Vicente Alonso

Phase II, randomized study of concomitant chemoradiotherapy followed by surgery and adjuvant capecitabine plus oxaliplatin (CAPOX) compared with induction CAPOX followed by concomitant chemoradiotherapy and surgery in magnetic resonance imaging-defined, locally advanced rectal cancer: Grupo cancer de recto 3 study.

PURPOSE The optimal therapeutic sequence of the adjuvant chemotherapy component of preoperative chemoradiotherapy (CRT) for patients with locally advanced rectal cancer is controversial. Induction chemotherapy before preoperative CRT may be associated with better efficacy and compliance. PATIENTS AND METHODS A total of 108 patients with locally advanced rectal cancer were randomly assigned to arm A-preoperative CRT with capecitabine, oxaliplatin, and concurrent radiation followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)-or arm B-induction CAPOX followed by CRT and surgery. The primary end point was pathologic complete response rate (pCR). Results On an intention-to-treat basis, the pCR for arms A and B were 13.5% (95% CI, 5.6% to 25.8%) and 14.3% (95% CI, 6.4% to 26.2%), respectively. There were no statistically significant differences in other end points, including downstaging, tumor regression, and R0 resection. Overall, chemotherapy treatment exposure was higher in arm B than in arm A for both oxaliplatin (P < .0001) and capecitabine (P < .0001). During CRT, grades 3 to 4 adverse events were similar in both arms but were significantly higher in arm A during postoperative adjuvant CT than with induction CT in arm B. There were three deaths in each arm during the treatment period. CONCLUSION Compared with postoperative adjuvant CAPOX, induction CAPOX before CRT had similar pCR and complete resection rates. It did achieve more favorable compliance and toxicity profiles. On the basis of these findings, a phase III study to definitively test the induction strategy is warranted.

Phase II study of trastuzumab and cisplatin as first-line therapy in patients with HER2-positive advanced gastric or gastroesophageal junction cancer

IntroductionHER2 over-expression and/or amplification are present in 9-38% of gastric or gastroesophageal junction (GEJ) cancers and are correlated to poor outcome. We conducted a multicentre phase II trial to evaluate trastuzumab in combination with cisplatin in patients with untreated HER2-positive advanced gastric or GEJ cancer.Materials and methodsChemo-naïve patients with measurable, non-resectable, advanced or metastatic gastric or GEJ adenocarcinoma, with HER2 over-expression and/or amplification (IHC 3+, or IHC 2+ and FISH+), age ≥18 years, ECOG ≤2, left ventricle ejection fraction ≥50% and adequate organ function were eligible. Treatment consisted of trastuzumab (8 mg/kg on cycle 1 day 1 as loading; 6 mg/kg in subsequent cycles) and cisplatin (75 mg/m2), both intravenously on day 1, every 21 days.ResultsTwenty-two out of 228 patients (10%) were HER2-positive and were included in this phase II trial. The median age was 66 years and ECOG 0/1 was 41%/59%. The median number of cycles was 4 (range 1–41). The confirmed ORR was 32% and disease control was achieved in 64% of patients. Median time to progression was 5.1 months. Grade 3 adverse events included asthenia (27%), neutropenia (18%), anorexia (14%), diarrhoea (9%) and abdominal pain (9%). There were no grade 4 toxicities or treatment-related deaths. Higher baseline HER extracellular domain (ECD) levels were associated with better outcome in terms of response and survival.ConclusionsTrastuzumab in combination with cisplatin is an active regimen and has a favourable toxicity profile in advanced HER2-positive gastric or gastroesophageal cancers.

