Current Options for Third-line and Beyond Treatment of Metastatic Colorectal Cancer. Spanish TTD Group Expert Opinion.

Colorectal cancer (CRC) is a public health problem: it is the third most common cancer in men (746,000 new cases/year) and the second in women (614,000 new cases/year), representing the second leading cause of death by cancer worldwide. The survival of patients with metastatic CRC (mCRC) has increased prominently in recent years, reaching a median of 25 to 30 months. A growing number of patients with mCRC are candidates to receive a treatment in third line or beyond, although the optimal drug regimen and sequence are still unknown. In this situation of refractoriness, there are several alternatives: (1) To administer sequentially the 2 oral drugs approved in this indication: trifluridine/tipiracil and regorafenib, which have shown a statistically significant benefit in progression-free survival and overall survival with a different toxicity profile. (2) To administer cetuximab or panitumumab in treatment-naive patients with RAS wild type, which is increasingly rare because these drugs are usually indicated in first- or second-line. (3) To reuse drugs already administered that were discontinued owing to toxicity or progression (oxaliplatin, irinotecan, fluoropyrimidine, antiangiogenics, anti-epidermal growth factor receptor [if RAS wild-type]). High-quality evidence is limited, but this strategy is often used in routine clinical practice in the absence of alternative therapies especially in patients with good performance status. (4) To use specific treatments for very selected populations, such as trastuzumab/lapatinib in mCRC human epidermal growth factor receptor 2-positive, immunotherapy in microsatellite instability, intrahepatic therapies in limited disease or primarily located in the liver, although the main recommendation is to include patients in clinical trials.

A randomised phase III intergroup trial comparing high-dose infusional 5-fluorouracil with or without folinic acid with standard bolus 5-fluorouracil/folinic acid in the adjuvant treatment of stage III colon cancer: the Pan-European Trial in Adjuvant Colon Cancer 2 study.

PURPOSE: To investigate whether infusional high-dose 5-flurouracil (HD-FU) provides a significant improvement in recurrence-free survival (RFS) and overall survival (OS) compared with a standard bolus 5-FU regimen (Mayo Clinic) in patients with curatively resectable stage III colon cancer. METHODS: Patients (n=1601) were randomised to receive either the Mayo Clinic regimen or one of the three HD-FU regimens; LV5FU2, the Arbeitsgemeinschaft Internistische Onkologie (AIO) or the Grupo Espanol para el Tratamiento Digestivos (TTD), the data from which were combined to provide the HD-FU arm for final analysis. RESULTS: Patients were evenly balanced for age, TMN, tumor grade and vascular and lymphatic invasion. Median follow-up was approximately 42months, RFS (hazard ratio [HR]=0.997) and OS (HR=0.96) (primary end-point) were not statistically different between the two treatment arms. Infusional HD-FU was generally better tolerated than bolus 5-FU regimen. CONCLUSIONS: Infusional HD-FU does not improve RFS and OS in curatively resected stage III colon cancer patients compared to the Mayo Clinic regimen, but is less toxic.

Pancreatic cancer risk and levels of trace elements.

BACKGROUND AND AIMS: Knowledge on the aetiology of exocrine pancreatic cancer (EPC) is scant. The best established risk factor for EPC is tobacco smoking. Among other carcinogens, tobacco contains cadmium, a metal previously associated with an increased risk of EPC. This study evaluated the association between concentrations of trace elements in toenails and EPC risk. METHODS: The study included 118 EPC cases and 399 hospital controls from eastern Spain. Levels of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. OR and 95% CI, adjusted for potential confounders, were calculated using logistic regression. RESULTS: Significantly increased risks of EPC were observed among subjects whose concentrations of cadmium (OR 3.58, 95% CI 1.86 to 6.88; p(trend)=5×10(-6)), arsenic (OR 2.02, 95% CI 1.08 to 3.78; p(trend)=0.009) and lead (OR 6.26, 95% CI 2.71 to 14.47; p(trend)=3×10(-5)) were in the highest quartile. High concentrations of selenium (OR 0.05, 95% CI 0.02 to 0.15; p(trend)=8×10(-11)) and nickel (OR 0.27, 95% CI 0.12 to 0.59; p(trend)=2×10(-4)) were inversely associated with the risk of EPC. CONCLUSION: Novel associations are reported of lead, nickel and selenium toenail concentrations with pancreas cancer risk. Furthermore, the results confirm previous associations with cadmium and arsenic. These novel findings, if replicated in independent studies, would point to an important role of trace elements in pancreatic carcinogenesis.

Coffee consumption, genetic susceptibility and bladder cancer risk.

