Summary Background Radiotherapy reduces the risk of local recurrence in rectal cancer. However, the optimal radiotherapy fractionation and interval between radiotherapy and surgery is still under ...debate. We aimed to study recurrence in patients randomised between three different radiotherapy regimens with respect to fractionation and time to surgery. Methods In this multicentre, randomised, non-blinded, phase 3, non-inferiority trial (Stockholm III), all patients with a biopsy-proven adenocarcinoma of the rectum, without signs of non-resectability or distant metastases, without severe cardiovascular comorbidity, and planned for an abdominal resection from 18 Swedish hospitals were eligible. Participants were randomly assigned with permuted blocks, stratified by participating centre, to receive either 5 × 5 Gy radiation dose with surgery within 1 week (short-course radiotherapy) or after 4–8 weeks (short-course radiotherapy with delay) or 25 × 2 Gy radiation dose with surgery after 4–8 weeks (long-course radiotherapy with delay). After a protocol amendment, randomisation could include all three treatments or just the two short-course radiotherapy treatments, per hospital preference. The primary endpoint was time to local recurrence calculated from the date of randomisation to the date of local recurrence. Comparisons between treatment groups were deemed non-inferior if the upper limit of a double-sided 90% CI for the hazard ratio (HR) did not exceed 1·7. Patients were analysed according to intention to treat for all endpoints. This study is registered with ClinicalTrials.gov , number NCT00904813. Findings Between Oct 5, 1998, and Jan 31, 2013, 840 patients were recruited and randomised; 385 patients in the three-arm randomisation, of whom 129 patients were randomly assigned to short-course radiotherapy, 128 to short-course radiotherapy with delay, and 128 to long-course radiotherapy with delay, and 455 patients in the two-arm randomisation, of whom 228 were randomly assigned to short-course radiotherapy and 227 to short-course radiotherapy with delay. In patients with any local recurrence, median time from date of randomisation to local recurrence in the pooled short-course radiotherapy comparison was 33·4 months (range 18·2–62·2) in the short-course radiotherapy group and 19·3 months (8·5–39·5) in the short-course radiotherapy with delay group. Median time to local recurrence in the long-course radiotherapy with delay group was 33·3 months (range 17·8–114·3). Cumulative incidence of local recurrence in the whole trial was eight of 357 patients who received short-course radiotherapy, ten of 355 who received short-course radiotherapy with delay, and seven of 128 who received long-course radiotherapy (HR vs short-course radiotherapy: short-course radiotherapy with delay 1·44 95% CI 0·41–5·11; long-course radiotherapy with delay 2·24 0·71–7·10; p=0·48; both deemed non-inferior). Acute radiation-induced toxicity was recorded in one patient (<1%) of 357 after short-course radiotherapy, 23 (7%) of 355 after short-course radiotherapy with delay, and six (5%) of 128 patients after long-course radiotherapy with delay. Frequency of postoperative complications was similar between all arms when the three-arm randomisation was analysed (65 50% of 129 patients in the short-course radiotherapy group; 48 38% of 128 patients in the short-course radiotherapy with delay group; 50 39% of 128 patients in the long-course radiotherapy with delay group; odds ratio OR vs short-course radiotherapy: short-course radiotherapy with delay 0·59 95% CI 0·36–0·97, long-course radiotherapy with delay 0·63 0·38–1·04, p=0·075). However, in a pooled analysis of the two short-course radiotherapy regimens, the risk of postoperative complications was significantly lower after short-course radiotherapy with delay than after short-course radiotherapy (144 53% of 355 vs 188 41% of 357; OR 0·61 95% CI 0·45–0·83 p=0·001). Interpretation Delaying surgery after short-course radiotherapy gives similar oncological results compared with short-course radiotherapy with immediate surgery. Long-course radiotherapy with delay is similar to both short-course radiotherapy regimens, but prolongs the treatment time substantially. Although radiation-induced toxicity was seen after short-course radiotherapy with delay, postoperative complications were significantly reduced compared with short-course radiotherapy. Based on these findings, we suggest that short-course radiotherapy with delay to surgery is a useful alternative to conventional short-course radiotherapy with immediate surgery. Funding Swedish Research Council, Swedish Cancer Society, Stockholm Cancer Society, and the Regional Agreement on Medical Training and Clinical Research in Stockholm.