The consensus Immunoscore in phase 3 clinical trial (N0147) and impact on patient management decisions.

The consensus Immunoscore is a routine assay quantifying the adaptive immune response within the tumor microenvironment. It has a prognostic value that has been confirmed in a phase 3 clinical trial (NCCTG N0147) in stage III colon cancers. Moreover, results from another phase 3 randomized trial revealed the predictive value of Immunoscore for response to adjuvant chemotherapy duration. These results highlight the clinical utility of Immunoscore. In its latest edition, the World Health Organization classification of Digestive System Tumors introduced for the first time the immune response as an essential and desirable diagnostic criterion for colorectal cancer. Within the tumor microenvironment, the immune response provides an important estimate of the risk of recurrence and death in colon cancer. The international validation of the prognostic value of the consensus Immunoscore together with its prognostic value in the N0147 trial and its predictive utility for response to chemotherapy in stage III patients provide valuable information for patient management.

Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals.

BACKGROUND: A previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak. METHODS: In order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). RESULTS: Of the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available. CONCLUSION: Off-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies.

Attitudinal barriers to participation in oncology clinical trials: factor analysis and correlates of barriers.

Patient participation in cancer clinical trials is low. Little is known about attitudinal barriers to participation, particularly among patients who may be offered a trial during an imminent initial oncology consult. The aims of the present study were to confirm the presence of proposed subscales of a recently developed cancer clinical trial attitudinal barriers measure, describe the most common cancer clinical trials attitudinal barriers, and evaluate socio-demographic, medical and financial factors associated with attitudinal barriers. A total of 1256 patients completed a survey assessing demographic factors, perceived financial burden, prior trial participation and attitudinal barriers to clinical trials participation. Results of a factor analysis did not confirm the presence of the proposed four attitudinal barriers subscale/factors. Rather, a single factor represented the best fit to the data. The most highly-rated barriers were fear of side-effects, worry about health insurance and efficacy concerns. Results suggested that less educated patients, patients with non-metastatic disease, patients with no previous oncology clinical trial participation, and patients reporting greater perceived financial burden from cancer care were associated with higher barriers. These patients may need extra attention in terms of decisional support. Overall, patients with fewer personal resources (education, financial issues) report more attitudinal barriers and should be targeted for additional decisional support.

Temsirolimus combined with sorafenib in hepatocellular carcinoma: a phase I dose-finding trial with pharmacokinetic and biomarker correlates.

BACKGROUND: Based upon preclinical evidence for improved antitumor activity in combination, this phase I study investigated the maximum-tolerated dose (MTD), safety, activity, pharmacokinetics (PK), and biomarkers of the mammalian target of rapamycin inhibitor, temsirolimus, combined with sorafenib in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Patients with incurable HCC and Child Pugh score ≤B7 were treated with sorafenib plus temsirolimus by 3 + 3 design. The dose-limiting toxicity (DLT) interval was 28 days. The response was assessed every two cycles. PK of temsirolimus was measured in a cohort at MTD. RESULTS: Twenty-five patients were enrolled. The MTD was temsirolimus 10 mg weekly plus sorafenib 200 mg twice daily. Among 18 patients at MTD, DLT included grade 3 hand-foot skin reaction (HFSR) and grade 3 thrombocytopenia. Grade 3 or 4 related adverse events at MTD included hypophosphatemia (33%), infection (22%), thrombocytopenia (17%), HFSR (11%), and fatigue (11%). With sorafenib, temsirolimus clearance was more rapid (P < 0.05). Two patients (8%) had a confirmed partial response (PR); 15 (60%) had stable disease (SD). Alpha-fetoprotein (AFP) declined ≥50% in 60% assessable patients. CONCLUSION: The MTD of sorafenib plus temsirolimus in HCC was lower than in other tumor types. HCC-specific phase I studies are necessary. The observed efficacy warrants further study.

Genetic variation in radiation and platinum pathways predicts severe acute radiation toxicity in patients with esophageal adenocarcinoma treated with cisplatin-based preoperative radiochemotherapy: results from the Eastern Cooperative Oncology Group.

