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.

Adjuvant FOLFOX +/- cetuximab in full RAS and BRAF wildtype stage III colon cancer patients.

Background: RAS mutations have been shown to confer resistance to anti- epidermal growth factor receptor (EGFR) treatment. We analysed the results of the PETACC8 trial (cetuximab + FOLFOX vs FOLFOX) in full RAS and BRAF wildtype (WT) patients (pts) with resected stage III colon cancer. Patients and methods: Exons 2, 3 and 4 of KRAS and NRAS, and BRAF exons 11 and 15, were sequenced using the Ampliseq colon-lung cancer panel version 2, in PETACC8 trial pts who consented to translational research. The impact of cetuximab on time to recurrence (TTR), disease-free survival (DFS) and overall survival (OS) was investigated in pts with tumours harbouring RAS and BRAF WT, and RAS mutations. The prognostic value of each individual mutation was also tested. Results: Among the 2559 pts analysed, 745 pts (29%) were known to have KRAS exon 2 mutations and 163 pts (6.4%) the BRAF V600E mutation. Of the remaining 1651 pts, 1054 were assessed by NGS, showing that a further 227 pts (21%) had KRAS exon 2, 3, 4 or NRAS exon 2, 3, 4 mutations, and that 46 pts (4.4%) had a newly diagnosed BRAF mutation. Cetuximab added to FOLFOX did not significantly improve TTR, DFS or OS in pts with RAS WT or RAS and BRAF WT tumours (HR 0.77-1.03, all P > 0.05). Cetuximab addition was not either significantly deleterious in RAS mutant pts or in pts with rare RAS or BRAF mutations. In the overall trial population, NRAS and KRAS codon 61 mutations were the only rare mutations with the same pejorative prognostic value as KRAS exon 2 or BRAF V600E mutations. Conclusion: Though not significant, the clinically relevant 0.76 adjusted HR observed for DFS in favour of adding cetuximab to FOLFOX, in full RAS and BRAF WT stage III colon cancer pts, may justify a new randomized controlled trial testing EGFR inhibitors in this setting. Clinical trial number: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.

Prognostic value of KRAS mutations in stage III colon cancer: post hoc analysis of the PETACC8 phase III trial dataset.

BACKGROUND: The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial. PATIENTS AND METHODS: We analyzed the prognostic impact of KRAS exon 2 mutations in stage III colon cancer patients (n = 1657) receiving adjuvant FOLFOX ± cetuximab therapy included in the PETACC8 trial. Patients with BRAF-mutated cancers were excluded and, as no difference was found for time to recurrence (TTR) and disease-free survival (DFS) between treatment arms, both were pooled for analysis. Associations with TTR and DFS were analyzed using a Cox proportional hazards model. RESULTS: KRAS mutations were found in 638 of 1657 tumors and linked to shorter TTR (P < 0.001). However, when specific mutations were compared with wild-type, codon 12 mutations [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.35-2.04; P < 0.001] but not codon 13 (HR 1.23, 95% CI 0.85-1.79; P = 0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal versus proximal), KRAS genotype affects differently on recurrence (P = 0.02) and DFS (P = 0.042). Subgroup analysis showed that KRAS only affected TTR and DFS in distal tumors (n = 1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR 1.96, 95% CI 1.51-2.56; P < 0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR 1.59, 95% CI 1.00-2.56; P = 0.051). CONCLUSION: KRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors. CLINICAL TRIAL NUMBER: This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.

HER2 in high-risk rectal cancer patients treated in EXPERT-C, a randomized phase II trial of neoadjuvant capecitabine and oxaliplatin (CAPOX) and chemoradiotherapy (CRT) with or without cetuximab.

