Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial.

IMPORTANCE: The prognosis for patients with pancreatic cancer is poor, even after resection with curative intent. Gemcitabine-based chemotherapy is standard treatment for advanced pancreatic cancer, but its effect on survival in the adjuvant setting has not been demonstrated. OBJECTIVE: To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival. DESIGN, SETTING, AND PATIENTS: CONKO-001 (Charité Onkologie 001), a multicenter, open-label, phase 3 randomized trial to evaluate the efficacy and toxicity of gemcitabine in patients with pancreatic cancer after complete tumor resection. Patients with macroscopically completely removed pancreatic cancer entered the study between July 1998 and December 2004 in 88 hospitals in Germany and Austria. Follow-up ended in September 2012. INTERVENTIONS: After stratification for tumor stage, nodal status, and resection status, patients were randomly assigned to either adjuvant gemcitabine treatment (1g/m2 d 1, 8, 15, q 4 weeks) for 6 months or to observation alone. MAIN OUTCOMES AND MEASURES: The primary end point was disease-free survival. Secondary end points included treatment safety and overall survival, with overall survival defined as the time from date of randomization to death. Patients lost to follow-up were censored on the date of their last follow-up. RESULTS: A total of 368 patients were randomized, and 354 were eligible for intention-to-treat-analysis. By September 2012, 308 patients (87.0% [95% CI, 83.1%-90.1%]) had relapsed and 316 patients (89.3% [95% CI, 85.6%-92.1%]) had died. The median follow-up time was 136 months. The median disease-free survival was 13.4 (95% CI, 11.6-15.3) months in the treatment group compared with 6.7 (95% CI, 6.0-7.5) months in the observation group (hazard ratio, 0.55 [95% CI, 0.44-0.69]; P < .001). Patients randomized to adjuvant gemcitabine treatment had prolonged overall survival compared with those randomized to observation alone (hazard ratio, 0.76 [95% CI, 0.61-0.95]; P = .01), with 5-year overall survival of 20.7% (95% CI, 14.7%-26.6%) vs 10.4% (95% CI, 5.9%-15.0%), respectively, and 10-year overall survival of 12.2% (95% CI, 7.3%-17.2%) vs 7.7% (95% CI, 3.6%-11.8%). CONCLUSIONS AND RELEVANCE: Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN34802808.

Outcome Quality After Colorectal Cancer Resection in Certified Colorectal Cancer Centers­Patient-Reported and Short-Term Clinical Outcomes.

BACKGROUND: In this observational study, patient-reported outcomes and short-term clinical outcome parameters in patients with colorectal cancer were studied 12 months after the start of treatment. Outcomes were also compared across German Certified Colorectal Cancer Centres. METHODS: Data were collected from 4239 patients with colorectal cancer who had undergone elective tumor resection in one of 102 colorectal cancer centers and had responded to a quality-of-life questionnaire before treatment (EORTC QLQ-C30 and -CR29). 3142 (74.1%) of these patients completed a post-treatment questionnaire 12 months later. Correlation analyses were calculated and case-mix adjusted comparisons across centers were made for selected patient-reported outcomes, anastomotic insufficiency, and 30-day-mortality. RESULTS: At 12 months, mild improvements were seen in mean quality-of-life scores (66 vs. 62 points), constipation (16 vs. 19), and abdominal pain (15 vs. 17). Worsening was seen in physical function (75 vs. 82) and pain (22 vs. 19). Better patient-reported outcomes at 12 months were associated with better scores before treatment. Better results in at least three of the five scores were associated with male sex, higher educational level, higher age, and private health insurance. Major worsening of fecal incontinence was seen among patients with rectal cancer without a stoma. The largest differences across centers were found with respect to physical function. Anastomotic insufficiency was found in 4.3% of colon cancer patients and 8.2% of rectal cancer patients. 1.9% of patients died within 30 days after their resection. CONCLUSION: Clinicians can use these findings to identify patients at higher risk for poorer patient-reported outcomes. The differences among cancer centers that were found imply that measures for quality improvement would be desirable.

Modified neoadjuvant short-course radiation therapy in uT3 rectal carcinoma: low local recurrence rate with unchanged overall survival and frequent morbidity.

PURPOSE: The purpose of this study is to investigate the value of a modified neoadjuvant short-course radiation therapy (SCRT) in uT3 rectal carcinoma, which, despite local R0 resectability, carries a greater risk of local recurrence than less invasive carcinomas. METHODS: Sixty-three patients with uT3 rectal carcinoma < or =10 cm above the anal verge received a modified 8 x 3 Gy pre-operative SCRT. Radiation-associated and peri-operative complications were recorded, and the patients were followed up for long-term oncological outcome and morbidity. RESULTS: In the study group, there were no severe adverse radiation-associated effects; the rate of peri-operative morbidity was 54.0% and that of in-hospital mortality is 4.8%. The probability (Kaplan-Meier estimate) of local recurrence was 3.9% with a probability of metachronic distant metastases of 26.8% (5-year rates). We found the probability of 5-year disease-free survival to be 70.5% and that of 5-year overall survival, 59.5%. Long-term complications were reported for 31.7% of patients. CONCLUSIONS: Compared to the literature-modified 8 x 3 Gy neoadjuvant SCRT and surgery in uT3, rectal carcinoma was associated with low local recurrence but frequent peri-operative complications. The decisive prognostic factor, distant metastasis, was unaffected. Difficulties included overestimation of tumour invasion depth by endosonography. Possible clinical consequences of the results are discussed.

