International outbreak of multiple Salmonella serotype infections linked to sprouted chia seed powder - USA and Canada, 2013-2014.

Salmonella is a leading cause of bacterial foodborne illness. We report the collaborative investigative efforts of US and Canadian public health officials during the 2013-2014 international outbreak of multiple Salmonella serotype infections linked to sprouted chia seed powder. The investigation included open-ended interviews of ill persons, traceback, product testing, facility inspections, and trace forward. Ninety-four persons infected with outbreak strains from 16 states and four provinces were identified; 21% were hospitalized and none died. Fifty-four (96%) of 56 persons who consumed chia seed powder, reported 13 different brands that traced back to a single Canadian firm, distributed by four US and eight Canadian companies. Laboratory testing yielded outbreak strains from leftover and intact product. Contaminated product was recalled. Although chia seed powder is a novel outbreak vehicle, sprouted seeds are recognized as an important cause of foodborne illness; firms should follow available guidance to reduce the risk of bacterial contamination during sprouting.

Outbreak of Salmonella Typhimurium associated with feeder rodents.

In December 2012, an increase in human Salmonella Typhimurium cases was identified in the province of Ontario, Canada launching an outbreak investigation. The outbreak spanned 3 years (2012-2014), with 134 cases reported from five Canadian provinces. There was a substantial burden of illness among children: 45% of cases were children 12 years old or under, and 23% of cases were under 5 years old. Epidemiologic, traceback and laboratory findings linked this outbreak to feeder rodents (used to feed snakes) supplied by a network of rodent breeders in Ontario. Cases likely acquired their illness through either direct or indirect contact with feeder rodents. This investigation not only contributes to the weight of evidence on the risk that feeder rodents pose, but also underscores the importance of investigating indirect animal contact and associated risks, especially for high-risk individuals.

Outbreak of Salmonella Reading in persons of Eastern Mediterranean origin in Canada, 2014-2015.

BACKGROUND: Salmonella Reading (S. Reading) is a rare serotype of Salmonella subspecies (spp.) in Canada with less than nine cases reported each year (2011-2013). An increase in S. Reading was identified in several Canadian provinces in early 2015, prompting the initiation of a national outbreak investigation. OBJECTIVES: To describe a multi-provincial S. Reading outbreak in Canada that affected over 30 people. METHODS: Cases were defined as laboratory-confirmed S. Reading with related pulsed-field gel electrophoresis (PFGE) patterns. Onset dates were between November 2014 and September 2015.​: Early in the investigation, investigators noted cases were predominantly of Eastern Mediterranean origin, mainly Afghan and Lebanese and many of those affected had consumed food items not typically captured on standard enteric outbreak hypothesis-generating questionnaires. An open-ended three day food consumption survey was conducted with a convenience sample of community informants to better understand food preferences of the affected ethnocultural populations. Results of the survey were used to design a focused questionnaire for case re-interviews and subsequent outbreak cases. Public health investigators obtained food samples from case homes and relevant food premises. Food safety authorities conducted traceback of suspected food items and collected food samples for laboratory testing. RESULTS: There were 31 confirmed cases (Ontario=23, Alberta=7, New Brunswick=1) and three probable (Ontario=2, Alberta=1) cases of S. Reading identified as part of the outbreak. The median age was 31 years (range less than one to 85 years) and 53% (18/34) of cases were female. Seven cases were hospitalized. No deaths were reported. Most cases were of Eastern Mediterranean origin (n=23) or had reported consuming Eastern Mediterranean foods (n=3). The predominant ethnic origins reported by cases were Afghan in Ontario (n=12) and Lebanese in Alberta (n=3). Genetic similarity of clinical isolates was further confirmed using whole genome sequencing.​: Three ethnic bakeries were identified as possible common exposures for the cases; however, traceback of foods of interest from these bakeries did not identify a common supplier and the source of the illness was not identified. In total, 227 food samples from retail premises (n=142), restaurants (n=13) and case homes (n=72) were tested; two food samples, kalonji seeds and tahini, were positive for S. Ruiru and S. Meleagridis. These products were recalled from the marketplace. CONCLUSION: Despite extensive epidemiological, microbiological and food traceback investigations, a common source was not identified for this S. Reading outbreak. Challenges included lack of familiarity with the food items consumed in affected ethnocultural groups, as well as a lack of background data on expected food exposures in the outbreak population. Engaging local partners helped build understanding of food preferences in affected communities. Given Canada's ethnic and cultural diversity, culturally competent approaches to enteric outbreak investigations and food consumption surveys may be useful.