PURPOSE: Germline genetic variations may partly explain the clinical observation that normal tissue tolerance to radiochemotherapy varies by individual. Our objective was to evaluate the association between single-nucleotide polymorphisms (SNPs) in radiation/platinum pathways and serious treatment-related toxicity in subjects with esophageal adenocarcinoma who received cisplatin-based preoperative radiochemotherapy. METHODS: In a multicenter clinical trial (E1201), 81 eligible treatment-naïve subjects with resectable esophageal adenocarcinoma received cisplatin-based chemotherapy concurrent with radiotherapy, with planned subsequent surgical resection. Toxicity endpoints were defined as grade ≥3 radiation-related or myelosuppressive events probably or definitely related to therapy, occurring during or up to 6 weeks following the completion of radiochemotherapy. SNPs were analyzed in 60 subjects in pathways related to nucleotide/base excision- or double stranded break repair, or platinum influx, efflux, or detoxification. RESULTS: Grade ≥3 radiation-related toxicity (mostly dysphagia) and myelosuppression occurred in 18 and 33% of subjects, respectively. The variant alleles of the XRCC2 5' flanking SNP (detected in 28% of subjects) and of GST-Pi Ile-105-Val (detected in 65% of subjects) were each associated with higher odds of serious radiation-related toxicity compared to the major allele homozygote (47% vs. 9%, and 31% vs. 0%, respectively; P = 0.005). No SNP was associated with myelosuppression. CONCLUSIONS: This novel finding in a well-characterized cohort with robust endpoint data supports further investigation of XRCC2 and GST-Pi as potential predictors of radiation toxicity.

The effects of bevacizumab on postoperative complications in patients undergoing colorectal and pancreatic cancer resection.

Bevacizumab (Avastin™; rhuMab VEGF), a monoclonal antibody targeting vascular endothelial growth factor (VEGF), has seen increased use in the perioperative treatment of colorectal and pancreatic cancer. Little is known, however, regarding its impact on surgical outcomes in patients undergoing resection. The objective of this review was to examine if the addition of bevacizumab to existing neoadjuvant regimens increases morbidity after cancer resection.

Effect of lymph node retrieval rates on the utilization of adjuvant chemotherapy in stage II colon cancer.

BACKGROUND: Failing to meet the benchmark of 12 lymph nodes in resection specimens is an indication for adjuvant chemotherapy in stage II colon cancer. METHODS: Among consecutive eligible patients with pathologic stage II colon cancer treated at eight NCI-designated comprehensive cancer centers between September 1, 2005 and February 19, 2008, we analyzed receipt of adjuvant chemotherapy, with less than 12 versus 12+ lymph nodes removed and examined the primary explanatory variable of interest. RESULTS: Among 258 patients, 46% received adjuvant chemotherapy. An oxaliplatin-containing regimen was used 67% of the time. Younger age (<50 years, P < 0.001), presence of lymphovascular invasion (P = 0.007), and higher T stage (P = 0.007) were independently associated with adjuvant chemotherapy use. There was significant inter-institutional variability in practice with the proportion receiving treatment ranging from 17% to 64% (P < 0.05). Notably, presence of less than 12 lymph nodes in the surgical specimen was a strong predictor of treatment (P = 0.008). CONCLUSIONS: Adjuvant chemotherapy use after resection of stage II colon cancer is common, but by no means standard practice at National Comprehensive Cancer Network (NCCN) institutions. More attention to achieving the recommended benchmark for lymph node dissection has the potential to decrease exposure to the toxicity of adjuvant treatment.

A phase II study of pegylated-camptothecin (pegamotecan) in the treatment of locally advanced and metastatic gastric and gastro-oesophageal junction adenocarcinoma.

