Phase I study of concurrent and consolidation cisplatin and docetaxel chemotherapy with thoracic radiotherapy in non-small cell lung cancer.

BACKGROUND: We designed a phase i study of concurrent chemoradiotherapy (ccrt) with docetaxel (D) and cisplatin (C), followed by consolidation dc, for unresectable stage iii non-small cell lung cancer (nsclc). METHODS: Patients with histologically proven and unresectable stage iii nsclc were eligible. During ccrt, C was given every 3 weeks (75 mg/m2) and D given weekly. The starting dose of D was 20 mg/m2, escalated in cohorts of 3 to define the maximum tolerated dose (mtd). Radiotherapy was prescribed to a dose of 60 Gy in 30 fractions. This was followed by 2 cycles of consolidation dc, which were dose escalated if ccrt was tolerated. RESULTS: Twenty-six patients were enrolled, with 1 excluded following evidence of metastatic disease. Nineteen patients completed both phases of treatment. There were 7 grade 3 events during ccrt (5 esophagitis, 2 nausea), and 8 grade 3 events during consolidation (2 neutropenia, 2 leukopenia, 1 esophagitis, 2 nausea, and 1 pneumonitis). Three patients had grade 4 neutropenia. No patients died due to toxicities. The mtd of concurrent weekly D was 20 mg/m2. Consolidation D and C were each dose escalated to 75 mg/m2 in 8 patients. The median overall survival (os) and progression-free survival (pfs) of all patients were 33.6 months and 17.2 months, respectively, with median follow-up of 26.6 months (range 0.43-110.8). CONCLUSIONS: The use of docetaxel 20 mg/m2 weekly and cisplatin 75 mg/m2 every 3 weeks concurrent with thoracic radiotherapy, followed by consolidation docetaxel and cisplatin, both given at 75 mg/m2 every 3 weeks, appears to be safe in this phase i trial.

Liver transplantation for symptomatic liver metastases of neuroendocrine tumours.

Numerous reports have demonstrated that liver transplantation for neuroendocrine tumour metastasis is feasible. However, perioperative risks and long-term recurrences remain significant concerns. When liver transplantation is combined with extensive intestinal or pancreatic resection, the risk is particularly high.We report our institutional experience of liver transplantations performed for liver metastases secondary to neuroendocrine tumours, and in combination with a review of the literature, we propose a set of selection criteria. The key points include unresectable hepatic metastases of neuroendocrine origin, absence of extrahepatic metastases, symptomatic disease that is refractory to medical therapy, a Ki-67 level less than 2%, previous resection of the primary disease, and previous therapy for metastatic neuroendocrine tumour.In our experience, the patient in the first case had, post-transplantation, rapid disease progression because of an unidentified primary, and patient in the second case had primary non-function of the liver graft, requiring urgent re-transplantation. More recently, two liver transplantations were successfully performed. The indications were, in the first case, refractory hormonal secretion and, in the other, secondary biliary cirrhosis attributable to hepatic artery therapy with tumour in situ. Subclinical and stable recurrent disease has been detected by scintigraphy in the mesentery and lumbar spine in the former patient. A mesenteric recurrence developed in the latter patient 2 years post transplantation and was subsequently completely resected. At 4 and 5 years post transplantation, both patients are symptom-free.Recurrence after transplantation remains a significant concern, even with careful patient selection, but recurrences may remain indolent. If recurrences are progressive, they may still be amenable to additional medical or surgical therapy. A national or international consensus between oncologists and transplant specialists regarding the indications for liver transplantation is vital, because future progress will depend on careful patient selection and prospective study.

Consensus recommendations for the diagnosis and management of well-differentiated gastroenterohepatic neuroendocrine tumours: a revised statement from a Canadian National Expert Group.

Well-differentiated neuroendocrine tumours (nets-previously called "carcinoid tumours") are relatively rare tumours originating from the diffuse neuroendocrine system; they are found most often in the bronchial or gastrointestinal systems. In Canada, gastroenterohepatic NETS represent less than 0.25% of oncology cases. Because of the relative rarity of these tumours, diagnostic and therapeutic approaches vary and are often based on individual physician experience. A number of European and North American groups have developed consensus guidelines for the diagnosis and management of well-differentiated gastroenterohepatic NETS, and in 2006, Canadian consensus guidelines were published by a Canadian expert group. The updated and expanded current Canadian guidelines are based on a consensus meeting held in Paris, France, in 2008 and are based on the most current literature.