Chemoradiation, surgery and adjuvant chemotherapy versus induction chemotherapy followed by chemoradiation and surgery: long-term results of the Spanish GCR-3 phase II randomized trial

BACKGROUND The primary results of our phase II randomized trial suggested that compared with conventional preoperative chemoradiation (CRT), the addition of chemotherapy (CT) before CRT and surgery allows most patients receive their planned treatment with a better toxicity profile without compromising the pathological complete response and complete resection rates. We now report the 5-year outcomes. PATIENTS AND METHODS Patients with distal or middle third, T3-T4 and/or N+ rectal adenocarcinoma selected by magnetic resonance imaging, were randomly assigned to arm A-preoperative CRT followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)-or arm B-four cycles of CAPOX followed by CRT and surgery. The following 5-year actuarial outcomes were assessed: the cumulative incidence of local relapse (LR) and distant metastases (DM), disease-free (DFS) and overall survival (OS). RESULTS A total of 108 eligible patients were randomly assigned to arm A (n = 52) or arm B (n = 56). With a median follow-up of 69.5 months, 5-year DFS was 64% in arm A and 62% in arm B (P = 0.85) and 5-year OS was 78% in arm A and 75% in arm B (P = 0.64). The 5-year cumulative incidence of LR was 2% and 5% (P = 0.61) and 5-year cumulative incidence of DM was 21% and 23%; (P = 0.79) in arms A and B, respectively. CONCLUSION Both treatment approaches yield similar outcomes. Given the lower acute toxicity and improved compliance with induction CT compared with adjuvant CT, integrating effective systemic therapy before CRT and surgery is a promising strategy and should be examined in phase III trials.

Phase I trial of weekly gemcitabine at 3-h infusion in refractory, heavily pretreated advanced solid tumors.

Gemcitabine (2′,2′-difluorodeoxycytidine) is a nucleoside analog with antitumor activity against a variety of malignancies. The critical enzyme cytidine kinase is saturated at plasma concentrations achieved after a 30-min infusion at conventional doses. Prolonged infusion time may yield higher intracellular dFdCTP concentrations. A phase I study was designed to determine the maximum tolerated dose (MTD) of gemcitabine, given by infusion for 3 h, in heavily pretreated patients. Twenty-seven patients (13 head and neck cancer, seven sarcoma, three esophageal cancer, three non-small-cell lung cancer and one ovarian cancer) were enrolled. Twenty patients were defined as refractory at first- or second-line chemotherapy. Four different entry dose levels (300, 400, 450 and 500 mg/m2) were evaluated for gemcitabine administered on days 1, 8 and 15 of a 28-day cycle. The MTD was defined as 450 mg/m2, with granulocytopenia, thrombocytopenia and asthenia being dose limiting. The maximum grade III/IV patient toxicities for hemoglobin, leukocytes, neutrophils and platelets for all doses were 7, 19, 19 and 11%, respectively. Non-hematological toxicities included asthenia, nausea/vomiting and diarrhea. Thus, gemcitabine administered at a fixed 3-h infusion was well tolerated up to 450 mg/m2 in heavily pretreated patients. Myelosupression and asthenia were dose-limiting toxicities.

Preoperative Chemotherapy in Patients With Intermediate-Risk Rectal Adenocarcinoma Selected by High-Resolution Magnetic Resonance Imaging: The GEMCAD 0801 Phase II Multicenter Trial