PURPOSE: Combination chemotherapy results in a significant survival advantage in patients with advanced gastric cancer compared to best supportive care. Nevertheless, the prognosis remains poor with a median survival of 8-10 months. Topoisomerase-I inhibitors such as irinotecan have activity in advanced gastric cancer. Pegamotecan may offer significant advantages over other topoisomerase-I inhibitors due to its prolonged circulating half-life, tolerability and passive tumour accumulation. PATIENTS AND METHODS: This was a non-randomised, multi-centre, two-step Fleming design phase II study. Eligible patients with locally advanced (inoperable) or metastatic gastric or gastro-oesophageal adenocarcinoma, with measurable disease, ECOG performance status < or =2, with adequate haematological, renal and hepatic function, who had received < or =1 prior chemotherapy regimen for advanced disease, were treated with 7,000 mg/m(2) of pegamotecan as a 1-h infusion every 21 days until disease progression or unacceptable toxicity. The primary efficacy measure was the objective response rate. RESULTS: Five of the 35 patients recruited into this study had a partial response (14.3%), with a median time to progression of 11.9 weeks (95% CI: 6.6, 13.1), and median overall survival of 38.1 weeks (95% CI: 29.0, 47.3). Grade 3/4 toxicities included neutropenia in 6 (17.1%) patients, thrombocytopenia in 4 (11.4%), fatigue in 8 (22.9%), nausea in 6 (17%), vomiting in 6 (17%) and anorexia in 4 (11.4%) patients. There were no episodes of febrile neutropenia and no toxic deaths. CONCLUSIONS: Pegamotecan has activity in this patient population and was generally well-tolerated. The favourable rate of haematological toxicities and diarrhoea compared with irinotecan in similar studies suggests that pegamotecan could be combined with other active agents in further studies in this disease.

A phase II trial of perifosine in locally advanced, unresectable, or metastatic pancreatic adenocarcinoma.

BACKGROUND: Perifosine, a heterocyclic alkylphosphocholine signal transduction inhibitor, has activity against multiple cell types in vitro. This is a phase II study to determine activity and toxicity of perifosine in pancreatic adenocarcinoma. PATIENTS AND METHODS: Previously untreated patients with locally advanced, unresectable, or metastatic pancreatic adenocarcinoma, performance status Eastern Cooperative Oncology Group 0 or 1, were enrolled. An oral loading dose of 900 mg was followed by 100 mg per day until progression or unacceptable toxicity. Response criteria in solid tumors (RECIST) methodology and a 2-stage design were used. Suspension could occur for inadequate response in the first cohort or for more than 25% grade 3 or greater toxicity. RESULTS: Ten patients were enrolled. Six received 1 month and 4 received 2 months of treatment. Four discontinued therapy as a result of progression and 2 because of clinical deterioration. Three died during treatment. One patient had stable disease but discontinued therapy as a result of unacceptable adverse events (95% confidence interval: 0.3-45%). There were no objective responses and all patients died of progressive disease. Median overall and progression-free survival was 1.85 months (95% confidence interval: 0.9-2.7) and 1.5 months (95% confidence interval: 0.9-1.9) respectively. CONCLUSION: The study was suspended and subsequently terminated as a result of unacceptable adverse events during the first stage. Perifosine does not appear to be worthy of further study in this group of patients.

A phase II study of high-dose bevacizumab in combination with irinotecan, 5-fluorouracil, leucovorin, as initial therapy for advanced colorectal cancer: results from the Eastern Cooperative Oncology Group study E2200.

AIM: Patients with untreated advanced colorectal cancer were enrolled to this single arm phase II multi-center cooperative group trial of bevacizumab combined with IFL. The first 20 patients received irinotecan (125 mg/m(2)), 5-fluorouracil (500 mg/m(2)) and leucovorin (20 mg/m(2)) weekly for four of six weeks and high-dose bevacizumab (10 mg/kg) every other week. Following a toxicity review of other trials using IFL, subsequent patients were enrolled at reduced doses of irinotecan (100 mg/m(2)) and 5-fluorouracil (400 mg/m(2)). RESULTS: Of the 92 patients accrued to the study, toxicity data are available for 87 patients and efficacy data for 81 patients. At a median follow-up of 37.5 months, median overall survival is 26.3 months, median progression free survival is 10.7 months and 1-year survival is 85%. The overall response rate is 49.4% (6.2% complete responses). A reduction in the starting doses of irinotecan and 5-fluorouracil decreased the occurrence of vomiting, diarrhea and neutropenia related complications. Bleeding occurred in 37 patients; all events but two were grade 1 or grade 2. There were nine reports of grade 3 or grade 4 thrombo-embolic events. Hypertension of any grade occurred in 13% of patients and proteinuria was infrequent. CONCLUSION: High-dose bevacizumab added to IFL is a well-tolerated and highly active regimen in patients with previously untreated metastatic colorectal cancer.

