Health utility scores from EQ-5D and health-related quality of life in patients with esophageal cancer: a real-world cross-sectional study.

Esophageal cancer and its treatment can cause serious morbidity/toxicity. These effects on health-related quality of life (HRQOL) can be measured using disease-specific scales such as FACT-E, generic scales such as EQ-5D-3L, or through symptoms. In a two-year cross-sectional study, we compared HRQOL across esophageal cancer patients treated in an ambulatory clinic and across multiple disease states, among patients with all stages of esophageal cancer. Consenting patients completed FACT-E, EQ-5D, a visual analog scale, and patient reported (PR)-ECOG. Symptom complexes were constructed from FACT-E domains. Responses were categorized by disease state: pre-, during, and post-treatment, surveillance, progression, and palliative chemotherapy. Spearman correlation and multivariable linear regression characterized these associations. In total, 199 patients completed 317 questionnaires. Mean FACT-E and subscale scores dropped from baseline through treatment and recovered during post-treatment surveillance (P < 0.001); EQ-5D health utility scores (HUS) displayed a similar pattern but with smaller differences (P = 0.07), and with evidence of ceiling effect. Among patients with stage II/III esophageal cancer, mean EQ-5D HUS varied across disease states (P < 0.001), along with FACT-E and subscales (P < 0.001). Among patients with advanced disease, there was no significant difference between baseline and on-treatment total scores, but improved esophageal cancer-specific scales were noted (P = 0.003). Strong correlation was observed between EQ-5D and FACT-E (R = 0.73), along with physical and functional subscales. In addition, the association between FACT-E and EQ-5D HUS was maintained in a multivariable model (P < 0.001). We interpret these results to suggest that in a real-world clinic setting, FACT-E, EQ-5D HUS, and symptoms were strongly correlated. Most HRQOL and symptom parameters suggested that patients had worse HRQOL and symptoms during curative therapy, but recovered well afterwards. In contrast, palliative chemotherapy had a neutral to positive impact on HRQOL/symptoms when compared to their baseline pre-treatment state.

Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC.

BACKGROUND: RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points. PATIENTS AND METHODS: Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored. RESULTS: At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1-26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0-29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9-1.6]. Median OS was 22.4 months (95% CI 18.6-33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8-33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9-1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences. CONCLUSIONS: Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals. CLINICAL TRIALS NUMBER: ClinicalTrials.gov identifier, NCT00903175.

Adjuvant sunitinib following chemoradiotherapy and surgery for locally advanced esophageal cancer: a phase II trial.

The prognosis for locally advanced esophageal cancer is poor despite the use of trimodality therapy. In this phase II study, we report the feasibility, tolerability and efficacy of adjuvant sunitinib. Included were patients with stage IIa, IIB or III cancer of the thoracic esophagus or gastroesophageal junction. Neoadjuvant therapy involved Irinotecan (65 mg/m2 ) + Cisplatin (30 mg/m2 ) on weeks 1 and 2, 4 and 5, 7 and 8 with concurrent radiation (50Gy/25 fractions) on weeks 4-8. Sunitinib was commenced 4-13 weeks after surgery and continued for one year. Sixty-one patients were included in the final analysis, 36 patients commenced adjuvant sunitinib. Fourteen patients discontinued sunitinib due to disease recurrence (39%) within the 12-month period, 12 (33%) discontinued due to toxicity, and 3 (8%) requested cessation of therapy. In the overall population, median survival was 26 months with a 2 and 3-year survival rate of 52% and 35%, respectively. The median survival for the 36 patients treated with sunitinib was 35 months and 2-year survival probability of 68%. In a historical control, a prior phase II study with the same trimodality therapy (n = 43), median survival was 36 months, with a 2-year survival of 67%. Initiation of adjuvant sunitinib is feasible, but poorly tolerated, with no signal of additional benefit over trimodality therapy for locally advanced esophageal cancer.

First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC.

BACKGROUND: Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design. METHODS: Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria. RESULTS: In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months. CONCLUSIONS: Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.

Neutrophil/lymphocyte ratio as a prognostic factor in biliary tract cancer.