Postoperative extended-volume external-beam radiation therapy in high-risk esophageal cancer patients: a prospective experience.

BACKGROUND AND PURPOSE: Extended-volume external-beam radiation therapy (RT) following esophagectomy is controversial. The present prospective study evaluates the feasibility of extended-volume RT treatment in high-risk esophagectomy patients with a cervical anastomosis receiving postoperative combined chemoradiation therapy. PATIENTS AND METHODS: From 2001 to 2006, 15 patients with resected esophageal cancer were prospectively accrued to this pilot study to evaluate the adverse effects of extended-volume RT. Postoperative management was carried out at London Regional Cancer Program. Eligibility criteria were pathology-proven esophageal malignancy (T3-4, N0-1), disease amenable to surgical resection, and esophagectomy with or without resection margin involvement. Patients with distant metastases (M1) and patients treated with previous RT were excluded. All 15 study patients received 4 cycles of 5-fluorouracil-based chemotherapy. External-beam RT was conducted using conformal computed tomography planning, with multi-field arrangement tailored to the pathology findings, with coverage of a clinical target volume encompassing the primary tumour bed and the anastomotic site in the neck. The radiation therapy dose was 50.40 Gy at 1.8 Gy per fraction. The RT was delivered concurrently with the third cycle of chemotherapy. The study outcomes-disease-free survival (DFS) and overall survival (OS)-were calculated by the Kaplan-Meier method. Treatment-related toxicities were assessed using the U.S. National Cancer Institute's Common Toxicity Criteria. RESULTS: The study accrued 10 men and 5 women of median age 64 years (range: 48-80 years) and TNM stages T3N0 (n = 1), T2N1 (n = 2), T3N1 (n = 11), and T4N1 (n = 1). Histopathology included 5 adenocarcinomas and 10 squamous-cell carcinomas. Resection margins were clear in 10 patients. The median follow-up time was 19 months (range: 3.5-53.4 months). Before radiation therapy commenced, delay in chemotherapy occurred in 20% of patients, and dose reduction was required in 13.3%. During the concurrent chemoradiation therapy phase, 20% of the patients experienced chemotherapy delay, and 6.6% experienced dose reduction. No patient experienced treatment-related acute and chronic esophagitis above grade 2. Disease recurred in 40% of the patients (6/15), and median time to relapse was 24 months. No tumour recurred at the anastomotic site. The median DFS was 23 months, and the median OS was 21 months. CONCLUSIONS: Extended-volume external-beam RT encompassing the tumour bed and the anastomotic site is feasible and safe for high-risk T3-4, N0-1 esophageal cancer patients after esophagectomy.

A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas.

Standard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity. A phase II study was designed to evaluate the efficacy, safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma (NEC). Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus. Patients were evaluated for tumour response, time to progression (TTP), overall survival (OS) and adverse events (AE). Twenty-two archival specimens, as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers. The intent-to-treat response rate was 5.6% (95% CI 0.6-18.7%), median TTP 6 months and 1-year OS rate 71.5%. The most frequent drug-related AE of all grades as percentage of patients were: fatigue (78%), hyperglycaemia (69%) and rash/desquamation (64%). Temsirolimus effectively inhibited the phosphorylation of S6 (P=0.02). Higher baseline levels of pmTOR (phosphorylated mammalian target of rapamycin) (P=0.01) predicted for a better response. Increases in pAKT (P=0.041) and decreases in pmTOR (P=0.048) after treatment were associated with an increased TTP. Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC. Pharmacodynamic analysis revealed effective mTOR pathway downregulation.

A National Cancer Institute of Canada Clinical Trials Group Study--IND.135: Phase I/II study of irinotecan (camptosar), oxaliplatin and raltitrexed (tomudex) (COT) in patients with advanced colorectal cancer.

