Biomedical subjects
Daniel G Haller
Publications and source records attributed to Daniel G Haller.
Chemotherapy for advanced pancreatic cancer.
Achieving substantial and meaningful improvements in the response and survival rates for advanced pancreatic cancer has proved to be an elusive goal for many years. 5-Fluorouracil (5-FU)-based chemotherapy has typically produced discouraging response rates or improved clinical benefit for patients, and attempts to improve these results by altering 5-FU dosages, administration schedules, or using a variety of drugs in combination with 5-FU have been unrewarding. A clinical benefit, however, was identified when gemcitabine first generated improvements in symptom control in patients with advanced disease. In a subsequent randomized trial, gemcitabine demonstrated superiority to 5-FU with respect to response rate, time to progression, and median survival. These improvements were also associated with improvement in clinical benefit. The findings of subsequent randomized Phase III trials have suggested a survival benefit for gemcitabine compared with several single agents or combinations. Gemcitabine has thus become the de facto standard of care for advanced pancreatic cancer, and current efforts are directed toward finding strategies that can capitalize on and extend these clinical benefits.
Rhabdomyolysis from cytochrome p-450 interaction of ketoconazole and simvastatin in prostate cancer.
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Accuracy of determining nodal negativity in colorectal cancer on the basis of the number of nodes retrieved on resection.
BACKGROUND: Correct determination of nodal status is pivotal to accurate staging and predicting survival. METHODS: This is a secondary analysis of INT0089, an intergroup trial of adjuvant chemotherapy for high-risk stage II and III colon cancer. A subset of patients was studied who underwent right or left hemicolectomy and from whom at least 10 lymph nodes were examined. A mathematical model was created to estimate the probability of a true negative result on the basis of the number of nodes examined. The number of nodes needed to predict nodal negativity with 85%, 50%, and 25% probability on the basis of tumor stage was calculated. RESULTS: In this analysis, 1585 patients were studied. The average number of nodes removed at surgery was comparable between treatment groups at 18.5 (median of 16 in all groups). With this model, when 18 nodes are removed at resection, there is a <25% probability of true node negativity in T1/T2 tumors, whereas <10 nodes need to be examined in T3 and T4 tumors to achieve the same probability. CONCLUSIONS: Tumor stage and the number of nodes retrieved at resection influence the accuracy of determining nodal status in colon cancer. Most patients are understaged. Underestimating nodal stage may influence decisions regarding adjuvant therapy, as well as overall prognosis.
Impact of T and N substage on survival and disease relapse in adjuvant rectal cancer: a pooled analysis.
PURPOSE: To determine the rates of survival and disease control by TNM and MAC stage in three randomized North American rectal adjuvant studies. MATERIALS AND METHODS: Data were merged from 2551 eligible patients on NCCTG 79-47-51 (n = 200), NCCTG 86-47-51 (n = 656), and INT 114 (n = 1695). All patients received postoperative radiation, and 96% were randomized to receive concomitant and maintenance chemotherapy. Five-year follow-up was available in 94% of patients and 7-yr follow-up in 84%. Kaplan-Meier curves were used to estimate the distribution of overall survival (OS) and disease-free survival (DFS), and p values were derived using the log-rank test. Time to local and distant relapse was estimated using cumulative incidence methodology. Analyses were adjusted for treatment effect using Cox proportional hazards models. RESULTS: OS and DFS were dependent on both TN stage and NT stage (N substage within T stage and T substage within N stage). Even among N2 patients (4 or more LN+), T stage influenced 5-yr OS (T1-2, 69%; T3, 48%; T4, 38%). Three risk groups of patients were defined: (1) intermediate: T3N0, T1-2N1; (2) moderately high: T4N0, T1-2N2, T3N1; and (3) high: T3N2, T4N1, T4N2. For Group 1, 5-yr OS was 74% and 81%, and 5-yr DFS was 66% and 74%. For Group 2, 5-yr OS ranged from 61% to 69%, and for Group 3, OS ranged from 33% to 48%. Cumulative incidence rates of local relapse and distant metastases revealed similar differences by TN and NT stage, as seen in the survival analyses. CONCLUSION: Patients with a single high-risk factor of either extension beyond the rectal wall (T3N0) or nodal involvement (T1-2N1) have improved OS, DFS, and disease control when compared to those with both high risk factors. Different treatment strategies may be indicated for intermediate- (T3N0, T1-2N1) vs. moderately high or high-risk patients in view of differential survival and rates of relapse. For future trial design, it may be preferable to perform separate studies, or a planned statistical analysis, for the "intermediate-risk" vs. the "moderately high" or "high-risk" subsets of patients.