Bolus versus infusion regimens of etoposide and cisplatin in treatment of non-small cell lung cancer: a study of the North Central Cancer Treatment group.

In an effort to test clinically the hypothesis that the duration of cellular exposure to etoposide (VP-16) and cisplatin (CDDP) is an important determinant of cytotoxicity, we performed a phase III randomized trial comparing an outpatient bolus regimen of combined VP-16 and CDDP with a sequential infusion over 72 hours of these same two drugs. All patients had stage IV non-small cell lung cancer, and survival was the primary end point. Of 113 patients randomly allocated to the study, 108 were assessable for response, survival, and toxicity. A major response was observed in 20 (37%) of 54 patients on the bolus regimen and in 16 (30%) of 54 patients receiving infusion therapy. The median time to progression was 61 and 88 days for bolus and infusion therapy, respectively. The median survival time was 148 and 157 days, respectively (P = .71). Study results were not consistent with the possibility that infusion therapy could be associated with a 50% improvement in median survival, i.e. from 5 months to 7 1/2 months. Toxicity was primarily myelosuppression and was significantly greater with the infusion regimen. We conclude that infusion therapy as tested in this protocol with VP-16 and CDDP does not offer any advantage in response rate, time to disease progression, or survival as compared with bolus therapy. In addition, infusion therapy is associated with a greater degree of neutropenia and more treatment-related deaths.

Controlled evaluation of three drug combination regimens versus fluorouracil alone for the therapy of advanced gastric cancer. North Central Cancer Treatment Group.

PURPOSE: The purpose of this study was to evaluate the therapeutic effectiveness of fluorouracil (5-FU), doxorubicin, and methyl lomustine (CCNU) (FAMe), 5-FU, doxorubicin, and cisplatin (FAP), and FAMe alternating with triazinate (TZT) when compared with a standard therapy of 5-FU alone in patients with advanced gastric cancer. PATIENTS AND METHODS: Two hundred fifty-two eligible patients selected for study had proven locally unresectable and/or metastatic gastric adenocarcinoma. The majority had nonmeasureable disease. They were randomly assigned to receive one of the three drug combination regimens or to 5-FU alone administered by rapid injection in 5-day course. Survival was the primary study end point. RESULTS: None of the three drug combinations showed a significant advantage over 5-FU alone in improved performance score, weight gain, or patient survival. Each of the three combinations was more toxic than 5-FU alone. CONCLUSION: FAMe, FAP, or FAMe alternating with TZT cannot be recommended for the therapy of advanced gastric carcinoma. Therapy of this disease should remain an experimental endeavor. It would seem reasonable to prove the value of any new treatment approach by a randomized comparison to simple therapy with 5-FU alone.

Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal cancer.

In a previous study (J Clin Oncol 7:1407-1417, 1989), we identified two dosage administration schedules of fluorouracil (5FU) combined with leucovorin that were superior to single-agent 5FU for the treatment of advanced colorectal cancer. In this same study, a regimen of 5FU plus high-dose methotrexate (MTX) demonstrated a suggestive advantage over 5FU alone. To permit a more definitive comparison, we have extended our evaluation of these three regimens to involve an additional 259 patients. In all, 457 patients with advanced colorectal cancer were randomly assigned to one of the following regimens: 5FU plus low-dose leucovorin, 5FU plus high-dose leucovorin, or 5FU plus high-dose MTX with leucovorin rescue. We have found that each of the 5FU/leucovorin regimens demonstrates a significant (P less than or equal to .01) advantage over 5FU plus high-dose MTX for objective tumor response and interval to tumor progression. Moreover, 5FU plus low-dose leucovorin confers a significant survival benefit (P less than or equal to .01) compared with 5FU plus high-dose MTX. The 5FU plus high-dose leucovorin regimen shows a survival benefit only in unadjusted analyses (P = .04), but this difference is not significant when adjusted for imbalances in prognostic variables (P = .44). Evaluation of the two 5FU/leucovorin regimens rules out a 10% decrease in death rate for the high-dose leucovorin regimen compared with the low-dose leucovorin regimen (P less than .05). The regimen of 5FU plus low-dose leucovorin has now been shown to offer a statistically significant survival advantage versus 5FU alone and versus 5FU plus high-dose MTX, a regimen that had shown promise in earlier trials. These data confirm the efficacy of leucovorin combined with 5FU in patients with advanced colorectal cancer and establish that it is not necessary to use high doses of leucovorin to achieve these results.