Thirty-one patients with metastatic colorectal cancer were enrolled in this phase I/II trial of a triple combination of camptosar (C), oxaliplatin (O) and tomudex (T), all given on day one of a convenient three-week schedule. Patients received 257 cycles (1-18) in five cohorts. Toxicity was manageable and haematological toxicity was mild to moderate. Diarrhoea was the main dose-limiting toxicity; nausea and vomiting were common. Fatigue was frequent, moderate in severity and a reason for discontinuation in some patients. The recommended phase II doses were (C) 220 mg/m(2), (O) 100mg/m(2), (T) 2.75 mg/m(2). A 50% response rate in 30 evaluable patients was confirmed by an independent radiology review board; progression-free survival and overall median survival were 7.3 months and 16.6 months, respectively. Of the 16 patients treated at the recommended dose, 9 (56.3%) experienced partial response. Further evaluation in a randomized study compared to sequential doublets is warranted. Triple combinations could be relevant in curative settings for high-risk patients.

Guidelines for the diagnosis and management of carcinoid tumours. Part 1: the gastrointestinal tract. A statement from a Canadian National Carcinoid Expert Group.

Carcinoid tumours are relatively rare and, in general, slow growing. They can be "non-functioning" tumours, presenting as a tumour mass, or "functioning" tumours secondary to the production of several biopeptides leading to the carcinoid syndrome. Though these tumours represent 0.25% of an oncology practice, a proper understanding of the clinical course of the disease and of the importance of appropriate diagnostic and therapeutic measures is very important. Proper patient management can lead to cure, particularly if the tumour can be fully resected, or to long-term palliation with medical treatment or cytoreductive surgery, or both, with significant prolongation of survival. A good understanding of the use of somatostatin analogues to achieve effective symptomatic control and of the importance of adequate follow-up and cardiac monitoring to prevent or effectively treat cardiac complications can contribute significantly to optimal control of this complex disease, ultimately improving the quality of life of affected patients. This article, developed by a group of Canadian experts, provides a framework that will assist clinicians in taking an optimal approach to managing their patients with carcinoid tumour.

Swallowing function and weight change observed in a phase I/II study of external-beam radiation, brachytherapy and concurrent chemotherapy in localized cancer of the esophagus (RTOG 9207).

BACKGROUND: A multi-institutional, prospective study was designed to determine the feasibility and tolerance of combined-modality chemotherapy, external-beam irradiation, and esophageal brachytherapy in a potentially curable group of patients with adenocarcinoma or squamous cell carcinoma of the esophagus. Swallowing function and weight were assessed before and after treatment. MATERIALS AND METHODS: Planned treatment was with 50 Gy of external-beam irradiation (25 fractions/5 weeks) followed 2 weeks later by esophageal brachytherapy (either a high dose rate of 5 Gy at weeks 8, 9, and 10 for a total of 15 Gy or a low dose rate of 20 Gy at week 8). Chemotherapy was given weeks 1, 5, 8, and 11 with cisplatinum, 75 mg/m2, and 5-fluorouracil, 1,000 mg/m2/24 hours in a 96-hour infusion. Swallowing was graded from 0 (no dysphagia) to 4 (complete obstruction for solids and liquids). Weight "loss" or weight gain was defined as a change in 3-month post- to pretherapy weight of < or = 5% or > 5%, respectively. RESULTS: The estimated survival rate at 1 and 2 years was 49% and 31%, respectively, and the estimated median survival was 11 months. Swallowing before treatment was graded as grade 1 in 14 patients, grade 2 in 22 patients, grade 3 in nine patients, and grade 4 in four patients. Swallowing grade after treatment was reported as improved in 29 patients (59%), unchanged in 12 patients (24.5%), and worse in eight patients (16.5%). The bestimproved dysphagia score after treatment in the 29 patients reporting improvement was grade 0 in 19 patients, grade 1 in five patients, grade 2 in four patients, and grade 3 in one patient. A posttreatment weight in 42 evaluable patients was categorized as a loss in 29 patients (69%), a gain in four patients (9.5%), and stable in nine patients (21.5%). Weight loss was significantly correlated with high swallowing grade, low performance status, and absence of a feeding tube. CONCLUSIONS: Swallowing function after brachytherapy and concurrent chemoradiation therapy is satisfactory in most surviving patients. Ninety-two percent of patients were able to swallow at least liquids at some point after therapy. Future plans are to compare this with other cooperative group studies that utilized chemoradiation or surgery, without brachytherapy.

Using treatment interruptions to palliate the toxicity from concurrent chemoradiation for limited small cell lung cancer decreases survival and disease control.