BACKGROUND The need for preoperative chemoradiation or short-course radiation in all T3 rectal tumors is a controversial issue. A multicenter phase II trial was undertaken to evaluate the efficacy and safety of neoadjuvant capecitabine and oxaliplatin combined with bevacizumab in patients with intermediate-risk rectal adenocarcinoma. METHODS We recruited 46 patients with T3 rectal adenocarcinoma selected by magnetic resonance imaging (MRI) who were candidates for (R0) resection located in the middle third with clear mesorectal fascia and who were selected by pelvic MRI. Patients received four cycles of neoadjuvant capecitabine and oxaliplatin combined with bevacizumab (final cycle without bevacizumab) before total mesorectal excision (TME). In case of progression, preoperative chemoradiation was planned. The primary endpoint was overall response rate (ORR). RESULTS On an intent-to-treat analysis, the ORR was 78% (n = 36; 95% confidence interval [CI]: 63%-89%) and no progression was detected. Pathologic complete response was observed in nine patients (20%; 95% CI: 9-33), and T downstaging was observed in 48%. Forty-four patients proceeded to TME, and all had R0 resection. During preoperative therapy, two deaths occurred as a result of pulmonary embolism and diarrhea, respectively, and one patient died after surgery as a result of peritonitis secondary to an anastomotic leak (AL). A 13% rate of AL was higher than expected. The 24-month disease-free survival rate was 75% (95% CI: 60%-85%), and the 2-year local relapse rate was 2% (95% CI: 0%-11%). CONCLUSION In this selected population, initial chemotherapy results in promising activity, but the observed toxicity does not support further investigation of this specific regimen. Nevertheless, these early results warrant further testing of this strategy in an enriched population and in randomized trials.

Role of circulating tumor cells as prognostic marker in resected stage III colorectal cancer

BACKGROUND The prognostic role of circulating tumor cells (CTC) in early colorectal cancer (CRC) has not been determined yet. We evaluated the potential prognostic value of CTC in stage III CRC patients. PATIENTS AND METHODS Prospective multicenter study of 519 patients with stage III CRC recruited between January 2009 and June 2010. CTC were enumerated with the CellSearch System after primary tumor resection and before the start of adjuvant therapy. A total of 472 patients were included in the analysis. RESULTS CTC ≥1, ≥2, ≥3 and ≥5 were detected in 166 (35%), 93 (20%), 57 (12%) and 34 (7%) patients, respectively. Median follow-up was 40 months. In the overall population, CTC ≥1 (disease-free survival (DFS): HR 0.97, P = 0.85; overall survival (OS): HR 1.03, P = 0.89), ≥2 (DFS: HR 1.07, P = 0.76; OS: HR 1.02, P = 0.95), ≥3 (DFS: HR 0.96, P = 0.87; OS: HR 0.74, P = 0.41) and ≥5 (DFS: HR 0.72, P = 0.39; OS: HR 0.48, P = 0.21) were not associated with worse DFS and OS. No clinicopathological characteristics were significantly associated with the presence of CTC. In patients with disease relapse, the proportion with CTC ≥1 was not significantly different between those with single versus multiple metastatic locations (37.9% versus 31.4%, P = 0.761). In the multivariate analysis, CTC ≥1 was not an independent prognostic factor for DFS (HR 0.97, P = 0.87) and OS (HR 0.96, P = 0.89). CONCLUSION CTC detection was not associated with worse DFS and OS in patients with stage III CRC. Given the scarcity of CTC in these patients, it is likely that CTC determined by CellSearch system does not have a prognostic role in this setting. However, a longer follow-up is needed.

Cetuximab Given Every 2 Weeks plus Irinotecan Is an Active and Safe Option for Previously Treated Patients with Metastatic Colorectal Cancer

Background: We gathered data from multiple institutions on the cetuximab regimen of patients with metastatic colorectal cancer. Methods: 126 patients from 19 centers were included from July 2006 to July 2007 in this prospective non-controlled study. Irinotecan-refractory metastatic colorectal cancer patients with Karnofsky ≧70 received cetuximab 500 mg/m2 every 2 weeks (q2w) in combination with irinotecan 180 mg/m2 q2w until disease progression or unacceptable toxicity. The primary endpoint was the progression-free rate at 12 weeks. Results: Median age was 65 years; 65.9% male; colon/rectum 64.3/34.1%; Karnofsky status ≤80/≧90% in 45.3/54.7% of the patients. The progression-free rate was 42.7 (95% CI 32.8–52.6) and 22.4% (95% CI 14.2–30.7) at 12 and 24 weeks, respectively. The main grade 3 or 4 toxicities were: diarrhea 13.5% and acne-like rash 10.3%. No grade 3 or 4 infusional or allergic reactions were reported. Conclusions: The progression-free rates confirm that cetuximab q2w in combination with irinotecan is an option, and is as active and safe as the standard weekly regimen.