Efficacy and safety of irinotecan-based chemotherapy for advanced colorectal cancer outside clinical trials: an observational study.

BACKGROUND: This prospective observational study in typical community-based outpatient clinics evaluated the efficacy and toxicity of weekly and biweekly irinotecan-based chemotherapies and their compatibility depending on age. METHODS: 601 patients with advanced or metastatic colorectal cancer receiving first-, second-, or third-line irinotecan-based therapy were regularly analyzed for response and toxicity until the end of therapy. RESULTS: The median age was 65 (28-87) years, approximately one-third of the patients were ≥70 years old. Of all patients, 405 were treated weekly and 68 biweekly. Median overall survival (OS) for first-line therapy was 26.5 months for the <70-year-old patients and 19.4 months for the ≥70-year-old patients. Toxicities were moderate in all groups. Tumor growth control rates (TCR) and median time to progression (TTP) were marginally better for patients <70 years old. Median TTP was 9.9 months in first-line therapy, 9.8 months after adjuvant therapy, 7.7 months in second-line, and 6.4 months in third-line therapy. CONCLUSIONS: Toxicity and response data from this observational study clearly confirm the positive results from previous clinical studies and show a slight ad-vantage in efficacy for the <70-year-old patients.

Matched-pair comparison of radioembolization plus best supportive care versus best supportive care alone for chemotherapy refractory liver-dominant colorectal metastases.

PURPOSE: This study was designed to evaluate overall survival after radioembolization or best supportive care (BSC) in patients with chemotherapy-refractory liver-dominant metastatic colorectal cancer (mCRC). METHODS: This was a matched-pair comparison of patients who received radioembolization plus BSC or BSC alone for extensive liver disease. Twenty-nine patients who received radioembolization were retrospectively matched with a contemporary cohort of >500 patients who received BSC from 3 centers in Germany. Using clinical databases, patients were initially matched for prior treatments and tumor burden and then 29 patients were consecutively identified with two or more of four matching criteria: synchronous/metachronous metastases, tumor burden, increased ALP, and/or CEA >200 U/ml. Survival was calculated from date of progression before radioembolization or BSC by using Kaplan-Meier analysis. RESULTS: Of 29 patients in each study arm, 16 pairs (55.2%) matched for all four criteria, and 11 pairs (37.9%) matched three criteria. Patients in both groups had a similar performance status (Karnofsky index, median 80% [range, 60-100%]). Compared with BSC alone, radioembolization prolonged survival (median, 8.3 vs. 3.5 months; P < 0.001) with a hazard ratio of 0.3 (95% confidence interval, 0.16-0.55; P < 0.001) in a multivariate Cox proportional hazard model. Treatment-related adverse events following radioembolization included: grade 1-2 fatigue (n = 20, 69%), grade 1 abdominal pain/nausea (n = 14, 48.3%), and grade 2 gastrointestinal ulceration (n = 3, 10.3%). Three cases of grade 3 radiation-induced liver disease were symptomatically managed. CONCLUSIONS: Radioembolization offers a promising addition to BSC in treatment-refractory patients for whom there are limited options. Survival was prolonged and adverse events were generally mild-to-moderate in nature and manageable.

Intraperitoneal versus intravenous CPT-11 given intra- and postoperatively for peritoneal carcinomatosis in a rat model.

PURPOSE: Peritoneal recurrence after resection of colorectal carcinoma is still a major concern. We investigated whether the novel cytostatic drug, CPT-11 (Irinotecan), delivered intraperitoneally (i.p.) and intravenously (i.v.), could inhibit intraperitoneal tumor spread in a rat model. METHODS: We induced intraperitoneal tumor growth using a tumor cell transfer model (10(6) cells) and divided the rats into the following five groups of eight: group IP1, given CPT-11 i.p. immediately after intraperitoneal tumor cell transfer; group IV1, given CPT-11 i.v. immediately after intraperitoneal tumor cell transfer; group IP2, given CPT-11 i.p. on postoperative days (PODs) 5, 10, and 15; group IV2, given CPT-11 on PODs 5, 10, and 15; and a control group. The rats were killed 30 days after tumor cell transfer, and the tumor weight, number of nodes in the greater omentum and peritoneum, presence of metastases in the liver and lungs, and ascites volume were determined. RESULTS: CPT-11 inhibited peritoneal tumor growth significantly. The direct intraoperative intraperitoneal application induced a more pronounced effect than the early postoperative intraperitoneal application, but both these application modes were superior to the intravenous route, which had no significant effect. CONCLUSION: CPT-11 was highly efficacious against peritoneal carcinomatosis in this experimental model. The combination of CPT-11 with other cytostatic agents and drugs generating different effector mechanisms may diminish or even prevent intraperitoneal tumor growth.