BACKGROUND: HER2 is an established therapeutic target in breast and gastric cancers. The role of HER2 in rectal cancer is unclear, as conflicting data on the prevalence of HER2 expression in this disease have been reported. We evaluated the prevalence of HER2 and its impact on the outcome of high-risk rectal cancer patients treated with neoadjuvant CAPOX and CRT±cetuximab in the EXPERT-C trial. PATIENTS AND METHODS: Eligible patients with available tumour tissue for HER2 analysis were included. HER2 expression was determined by immunohistochemistry (IHC) in pre-treatment biopsies and/or surgical specimens (score 0-3+). Immunostaining was scored according to the consensus panel recommendations on HER2 scoring for gastric cancer. Tumours with equivocal IHC result (2+) were tested for HER2 amplification by D-ISH. Tumours with IHC 3+ or D-ISH ratio ≥2.0 were classified as HER2+. The impact of HER2 on primary and secondary end points of the study was analysed. RESULTS: Of 164 eligible study patients, 104 (63%) biopsy and 114 (69%) surgical specimens were available for analysis. Only 3 of 104 (2.9%) and 3 of 114 (2.6%) were HER2+, respectively. In 77 patients with paired specimens, concordance for HER2 status was found in 74 (96%). Overall, 141 patients were assessable for HER2 and 6 out of 141 (4.3%) had HER2 overexpression and/or amplification. The median follow-up was 58.6 months. HER2 was not associated with a difference in the outcome for any of the study end points, including in the subset of 90 KRAS/BRAF wild-type patients treated±cetuximab. CONCLUSIONS: Based on the low prevalence of expression as recorded in the EXPERT-C trial, HER2 does not appear to represent a useful therapeutic target in high-risk rectal cancer. However, the role of HER2 as a potential predictive biomarker of resistance to anti-EGFR-based treatments and a therapeutic target in anti-EGFR refractory metastatic colorectal cancer (CRC) warrants further investigation. TRIAL REGISTRATION: ISRCTN Register: 99828560.

Colorectal cancer metastasis resectability after treatment with the combination of oxaliplatin, irinotecan and 5-fluorouracil. Final results of a phase II study.

PURPOSE: To investigate the response rate of the triple combination of oxaliplatin (L-OHP) in combination with irinotecan (CPT-11) and 5-fluorouracil (5-FU) and to assess its impact on secondary resectability of previously non-resectable liver metastasis (LM). PATIENTS AND METHODS: Patients > or = 18 with MCRC, ECOG grade 0-2, and no prior treatment received L-OHP (85 mg/m(2)), CPT-11 (150 mg/m(2)) and 5-FU (2 250 mg/m(2) in 48 h CI) on D1 every 15 days. RESULTS: Forty-seven patients with initially non-resectable metastatic disease were included. Median age 62 years (38-76); 28 males; 26 patients with 0 performance status (ECOG) 40 patients had prior surgery and four adjuvant chemotherapy. All patients were evaluable for toxicity and 42 for response. Main grade 3-4 toxicities were neutropenia (40%), febrile neutropenia (4%), diarrhea (21%), nausea/vomiting (11%/15%), fatigue (11%), anemia and alopecia (9% each); grade 3-4 neurotoxicity was observed in 28% patients. Secondary surgery was possible in 15 of 47 (31.9%) patients and 12/30 (40%) patients with only LM: in this cohort, median OS has not been reached at 22 months median follow-up, with 2/12 patients having died. Overall response rate was 69% (95% CI, 53-82%); 13 (31%) had stable disease. Median time to progression and overall survival (OS) were 10.9 (95% CI, 9.9-13.2) and 19.9 (95% CI, 11.7-TBD) months, respectively. CONCLUSION: This combination has shown promising activity with manageable toxicity as front-line treatment in MCRC, and has allowed the resectability of LM in a considerable number of patients, offering them the possibility of long-term survival.

Guides for adjuvant treatment of colon cancer. TTD Group (Spanish Cooperative Group for Gastrointestinal Tumor Therapy).