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Previous results of the EORTC intergroup trial 40983 showed that perioperative chemotherapy with FOLFOX4 (folinic acid, fluorouracil, and oxaliplatin) increases progression-free ...survival (PFS) compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Here we present overall survival data after long-term follow-up. Methods This randomised, controlled, parallel-group, phase 3 study recruited patients from 78 hospitals across Europe, Australia, and Hong Kong. Eligible patients aged 18–80 years who had histologically proven colorectal cancer and up to four liver metastases were randomly assigned (1:1) to either perioperative FOLFOX4 or surgery alone. Perioperative FOLFOX4 consisted of six 14-day cycles of oxaliplatin 85mg/m2 , folinic acid 200 mg/m2 (DL form) or 100 mg/m2 (L form) on days 1–2 plus bolus, and fluorouracil 400 mg/m2 (bolus) and 600 mg/m2 (continuous 22 h infusion), before and after surgery. Patients were centrally randomised by minimisation, adjusting for centre and risk score and previous adjuvant chemotherapy to primary surgery for colorectal cancer, and the trial was open label. Analysis of overall survival was by intention to treat in all randomly assigned patients. This trial is registered with ClinicalTrials.gov , number NCT00006479. Findings Between Oct 10, 2000, and July 5, 2004, 364 patients were randomly assigned to a treatment group (182 patients in each group, of which 171 per group were eligible and 152 per group underwent resection). At a median follow-up of 8·5 years (IQR 7·6–9·5), 107 (59%) patients in the perioperative chemotherapy group had died versus 114 (63%) in the surgery-only group (HR 0·88, 95% CI 0·68–1·14; p=0·34). In all randomly assigned patients, median overall survival was 61·3 months (95% CI 51·0–83·4) in the perioperative chemotherapy group and 54·3 months (41·9–79·4) in the surgery alone group. 5-year overall survival was 51·2% (95% CI 43·6–58·3) in the perioperative chemotherapy group versus 47·8% (40·3–55·0) in the surgery-only group. Two patients in the perioperative chemotherapy group and three in the surgery-only group died from complications of protocol surgery, and one patient in the perioperative chemotherapy group died possibly as a result of toxicity of protocol treatment. Interpretation We found no difference in overall survival with the addition of perioperative chemotherapy with FOLFOX4 compared with surgery alone for patients with resectable liver metastases from colorectal cancer. However, the previously observed benefit in PFS means that perioperative chemotherapy with FOLFOX4 should remain the reference treatment for this population of patients. Funding Norwegian and Swedish Cancer Societies, Cancer Research UK, Ligue Nationale Contre Cancer, US National Cancer Institute, Sanofi-Aventis.
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Summary Background The TME trial investigated the value of preoperative short-term radiotherapy in combination with total mesorectal excision (TME). Long-term results are reported after a median ...follow-up of 12 years. Methods Between Jan 12, 1996, and Dec 31, 1999, 1861 patients with resectable rectal cancer without evidence of distant disease were randomly assigned to TME preceded by 5 × 5 Gy radiotherapy or TME alone (ratio 1:1). Randomisation was based on permuted blocks of six with stratification according to centre and expected type of surgery. The primary endpoint was local recurrence, analysed for all eligible patients who underwent a macroscopically complete local resection. Findings 10-year cumulative incidence of local recurrence was 5% in the group assigned to radiotherapy and surgery and 11% in the surgery-alone group (p<0·0001). The effect of radiotherapy became stronger as the distance from the anal verge increased. However, when patients with a positive circumferential resection margin were excluded, the relation between distance from the anal verge and the effect of radiotherapy disappeared. Patients assigned to radiotherapy had a lower overall recurrence and when operated with a negative circumferential resection margin, cancer-specific survival was higher. Overall survival did not differ between groups. For patients with TNM stage III cancer with a negative circumferential resection margin, 10-year survival was 50% in the preoperative radiotherapy group versus 40% in the surgery-alone group (p=0·032). Interpretation For all eligible patients, preoperative short-term radiotherapy reduced 10-year local recurrence by more than 50% relative to surgery alone without an overall survival benefit. For patients with a negative resection margin, the effect of radiotherapy was irrespective of the distance from the anal verge and led to an improved cancer-specific survival, which was nullified by an increase in other causes of death, resulting in an equal overall survival. Nevertheless, preoperative short-term radiotherapy significantly improved 10-year survival in patients with a negative circumferential margin and TNM stage III. Future staging techniques should offer possibilities to select patient groups for which the balance between benefits and side-effects will result in sufficiently large gains. Funding The Dutch Cancer Society, the Dutch National Health Council, and the Swedish Cancer Society.