BACKGROUND AND PURPOSE: We analyzed the impact on survival outcomes of treatment interruptions due to toxicity arising during the concurrent phase of chemotherapy/radiotherapy (ChT/RT) for our limited-stage small-cell cancer (LSCLC) population over the past 10 years. MATERIALS AND METHODS: From 1989 to 1999, 215 patients received treatment for LSCLC, consisting of six cycles of alternating cyclophosphamide/doxorubicin or epirubicin/vincristine (CAV; CEV) and etoposide/cisplatin (EP). Thoracic RT was started with EP at either the second or third cycle (85% of patients). RT dose was either 40 Gy in 15 fractions over 3 weeks or 50 Gy in 25 fractions over 5 weeks, delivered to a target volume encompassing gross disease and suspected microscopic disease with a 2 cm margin. Treatment breaks arising during concurrent ChT+RT were used to manage severe symptomatic or hematologic toxicities. We used the interruptions in thoracic RT as the 'marker' for any concurrent break and measured 'break duration' by the total length of time (in days) RT was interrupted, since that also signaled that ChT could be re-initiated. Patient results were analyzed for the impact of interruptions/treatment prolongation on overall and disease-free survival. RESULTS: For all patients, 2-year and 5-year overall and disease-specific survivals were 22.7 and 7.2, 27.6 and 9.3%, respectively; overall and disease-specific median survivals were 14.7 months each. A total of 56 patients (26%) had treatment breaks due to toxicity. Hematologic depression caused the majority of breaks (88%). The median duration of breaks was 5 days (range 1-18). Patients with and without interruptions were compared for a range of prognostic factors and were not found to have any significant differences. Comparing interrupted/uninterrupted courses, median survivals were 13.8 versus 15.6 months, respectively, and 5-year overall survivals were 4.2 versus 8.3%, respectively. There was a statistical difference between overall survival curves which favored the uninterrupted group (P=0.01). When comparing a series of prognostic variables, multivariable analysis found that the most significant factor influencing survival in the present study was the presence of treatment breaks (P=0.006). There was a trend for development of any recurrence in the patients with breaks (P=0.08). When controlling for the use of prophylactic cranial irradiation (PCI) in the two groups, the rate of failure in the chest was higher in the patients with RT breaks (58 vs. 33%). The rate of failure in the brain was dependent on the use of PCI only. CONCLUSIONS: Interruptions in treatment to palliate the toxicity from concurrent chemoradiation result in poorer local control and decreased survival.

Metallothionein expression in patients with small cell carcinoma of the lung: correlation with other molecular markers and clinical outcome.

BACKGROUND: Patients with small cell carcinoma of the lung (SCLC) are known to have an extremely poor prognosis, with a 5-year survivor rate of only 5%. Chemotherapeutic drug resistance is a major obstacle to curative therapy in patients with SCLC. METHODS: The authors evaluated retrospectively the expression of metallothionen (MT), proliferating cell nuclear antigen (PCNA), p53, and retinoblastoma gene product (RBGP) in biopsy samples from 58 patients with SCLC prior to standard chemotherapy. The objective was to study the correlation between MT and other molecular markers in SCLC and correlate these data with the clinical outcome of patients. The authors studied 28 short-term survivors (STS; survival < 24 months) and 30 long-term survivors (LTS; survival > 24 months). RESULTS: In line with expectations, the authors found a strong inverse association between stage and survival. Of 58 patients with SCLC, 26 patients (45%; 17 STS and 9 LTS) showed MT expression, 55 patients (94%; 28 STS and 27 LTS) were positive for PCNA, 28 patients (48%; 16 STS and 12 LTS) were positive for p53, and only 6 patients (10%; 1 STS and 5 LTS) showed positivity for RBGP. On comparing the percent positivity of various markers in the two survivor groups, there was greater frequency of expression of MT, PCNA, and p53 and lower RBGP expression in the STS group compared with the LTS group. However, only the difference in expression of MT between the two survivor groups was statistically significant (Fisher exact test; P = 0.034). Multivariable analysis using a logistic regression model showed a significant association between MT expression and patient survival after adjusting for disease stage (chi-square test; P = 0.022). There was also a statistically significant association between MT expression and p53 expression (chi-square test; P = 0.001). CONCLUSIONS: In this study, of the molecular markers studied, the authors demonstrated that only MT overexpression was independently predictive of short-term survival in patients with SCLC undergoing chemotherapy.

Comparison of oral capecitabine versus intravenous fluorouracil plus leucovorin as first-line treatment in 605 patients with metastatic colorectal cancer: results of a randomized phase III study.