Phase III evaluation of four doses of megestrol acetate as therapy for patients with cancer anorexia and/or cachexia.

PURPOSE: Several placebo-controlled randomized clinical trials have demonstrated that megestrol acetate can result in appetite stimulation and nonfluid weight gain in patients with cancer anorexia/cachexia. The present trial was designed to compare megestrol acetate doses ranging from 160 to 1,280 mg/d. METHODS: This trial randomized 342 assessable patients with cancer anorexia/cachexia to receive oral megestrol acetate at doses of 160, 480, 800, or 1,280 mg/d. Patients were evaluated monthly by history, examination, patient-completed questionnaires, and serum albumin levels. RESULTS: The data demonstrate that there is a positive dose-response effect for megestrol acetate on appetite stimulation (P < or = .02). In concert, there was a trend for more nonfluid weight gain with higher drug doses. Megestrol acetate was well tolerated in this group of patients with advanced malignant disease. CONCLUSION: The positive dose-response effect that we observed for megestrol acetate on appetite stimulation supports both our prestudy hypothesis and other available literature. Nonetheless, based primarily on the cost and inconvenience associated with the use of higher doses of this drug, it is reasonable to use 160 mg/d for the initial treatment of cancer anorexia/cachexia in routine clinical practice.

Biochemical modulation of fluorouracil: evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma.

The purpose of this study was to evaluate the effectiveness of several new approaches designed to enhance the activity of fluorouracil (5-FU) in the management of advanced colorectal cancer. A total of 429 patients were randomized to one of the following regimens: single-agent 5-FU, given by standard 5-day, intensive-course intravenous bolus technique; 5-FU plus high-dose folinic acid (leucovorin) or 5-FU plus low-dose leucovorin; 5-FU plus high-dose methotrexate (MTX) with oral leucovorin rescue; 5-FU plus low-dose MTX; and 5-FU plus cisplatin (CDDP). The median survival for patients receiving 5-FU alone was 7.7 months. The high- and low-dose leucovorin plus 5-FU regimens had median survivals of 12.2 and 12.0 months, respectively, and offered a significant survival advantage over 5-FU alone with one-sided P values of .037 and .050, respectively (P = .051 for each treatment after correction for prognostic variables). The only other regimen possibly associated with improved survival was high-dose MTX plus 5-FU, with a median survival of 10.5 months (P = .21, P = .076 corrected). In addition, both high- and low-dose leucovorin plus 5-FU regimens were associated with significantly improved tumor response rates (P = .04 and .001) and significantly improved interval-to-tumor-progression rates (P = .015 and .007) when compared with 5-FU alone. Only the low-dose leucovorin plus 5-FU regimen was associated with significant (P less than .05) superiority in each of the following parameters of quality of life: performance status, weight gain, and symptomatic relief. The overall most therapeutically favorable regimen in this trial was 5-FU given with low-dose leucovorin; fortuitously, this regimen is associated with very low drug cost. Whereas this is the first study to demonstrate both improved palliation and survival for any regimen compared with 5-FU given by rapid intravenous (IV) injection for 5 consecutive days at a dose of 500 mg/m2/d in patients with advanced colorectal cancer, the magnitude of the gain is still relatively small. Our low-dose leucovorin plus 5-FU regimen is currently being studied in a national trial with the hope that this increased advanced disease activity may produce more substantive gains in the surgical adjuvant setting.

Phase III comparative evaluation of PCNU and carmustine combined with radiation therapy for high-grade glioma.