Outcomes and toxicity in african-american and caucasian patients in a randomized adjuvant chemotherapy trial for colon cancer.
BACKGROUND: Previous studies have demonstrated that African-Americans with colon cancer have worse overall and stage-specific survival rates than Caucasians. Such differences could reflect variation in access to health care, in tumor biology, or in treatment efficacy. Little is known about potential differences in chemotherapy-related toxicities between African-Americans and Caucasians. In this study, we examined survival and toxic effects among African-American and Caucasian patients enrolled in a large, randomized phase III trial of adjuvant chemotherapy for resected colon cancer. METHODS: We analyzed data on 3380 patients (344 African-Americans and 3036 Caucasians) enrolled in a randomized trial of adjuvant 5-fluorouracil-based chemotherapy in patients with stage II (high risk) and stage III colon cancer to evaluate differences in outcomes and toxicity. We compared disease-free survival (DFS) and overall survival (OS) between African-Americans and Caucasians by the Kaplan-Meier method, computed Cox proportional hazards by multivariable analysis, and compared treatment-related toxicity rates by Fisher's exact test. All statistical tests were two-sided. RESULTS: We found no differences in DFS or OS between African-American and Caucasian patients. Five-year DFS was 57% (95% confidence interval [CI] = 52% to 62%) for African-Americans and 58% (95% CI = 56% to 60%) for Caucasians (P =.15), and 5-year OS was 65% (95% CI = 60% to 70%) for African-Americans and 66% (95% CI = 64% to 68%) for Caucasians (P =.38). On multivariable analysis, no statistically significant difference in disease recurrence or death was detected between the racial/ethnic groups (hazard ratios for African-Americans versus Caucasians: disease recurrence = 1.1, 95% CI = 0.9 to 1.3; death = 1.1, 95% CI = 0.9 to 1.3). Treatment-related toxicity differed between the African-American and Caucasian patients, with African-Americans experiencing statistically significantly lower rates of diarrhea (P<.001), nausea (P<.001), vomiting (P =.01), stomatitis (P<.001), and overall toxicity (P =.005). CONCLUSIONS: In this study of patients with similar access to health care resources and treatment with adjuvant chemotherapy, we found similar 5-year DFS and OS in African-Americans and Caucasians with stage II and III colon cancer. The two groups derived similar benefits from adjuvant chemotherapy. Moreover, African-Americans appeared to experience less treatment-related toxicity.
Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group Trial E2297.