OBJECTIVE: We evaluated the bladder cancer risk associated with coffee consumption in a case-control study in Spain and examined the gene-environment interactions for genetic variants of caffeine-metabolizing enzymes. METHODS: The analyses included 1,136 incident cases with urothelial carcinoma of the urinary bladder and 1,138 controls. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for area, age, gender, amount of cigarette smoking, and years since quitting among former smokers. RESULTS: The OR (95% CI) for ever consumed coffee was 1.25 (0.95-1.64). For consumers of 1, 2, 3, and 4 or more cups/day relative to never drinkers, OR were, respectively, 1.24 (0.92-1.66), 1.11 (95% CI 0.82-1.51), 1.57 (1.13-2.19), and 1.27 (0.88-1.81). Coffee consumption was higher in smokers compared to never smokers. The OR for drinking at least 4 cups/day was 1.13 (0.61-2.09) in current smokers, 1.57 (0.86-2.90) in former smokers, and 1.23 (0.55-2.76) in never smokers. Gene-coffee interactions evaluated in NAT2, CYP1A2, and CYP2E1-02 and CYP1A1 were not identified after adjusting for multiple testing. CONCLUSION: We observed a modest increased bladder cancer risk among coffee drinkers that may, in part, be explained by residual confounding by smoking. The findings from the gene-coffee interactions need replication in further studies.

Raltitrexed (Tomudex) versus standard leucovorin-modulated bolus 5-fluorouracil: Results from the randomised phase III Pan-European Trial in Adjuvant Colon Cancer 01 (PETACC-1).

OBJECTIVES: PETACC-1 assessed if raltitrexed is non-inferior to 5-fluorouracil and leucovorin for relapse-free survival (RFS) and overall survival (OS) in adjuvant stage III colon cancer. METHODS: Non-inferiority required both HR for RFS and OS<1.25 at 1-sided alpha=0.05. Patients (1921) were randomised to six cycles of 5-FU/LV (n=969) or eight cycles of raltitrexed (n=952). We report the final results in 993 eligible patients who started and completed the allocated treatment (489 5-FU/LV and n=504 Raltitrexed) of whom respectively 146 and 148 died, respectively. RESULTS: The trial closed prematurely when 17 (1.9%) raltitrexed-related deaths were reported. Haematological and gastrointestinal toxicities were more frequent with 5-FU/LV, liver toxicities with raltitrexed. Raltitrexed was stopped for toxicity in 13.2% and 5-FU/LV in 8.5%. Sixty-day mortality was 9% versus 7%. With 4.1 years median follow-up, the HR for RFS was 1.16 (90% CI 0.99-1.37) and that for OS was 1.01 (90% CI 0.84-1.23). CONCLUSION: The trial failed to demonstrate non-inferiority of raltitrexed. FUNDING: Free drugs and financial support from AstraZeneca.

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.

Phase III study of capecitabine plus oxaliplatin compared with continuous-infusion fluorouracil plus oxaliplatin as first-line therapy in metastatic colorectal cancer: final report of the Spanish Cooperative Group for the Treatment of Digestive Tumors Trial.

PURPOSE: The aim of this phase III trial was to compare the efficacy and safety of capecitabine plus oxaliplatin (XELOX) versus Spanish-based continuous-infusion high-dose fluorouracil (FU) plus oxaliplatin (FUOX) regimens as first-line therapy for metastatic colorectal cancer (MCRC). PATIENTS AND METHODS: A total of 348 patients were randomly assigned to receive XELOX (oral capecitabine 1,000 mg/m2 bid for 14 days plus oxaliplatin 130 mg/m2 on day 1 every 3 weeks) or FUOX (continuous-infusion FU 2,250 mg/m2 during 48 hours on days 1, 8, 15, 22, 29, and 36 plus oxaliplatin 85 mg/m2 on days 1, 15, and 29 every 6 weeks). RESULTS: There were no significant differences in efficacy between XELOX and FUOX arms, which showed, respectively, median time to tumor progression (TTP; 8.9 v 9.5 months; P = .153); median overall survival (18.1 v 20.8 months; P = .145); and confirmed response rate (RR; 37% v 46%; P = .539). The safety profile of the two regimens was similar, although there were lower rates of grade 3/4 diarrhea (14% v 24%) and grade 1/2 stomatitis (28% v 43%), and higher rates of grade 1/2 hyperbilirubinemia (37% v 21%) and grade 1/2 hand-foot syndrome (14% v 5%) with XELOX versus FUOX, respectively. CONCLUSION: This randomized study shows a similar TTP of XELOX compared with FUOX in the first-line treatment of MCRC, although there was a trend for slightly lower RR and survival. XELOX can be considered as an alternative to FUOX.

Food and nutrient intakes and K-ras mutations in exocrine pancreatic cancer.

BACKGROUND: No studies have investigated the relation between K-ras mutations and dietary factors in exocrine pancreatic cancer (EPC), and fewer than 10 studies have done so in other neoplasms. PATIENTS AND METHODS: Incident cases of EPC were prospectively identified, and interviewed face-to-face during hospital admission. Food and nutrient intakes were measured with a food frequency questionnaire. Logistic regression was used to compare EPC cases (n = 107) with and without K-ras mutations (case-case study). RESULTS: K-ras mutations were more common among daily consumers of milk and other dairy products than among non-daily consumers: the odds ratio adjusted by total energy, age, sex, smoking, alcohol and coffee consumption (ORa) was 5.1 (95% CI 1.1 to 24.5, p = 0.040). For all dairy products, including butter, the ORa for the medium and upper tertiles of intake were 5.4 and 11.6, respectively (p for trend = 0.023). The ORa for regular coffee drinkers further adjusted by dairy consumption was 4.7 (95% CI 1.1 to 20.7, p = 0.043). K-ras mutated cases reported a lower intake of vitamin E (ORa = 0.2, p for trend = 0.036), polyunsaturated fats and omega 3 fatty acids (ORa = 0.2; p for trend <0.03). CONCLUSIONS: Results support the hypothesis that in EPC exposure to specific dietary components or contaminants may influence the occurrence or persistence of K-ras mutations.