BACKGROUND: Biliary tract cancers (BTCs) include intrahepatic (IHC), hilar, distal bile duct (DBD) and gallbladder carcinoma (GBC). Neutrophil/lymphocyte ratio (NLR), a marker of host inflammation, is prognostic in several cancers but has not been reviewed in large BTC series, or advanced BTC (ABTC) at diagnosis. PATIENTS AND METHODS: Baseline demographics and NLR at diagnosis were retrospectively evaluated in 864 consecutive patients with BTC treated from January 1987 to December 2012. The association between NLR and overall survival (OS) was determined using a multivariable Cox proportional hazards model. RESULTS: Eight hundred and sixty-four patients were included in the analysis, of which 62% had ABTC and 38% had surgery with curative intent. Median age was 65 years, 444 (51%) were male and 727 (84%) had performance status (PS) ⩽ 2. A NLR ⩾ 3.0, PS >2, IHC primary, stage, lack of surgery, haemoglobin <110 g/L and albumin <40 g/L were associated with significantly worse OS on multivariable analysis. A NLR ⩾ 3.0 was an independent prognostic factor for OS for the entire cohort; median OS was 21.6 months versus 12.0 months for patients with NLR <3.0 versus NLR ⩾ 3.0 respectively (adjusted hazard ratio (HR)-1.26, 95% confidence interval (CI); 1.06-1.50, P = 0.01). NLR was also prognostic in patients with ABTC (HR-1.26, 95% CI; 1.02-1.56, P = 0.035) and hilar cancer: overall group (N = 149) (HR-1.70, 95% CI; 1.10-2.50, P = 0.01) and advanced group (N = 111) (HR-1.57, 95% CI; 1.04-2.44, P = 0.048). CONCLUSION: Baseline NLR is a readily available and inexpensive prognostic biomarker in patients with BTC and likely warrants validation in large prospective clinical trials.

Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Abiraterone acetate (abiraterone) prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC). This study's objective was to retrospectively identify factors associated with prostate-specific antigen (PSA) response to abiraterone and validate them in an independent cohort. We hypothesized that the neutrophil/lymphocyte ratio (NLR), thought to be an indirect manifestation of tumor-promoting inflammation, may be associated with response to abiraterone. PATIENTS AND METHODS: All patients receiving abiraterone at the Princess Margaret (PM) Cancer Centre up to March 2013 were reviewed. The primary end point was confirmed PSA response defined as PSA decline ≥50% below baseline maintained for ≥3 weeks. Potential factors associated with PSA response were analyzed using univariate and multivariable analyses to generate a score, which was then evaluated in an independent cohort from Royal Marsden (RM) NHS foundation. RESULTS: A confirmed PSA response was observed in 44 out of 108 assessable patients (41%, 95% confidence interval 31%-50%). In univariate analysis, lower pre-abiraterone baseline levels of lactate dehydrogenase, an NLR ≤ 5 and restricted metastatic spread to either bone or lymph nodes were each associated with PSA response. In multivariable analysis, only low NLR and restricted metastatic spread remained statistically significant. A score derived as the sum of these two categorical variables was associated with response to abiraterone (P = 0.007). Logistic regression analysis on an independent validation cohort of 245 patients verified that this score was associated with response to abiraterone (P = 0.003). It was also associated with OS in an exploratory analysis. CONCLUSIONS: A composite score of baseline NLR and extent of metastatic spread is associated with PSA response to abiraterone and OS. Our data may help understand the role of systemic inflammation in mCRPC and warrant further research.

Outcomes of patients with metastatic renal cell carcinoma that do not meet eligibility criteria for clinical trials.

BACKGROUND: Targeted therapies in metastatic renal cell carcinoma (mRCC) have been approved based on registration clinical trials that have strict eligibility criteria. The clinical outcomes of patients treated with targeted agents but are ineligible for trials are unknown. PATIENTS AND METHODS: mRCC patients treated with vascular endothelial growth factor-targeted therapy were retrospectively deemed ineligible for clinical trials (according to commonly used inclusion/exclusion criteria) if they had a Karnofsky performance status (KPS) <70%, nonclear-cell histology, brain metastases, hemoglobin ≤9 g/dl, creatinine >2× the upper limit of normal, corrected calcium ≥12 mg/dl, platelet count of <100 × 10(3)/uL, or neutrophil count <1500/mm(3). RESULTS: Overall, 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials by the above criteria. Between ineligible versus eligible patients, the response rate, median progression-free survival (PFS) and median overall survival of first-line targeted therapy were 22% versus 29% (P = 0.0005), 5.2 versus 8.6 months, and 12.5 versus 28.4 months (both P < 0.0001), respectively. Second-line PFS (if applicable) was 2.8 months in the trial ineligible versus 4.3 months in the trial eligible patients (P = 0.0039). When adjusted by the IMDC prognostic categories, the HR for death between trial ineligible and trial eligible patients was 1.55 (95% confidence interval 1.378-1.751, P < 0.0001). CONCLUSIONS: The number of patients that are ineligible for clinical trials is substantial and their outcomes are inferior. Specific trials addressing the unmet needs of protocol ineligible patients are warranted.