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Summary Background Surgical resection alone is regarded as the standard of care for patients with liver metastases from colorectal cancer, but relapse is common. We assessed the combination of ...perioperative chemotherapy and surgery compared with surgery alone for patients with initially resectable liver metastases from colorectal cancer. Methods This parallel-group study reports the trial's final data for progression-free survival for a protocol unspecified interim time-point, while overall survival is still being monitored. 364 patients with histologically proven colorectal cancer and up to four liver metastases were randomly assigned to either six cycles of FOLFOX4 before and six cycles after surgery or to surgery alone (182 in perioperative chemotherapy group vs 182 in surgery group). Patients were centrally randomised by minimisation, adjusting for centre and risk score. The primary objective was to detect a hazard ratio (HR) of 0·71 or less for progression-free survival. Primary analysis was by intention to treat. Analyses were repeated for all eligible (171 vs 171) and resected patients (151 vs 152). This trial is registered with ClinicalTrials.gov , number NCT00006479. Findings In the perioperative chemotherapy group, 151 (83%) patients were resected after a median of six (range 1–6) preoperative cycles and 115 (63%) patients received a median six (1–8) postoperative cycles. 152 (84%) patients were resected in the surgery group. The absolute increase in rate of progression-free survival at 3 years was 7·3% (from 28·1% 95·66% CI 21·3–35·5 to 35·4% 28·1–42·7; HR 0·79 0·62–1·02; p=0·058) in randomised patients; 8·1% (from 28·1% 21·2–36·6 to 36·2% 28·7–43·8; HR 0·77 0·60–1·00; p=0·041) in eligible patients; and 9·2% (from 33·2% 25·3–41·2 to 42·4% 34·0–50·5; HR 0·73 0·55–0·97; p=0·025) in patients undergoing resection. 139 patients died (64 in perioperative chemotherapy group vs 75 in surgery group). Reversible postoperative complications occurred more often after chemotherapy than after surgery (40/159 25% vs 27/170 16%; p=0·04). After surgery we recorded two deaths in the surgery alone group and one in the perioperative chemotherapy group. Interpretation Perioperative chemotherapy with FOLFOX4 is compatible with major liver surgery and reduces the risk of events of progression-free survival in eligible and resected patients. Funding Swedish Cancer Society, Cancer Research UK, Ligue Nationale Contre le Cancer, US National Cancer Institute, Sanofi-Aventis.
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Summary Background Several studies in patients undergoing chemotherapy for advanced pancreatic carcinoma have linked a decrease in the concentration of the tumour marker carbohydrate antigen (CA) ...19-9 to lengthened survival. The aim of this study was to test the hypotheses that an early decrease in baseline serum CA 19-9 concentration (on day 42, after two cycles of chemotherapy) by at least 50% is associated with lengthened survival, and that a decrease in CA 19-9 concentration of at least 50% from the baseline concentration to the lowest value measured at any time during treatment (nadir) is of prognostic significance, enabling its use as a surrogate endpoint for survival. Methods CA 19-9 serum concentration was measured at baseline and every 3 weeks thereafter in patients with histologically proven advanced pancreatic carcinoma enrolled in a randomised trial of gemcitabine versus gemcitabine plus capecitabine. Patients were excluded if baseline serum CA 19-9 concentration was below the upper limit of normal (ULN) in the laboratory or if this measurement was missing. Comparisons of survival between patients with and without a CA 19-9 response were corrected for the guarantee-time bias by the landmark method. The trial on which this study is based is registered on the clinical trials site of the US National Cancer Institute website http://www.clinicaltrials.gov/ct/show/NCT00030732. Findings 247 of 319 randomised patients were assessable for analysis of baseline serum CA 19-9 concentration, and, of these, 175 patients were assessable for tumour-marker response to treatment. Median overall survival for patients with a baseline CA 19-9 concentration equal to or above the median value (ie, 59×ULN) was 5·8 months (95% CI 5·1–7·0), which was significantly shorter than that for patients with baseline concentrations below the median value (10·3 months 95% CI 8·6–12·8, p<0·0001). An early decrease in CA 19-9 concentration of at least 50% after two cycles of chemotherapy was not associated with a longer overall survival compared with patients who did not have a decrease of at least 50% (median 10·1 months 9·2–12·7 vs 8·6 months 6·9–11·2, p=0·53; hazard ratio for death 1·11 0·81–1·52). Furthermore, a decrease in CA 19-9 concentration of at least 50% reached at the CA 19-9 nadir concentration was not associated with a longer overall survival compared with those patients who did not have a decrease of at least 50% (median 7·8 months 6·5–10·1 vs 6·7 months 5·5–9·8, p=0·74; 0·95 0·69–1·31) after adjusting for the guarantee-time bias. Interpretation Pretreatment serum CA 19-9 concentration is an independent prognostic factor for survival, but a decrease in concentration during chemotherapy is not significantly associated with lengthened survival compared with those who did not have a corresponding decrease. Our data suggest that CA 19-9 response during chemotherapy is not a valid surrogate endpoint for survival in clinical trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with ...resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. Methods We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. Findings Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5–31·5) compared with 25·5 months (22·7–27·9) in the gemcitabine group (hazard ratio 0·82 95% CI 0·68–0·98, p=0·032). 608 grade 3–4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3–4 adverse events in 196 of 366 patients in the gemcitabine group. Interpretation The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. Funding Cancer Research UK.
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