Capecitabine as adjuvant treatment for stage III colon cancer.

BACKGROUND: Intravenous bolus fluorouracil plus leucovorin is the standard adjuvant treatment for colon cancer. The oral fluoropyrimidine capecitabine is an established alternative to bolus fluorouracil plus leucovorin as first-line treatment for metastatic colorectal cancer. We evaluated capecitabine in the adjuvant setting. METHODS: We randomly assigned a total of 1987 patients with resected stage III colon cancer to receive either oral capecitabine (1004 patients) or bolus fluorouracil plus leucovorin (Mayo Clinic regimen; 983 patients) over a period of 24 weeks. The primary efficacy end point was at least equivalence in disease-free survival; the primary safety end point was the incidence of grade 3 or 4 toxic effects due to fluoropyrimidines. RESULTS: Disease-free survival in the capecitabine group was at least equivalent to that in the fluorouracil-plus-leucovorin group (in the intention-to-treat analysis, P<0.001 for the comparison of the upper limit of the hazard ratio with the noninferiority margin of 1.20). Capecitabine improved relapse-free survival (hazard ratio, 0.86; 95 percent confidence interval, 0.74 to 0.99; P=0.04) and was associated with significantly fewer adverse events than fluorouracil plus leucovorin (P<0.001). CONCLUSIONS: Oral capecitabine is an effective alternative to intravenous fluorouracil plus leucovorin in the adjuvant treatment of colon cancer.

Two consecutive phase II trials of biweekly oxaliplatin plus weekly 48-hour continuous infusion of nonmodulated high-dose 5-fluorouracil as first-line treatment for advanced colorectal cancer.

The combination of 5-fluorouracil (5-FU) plus leucovorin (LV) with oxaliplatin has become one of the standard treatments for advanced colorectal cancer (CRC). Two consecutive phase II trials assessed the efficacy and safety of combined therapy with oxaliplatin and high-dose 5-FU without LV for patients with advanced CRC. A total of 89 patients were enrolled in both trials. Fifty-nine patients in trial A underwent a scheduled regimen of biweekly oxaliplatin 85 mg/m(2) and weekly nonmodulated 5-FU 3.0 g/m(2). Increased incidence of toxicity led to a 25% reduction in the starting dose of 5-FU (2.25 g/m(2)) for trial B. Patients treated in trial B showed a higher cumulative dose and relative dose intensity for oxaliplatin and 5-FU than those treated in trial A. Response to treatment, time to progression (TTP), overall survival (OS), and duration of response were evaluated as efficacy variables. Overall response rate was preserved despite the reduction in 5-FU dose (55.9% and 63.0%, respectively). Median durations of responses were 10.6 and 10.4 months, median TTPs were 7.7 and 7.3 months, and OS times were 21.7 and 13.1 months, respectively. Reduction in the starting 5-FU dose from 3.0 to 2.25 g/m(2) resulted in a decrease in the main grade 3/4 hematologic toxicities (neutropenia, 22.0% to 10.0%) and nonhematologic toxicities (diarrhea, 52.5% to 23.3%; nausea/vomiting, 18.6% to 3.3%). Neurosensory toxicity was similar in both trials (16.9% and 16.7%). Biweekly oxaliplatin in combination with nonmodulated high-dose 5-FU is an active, well-tolerated treatment that offers a lower cost than a modulated schedule for patients with advanced, metastatic CRC.

Adjuvant therapy of resected gastric cancer is necessary.

The currently reported 5-year survival rates for patients with resected stage II, IIIA, IIIB, and IV gastric cancer are 34%, 20%, 8%, and 7%, respectively. A subtotal or total gastrectomy with a D1 en bloc dissection of lymphatic tissue is the standard surgical treatment. Several meta-analyses of post-operative adjuvant trials have reported a significant benefit for chemotherapy-treated patients. Because most relapses occur locally, post-operative adjuvant chemoradiotherapy was studied in patients who received surgery alone or surgery followed by 5-fluorouracil and leucovorin (5-FU/LV, Mayo Clinic regimen) given before, after, and concurrently with radiotherapy in the Intergroup 0116 trial. The 3-year survival and 3-year disease-free survival rates were significantly higher in the adjuvant treatment group, making this regimen the adjuvant standard in the United States. A second trial, the MAGIC trial, also showed improved survival and disease-free survival with epirubicin, cisplatin, and 5-FU (ECF) given every 3 weeks pre- and post-operatively. Other agents in combination with perioperative radiotherapy and surgery are being investigated to treat patients with gastric cancer. New target-oriented agents, as well as tailored therapy based on the molecular profile of both the tumor and the patient, might also contribute to improved results.