CC). We report here the long-term survival results (S-AVANT). PATIENTS AND METHODS: Patients with curatively resected stage III CC were randomly assigned to FOLFOX4, FOLFOX4-bevacizumab, or XELOX-bevacizumab. RESULTS: A total of 2867 patients were randomized: FOLFOX4: n = 955, FOLFOX4-bevacizumab: n = 960, XELOX-bevacizumab: n = 952. With a median of 6.73 years follow-up (interquartile range 5.51-10.54), 672 patients died, of whom 198 (20.7%), 250 (26.0%), and 224 (23.5%) were in the FOLFOX4, FOLFOX4-bevacizumab, and XELOX-bevacizumab arms, respectively. The 10-year overall survival (OS) rates were 74.6%, 67.2%, and 69.9%, (P = 0.003) and 5-year disease-free survival (DFS) rates were 73.2%, 68.5%, and 71.0% (P = 0.174), respectively. OS and DFS hazard ratios were 1.29 [95% confidence interval (CI) 1.07-1.55; P = 0.008] and 1.16 (95% CI 0.99-1.37; P = 0.063) for FOLFOX4-bevacizumab versus FOLFOX4 and 1.15 (95% CI 0.95-1.39; P = 0.147) and 1.1 (95% CI 0.93-1.29; P = 0.269) for XELOX-bevacizumab versus FOLFOX4, respectively. CC-related deaths (n = 542) occurred in 157 (79.3%) patients receiving FOLFOX4, 205 (82.0%) receiving FOLFOX4-bevacizumab, and 180 (80.4%) receiving XELOX-bevacizumab (P = 0.764), while non-CC-related deaths occurred in 41 (20.7%), 45 (18.0%), and 44 (19.6%) patients, respectively. Cardiovascular-related and sudden deaths during treatment or follow-up were reported in 13 (6.6%), 17 (6.8%), and 14 (6.3%) patients, in the FOLFOX4, FOLFOX4-bevacizuamb, and XELOX-bevacizumab arms, respectively (P = 0.789). Treatment arm, sex, age, histological differentiation, performance status, T/ N stages, and localization of primary tumor were independent prognostic factors of OS in stage III. CONCLUSIONS: S-AVANT confirms the initial AVANT report. No benefit of the bevacizumab addition to FOLFOX4 adjuvant therapy in patients with stage III CC was observed in terms of DFS with a negative effect in OS, without increase in non-CC related deaths. CLINICAL TRIAL IDENTIFICATION: NCT00112918.

Capecitabine chemoradiation for rectal cancer after curative surgery.

This study reports the tolerability and feasibility of capecitabine, an oral fluoropyrimidine, chemoradiation as postoperative treatment. Stage II-III rectal cancer patients received 2 cycles of bolus 5-FU (425 mg/m2) and leucovorin (LV) (20 mg/m2) on days 1-5 q3w followed by oral capecitabine (800 mg/m2 bid) continuously during pelvic radiotherapy (total 50.4 Gy). Two additional cycles of 5-FU/LV were finally administered. Forty-one radically resected patients (median age: 61 years) were enrolled. All patients were evaluable for safety. Grade 3 adverse events included: proctitis (n = 3, 7%), diarrhea (n = 5, 12%), and leukopenia (n = 1, 2%). The overall rate of grade 3 diarrhea and leukopenia was 15% (95% confidence interval, 5-29%). Capecitabine chemoradiation in the adjuvant setting is well tolerated and is convenient to administer. These results support the use and further study of capecitabine chemoradiation in radically resected rectal cancer patients.

Phase II study of pemetrexed disodium (Alimta) administered with oral folic acid in patients with advanced gastric cancer.