A phase II study of gemcitabine and cisplatin in patients with advanced hepatocellular carcinoma.

The primary objective of this study was to determine the response rates of a combination of gemcitabine and cisplatin in unresectable hepatocellular carcinoma (HCC) in Indian patients. The secondary objectives were to evaluate the toxicity, time to progressive disease and overall survival for this combination. Chemonaive patients with histopathologically proven, bidimensionally measurable, stage Ill or IV unresectable HCC were enrolled into this study. All the patients were required to have a Zubrod's performance status not greater than 2, should not have undergone prior radiotherapy and were required to have adequate major organ function. Patients received gemcitabine (1250 mg/m2 intravenously over 30 to 60 min) on days 1 and 8, and cisplatin (70 mg/m2 intravenously over 2 hours) on day land every 21 days. Response assessment was done by a Computed Tomography scan after every two cycles of chemotherapy. From May to December 1999, 30 patients were enrolled in the study; they were all eligible for efficacy and toxicity analysis. Six (20%) patients achieved a partial response and 13 (43%) patients demonstrated stable disease with 11 (37%) patients showing disease progression. The median time to progression was 18 weeks (range 1 to 74 weeks) and the median duration of response was 13 weeks (range 4 to 68 weeks). The 1-year survival rate was 27% and the median overall survival was 21 weeks (95% CI: 17 to 43 weeks). WHO grade 3 and 4 anemia was seen in 11 (37%) and 2 (7%) patients, respectively. Four (13%) patients each experienced grade 3 and 4 neutropenia and grade 3 and 4 thrombocytopenia was seen in 2 (7%) patients each. Major, non-hematologic toxicities were grade 4 elevated bilirubin levels and grade 3 oral toxicity, in 1 patient (3%) each. This regimen was well tolerated and did show activity in Indian patients with advanced unresectable HCC. There is a need to further evaluate this combination in order to define its role in the treatment of HCC.

Oral eniluracil/5-fluorouracil in patients with inoperable hepatocellular carcinoma.

BACKGROUND: Conventional systemic chemotherapy currently available for patients with inoperable hepatocellular carcinoma is ineffective. The purpose of this study was to evaluate the safety and efficacy of eniluracil/5-fluorouracil (5-FU) in the treatment of patients with this highly refractory disease. PATIENTS AND METHODS: This multicenter, open-label study evaluated a 28-day oral regimen of 5-FU (1 mg/m2 twice daily) plus the dihydropyrimidine dehydrogenase inhibitor, eniluracil (10 mg/m2 twice daily), in patients with chemotherapy-naive or anthracycline-refractory inoperable hepatocellular carcinoma. RESULTS: A total of 36 patients enrolled into the study. No patient showed a confirmed partial or complete tumor response, although nine patients (25%) had a best response of stable disease. The median duration of progression-free survival was 9.6 weeks [95% confidence interval (CI) 9.1-10.6 weeks], and the median duration of overall survival was 32.7 weeks (95% CI 17.4-71.6 weeks). Eniluracil/5-FU was well tolerated. Diarrhea, the most frequent treatment-related non-hematological toxicity, occurred in 11 patients (31%). Hematological toxicities were infrequent and usually mild. CONCLUSIONS: Eniluracil/5-FU as a 28-day oral outpatient regimen is well tolerated by patients with inoperable hepatocellular carcinoma, although minimal activity was observed when given as monotherapy at the dose used in this study.

Adjuvant therapy in rectal cancer: analysis of stage, sex, and local control--final report of intergroup 0114.