Phase I trial of weekly irinotecan combined with UFT as second-line treatment for advanced colorectal cancer

The aim of this study was to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of weekly Irinotecan (CPT-11) plus UFT, and to assess the antitumour activity of this combination as second-line chemotherapy in patients with advanced colorectal carcinoma, 31 patients with measurable advanced colorectal carcinoma were treated. Cohorts of 3 patients received increasing dose levels of the combination. Levels 1 to 4 included a fixed dose of oral (p.o.) UFT (250 mg/m(2)/day) for 21 days of a 28-day cycle combined with increasing intravenous (i.v.) doses of CPT-11 (80, 100, 110 and 120 mg/m(2)) on days 1, 8 and 15. Levels 5 and 6 included a higher fixed dose of oral UFT (300 mg/m(2)) combined with increasing i.v. doses of CPT-11 (100 and 110 mg/m(2)) on days 1, 8 and 15. 147 courses were administered. MTD were reached at level 4 (2 cases of grade 4 diarrhoea and 1 grade 3 asthenia), and level 6 (1 grade 4 diarrhoea, 1 grade 3 diarrhoea and 1 grade 3 febrile neutropenia). Responses in 30 evaluable patients were: 3 partial responses (10%), 15 stable disease (50%) and progressive disease in 12 patients (40%). Median time to progression was 4.5 months (95% Confidence Interval (CI): 3.4-6.6 months) and median survival was 11 months (95% CI: 7.9-14.1 months). The recommended doses for phase II trials are: (a) CPT-11 110 mg/m(2) i.v. on days 1, 8 and 15 every 28 days plus UFT 250 mg/m(2) p.o. on days 1 through to 21 or (b) CPT-11 100 mg/m(2) and UFT 300 mg/m(2).

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≥18 with MCRC, ECOG grade 0–2, and no prior treatment received L-OHP (85 mg/m2), CPT-11 (150 mg/m2) and 5-FU (2 250 mg/m2 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.

Gene-expression signature of tumor recurrence in patients with stage II and III colon cancer treated with 5'fluoruracil-based adjuvant chemotherapy.

Although receiving adjuvant chemotherapy after radical surgery, a disappointing proportion of patients with colorectal cancer will develop tumor recurrence. Probability of relapse is currently predicted from pathological staging, there being a need for additional markers to further select high‐risk patients. This study was aimed to identify a gene‐expression signature to predict tumor recurrence in patients with Stages II and III colon cancer treated with 5′fluoruracil (5FU)‐based adjuvant chemotherapy. Two‐hundred and twenty‐eight patients diagnosed with Stages II–III colon cancer and treated with surgical resection and 5FU‐based adjuvant chemotherapy were included. RNA was extracted from formalin‐fixed, paraffin‐embedded tissue samples and expression of 27 selected candidate genes was analyzed by RT‐qPCR. A tumor recurrence predicting model, including clinico‐pathological variables and gene‐expression profiling, was developed by Cox regression analysis and validated by bootstrapping. The regression analysis identified tumor stage and S100A2 and S100A10 gene expression as independently associated with tumor recurrence. The risk score derived from this model was able to discriminate two groups with a highly significant different probability of tumor recurrence (HR, 2.75; 95%CI, 1.71–4.39; p = 0.0001), which it was maintained when patients were stratified according to tumor stage. The algorithm was also able to distinguish two groups with different overall survival (HR, 2.68; 95%CI, 1.12–6.42; p = 0.03). Identification of a new gene‐expression signature associated with a high probability of tumor recurrence in patients with Stages II and III colon cancer receiving adjuvant 5FU‐based chemotherapy, and its combination in a robust, easy‐to‐use and reliable algorithm may contribute to tailor treatment and surveillance strategies.