PURPOSE: We performed a randomized trial to compare survival distributions and toxicity of radiation therapy (RT) and PCNU with those of RT and carmustine (BCNU) in patients with malignant glioma. PATIENTS AND METHODS: A total of 346 patients with histologically verified supratentorial grade 3 and grade 4 astrocytoma were studied. After surgery, patients were randomly assigned to receive RT 60 Gy in 30 fractions and either PCNU 100 mg/m2 or BCNU 200 mg/m2 every 7 weeks for 1 year and every 10 weeks for the second year. RT and chemotherapy were started within 72 hours of randomization and usually on the same day. Of 334 assessable patients, 72% had partial or radical resection and 71% had grade 4 tumors. Median age was 59 years, and 85% had performance scores of 0 to 2 (Eastern Cooperative Oncology Group [ECOG]). The follow-up duration of 51 living patients ranged from 10.3 to 63.2 months, with a median of 36.2 months. RESULTS: The median survival duration in each group was 47 weeks, and median time to progression was 28 weeks. PCNU produced significantly more leukopenia and thrombocytopenia, whereas BCNU produced significantly more nausea, vomiting, and irritation. CONCLUSION: PCNU has no therapeutic advantage at this dose and schedule and does not warrant further study as a single agent for patients with high-grade glioma.

Phase III trial of recombinant interferon gamma in complete responders with small-cell lung cancer.

PURPOSE: We evaluated the effect of recombinant interferon gamma (rIFN-gamma) on survival and toxicity in small-cell lung cancer (SCLC) patients in complete remission (CR). PATIENTS AND METHODS: One hundred patients in CR following treatment with six cycles of combination chemotherapy, thoracic radiotherapy (TRT), and prophylactic cranial irradiation (PCI) were studied. All patients had been enrolled onto a cooperative group trial (North Central Cancer Treatment Group [NCCTG] 86-20-51). Patients received observation only or rIFN-gamma at a dose of 4 x 10(6) U subcutaneously per day for 6 months. RESULTS: Six patients (12%) did not comply with rIFN-gamma treatment. Substantial nonhematologic toxicities consisting of chills, myalgia, lethargy, and alteration of mood-personality were observed. No patient experienced life-threatening or fatal toxicity. The median times to progression for rIFN-gamma treatment or observation were 6.9 and 8.1 months (P = .54). The median survival times were 13.3 and 18.8 months, respectively (P = .43). Approximately 70% of all patients relapsed within 2 years. CONCLUSION: Time to progression and survival were inferior in patients treated with rIFN-gamma compared with randomized control subjects, although this difference was not statistically significant. These data indicate that rIFN-gamma treatment is not associated with a 33% improvement in survival (P = .04). Because of the high rate of relapse, SCLC patients in CR are an ideal group in which to evaluate novel and minimally toxic agents.

Randomized double-blind placebo-controlled trial of cisplatin and etoposide plus megestrol acetate/placebo in extensive-stage small-cell lung cancer: a North Central Cancer Treatment Group study.

PURPOSE: Megestrol acetate has been reported to improve appetite and quality of life and to decrease nausea and vomiting in patients with cancer anorexia/cachexia. The present trial was formulated to evaluate the impact of megestrol acetate on quality of life, toxicity, response, and survival in individuals with extensive-stage small-cell lung cancer who received concomitant chemotherapy. PATIENTS AND METHODS: Patients were randomized to receive megestrol acetate 800 mg/d orally or placebo. In addition, all patients were scheduled to receive a maximum of four cycles of cisplatin and etoposide chemotherapy. Quality of life was self-assessed at entry onto study, with every cycle of chemotherapy, and 4 months thereafter with a linear visual analog scale. Toxicity was evaluated by patient questionnaire and investigator reports. RESULTS: A total of 243 eligible patients were randomized. Those who received megestrol acetate had increased nonfluid weight gain (P = .004) and significantly less nausea (P = .0002) and vomiting (P = .02). Significant thromboembolic phenomena occurred more often in patients who received megestrol acetate versus placebo (9% v 2%, P = .01). Patients who received megestrol acetate had more edema (30% v 20%, P = .002), an inferior response rate to chemotherapy (68% v 80%, P = .03), and a trend for inferior survival duration (median, 8.2 v 10.0 months, P = .49). These findings may have been influenced by a poorer quality of life of the megestrol acetate group at study initiation. There were no significant changes in quality of life scores over time between either of the study arms. CONCLUSION: Megestrol acetate cannot be routinely recommended for all patients with small-cell lung cancer at the time of chemotherapy initiation. Rather, its therapeutic ratio may be more favorable for patients with problematic cancer anorexia/cachexia.