PURPOSE: The gastrointestinal Intergroup studied postoperative adjuvant chemotherapy and radiation therapy in patients with T3/4 and N+ rectal cancer after potentially curative surgery to try to improve chemotherapy and to determine the risk of systemic and local failure. PATIENTS AND METHODS: All patients had a potentially curative surgical resection and were treated with two cycles of chemotherapy followed by chemoradiation therapy and two additional cycles of chemotherapy. Chemotherapy regimens were bolus fluorouracil (5-FU), 5-FU and leucovorin, 5-FU and levamisole, and 5-FU, leucovorin, and levamisole. Pelvic irradiation was given to a dose of 45 Gy to the whole pelvis and a boost to 50.4 to 54 Gy. RESULTS: One thousand six hundred ninety-five patients were entered and fully assessable, with a median follow-up of 7.4 years. There was no difference in overall survival (OS) or disease-free survival (DFS) by drug regimen. DFS and OS decreased between years 5 and 7 (from 54% to 50% and 64% to 56%, respectively), although recurrence-free rates had only a small decrease. The local recurrence rate was 14% (9% in low-risk [T1 to N2+] and 18% in high-risk patients [T3N+, T4N]). Overall, 7-year survival rates were 70% and 45% for the low-risk and high-risk groups, respectively. Males had a poorer overall survival rate than females. CONCLUSION: There is no advantage to leucovorin- or levamisole-containing regimens over bolus 5-FU alone in the adjuvant treatment of rectal cancer when combined with irradiation. Local and distant recurrence rates are still high, especially in T3N+ and T4 patients, even with full adjuvant chemoradiation therapy.

Indications and results of liver resection and hepatic chemoembolization for metastatic gastrointestinal neuroendocrine tumors.

BACKGROUND: We reviewed 36 patients with liver metastases from islet cell tumors of the pancreas (n = 18) and carcinoid tumors (n = 18) who were treated with surgical resection (n = 16) or hepatic chemoembolization (n = 20). METHODS: All resections were complete and included 4 lobectomies, 6 segmental resections, and 6 wedge resections. There were no operative deaths. RESULTS: Median survival has not yet been reached, and the actuarial 5-year survival rate is 70%. Prognostic variables associated with improved disease-free survival included prior resection of the primary tumor and 4 or fewer metastases resected (P <.05). With an average of 3 chemoembolization procedures per patient, 17 of 20 patients (90%) demonstrated either a significant radiographic response (n = 5), stabilization of tumor mass (n = 2), or improvement of clinical symptoms (n = 10). Factors related to a sustained response (more then 1 year) included surgical resection of the primary tumor, 4 or more chemoembolization procedures, and liver metastases of 5 cm or smaller. Median survival after treatment was 32 months (range, 7-63 months), and the actuarial 5-year survival rate was 40%. CONCLUSIONS: Surgical resection of metastatic neuroendocrine tumors provides the best chance for extended survival. Chemoembolization effectively improves clinical symptoms and, in selected patients, may provide sustained tumor control.

Fluorouracil modulation in colorectal cancer: lack of improvement with N -phosphonoacetyl- l -aspartic acid or oral leucovorin or interferon, but enhanced therapeutic index with weekly 24-hour infusion schedule--an Eastern Cooperative Oncology Group/Cancer and Leukemia Group B Study.

PURPOSE: To investigate mechanism-directed regimens in maximizing the efficacy of fluorouracil (5-FU) in advanced colorected cancer. PATIENTS AND METHODS: Based on promising phase II data, a randomized comparison of various methods for the biochemical modulation of 5-FU was undertaken in patients with advanced colorectal cancer. The control group received single-agent 5-FU as a 24-hour infusion weekly. Patients (N = 1,120) with no prior chemotherapy for metastatic disease were randomized to one of the following arms: arm A, 5-FU 2,600 mg/m2 by 24-hour infusion, weekly; arm B, N-phosphonoacetyl-l-aspartic acid 250 mg/m2 day l, 5-FU 2,600 mg/m2 by 24-hour infusion day 2, weekly; arm C, 5-FU 600 mg/m2 with oral leucovorin (LV) 125 mg/m2 hourly for the preceding 4 hours, weekly; arm D, 5-FU 600 mg/m2 with intravenous (IV) LV 600 mg/m2, weekly; arm E, 5-FU 750 mg/m2/d IV by continuous infusion for 5 days, then 750 mg/m2 weekly, and recombinant interferon alfa-2a 9 million units subcutaneously three times weekly. Median follow-up was 4.8 years. RESULTS: Of the 1,098 assessable patients, 57% had measurable disease. The toxicity of all the regimens was tolerable. Grade 4 or worse toxicity occurred in 11%, 11%, 30%, 24%, and 22% on each arm, respectively; diarrhea was the most common adverse effect. These toxicity patterns favored significantly (P <.001) the 24-hour infusion arms. Median survival (months) by arm was A, 14.8; B, 11.9; C, 13.5; D, 13.6; and E, 15.2. These survival durations did not differ significantly. CONCLUSION: We conclude that a weekly infusion regimen of 5-FU is significantly less toxic than and as effective as 5-FU bolus regimens modulated by either LV or interferon in patients with metastatic colorectal cancer.