PURPOSE: To compare the response rate, efficacy parameters, and toxicity profile of oral capecitabine with bolus intravenous (IV) fluorouracil plus leucovorin (5-FU/LV) as first-line treatment in patients with metastatic colorectal cancer. PATIENTS AND METHODS: We prospectively randomized 605 patients to treatment with oral capecitabine for 14 days every 3 weeks or 5-FU/LV by rapid IV injection daily for 5 days in 4-week cycles. RESULTS: The overall objective tumor response rate among all randomized patients was significantly higher in the capecitabine group (24.8%) than in the 5-FU/LV group (15.5%; P =.005). In the capecitabine and 5-FU/LV groups, median times to disease progression were 4.3 and 4.7 months (log-rank P =.72), median times to treatment failure were 4.1 and 3.1 months (P =.19), and median overall survival times were 12.5 and 13.3 months (P =.974), respectively. Capecitabine, compared with bolus 5-FU/LV treatment, produced a significantly lower incidence (P <.0002) of diarrhea, stomatitis, nausea, and alopecia. Patients treated with capecitabine also displayed lower incidences of grade 3/4 stomatitis and grade 3/4 neutropenia (P <.0001) leading to significantly less neutropenic fever/sepsis. Grade 3 hand-foot syndrome (P <.00001) and grade 3/4 hyperbilirubinemia were the only toxicities more frequently associated with capecitabine than with 5-FU/LV treatment. CONCLUSION: Oral capecitabine was more active than 5-FU/LV in the induction of objective tumor responses. Time to disease progression and survival were at least equivalent for capecitabine compared with the 5-FU/LV arm. Capecitabine also demonstrated clinically meaningful benefits over bolus 5-FU/LV in terms of tolerability.

Thymidylate synthase expression in stage II and III colon cancer: a retrospective review.

This study is a retrospective analysis of thymidylate synthase (TS) levels in patients with stage II (T3 or T4) and III colon cancer. Two groups of patients were identified: one undergoing surgery alone (98 patients) and the second receiving adjuvant 5-fluorouracil chemotherapy (112 patients). TS analyses were carried out using the 106 monoclonal antibody and a published grading system dividing staining into high and low intensity. The distribution of patients with low versus high TS levels was similar in the two groups. There was no association between TS staining intensity and grade, stage or location of primary. Seventy-nine patients have relapsed: 46 (48%) in the surgery only group, 33 (30%) in the adjuvant therapy group (median follow-up: 51 and 61 months). Similar proportions relapsed when analyzed according to TS: in the surgery only group, 41% of patients with low TS, 48% with high TS; in the adjuvant group, 31% with low TS, 30% with high TS. In the surgery only group, a trend toward improved disease-free survival (DFS) was seen in the low TS group (84 versus 63% at 2 years, p = 0.08). No difference was seen in overall survival. There were no differences in DFS or overall survival in patients receiving adjuvant therapy according to TS intensity. The trend for worse outcome in patients with high TS is consistent with previous reports. The lack of difference in outcome for patients with low and high TS receiving chemotherapy suggests that high TS levels may predict greater benefit from adjuvant treatment.

Survival benefit of chemotherapy in metastatic colorectal cancer: a meta-analysis of randomized controlled trials.

To estimate the magnitude of benefit of chemotherapy in prolonging survival for patients with metastatic colorectal cancer, a meta-analysis of randomized controlled trial was performed. A systematic search was performed to identify randomized trials comparing chemotherapy with observation or supportive care alone. Trials were assessed for quality of reporting, publication bias and heterogeneity. Relative risks for outcomes from published data were pooled using a random-effects model. Seven trials with 614 patients were included. All trials used fluoropyrimidine-based chemotherapy, through a variety of routes and schedules, including intravenous, intra-portal and hepatic arterial infusion. Compared with the 'no-chemotherapy' arm, chemotherapy significantly reduced 1-year mortality (risk ratio 0.69; 95% confidence interval (CI) 0.60-0.81, P < 0.00001). The mortality at 2 years was not significantly different (risk ratio 0.93; 95% CI 0.87-1.00, P = 0.053). Between-trial comparisons demonstrated benefit with a variety of routes and schedules. Chemotherapy significantly prolongs 1-year survival for patients with metastatic colorectal cancer, and should be offered to those with good performance status.