A simple stratification factor prognostic for survival in advanced cancer: the good/bad/uncertain index.

PURPOSE: This article summarizes the third step of a research program to identify variables that supplement the predictive power of the the Eastern Cooperative Oncology Group (ECOG) performance status (PS) for survival. The objective was to produce a simple, practical, stratification factor for phase III oncology clinical trials involving patients with advanced malignant disease. PATIENTS AND METHODS: A questionnaire was administered to 729 patients with metastatic colorectal or lung cancers. Patients provided a Karnofsky index and appetite rating while physicians provided a survival estimate and the ECOG-PS. Scores for each item were categorized as having a positive, neutral, or negative indication for survival. A patient was classified as having a relatively good prognosis if three or more of the four items showed a positive indication, a bad prognosis if three or more items were negative, and an uncertain prognosis otherwise (Good/Bad/Uncertain [GBU] index). RESULTS: The GBU index improved on the prognostic power of a Cox model quartile index and PS alone and increased the accuracy of survival classification estimates by 5% to 10% more than ECOG-PS alone. For patients with PS of 0 or 1, significant survival patterns exist between GBU groups (P=.002 and.0001, respectively). CONCLUSION: The GBU index may be recommended as a supplementary stratification factor for certain future phase III trials in metastatic lung or colorectal cancer where patient heterogeneity is a particular concern. The GBU represents a relatively modest increase to the cost and patient burden of a clinical trial given the additional control that is achieved over the potentially confounding concomitant to the treatment variable.

Evaluation of external-beam radiation therapy plus 5-fluorouracil (5-FU) versus external-beam radiation therapy plus hycanthone (HYC) in confined, unresectable pancreatic cancer.

From March 1981 to November 1987, 87 patients with histologically confirmed pancreatic adenocarcinoma, unresectable but confined to the pancreatic region, were randomized to two treatments. The standard treatment was 40-50 Gy external-beam radiation therapy (RT) to gross tumor plus potential microscopic tumor with a 5 Gy boost to gross tumor plus a 1.5-2.0 cm margin, using multiple fields and 5-fluorouracil (5-FU) 500 mg/m2/d intravenously by rapid infusion. The 5-FU was given each of the initial 3 days of each of three 20 Gy radiation courses. The experimental treatment used identical radiation fields, but the two Gy daily radiation fractions were administered in a continuous course to a total dose of 50 Gy. Hycanthone was administered 60 mg/m2 intravenously within 2 to 4 hr during each day of the 5-day course of infusions during the first and fifth weeks of radiation therapy. There was no statistically significant difference between treatment arms in survival (p = 0.82) or disease-free survival (p = 0.27). Seven percent of hycanthone-treated patients demonstrated hepatic toxicity which was usually mild in nature. There was, however, one death due to hepatic toxicity.

Intra-arterial floxuridine vs systemic fluorouracil for hepatic metastases from colorectal cancer. A randomized trial.

Seventy-four patients with liver metastasis from proved colorectal primary adenocarcinoma were entered into a prospective, randomized clinical trial to evaluate treatment with intra-arterial floxuridine compared with standard outpatient therapy with fluorouracil delivered by intravenous bolus injection. Eligible patients were randomized to hepatic arterial chemotherapy with an implanted infusion pump or systemic chemotherapy. No crossover between treatment arms was permitted, and patients were followed up to progression and death. Objective tumor response was observed in 48% of patients receiving intra-arterial floxuridine and in 21% of patients receiving intravenous fluorouracil. Time to hepatic progression was significantly longer in the group given intra-arterial therapy: 15.7 vs 6.0 months. However, time to overall progression (6.0 vs 5.0 months) and survival (12.6 vs 10.5 months) were not statistically different. Based on these data, we cannot recommend treatment with intra-arterial floxuridine as given in this study for metastatic colorectal cancer to the liver.