Molecular predictors of survival after adjuvant chemotherapy for colon cancer.

BACKGROUND: Adjuvant chemotherapy improves survival among patients with stage III colon cancer, but no reliable molecular predictors of outcome have been identified. METHODS: We evaluated loss of chromosomal material (also called loss of heterozygosity or allelic loss) from chromosomes 18q, 17p, and 8p; cellular levels of p53 and p21(WAF1/CIP1) proteins; and microsatellite instability as molecular markers. We analyzed tumor tissue from 460 patients with stage III and high-risk stage II colon cancer who had been treated with various combinations of adjuvant fluorouracil, leucovorin, and levamisole to determine the ability of these markers to predict survival. RESULTS: Loss of heterozygosity at 18q was present in 155 of 319 cancers (49 percent). High levels of microsatellite instability were found in 62 of 298 tumors (21 percent), and 38 of these 62 tumors (61 percent) had a mutation of the gene for the type II receptor for transforming growth factor beta1 (TGF-beta1). Among patients with microsatellite-stable stage III cancer, five-year overall survival after fluorouracil-based chemotherapy was 74 percent in those whose cancer retained 18q alleles and 50 percent in those with loss of 18q alleles (relative risk of death with loss at 18q, 2.75; 95 percent confidence interval, 1.34 to 5.65; P=0.006). The five-year survival rate among patients whose cancer had high levels of microsatellite instability was 74 percent in the presence of a mutated gene for the type II receptor for TGF-beta1 and 46 percent if the tumor did not have this mutation (relative risk of death, 2.90; 95 percent confidence interval, 1.14 to 7.35; P=0.03). CONCLUSIONS: Retention of 18q alleles in microsatellite-stable cancers and mutation of the gene for the type II receptor for TGF-beta1 in cancers with high levels of microsatellite instability point to a favorable outcome after adjuvant chemotherapy with fluorouracil-based regimens for stage III colon cancer.

Oral eniluracil/5-FU for advanced colon and breast carcinomas.

5-fluorouracil (5-FU) is irreversibly catabolized to dihydrofluorouracil, an inactive metabolite, by the enzyme dihydropyrimidine dehydrogenase (DPD). This catabolic pathway is a critical step in determining 5-FU availability for conversion to nucleotides and eventual incorporation into either RNA or DNA. Inactivation of DPD, therefore, is an approach to enhance the availability of 5-FU for potential improved therapeutic effect. Preclinical animal and human studies have demonstrated that eniluracil is an effective inactivator of DPD. Phase I studies have been completed showing the tolerability of two dosing schedules, including (1) a chronic schedule with twice-daily administration of eniluracil plus oral fluorouracil (5-FU) (10:1 ratio) for 28 days, and (2) a schedule of eniluracil administered daily on days 1-7 with oral 5-FU once daily on days 2-6. The phase I trials have demonstrated limited toxicities including diarrhea, mucositis, and neutropenia. Follow-up clinical trials have targeted colon and breast cancers in particular.

Impact of number of nodes retrieved on outcome in patients with rectal cancer.