BACKGROUND: The aim of this study was to assess the activity of pemetrexed in patients with advanced gastric cancer. PATIENTS AND METHODS: Thirty-eight eligible patients (median age 60 years) received pemetrexed 500 mg/m(2) every 3 weeks. Since toxicity was considerable in the first six patients, the protocol was amended to supplement subsequent patients with oral folic acid (5 mg/day on days -2 to +2 of every cycle). RESULTS: Among 36 stage IV patients evaluable for efficacy (six non-supplemented\30 supplemented), there were two complete and six partial responses. The response rate was 21% (95% confidence interval 8% to 32%) according to intention-to-treat analysis. All responding patients were in the supplemented group. The median duration of response was 4.6 months and the median survival was 7.8 months. Five of six non-supplemented patients (83%) developed grade 3/4 neutropenia; two (33%) unsupplemented patients discontinued; two (33%) patients died due to toxicity. In the supplemented group, 12 of 32 patients (37%) had grade 3/4 neutropenia. None of the supplemented patients discontinued treatment due to hematological toxicity. Severe non-hematological toxicities were infrequent. CONCLUSIONS: The activity of pemetrexed is promising in light of the tumor burden in these patients (all patients were stage IV and 39% had three or more organs involved). Toxicities were remarkably decreased with folic acid supplementation. Combination studies are warranted.

Oral doxifluridine plus levoleucovorin in elderly patients with advanced breast cancer.

BACKGROUND: There currently is no agreement regarding the appropriate treatment of elderly patients with advanced breast carcinoma (ABC). Doxifluridine (5-dFUR), a prodrug of 5-fluorouracil, has been found to be effective in this entity, but its use is limited by neurotoxicity and cardiotoxicity that are not observed when the oral formulation is used. The objective of this Phase II trial was to evaluate the effectiveness and tolerability of oral 5-dFUR, biomodulated with levoleucovorin (1-leucovorin), in elderly patients (age > 70 years) with ABC. METHODS: 5-dFUR was administered orally at 600 mg/m2 twice daily for 4 consecutive days every 12 days, and oral 1-leucovorin was administered as 25 mg 2 hours before each 5-dFUR administration. Response was assessed every five cycles according to the World Health Organization criteria. In the presence of response or stable disease, the patients were treated for a maximum of 15 cycles. RESULTS: Seventy-three eligible patients were enrolled, 27 of whom had been pretreated with chemotherapy and/or hormonotherapy; all were assessable for response and toxicity after a median follow-up of 15 months. The objective response rate was 26% (95% confidence interval, 17.4-45.4). Regression predominantly occurred in the presence of soft tissue involvement (skin, lymph nodes, and breast). The median time to response was 2 months (range, 1-2 months) and the median response duration was 7 months (range, 2-17+ months). The median survival was 24 months (range, 2-42+ months). The treatment was very well tolerated, and the side effects were manageable and always reversible. CONCLUSIONS: The results of the current study show that 5-dFUR plus 1-leucovorin, both given orally, are associated with excellent patient compliance. Although the results are suboptimal in terms of an objective response, this characteristic could allow 5-dFUR to be used in elderly patients considered unsuitable for "aggressive" chemotherapy.

Glutamine supplementation in cancer patients receiving chemotherapy: a double-blind randomized study.

The purpose of this study was to evaluate the efficacy of glutamine in preventing doxifluridine-induced diarrhea and the potential impact of glutamine on the tumor growth. We investigated 65 patients with advanced breast cancer receiving doxifluridine in a double-blind randomized fashion: 33 patients took glutamine (30 g/d, divided in 3 doses of 10 g each) for 8 consecutive days (5-12h) during each interval between chemotherapy, which was administered from day 1 to 4. Thirty-two patients took an equal dose of placebo (maltodextrine). The incidence of diarrhea was registered after each cycle of chemotherapy and severity was scored by the National Cancer Institute (NCI), Bethesda, Maryland, classification. The tumor response was evaluated by the World Health Organization (WHO) criteria. A total of 278 and 259 cycles (median 10 cycles), respectively, were delivered in glutamine and placebo groups. There were 34 and 32 episodes of diarrhea in glutamine and placebo groups, with no statistical difference overall, in the severity and duration of tumor growth, there was no difference in the response rate (21% and 28% of complete or partial response, respectively), in median time to response (2 mo), or in median duration of response. In conclusion, glutamine did not prevent the occurrence of the doxifluridine-induced diarrhea and did not have any impact on tumor response to chemotherapy.