The choice of the most suitable chemotherapy schedule for the adjuvant treatment of colon cancer has been reviewed by the TTD group, as well as the principles of risk assessment for patients with stage II disease. In the light of data now available, oxaliplatin- based schedules (FOLFOX4 or FLOX) are recommended. Alternatives in special situations are monotherapy with capecitabine, UFT/LV, or 5- FU/LV in infusion. In patients with stage II disease, the indication of chemotherapy must be individualized and based on the patient's risk of recurrence (perforation, obstruction, peritumoral lymphovascular involvement, poorly differentiated histology, number of lymph nodes examined < or = 11, pre-surgical CEA), and comorbidities that can compromise the safety of treatment or survival of the patient.

Serial topoisomerase II expression in primary breast cancer and response to neoadjuvant anthracycline-based chemotherapy.

OBJECTIVE: We analyzed the value of topoisomerase IIalpha (Topo II) in predicting the clinical response to anthracycline-based neoadjuvant chemotherapy in breast cancers and the potential changes in Topo II after chemotherapy. In parallel, HER2, which is commonly coexpressed with Topo II, and p53, a modulator of chemotherapy activity, were also analyzed. METHODS: Forty-one patients with primary breast cancer and treated with neoadjuvant anthracycline-based chemotherapy (FAC or FEC) were included for the present study. Topo II, HER2 and p53 expression were measured by immunohistochemistry in pre and post chemotherapy (at the time of surgery), tumor specimens and the results were correlated with the clinical response. RESULTS: Topo II was overexpressed in 16 of 41 (31%) tumors before treatment, and this overexpression was significantly associated with clinical response (p = 0.03). HER2 and p53 were unrelated to response. Notably, Topo II overexpression, but not HER2 or p53, was lost in specimens after chemotherapy (p = 0.01). CONCLUSION: The observed link between Topo II and the clinical response to neoadjuvant anthracycline-based chemotherapy, together with its loss after chemotherapy, implies that Topo II deserves further testing in a prospective setting as a predictive marker.

Weekly docetaxel in breast cancer: applying clinical data to patient therapy.

The use of weekly 35-40 mg/m2 docetaxel, typically on a schedule of 6 weeks of therapy followed by a 2-week break, has produced response rates ranging from 33%-50% in patients with advanced breast cancer, the majority of whom have already received chemotherapy. These encouraging levels of response are seen across disease sites and in patients with prior anthracycline exposure. Importantly, the weekly administration of docetaxel allows prolonged treatment to a high cumulative dose: the weekly regimen is minimally myelotoxic, and neuropathy and other adverse events are infrequent. Weekly single-agent docetaxel may be a useful therapy in particular groups of patients such as those with reduced bone marrow reserve. It may also be a helpful means of delivering a highly active cytotoxic drug in combination with radiation therapy, other proven chemotherapy agents such as doxorubicin, and new, highly promising biological agents such as HERCEPTIN:

Infectious complications in 126 patients treated with high-dose chemotherapy and autologous peripheral blood stem cell transplantation.

The effect of an extensive prophylactic antimicrobial regimen was prospectively assessed in 126 patients after high-dose chemotherapy and autologous PBSC. They received ciprofloxacin (500 mg/12 h), acyclovir (200 mg/6 h), and itraconazole (200 mg/12 h) orally until neutrophil recovery. Febrile patients received i.v. imipenem (500 mg/6 h) to which vancomycin and amikacin were added if fever persisted for 2-3 and 5 days, respectively. Amphotericin B lipid complex was further given on day 7 or 8 of fever. Median times for a neutrophil count of >0.5 x 10(9)/l and a platelet count of >20 x 10(9)/l were 9 and 11 days. Severe neutropenia (<0.1 x 10(9)/l) lasted for a median of 5 days in which 72% of febrile episodes and 50% of cases of bacteremia occurred. Gram-positive bacteria were isolated in 30 of 40 episodes of bacteremia, 25 of which were caused by Staphylococcus epidermidis. Clinical foci were the intravascular catheter in 35 cases, respiratory infection in 11, cellulitis in two, anal abscess in one, and neutropenic enterocolitis in one. The high incidence of febrile episodes (94%) and bacteremias (31%) may be due to the lack of efficacy of antimicrobial prophylaxis and the persistence of a 5-day period of severe neutropenia.