Translating clinical trials to clinical practice: outcomes of men with metastatic castration resistant prostate cancer treated with docetaxel and prednisone in and out of clinical trials.

BACKGROUND: Multiple factors can influence outcomes of patients receiving identical interventions in clinical trials and in routine practice. Here, we compare outcomes of men with metastatic castrate-resistant prostate cancer (mCRPC) treated with docetaxel and prednisone in routine practice and in clinical trials. PATIENTS AND METHODS: We reviewed patients with mCRPC treated with docetaxel at Princess Margaret Cancer Centre. Primary outcomes were overall survival and PSA response rate. Secondary outcomes were reasons for discontinuation and febrile neutropenia. Outcomes were compared for men treated in routine practice and in clinical trials, and with data from the TAX 327 study. RESULTS: From 2001 to 2011, 438 men were treated, of whom 357 received 3-weekly docetaxel as first-line chemotherapy: 314 in routine practice and 43 in clinical trials. Trial patients were younger and had better performance status. Median survival was 13.6 months [95% confidence interval (95% CI) 12.1-15.1 months] in routine practice and 20.4 months (95% CI 17.4-23.4 months, P = 0.007) within clinical trials, compared with 19.3 months (95% CI 17.6-21.3 months, P < 0.001) in the TAX 327 study. PSA response rates were 45%, 54%, and 53%, respectively (P = NS). Reasons for treatment discontinuation were similar although trial patients received more cycles (median: 6 versus 8 versus 9.5, P < 0.001). Rates of febrile neutropenia were 9.6, 0, and 3% (P < 0.001) while rates of death within 30 days of last dose were 4%, 0%, and 3%, respectively (P = NS). CONCLUSIONS: Survival of patients with mCRPC treated with docetaxel in routine practice is shorter than for men included in trials and is associated with more toxicity.

Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy.

BACKGROUND: A subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria. METHODS: Data from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. RESULTS: One thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors. CONCLUSIONS: Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.

Multidisciplinary Canadian consensus recommendations for the management and treatment of hepatocellular carcinoma.

Globally, hepatocellular carcinoma (hcc) is the third most common cause of death from cancer, after lung and stomach cancer. The incidence of hcc in Canada is increasing and is expected to continue to increase over the next decade. Given the high mortality rate associated with hcc, steps are required to mitigate the impact of the disease. To address this challenging situation, a panel of 17 hcc experts, representing gastroenterologists, hepatologists, hepatobiliary surgeons, medical oncologists, pathologists, and radiologists from across Canada, convened to provide a framework that, using an evidence-based approach, will assist clinicians in optimizing the management and treatment of hcc. The recommendations, summarized here, were developed based on a rigorous methodology in a pre-specified process that was overseen by the steering committee. Specific topics were identified by the steering committee and delegated to a group of content experts within the expert panel, who then systematically reviewed the literature on that topic and drafted the related content and recommendations. The set of recommendations for each topic were reviewed and assigned a level of evidence and grade according to the levels of evidence set out by the Centre for Evidence-based Medicine, Oxford, United Kingdom. Agreement on the level of evidence for each recommendation was achieved by consensus. Consensus was defined as agreement by a two-thirds majority of the 17 members of the expert panel. Recommendations were subject to iterative review and modification by the expert panel until consensus could be achieved.

Capecitabine or infusional 5-fluorouracil for gastroesophageal cancer: a cost-consequence analysis.