A phase I/II study of external beam radiation, brachytherapy, and concurrent chemotherapy for patients with localized carcinoma of the esophagus (Radiation Therapy Oncology Group Study 9207): final report.

BACKGROUND: A multiinstitutional, prospective study of the Radiation Therapy Oncology Group (RTOG) was designed to determine the feasibility and toxicity of chemotherapy, external beam radiation, and esophageal brachytherapy (EB) in a potentially curable group of patients with adenocarcinoma or squamous cell carcinoma of the esophagus. A preliminary analysis indicated a 17% 1-year actuarial risk of treatment-related fistulas. A final analysis of this study was considered important to determine the median survival time, local control, and late toxicity associated with this treatment regimen. METHODS: Planned treatment was 50 grays (Gy) of external beam radiation (25 fractions given over 5 weeks) followed 2 weeks later by EB (either high-dose-rate 5 Gy during Weeks 8, 9, and 10, for a total of 15 Gy, or low-dose-rate 20 Gy during Week 8). Chemotherapy was given during Weeks 1, 5, 8, and 11, with cisplatin 75 mg/m(2) and 5-fluorouracil 1000 mg/m(2)/24 hours in a 96-hour infusion. RESULTS: Of the 49 eligible patients, 45 (92%) had squamous histology and 4 (6%) had adenocarcinoma. Forty-seven patients (96%) completed external beam radiation plus at least 2 courses of chemotherapy, whereas 34 patients (69%) were able to complete external beam radiation, EB, and at least 2 courses of chemotherapy. The estimated survival rate at 12 months was 49%, with an estimated median survival of 11 months. Life-threatening toxicity or treatment-related death occurred in 12 (24%) and 5 (10%) cases, respectively. Treatment-related esophageal fistulas occurred in 6 cases (12% overall, 14% of patients starting EB) at 0.5-6.2 months from the first day of brachytherapy, leading to death in 3 cases. CONCLUSIONS: In this study, severe toxicity, including treatment-related fistulas, occurred within 7 months of brachytherapy. Based on the 12% incidence of fistulas, the authors continue to urge caution in employing EB, particularly when used in conjunction with chemotherapy.

Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study.

PURPOSE: To evaluate in patients with advanced colorectal cancer (CRC) three treatment regimens of oral capecitabine in order to select the most appropriate regimen for testing in phase III. PATIENTS AND METHODS: Three capecitabine schedules were evaluated in a randomized phase II design: arm A, 1,331 mg/m(2)/d bid continuously; arm B, 2,510 mg/m(2)/d bid intermittently (2 weeks on/1 week off); and arm C, 1,657 mg/m(2)/d plus oral leucovorin 60 mg/d bid intermittently (2 weeks on/1 week off). RESULTS: One hundred nine patients were randomized; 39 patients were assessable for efficacy in arm A, 34 in arm B, and 35 in arm C. Patient characteristics were balanced in the arms. Confirmed tumor responses (partial response [PR] + complete response [CR]) were reported for eight patients with two CRs (21%; 95% confidence interval [CI], 9% to 36%) in arm A, eight patients with one CR (24%; 95% CI, 11% to 41%) in arm B, and eight patients with two CRs (23%; 95% CI, 10% to 40%) in arm C. Median times to progression (TTP) in arms A, B, and C were 127, 230, and 165 days, respectively. Overall, more toxicity was seen with capecitabine plus leucovorin, particularly diarrhea and hand-foot syndrome. There was no grade 3 or 4 marrow toxicity. CONCLUSION: Capecitabine offers a new, effective treatment option as an oral single agent in advanced CRC. Promising overall response rates were reported for all three regimens. The addition of leucovorin to the intermittent regimen had no marked effect on tumor response or median TTP. The intermittent single-agent capecitabine schedule is proposed for phase III evaluation, based on considerations of toxicity, dose-intensity, response rate, and TTP.

Standard dose (Mayo regimen) 5-fluorouracil and low dose folinic acid: prohibitive toxicity?