Pilot study evaluating local anesthetics administered systemically for treatment of pain in patients with advanced cancer.

Based on evidence that suggested that systemically administered local anesthetics might be useful in chronic pain, we initiated a pilot study to evaluate the activity and toxicity of mexiletene and flecainide in the treatment of cancer pain. Twenty-one courses of either mexiletine or flecainide were administered to patients with an Eastern Cooperative Oncology Group performance status of three or better, who were suffering from cancer pain inadequately controlled with opioid analgesics. Pain control was assessed by patient questionnaires to monitor benefit and toxicity. In 17 cases, there was no suggestion of benefit. Two cases had relatively clear-cut analgesic benefit, and two others had some suggestion of mild-to-moderate analgesic relief. Flecainide was relatively well tolerated, but mexiletine appeared to cause nausea and/or vomiting in five of eight patients. This pilot trial suggests that systemically administered local anesthetics can relieve pain in a minority of patients with cancer pain.

Phase II evaluation of recombinant interferon alpha and BCNU in recurrent glioma.

The goal of this study was to determine the antitumor activity and toxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) plus recombinant interferon-alpha (IFN-alpha) in patients with recurrent glioma. As single agents, both BCNU and IFN-alpha can cause tumor regression in patients with recurrent glioma. In vitro studies suggest synergy between the two agents. Thirty-five patients in whom computerized tomography (CT) or magnetic resonance (MR) evidence was obtained of progressive astrocytoma, oligoastrocytoma, or oligodendroglioma received recombinant IFN-alpha 2a (12 x 10(6) U/m2 intramuscularly) on Days 1 through 3 and BCNU (150 mg/m2 intravenously) on Day 3 of each 6-week cycle. All patients had tumor progression despite radiation therapy and had received no prior chemotherapy. Response was assessed by CT or MR evidence and by neurological examination while the patients were on a regimen of stable or decreasing doses of corticosteroids. All patients could be evaluated for response and toxicity. Twenty-nine percent of the patients demonstrated objective tumor regression; 37% remained stable for more than 6 months and 25% were stable for less than 6 months. The median duration of response to IFN-alpha and BCNU was 9.9 months and the median survival for all patients was 13.3 months. Toxicity consisted primarily of moderate myelosuppression, venous irritation, vomiting, flulike symptoms, and transient reversible exacerbation of underlying neurological symptoms. The use of BCNU plus IFN-alpha is a safe, active regimen in the treatment of patients with recurrent glioma who have failed to respond to prior radiation therapy. The contribution of IFN to the antitumor activity observed in this study compared with that previously described with BCNU alone cannot be assessed from this trial.

Epidemiologic features of pain in pediatric cancer patients: a co-operative community-based study. North Central Cancer Treatment Group and Mayo Clinic).

The prevalence, etiology, and management of pain in pediatric cancer patients seen at the Mayo Clinic and member institutions of the North Central Cancer Treatment Group were assessed. Participating centers, including both primary care and referral institutions, surveyed all patients seen during a 1-week period (Monday through Friday); procedure-related pain was excluded. Of the 160 children surveyed, 28 reported pain of which 57.8% was related to a side effect of anticancer treatment, 21.1% was unrelated to the malignancy, and 21.1% arose directly from the cancer. Pain intensity assessment was performed by both health-care professional and patient using a variety of measurement tools. Correlation between assessors was close except in young children. The predominance of treatment-related rather than cancer-related pain differs from results in series in adult cancer patients.

Phase II study of 2-chlorodeoxyadenosine in combination with chlorambucil in previously untreated B-cell chronic lymphocytic leukemia.