BACKGROUND: In patients with advanced gastroesophageal cancer, the phase iii Randomized ECF for Advanced and Locally Advanced Esophagogastric Cancer 2 (real-2) trial demonstrated equivalent clinical efficacy when capecitabine (x) was substituted for 5-fluorouracil (5fu) in the epirubicin-cisplatin-5fu (ecf) regimen. The present analysis compares the direct medical costs associated with both regimens. METHODS: This cost-consequence analysis of direct medical costs took resource utilization data from the real-2 trial where available. Direct medical costs were derived from the perspective of the Canadian public health care system in 2008 Canadian dollars. Mean cost per patient on each treatment arm was calculated. RESULTS: Drug costs from start of treatment until first progression, including pre- and post-chemotherapy medications and administration costs, totalled $5,344 for ecx as compared with $3,187 for ecf. Costs for treatment of adverse events were estimated at $2,621 for ecx as compared with $3,397 for ecf. An additional cost of $873 was associated with insertion of an implanted venous access. Total incremental cost of ecx over ecf was $508. CONCLUSIONS: In advanced gastroesophageal cancer, capecitabine is an attractive alternative to 5fu. Although the drug cost per se is greater, use of capecitabine is associated with decreased consumption of hospital resources. Not only does capecitabine fit with patient preference for oral therapy, it also avoids the inconvenience and complications of central venous access.

Adjuvant chemoradiation for gastric cancer with infusional 5-fluorouracil and cisplatin: a phase I study.

OBJECTIVE: This phase I study aimed to determine the maximal tolerated dose of cisplatin administered every 2 weeks with infusional 5-fluorouracil (5FU) and concurrent radiation therapy (RT) in patients after complete resection of gastric adenocarcinoma. METHODS: Patients with resected stage IB to IV (M0) gastric adenocarcinoma were treated with 12 weeks of infusional 5FU (200 mg/m(2) daily) and with RT (45 Gy in 25 fractions starting on day 16). Cisplatin was administered in escalating doses (0, 20, 30, and 40 mg/m(2)) in weeks 1, 3, 5, and 7. In the final cohort, patients received an additional dose of cisplatin (40 mg/m(2)) in week 9. RESULTS: Among the 34 patients [median age: 56 years (range: 31-77 years)] who were assessable for toxicity, 5 experienced dose-limiting toxicities: 1 sepsis (cohort 1), 1 fatigue (cohort 2), 3 upper gastrointestinal toxicity (1 in cohort 2, 2 in cohort 5). Cohort 5 exceeded the maximal tolerated dose. Median follow-up was 2.5 years (range: 0.3-5 years). The 3-year overall and relapse-free survival rates were 86% and 71% respectively; median survival was not reached. CONCLUSIONS: Cisplatin was well tolerated in combination with infusional 5FU and RT, showing promising activity in the adjuvant treatment of gastric cancer. Infusional 5FU 200 mg/m(2) daily for 12 weeks with cisplatin 40 mg/m(2) in weeks 1, 3, 5, and 7 and with concurrent RT 45 Gy in 25 fractions, starting at day 16, is being explored in a phase II study at our institution.

Targeted therapies for renal cell carcinoma: more gains from using them again.

The development of molecularly targeted agents that inhibit pathways critical to the development of renal cell carcinoma has significantly improved outcomes in patients with these cancers. Compelling scientific and phase iii data have made the use of molecularly targeted agents the standard of care in first-line treatment. Now, available data show that re-treating patients with other tyrosine kinase inhibitors after they progress on sunitinib or sorafenib, or both, is beneficial. A large phase iii trial recently showed that, as compared with placebo, treatment with everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), almost halved the risk of progression (37% vs. 65%) and doubled the median progression-free survival (4 months vs. 2 months). Overall survival was not improved in that study, likely reflecting treatment crossover in the placebo arm, but these data position everolimus as the second-line standard of care. A consistent and growing body of literature also suggests that re-treatment with other kinase inhibitors that the patient has not previously encountered is a reasonable option. Outcomes of initial treatment with sunitinib or sorafenib (or both) should not deter the use of second-line targeted therapy, because the first-line use of targeted agents does not appear to be predictive of outcomes with second-line therapy. However, in view of poor absolute outcomes after second-line treatment and the benefits seen with rationally developed targeted agents in the first-line setting, enrolment of second- and subsequent-line patients in further trials would be preferable.

Managing toxicities and optimal dosing of targeted drugs in advanced kidney cancer.

The toxicities of new, targeted drugs may diminish their effectiveness in advanced kidney cancer if those toxicities are not recognized and properly addressed early in patient treatment. Most of the drug-related toxicities in advanced kidney cancer are manageable with supportive care, obviating a need for long interruptions, dose reductions, or permanent discontinuation of the treatment.

Transarterial chemoembolisation for advanced hepatocellular carcinoma: results from a North American cancer centre.