Doxifluridine in colorectal cancer patients resistant to 5-fluorouracil (5-FU) containing regimens.

Doxifluridine (5-dFUR) is a fluoropyrimidine derivative, which is preferentially converted to 5-fluorouracil (5-FU) within tumour tissues. Although the activity of 5-FU in metastatic colorectal cancer is well recognised, resistance to this agent is frequently observed and remains its major limitation. The aim of this phase II study was to evaluate the activity of oral and i.v. 5-dFUR in metastatic or locally advanced colorectal cancer patients, who had been previously treated with a 5-FU containing regimen in either an adjuvant or metastatic setting. We treated 48 patients who, on the basis of tumour progression during, or within 8 weeks of the discontinuation of 5-FU therapy, were considered 5-FU resistant, 14 of the patients received 5-dFUR 3000 mg/m2 as a 1-h i.v. infusion, combined with L-leucovorin 25 mg/dose on days 1-5, every 3 weeks; the remaining 34 received oral 5-dFUR 1200 mg/m2 for 5 days followed by 5 days off. Oral L-leucovorin 25 mg/dose was administered 2 h before 5-dFUR. On the basis of WHO criteria, 4/14 (29%, 95% CI 4-51) partial responses were noted in the i.v. treated patients, and 4/34 (12%, 95% CI 1-23) in those treated orally. The radiological examinations documenting the response were a CT scan in 4 cases, ultrasound in 2 and NMR in 2. The median response duration was 6 months (range 3-11+), whereas the median time to treatment failure was 4 months (range 2-17). The responses were achieved in cases previously treated with a median of 9250 mg/m2 (range 5500-18,650) of 5-FU. No CTC-NC1 grade 4 toxicity was observed, although grade 3 diarrhoea occurred in 5 of the orally treated and in 3 of the intravenously treated patients. This is the first report documenting the efficacy of 5-dFUR in patients resistant to 5-FU therapy, and suggests that there is an absence of complete cross-resistance between these two fluoropyrimidines.

Formestane: an effective first-line endocrine treatment for advanced breast cancer.

Formestane, a new selective aromatase inhibitor devoid of severe side-effects, has been shown to be active in patients with advanced breast cancer. To investigate the clinical activity and endocrinological effects of formestane as a first-line treatment, 52 patients were administered two different doses: 24 received 250 mg formestane and 28 received 500 mg formestane i.m. fortnightly. All of the patients had a performance status of 2 or less (ECOG scale), 34 (65%) had a disease-free interval of at least 2 years and 21 (40%) were both oestrogen-receptor- and progesterone-receptor-positive; 20 patients received hormone and 13, received chemotherapeutical adjuvant treatment. Objective responses were obtained in 8 patients in the 250-mg group (33%; 95% CI: 14%-52%) and in 13 patients in the 500-mg group (46%; 95% CI: 28%-64%). The median response duration in the two groups was respectively 11 and 12 months. E2 serum levels of oestradiol had significantly (P < 0.001) decreased to more than 40% below the baseline value in both groups after 15 days of treatment, and remained unchanged thereafter. Local and systemic tolerability was satisfactory. We conclude that formestane is an effective and well-tolerated agent in previously untreated patients, and that these results should be confirmed by further studies.

Efficacy and tolerability of 4-hydroxyandrostenedione (4-OHA) as first-line treatment in postmenopausal patients with breast cancer after adjuvant therapy.

Aromatase inhibitors are known to be effective in the treatment of advanced postmenopausal breast cancer. To assess the efficacy of the aromatase inhibitor 4-hydroxyandrostenedione (4-OHA) as first-line treatment in patients who were either resistant to or had relapsed after adjuvant therapy, 50 eligible patients received intramuscular 4-OHA either 250 mg or 500 mg fortnightly until disease progression or severe adverse events. Of the 43 patients evaluable for clinical response (UICC criteria), 15 (36%) showed objective response (CR+PR), 6 (14%) stable disease (SD). In relation to disease site, objective responses were obtained in 55% of cases with soft tissue metastases (16/29); in 33% with visceral metastases (8/24), and in 24% with bone involvement (5/21). In relation to previous adjuvant treatment, there were eight objective responses among the 17 patients treated with chemotherapy (47%), and seven objective responses among the 24 treated with tamoxifen (29%). The treatment was well tolerated. These results support the hypothesis that adjuvant therapy, whether hormonal or chemotherapy, may make patients less responsive to subsequent treatment.

Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes.

To improve current adjuvant results in high-risk breast cancer, in February 1982 we activated a prospective randomized trial using both intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) and Adriamycin (doxorubicin; Farmitalia-Carlo Erba, Milan, Italy) involving patients with resectable mammary carcinoma and more than three positive axillary lymph nodes. The objective of the study was to assess the effectiveness of four courses of Adriamycin followed by eight courses of CMF versus two courses of CMF alternated with one course of Adriamycin for a total of 12 courses. All drug courses were recycled every 3 weeks. Rather than temporarily reducing doses in the event of myelosuppression on the planned day of treatment, drug administration was delayed for 1 to 2 weeks. At a median follow-up of 59 months, treatment outcome was significantly superior for patients who received Adriamycin followed by CMF (Adriamycin----CMF) than for those given alternating regimens (CMF/Adriamycin). The 5-year relapse-free survival was superior post-Adriamycin----CMF (61%) compared with post-CMF/Adriamycin administration (38%; P = .001). The corresponding figures for the 5-year total survival were 78% and 62%, respectively (P = .005). The benefit of Adriamycin----CMF was observed in all patient subsets. Treatment was fairly well tolerated, and we documented only one case of fatal congestive heart failure in a patient who received postoperative irradiation to the left breast in addition to Adriamycin. Present findings indicate that in women with extensive nodal involvement, Adriamycin----CMF yielded superior results compared with CMF/Adriamycin.

Adjuvant chemotherapy after conservative surgery plus irradiation versus modified radical mastectomy. Analysis of drug dosing and toxicity.

In a cohort of 764 evaluable patients with primary breast cancer, we have compared the ability to deliver full doses of adjuvant chemotherapy in two patient groups: one undergoing conservative breast surgery plus irradiation and the other having modified radical mastectomy as primary treatment for the cancer. We have also analyzed the toxicities of the concurrent radiation and chemotherapy. The group having irradiation had significantly more moderate leucopenia, which caused a short delay (median, three weeks) in the overall time necessary to complete the planned chemotherapy. However, among those patients who completed the planned chemotherapy cycles, the fraction who received more than 85 percent average drug doses was 96 percent or higher in all but one small subgroup. Interaction between the irradiation and chemotherapy caused mild breast skin reactions in 42 percent of patients so analyzed and worse reactions in 12 percent. When follow-up tracings were performed, mild electrocardiogram abnormalities occurred in 19 percent of patients, apparently because of the irradiation. We conclude that intravenous adjuvant chemotherapy, as administered in this study, can be delivered as intensely with conservative primary treatment as after mastectomy and that toxicity is mild, rarely requiring intervention or treatment discontinuation.

Liver assessment in women receiving adjuvant CMF chemotherapy.

The medical records of women taking part in the first 2 prospective adjuvant CMF (cyclophosphamide, methotrexate, fluorouracil) programs were reviewed to evaluate the incidence of liver damage which could be attributable to prolonged methotrexate administration. In 802 evaluable patients abnormal liver studies occurred in 7 of 170 controls (4.1%) and 20 of 632 CMF-treated patients (3.2%). In 22 of 27 patients they were reversible, while the persistence of enzyme abnormalities in 2 patients treated with 12 CMF cycles was followed by the occurrence of viral hepatitis and osseous metastases, respectively. Adjuvant CMF was never discontinued in the presence of liver function abnormalities. In 22 women liver biopsies through laparoscopy were performed for various diagnostic purposes. They yielded an incidence of aspecific histologic changes (fatty metamorphosis, subcapsular fibrosis) which was similar between controls and CMF-treated patients. Present analysis failed to demonstrate a higher incidence of acute and/or chronic liver changes in patients treated with cyclical CMF compared to controls treated with surgery alone.