The objective was to determine the safety and efficacy of adding a maximally tolerated dose of 2-chlorodeoxyadenosine (2-CdA) to standard chlorambucil (CLB) therapy in previously untreated B-cell chronic lymphocytic leukemia (CLL). Thirty patients with CLL (median age, 64 years) received two courses of 2-CdA given intravenously (2 mg/m2 daily for 7 days) added to biweekly administration of CLB at 30 mg/m2 given orally. The diagnosis of CLL, treatment indications, and response criteria were according to the National Cancer Institute established guidelines. Sixteen patients (53%) had advanced-stage disease, and four (13%) had trisomy 12 abnormality. The overall remission rate was 80%, including 20% complete remission (CR), 30% nodular partial remission (nPR), and 30% partial remission (PR). Minimal residual disease was detected phenotypically in two of five patients with CR and in eight of nine with nPR. Overall, CR, nPR, and PR rates were not influenced significantly by the presence of cytogenetic abnormalities or advanced clinical stage. With a median follow-up of 33 months, 58% of patients who had a response had relapse. Median time to progression in all 30 patients was 30 months, and time to progression and progression-free survival were not significantly different for the different response groups, clinical stages, or cytogenetic groups. Severe neutropenia and thrombocytopenia occurred in 33% and 7% of patients, respectively. Only two patients had documented bacterial infections, and four had herpetic infections. Concurrent combination chemotherapy with abbreviated doses of 2-CdA and standard-dose CLB is feasible and safe in previously untreated CLL. Antitumor activity may be superior to that of CLB alone given in conventional doses. Whether a different schedule of combining these two agents would result in improved outcome is being investigated.

Alternating chemotherapy with or without VP-16 in extensive-stage small-cell lung cancer.

In this study, we evaluated the role of alternating chemotherapy with or without etoposide (VP-16) in patients with extensive-stage small-cell carcinoma (SCC) of the lung. All patients received initial treatment with CMC [cyclophosphamide, methotrexate, and chloroethyl-cyclohexyl-nitrosourea (CCNU)]. Four weeks after initial treatment, patients were stratified by performance score, central nervous system (CNS) metastasis, age, and response to initial CMC therapy and randomized to receive AO (doxorubicin and vincristine) or AVO (doxorubicin, VP-16, and vincristine) alternating with CMC. One hundred eighty-two eligible patients were treated with the initial cycle of CMC and 98 responded (54%). One hundred fifty-four patients were randomized to either AO/CMC or AVO/CMC. The response rates to AO/CMC and AVO/CMC were similar (72 vs. 68%). The time to progression and survival were not significantly different on the two treatment regimens. Toxicity was significantly greater for patients receiving AVO/CMC with six treatment-related deaths. Etoposide as used in this regimen did not significantly influence response rates, time to progression, or survival of patients with extensive small-cell lung cancer.

Phase II evaluation of continuous-infusion 5-fluorouracil, leucovorin, mitomycin-C, and oral dipyridamole in advanced measurable pancreatic cancer: a North Central Cancer Treatment Group Trial.

At present there remains a need for more effective systemic therapy in advanced pancreatic cancer. Some studies have suggested that infusional chemotherapy schedules and biomodulation of 5-fluorouracil (5-FU) may improve the therapeutic outcome in advanced colon cancer. One such regimen that uses continuous infusion 5-FU, weekly leucovorin, daily dipyridamole, and intermittent mitomycin-C has activity in both colon and unresectable pancreatic carcinoma. The intent of this trial was to test the effectiveness of this four-drug regimen in advanced pancreatic cancer. Patients received 5-FU 200 mg/m2 daily by continuous infusion, leucovorin 30 mg/m2 IV weekly, mitomycin-C 10 mg/m2 day 1, and dipyridamole 75 mg orally four times daily for 5 weeks. After a 1-week break, treatment cycles were repeated every 6 weeks. Eligibility included biopsy-proven advanced measurable pancreatic cancer, Eastern Cooperative Oncology Group performance status 0 and 2, and no prior systemic chemotherapy. Of 46 evaluable patients, 9 partial responses and 1 complete tumor response were seen, for an overall response rate of 22% (95% confidence interval 11-36%). The median survival in the group of 50 patients registered to this trial was 4.6 months, with a range of 0.33 to 40.2 months. Toxicity was manageable, with the most common toxicities (> or =grade III National Cancer Institute Common Toxicity Criteria) being anorexia (13%), stomatitis (17%), and hand-foot syndrome (13%). Of note, little severe hematologic toxicity and no significant headaches were reported. Although some patients did respond, the therapeutic results are not encouraging enough to take this regimen to phase III testing.