AIMS: In Asian countries, transarterial chemoembolisation (TACE) has long been used for palliation of unresectable hepatocellular carcinoma (HCC) without strong evidence of improved survival or quality of life. In 2002, a survival benefi of TACE was shown in two randomised controlled trials in Europe and Hong Kong. The effectiveness of interventions fo HCC is influenced by geographical factors related to diverse patient characteristics and protocols. Therefore, the validation of TACE as palliative modality for unresectable HCC requires confirmation in diverse patient populations. The aim of the present study was to assess the effectiveness of TACE for HCC in a North American population. MATERIALS AND METHODS: This was a single centre prospective cohort study. Child-Pugh A cirrhosis or better patients wit unresectable HCC and without radiological evidence of metastatic disease or segmental portal vein thrombosis wer assessed between November 2001 and May 2004. Of 54 patients who satisfied the inclusion criteria, 47 underwent 80 TACE sessions. Chemoembolisation was carried out using selective hepatic artery injection of 75 mg/m(2) doxorubicin and lipiodol followed by an injection of embolic particles when necessary. Repeat treatments were carried out at 2-3 month intervals for recurrent disease. The primary outcome was overall survival; secondary outcomes were morbidity and tumour response. RESULTS: The survival probabilities at 1, 2 and 3 years were 76.6, 55.5 and 50%, respectively. At 6 months after the first intervention, 31% of patients had a partial response and 60% had stable disease by RECIST criteria. Minor adverse events occurred after 39% of TACEs and major adverse events after 20% of sessions, including two treatment-related deaths (4% of patients). One patient had complete cancer remission after undergoing three TACE treatments. Further progression of tumour growth was prevented in 91% of tumours at the 6 month point after the first TACE. At 3 months, serum levels of the tumour marker alpha-feto protein were significantly reduced in patients with elevated levels before TACE. CONCLUSIONS: The survival probabilities at 1 and 2 years after TACE were comparable with results in randomised studies from Europe and Asia. Most patients tolerated TACE well, but clinicians need to be aware that moderately severe sideeffects require close monitoring and prompt intervention.

Gemcitabine concurrent with continuous infusional 5-fluorouracil in advanced biliary cancers: a review of the Princess Margaret Hospital experience.

BACKGROUND: Unresectable biliary tract cancer has a very poor prognosis. A combination of weekly gemcitabine plus continuous infusional 5-fluorouracil (5-FU) (GEM/CVI 5-FU) was evaluated as therapy for this cancer. PATIENTS AND METHODS: The charts of 27 patients with advanced biliary tract adenocarcinoma treated with GEM/CVI 5-FU at the Princess Margaret Hospital were evaluated for response, survival and toxicity. The treatment consisted of a 30-min infusion of gemcitabine at 900 mg/m(2) on days 1, 8 and 15 of a 28-day cycle plus 5-FU given via a peripherally inserted central line at 200 mg/m(2)/day continuously for 21 days, every 28 days. RESULTS: Objective responses were observed in nine patients (33%; 95% confidence interval 17% to 54%). An additional eight patients (30%) achieved stable disease for a median of 4 months (range 2.3-11). Median time to progression and overall survival were 3.7 and 5.3 months, respectively. Direct chemotherapy-related toxicity was mild, with only 11% grade > or =3 myelosuppression. Central venous catheter complications were common (26%). There were no treatment-related deaths. CONCLUSIONS: This study shows that GEM/CVI 5-FU is active and well tolerated in advanced and metastatic biliary tract cancers.

Treatment of hormone refractory prostate cancer.

Hormone refractory prostate cancer (HRPC) is a difficult clinical problem. These patients are intolerant of aggressive cytotoxic therapies because of their age and poor performance status. Systemic chemotherapy, whether administered as single agents or in multidrug combinations, has not been shown to prolong survival. It is only recently that palliative endpoints, such as quality of life analyses, have been formally evaluated in the clinical trials of HRPC. As a result, mitoxantrone plus prednisone has been demonstrated to be a useful palliative therapy that provides improvements in pain and quality of life for approximately 40% of those treated. Other promising regimens, such as the estramustine combinations or docetaxel, are currently undergoing phase III trials designed to prove superiority to mitoxantrone plus prednisone. Suramin has been extensively studied, but due to its poor activity seen in recent randomized trials, as well as the toxicity and inconvenience, it will likely not be further developed in HRPC. In recent years, there has been a tremendous increase in the development of biological targets for cancer therapy and a number of these are in early trials for HRPC. Given the relative insensitivity of prostate cancer to cytotoxic agents, this area holds much potential.