Randomized trial comparing monthly low-dose leucovorin and fluorouracil bolus with weekly high-dose 48-hour continuous-infusion fluorouracil for advanced colorectal cancer: a Spanish Cooperative Group for Gastrointestinal Tumor Therapy (TTD) study.

PURPOSE: The objective of this multicenter study was to compare the efficacy and toxicity profiles of a combination of 5-fluorouracil (5-FU) given by bolus injection together with intravenous leucovorin (LV) versus high-dose 5-FU in continuous infusion (CI) in the treatment of advanced colorectal cancer. PATIENTS AND METHODS: A total of 306 patients were randomized to receive either 5-FU 425 mg/m2 given by bolus injection on days 1-5 plus intravenous (i.v.) LV 20 mg/m2 every four to five weeks or 5-FU 3.5 g/m2/week in a 48-hour CI. Therapy was continued until disease progression. Second-line chemotherapy was allowed in both arms. RESULTS: The response rates in 306 patients with measurable lesions were 19.2% (modulated arm) and 30.3% (CI arm, P < 0.05). The median progression-free survival times were 23.5 weeks (modulated arm) and 25 weeks (CI arm, P = NS). Median survival times were 42.5 weeks (modulated arm) and 48 weeks (CI arm, P = NS). There were no significant differences in grade 3-4 toxicity profiles but if we consider all grades we observed more mucositis in the modulated arm and more hand-foot syndrome in the CI arm. CONCLUSIONS: In terms of response rate, the continuous infusion regimen was more effective than the modulated regimen. There was no significant difference in survival and time to progression, and none in grade 3-4 toxicity.

A phase III randomized trial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF) versus cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer.

One hundred patients with metastatic breast cancer were randomly selected to receive combined chemotherapy treatment with adriamycin (50 mg/m2) or mitoxantrone (12 mg/m2) associated with 5-fluorouracil (600 mg/m2) and cyclophosphamide (600 mg/m2) administered intravenously every 21 days with a maximum of ten cycles. All patients included in this study were under 75 years of age and had ECOG performance status of less than 4. They had not been treated previously with chemotherapy for metastatic disease. Patients treated with adjuvant chemotherapy, which could not have included anthracyclines, had to have relapsed at least 12 months after the completion of therapy. There were no statistically significant differences in pretreatment characteristics or metastatic disease location between the two groups. Ninety-four patients were assessable for response. No differences were observed in response rate or in survival between the groups. The response rate (complete response (CR) and partial response (PR)) was 68% (13% CR and 55% PR for CAF; 0% CR and 68% PR for CNF). Median survival for all patients was 19 months (18 months with CAF and 19 months with CNF). All patients were assessable for toxicity. There were no differences in gastrointestinal and cardiac toxicity. More grade I-II hematologic toxicity episodes (p < 0.001) and treatment delays (p = 0.05) due to leucopenia were observed with the CNF group, and more grade III alopecia (p < 0.001) was observed with the CAF group. Patients received further therapeutic manoeuvres after finishing the study with a sequential treatment consisting of hormonal therapy and chemotherapy with mitomycin (M) -vinblastine (Vbl) (M 10 mg/m2 day 1, Vbl 5 mg/m2 days 1, 15 and 29; maximum 5 cycles). This chemotherapy treatment was received by 32 patients, with a response rate of 34% and grade III-IV hematologic toxicity of 37%. Treatment with CNF can be considered a good alternative to CAF for first-line treatment of metastatic breast cancer. M-Vbl treatment is useful as second-line treatment in patients with prior adriamycin exposure.