PURPOSE: Gemcitabine is generally considered to constitute first-line therapy for pancreatic cancer. To determine whether the addition of fluorouracil (5-FU) improves on the results from single-agent gemcitabine, the Eastern Cooperative Oncology Group (ECOG) compared gemcitabine plus bolus 5-FU with gemcitabine alone for patients with advanced pancreatic carcinoma. PATIENTS AND METHODS: This trial involved patients with biopsy-proven, advanced carcinoma of the pancreas not amenable to surgical resection. Patients were randomized to receive either gemcitabine alone (1,000 mg/m(2)/wk) weekly for 3 weeks of every 4 or to receive gemcitabine (1,000 mg/m(2)/wk) followed by 5-FU (600 mg/m(2)/wk) weekly on the same schedule. The primary end point of the trial was survival, with secondary end points of time to progression and response rate. RESULTS: Of 327 patients enrolled over 18 months, 322 were eligible. Overall, the median survival was 5.4 months for gemcitabine alone and 6.7 months for gemcitabine plus 5-FU (P =.09). Progression-free survival for gemcitabine alone was 2.2 months, compared with 3.4 months for gemcitabine plus 5-FU (P =.022). Objective responses were uncommon and were observed in only 5.6% of patients treated with gemcitabine and 6.9% of patients treated with gemcitabine plus 5-FU. Most toxicities were hematologic or gastrointestinal; no significant differences were noted between the two treatment arms. CONCLUSION: 5-FU, administered in conjunction with gemcitabine, did not improve the median survival of patients with advanced pancreatic carcinoma compared with single-agent gemcitabine. Further studies with other combinations of gemcitabine and 5-FU are not compelling, and clinical trial resources should address other combinations and novel agents.
Surveillance for second primary colorectal cancer after adjuvant chemotherapy: an analysis of Intergroup 0089.
BACKGROUND: The incidence of second primary colorectal cancer in patients with a history of colon cancer, compared with patients with a history of adenomatous polyps, is unknown. It is unclear whether guidelines for colonoscopy screening in patients with polyps are appropriate for patients with previous colon cancer. OBJECTIVE: To determine the incidence of second primary colorectal cancer after treatment for localized colon cancer and to compare this incidence with that of first primary colorectal cancer in both the general population and high-risk patients. DESIGN: Historical cohort study. SETTING: An international, multi-institutional trial of adjuvant 5-fluorouracil-based chemotherapy for localized colon cancer. PATIENTS: 3278 patients with resected stage II and stage III colon cancer. MEASUREMENTS: Occurrence of endoscopic or radiologic colon surveillance and incidence of second primary colorectal cancer. RESULTS: Forty-two cases of second primary invasive colon cancer were found over 15 345 person-years of follow-up, yielding an incidence rate of 274 per 100 000 person-years (95% CI, 196 to 369 per 100 000 person-years) and a cumulative incidence of 1.5% (CI, 1.1% to 2.0%) at 5 years. This rate was compared with rates of first colon cancer in two reference groups: the general population and patients who had undergone frequent colonoscopy and polypectomy because of a history of adenomatous polyps; standardized incidence ratios were 1.6 (CI, 1.2 to 2.2) and 6.8 (CI, 2.7 to 22.0), respectively. CONCLUSION: The incidence of second primary colorectal cancer remains high despite intensive surveillance strategies.
Chemotherapy for colorectal cancer.
With effective chemotherapy as adjuvant treatment, the survival benefit is clearly achieved for certain (stage III) colorectal cancer patients, though there still exist many unsettled issues including the controversies in the treatment of stage II disease. Advances in the development of a new generation of cytotoxic agents in the past several years have allowed us to move forward from the "fluorouracil-only era" in the treatment of advanced/metastatic colorectal cancer. It is still not very clear how best to minimize toxicity without compromising efficacy of the combination therapy with newer agents, or how to maximize the benefit of chemotherapy (concurrent versus sequential). There are many current ongoing clinical trials designed to address these issues. With better understanding of the signal transduction and molecular biology characteristics of colorectal cancer, and the development of biologic and molecular target agents, the outcomes of patients with colorectal cancer will be improved further. Future clinical trials should be focused on optimizing and individualizing therapy for patients based on their molecular profiles to achieve maximal clinical benefit.
Future directions in the treatment of pancreatic cancer.