Despite the perception that standard 5-fluorouracil/folinic acid (5-FU/FA) (425 mg/m2 per day and 20 mg/m2 per day intravenously once daily x 5 every 4 or 5 weeks) is well tolerated, we have been impressed by toxicity seen and frequent need for dose modification. We performed a retrospective analysis to quantitate the proportion of patients experiencing toxicity and attempted to identify associated clinical characteristics. One hundred thirty-four patients received 5-FU/FA at standard doses described by the Mayo regimen. Patient characteristics were as follows: female 35%, median age 66 years, Eastern Cooperative Oncology Group performance status less than or equal to 2, 96%. Sixty-eight percent received chemotherapy for metastatic disease. Forty-seven patients (35%+/-8%) experienced significant toxicity and were unable to receive the second cycle as scheduled: 76% required dose reduction, 11% discontinued therapy (including two toxic deaths), 11% discontinued therapy during the first cycle, and 2% required dose delay. Logistic regression was used to explore the following as predictors of toxicity: age, sex, performance status, adjuvant versus metastatic setting, prior chemotherapy, prior radiation, mean corpuscular volume, red blood cell distribution width, albumin, alkaline phosphatase, aspartate aminotransferase, bilirubin, and calculated creatinine clearance. No clinical characteristic was found to predict toxicity. Only high bilirubin approached statistical significance. We conclude that standard 5-FU/FA, when used in the general population, is associated with significant toxicity. Known clinical characteristics are not helpful in predicting toxicity. The lack of previous formal phase I evaluation of this regimen of 5-FU/FA raises concerns regarding its safety and generalizability in clinical practice.

HIV complicates the management of oncological emergencies: a case involving the superior vena cava syndrome.

An association exists between human immunodeficiency virus (HIV) and an increased incidence of lung cancer. Superior vena cava syndrome (SVCS) is an oncological emergency seen in the presence of chest tumours. We report on an otherwise well HIV-positive male who presented with SVCS due to lung cancer. He was commenced on dexamethasone and radiotherapy with curative intent. Treatment was complicated by accelerated steroid- and radiation-induced morbidity. The patient died of disseminated aspergillosis after receiving 27 of 35 planned radiotherapy fractions. The management of SVCS in those with HIV is challenging and requires the judicious use of steroids, antifungal prophylaxis and palliative radiotherapy doses.

Analysis of the clinical benefit of 5-fluorouracil and radiation treatment in locally advanced pancreatic cancer.

PURPOSE: To assess the palliative benefit of 5-fluorouracil (5-FU) and radiotherapy in patients with surgically unresectable localized pancreatic cancer. METHODS AND MATERIALS: Twenty-five patients with locally advanced surgically unresectable symptomatic pancreatic cancer received 5-FU chemotherapy and local radiation therapy. They were retrospectively reviewed in regard to their clinical benefit response (a composite of measurement of pain assessment, weight, and Karnofsky performance status [KPS]), as well as radiological response, time to progression, and overall survival. RESULTS: Median survival for the 25 patients was 9 months and median progression-free survival was 6 months. Thirty-two percent of patients survived in excess of 1 year. Analgesic requirements increased >50% in 2 patients and KPS deteriorated in 10 patients. Of the 13 remaining patients, 2 sustained a >7% weight loss and 2 gained weight post-treatment. Six patients improved in one parameter of analgesic consumption, weight loss or KPS without deteriorating in any others. Thus, the clinical benefit response index for 5-FU-radiation was 6/25 (24%). In terms of tumor response, 8 patients (44%) demonstrated a reduction in tumor volume post-treatment, 4 of whom (22%) experienced a >50% reduction. Four additional patients had radiologically stable disease. CONCLUSION: In this retrospective analysis, the clinical benefit response index for 5-FU-radiation was 24%, a value similar to the 23.8% reported for single agent gemcitabine. The median survival of 7 months was also similar to the 5.65 months reported for gemcitabine. The radiological partial response rate of 22% and the 1-year survival of 32% were higher for 5-FU-radiation than the reported values for gemcitabine. A randomized trial would be necessary to compare 5-FU-radiation to gemcitabine directly; however, from this review it did not appear that the overall palliative benefit of 5-FU-radiation was inferior to gemcitabine.

The role of medical organizations in supporting doctor-patient communication.