PURPOSE: We postulated that the pathologic evaluation of the lymph nodes of surgical specimens from patients with rectal cancer can have a substantial impact on time to relapse and survival. PATIENTS AND METHODS: We analyzed data from 1,664 patients with T3, T4, or node-positive rectal cancer treated in a national intergroup trial of adjuvant therapy with chemotherapy and radiation therapy. Associations between the number of lymph nodes found by the pathologist in the surgical specimen and the time to relapse and survival outcomes were investigated. RESULTS: Patients were divided into groups by nodal status and the corresponding quartiles of numbers of nodes examined. The number of nodes examined was significantly associated with time to relapse and survival among patients who were node-negative. For the first through fourth quartiles, the 5-year relapse rates were 0.37, 0.34, 0.26, and 0.19 (P: = .003), and the 5-year survival rates were 0.68, 0.73, 0.72, and 0.82 (P: = .02). No significant differences were found by quartiles among patients determined to be node-positive. We propose that observed differences are primarily related to the incorrect determination of nodal status in node-negative patients. Approximately 14 nodes need to be studied to define nodal status accurately. CONCLUSION: These results suggest that the pathologic assessment of lymph nodes in surgical specimens is often inaccurate and that examining greater number of nodes increases the likelihood of proper staging. Some patients who might benefit from adjuvant therapy are misclassified as node-negative due to incomplete sampling of lymph nodes.

A phase II study of irinotecan with 5-fluorouracil and leucovorin in patients with previously untreated gastric adenocarcinoma.

BACKGROUND: A phase II study testing the safety and efficacy of irinotecan (CPT-11). 5-fluorouracil (5-FU), and leucovorin (LCV) was conducted in patients with advanced gastric adenocarcinomas. PATIENTS AND METHODS: Patients with metastatic or recurrent adenocarcinoma of the gastroesophageal junction (GEJ) or stomach were entered onto this study. Previous chemotherapy for metastatic disease was not allowed. Treatment consisted of repeated 6-week cycles comprising CPT-11 125 mg/m2 intravenously (i.v.) followed immediately by LCV 20 mg/m2 i.v. and 5-FU 500 mg/m2 i.v., all given weekly for four weeks followed by a two-week rest. RESULTS: Thirty-eight patients were enrolled and 36 eligible patients received protocol therapy. Grade 3-5 toxicities consisted primarily of neutropenia (36%) and diarrhea (28%). Neutropenic infection was observed in 14% of patients, with 3 (8%) dying of neutropenic sepsis. The overall response rate was 22% (95% confidence interval [CI] 8.5% to 35.5%). Median survival was 7.6 months, and median time to progression was 4.4 months. CONCLUSION: This weekly regimen of CPT-11 with bolus 5-FU/LCV is active in patients with advanced adenocarcinomas of the stomach or gastroesophageal junction. While rates of grade 3-4 neutropenia and diarrhea were similar to those observed historically in patients receiving this regimen for colorectal cancer, neutropenic fever/sepsis appeared to be more frequent, and dose modifications were substantial. Future trials of this combination in patients with gastric cancer should decrease the absolute starting drug doses and/ or employ altered scheduling that better accommodates the pattern of toxicity.

Eastern Cooperative Oncology Group Phase I trial of protracted venous infusion fluorouracil plus weekly gemcitabine with concurrent radiation therapy in patients with locally advanced pancreas cancer: a regimen with unexpected early toxicity.

PURPOSE: We performed a phase I trial of protracted venous infusion (PVI) fluorouracil (5-FU) plus weekly gemcitabine with concurrent radiation therapy in patients with locally advanced pancreas cancer to determine the maximum-tolerated dose of gemcitabine that could be safely administered. We also sought to identify the toxicities associated with this treatment protocol. PATIENTS AND METHODS: Seven patients with locally advanced pancreas cancer were treated with planned doses of radiation (59.4 Gy) and PVI of 5-FU (200 mg/m(2)/d) with gemcitabine doses of 50 to 100 mg/m(2)/wk. RESULTS: Two of three patients at the 100-mg/m(2)/wk dose level experienced dose-limiting toxicity (DLT), as did three of four at the 50-mg/m(2)/wk dose level. One patient experienced a mucocutaneous reaction described as a Stevens-Johnson syndrome that was attributed to chemotherapy. Three patients developed gastric or duodenal ulcers with severe bleeding requiring transfusion. One patient developed severe thrombocytopenia lasting longer than 4 weeks. Three of the five episodes of DLT developed at radiation doses < or = 36 Gy. CONCLUSION: Based on this experience, we cannot recommend further investigation of regimens incorporating gemcitabine into regimens of radiation with PVI 5-FU. The mechanism of this synergistic toxicity remains to be determined.