Fewer than 20% of patients with pancreatic cancer present with disease macroscopically confined to the pancreas, and approximately 40% already have locally advanced disease. Based on data from the Gastrointestinal Tumor Study Group, adjuvant therapy with radiation and 5-fluorouracil has become standard practice in the United States; however, in other countries, adjuvant treatment has not been as widely accepted. Other issues include the potential of neoadjuvant therapy and optimal systemic management. The issue of second-line therapy has also been raised in the treatment of pancreatic carcinoma, after the establishment of gemcitabine as a first-line standard treatment approach, in which it achieves a significant clinical benefit response. Other combination partners with gemcitabine under investigation include the antimetabolite 5-fluorouracil, the topoisomerase-I inhibitor irinotecan, the taxane docetaxel, the platinum oxaliplatin, the multitargeted antifolate pemetrexed, the farnesyl transferase inhibitor R-115777, the anti-HER2/neu antibody trastuzumab, and the epidermal growth factor inhibitor cetuximab. Combined-modality approaches with gemcitabine and radiation are also under active investigation.
Docetaxel in advanced gastric cancer.
Standard chemotherapy for advanced gastric cancer remains undefined. Two of the most popular regimens-ECF [epirubicin-cisplatin-5-fluorouracil (5-FU)] and PELF (cisplatin-epirubicin-5-FU-leucovorin)-have been shown to be active, but each has limitations. Phase II trials show that single-agent docetaxel is an active agent in advanced gastric cancer, producing overall response rates (ORRs) of 17.5-24%. Docetaxel has also been shown to lack cross-resistance with other drugs in gastric cancer, and is likely to be at least additive to cisplatin and 5-FU. Phase II results of docetaxel combinations in advanced gastric cancer are encouraging. Docetaxel-cisplatin has yielded response rates similar to those achieved by ECF and PELF. Adding 5-FU to docetaxel-cisplatin has achieved an ORR of 52 versus 45% for docetaxel-cisplatin in a randomized phase II trial. Docetaxel-based regimens demonstrate acceptable tolerability despite predictable hematotoxicity. Neutropenia, the major toxicity, is manageable by dose modification or by using prophylactic granulocyte colony stimulating factor. Several phase III trials are now ongoing, including a large-scale trial of docetaxel-cisplatin-5-FU versus cisplatin-5-FU. Results will show whether docetaxel improves overall response and survival, as suggested in the phase II setting.
A Phase I trial of the farnesyltransferase inhibitor L-778,123 and radiotherapy for locally advanced lung and head and neck cancer.
PURPOSE: Preclinical data have demonstrated that farnesyltransferaseinhibitors (FTIs) are radiation sensitizers in selected cell lines. The objective of this Phase I trial was to determine the maximally tolerated dose of the FTI L-778,123 in combination with radiotherapy in non-small cell lung cancer (NSCLC) and head and neck cancer (HNC). EXPERIMENTAL DESIGN: L-778,123 was given by continuous i.v. infusion and dose escalated in conjunction with standard radiotherapy. The presence of a ras mutation was not required for study entry. RESULTS: Nine patients (six NSCLC patients and three HNC patients) were enrolled on two dose levels of FTI. No dose-limiting toxicities were observed at the first dose level of 280 mg/m2/day during weeks 1, 2, 4, and 5 of radiotherapy. One episode of dose-limiting toxicity, grade IV neutropenia, was observed in one of three patients treated at 560 mg/m2/day during weeks 1, 2, 4, 5, and 7. No episodes of dose-limiting mucositis, esophagitis, or pneumonitis were observed. Of the four patients with NSCLC with evaluable disease, three patients had a complete response to treatment and one patient had a partial response. A complete clinical response to treatment was observed in two patients with HNC. In vitro studies in tumor cells obtained from a NSCLC patient on this trial showed radiosensitization with FTI and that tumor cells accumulated in G2-M after L-778,123 treatment. CONCLUSIONS: The combination of L-778,123 and radiotherapy at dose level 1 is associated with acceptable toxicity. Local responses have been observed in four NSCLC patients without a clear increase in radiotherapy-associated toxicities.