The clinical competence of physicians depends largely on the education, accreditation, certification and licensing programs offered by the various Canadian medical organizations. In virtually all of these, doctor-patient communication is a required element. Educational programs at all levels are subject to accreditation by a number of different organizations including undergraduate medical programs (Committee on Accreditation of Canadian Medical Schools), residency training (College of Family Physicians of Canada and Royal College of Physicians and Surgeons of Canada) and continuing medical education (CFPC and RCPSC). Doctor-patient communication is a key element in teaching at all levels. The two colleges also emphasize communications in the certification process. The provincial licensing authorities are aware of the importance of effective communication between physicians and patients. Several of the them have physician assessment programs, and recently they have started to assess a model of mandatory performance review. Both of these approaches assess physician-patient communication. There is increasing pressure, with strong support from consumers, that some level of communication skills competency should be imposed by the licensing authorities. Most approaches to exposing physicians to communications focus on rewards rather than coercion but a number of possible schemes could be considered to promote communication skills.

The use of gemcitabine in non-small-cell lung cancer. Provincial Lung Cancer Disease Site Group. Provincial Systemic Treatment Disease Site Group.

GUIDELINE QUESTION: Is there a role for the use of gemcitabine in the treatment of patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC)? OBJECTIVE: To make recommendations about the use of gemcitabine in the management of medically appropriate patients with stage IIIB-IV NSCLC. OUTCOMES: The outcomes of interest were survival, response rate, symptomatic response, response duration and toxicity. PERSPECTIVE (VALUES): Evidence was selected and reviewed by 2 members of the Provincial Lung Cancer Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The practice guideline report was reviewed by the Provincial Lung Cancer DSG and by the Systemic Treatment Disease Site Group. These committees comprise medical and radiation oncologists, surgeons, pathologists, nurses, a psychologist, a medical sociologist and administrators. One community representative participated in the development of this practice guideline. QUALITY OF EVIDENCE: Five phase II studies of single-agent gemcitabine in advanced NSCLC were reviewed. Four of these are published as full reports. Two randomized phase II studies comparing single-agent gemcitabine with etoposide plus cisplatin were also reviewed. One of these studies is fully published. Seven phase II studies of gemcitabine in combination with cisplatin and I phase II study of gemcitabine in combination with ifosfamide were reviewed. Three randomized controlled trials (RCTs) and 1 randomized phase II study, published in abstract form, compared gemcitabine combination chemotherapy with cisplatin combination chemotherapy. An additional phase II study, published in abstract form, of gemcitabine as salvage therapy in previously treated patients was also included. BENEFITS: Four phase II studies of single-agent gemcitabine at a dose of 1000 mg/m2 or more showed a combined response rate of 19% (intention-to-treat analysis; 95% confidence interval [CI] 15% to 24%) or 21% (efficacy analysis; 95% CI 17% to 26%) in advanced NSCLC. Median survival ranged from 7 to 9 months. Improvement from baseline in cough, hemoptysis and dyspnea was comparable to what would be expected with radiation therapy and with standard combination chemotherapy regimens. Improvement from baseline in their performance status was reported in 52% of treated patients. The 2 randomized phase II studies reported equivalent response rates for gemcitabine compared with etoposide plus cisplatin; the response data were pooled, which resulted in a nonsignificant benefit for gemcitabine (common odds ratio [OR] 0.90; 95% CI 0.43 to 1.90; p = 0.78). Gemcitabine has most frequently been combined with cisplatin, yielding a combined response rate of 44% (intention-to-treat; 95% CI 36% to 47%) or 45% (efficacy; 95% CI 39% to 51%) from 7 phase II studies. Median survival times ranged from 10 to 14 months. One phase II randomized study compared gemcitabine-cisplatin-vinorelbine vs. cisplatin-epirubicin-vindesine plus lonidamine and demonstrated a higher response rate (62% vs. 35%) in favour of the gemcitabine combination. Three RCTs demonstrated increased response rates for the combination of gemcitabine-cisplatin over either cisplatin alone or other combination regimens [(gemcitabine-cisplatin 35% vs. etoposide-cisplatin 12%; p = 0.001), (gemcitabine-cisplatin 31% vs. cisplatin 9%; p = 0.0001), (gemcitabine-cisplatin 40% vs. mitomycin, ifosfamide, cisplatin 28%; p = 0.03)]. HARMS: The major dose-limiting toxicity is neutropenia. Despite this, infection rates are low. Significant adverse effects that have an impact on the patient's quality of life or require the discontinuance of treatment are reported to be less than with any other single agent or combination of agents. Grade 3 or 4 dyspnea has been reported to occur in fewer than 2% of cases and may be drug related. (ABSTRACT TRUNCATED)