Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501).

BACKGROUND: In 2004, level I evidence was established for the postoperative adjuvant treatment of patients with selected high-risk locally advanced head and neck cancers, with the publication of the results of two trials conducted in Europe (European Organization Research and Treatment of Cancer; EORTC) and the United States (Radiation Therapy Oncology Group; RTOG). Adjuvant chemotherapy-enhanced radiation therapy (CERT) was shown to be more efficacious than postoperative radiotherapy for these tumors in terms of locoregional control and disease-free survival. However, additional studies were needed to identify precisely which patients were most suitable for such intense treatment. METHODS: Both studies compared the addition of concomitant relatively high doses of cisplatin (on days 1, 22, and 43) to radiotherapy vs radiotherapy alone given after surgery in patients with high-risk cancers of the oral cavity, oropharynx, larynx, or hypopharynx. A comparative analysis of the selection criteria, clinical and pathologic risk factors, and treatment outcomes was carried out using data pooled from these two trials. RESULTS: Extracapsular extension (ECE) and/or microscopically involved surgical margins were the only risk factors for which the impact of CERT was significant in both trials. There was also a trend in favor of CERT in the group of patients who had stage III-IV disease, perineural infiltration, vascular embolisms, and/or clinically enlarged level IV-V lymph nodes secondary to tumors arising in the oral cavity or oropharynx. Patients who had two or more histopathologically involved lymph nodes without ECE as their only risk factor did not seem to benefit from the addition of chemotherapy in this analysis. CONCLUSIONS: Subject to the usual caveats of retrospective subgroup analysis, our data suggest that in locally advanced head and neck cancer, microscopically involved resection margins and extracapsular spread of tumor from neck nodes are the most significant prognostic factors for poor outcome. The addition of concomitant cisplatin to postoperative radiotherapy improves outcome in patients with one or both of these risk factors who are medically fit to receive chemotherapy.

The impact of smoking status, disease stage, and index tumor site on second primary tumor incidence and tumor recurrence in the head and neck retinoid chemoprevention trial.

Second primary tumors (SPTs) develop at an annual rate of 3-7% in patients with head and neck squamous cell cancer (HNSCC). In a previous Phase III study, we observed that high doses of 13-cis-retinoic acid reduced the SPT rate in this disease. In 1991, we launched an intergroup, placebo-controlled, double-blind study to evaluate the efficacy of low-dose 13-cis-retinoic acid in the prevention of SPTs in patients with stage I or II squamous cell carcinoma of the larynx, oral cavity, or pharynx who had been previously successfully treated with surgery, radiotherapy, or both, and whose diagnoses had been established within 36 months of study entry. As of September 16, 1999, the Retinoid Head and Neck Second Primary (HNSP) Trial had completed accrual with 1384 registered patients and 1191 patients randomized and eligible. All of the patients were followed for survival, SPT development, and index cancer recurrence. Smoking status was assessed at study entry and during study. Smoking cessation was confirmed biochemically by measurement of serum cotinine levels. The annual rate of SPT development was analyzed in terms of smoking status and tumor stage. As of May 1, 2000, SPTs have developed in 172 patients. Of these, 121 (70.3%) were tobacco-related SPTs, including 113 in the aerodigestive tract (57 lung SPTs, 50 HNSCC SPTs, and 6 esophageal SPTs) and 8 bladder SPTs. The remaining 51 cases included 23 prostate adenocarcinomas, 8 gastrointestinal malignancies, 6 breast cancers, 3 melanomas, and 11 other cancers. The annual rate of SPT development observed in our study has been 5.1%. SPT development related to smoking status was marginally significant (active versus never, 5.7% versus 3.5%; P = 0.053). Significantly different smoking-related SPT development rates were observed in current, former, and never smokers (annual rate = 4.2%, 3.2%, and 1.9%, respectively, overall P = 0.034; current versus never smokers, P = 0.018). Stage II HNSCC had a higher overall annual rate of SPT development (6.4%) than did stage I disease (4.3%; P = 0.004). When evaluating the development of smoking-related SPTs, stage was also highly significant (4.8% for stage II versus 2.7% for stage I; P = 0.001). Smoking-related SPT incidence was significant for site as well (larynx versus oral cavity, P = 0.015; larynx versus pharynx, P = 0.011). Primary tumors recurred at an annual rate of 2.8% in a total of 97 patients. The rate of recurrence was higher in patients with stage II disease (4.1% versus 2.2%, P = 0.004) as well as oral cavity site when compared with larynx (P = 0.002). This is the first large-scale prospective chemoprevention study evaluating smoking status and its impact on SPT development and recurrence rate in HNSCC. The results indicate significantly higher SPT rates in active smokers versus never smokers and significantly higher smoking-related SPT rates in active smokers versus never smokers, with intermediate rates for former smokers.

A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003.

PURPOSE: The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial. The objective of this randomized trial was to test the efficacy of hyperfractionation and two types of accelerated fractionation individually against standard fractionation. METHODS AND MATERIALS: Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1. 2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive. RESULTS: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control (p = 0.045 and p = 0.050 respectively) than those treated with standard fractionation. There was also a trend toward improved disease-free survival (p = 0.067 and p = 0.054 respectively) although the difference in overall survival was not significant. Patients treated with accelerated fractionation with split had similar outcome to those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation. However, there was no significant increase of late effects. CONCLUSIONS: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.

College of American Pathologists Conference XXXV: solid tumor prognostic factors-which, how and so what? Summary document and recommendations for implementation. Cancer Committee and Conference Participants.

The College of American Pathologists convened a prognostic factor conference in June 1999 to consider prognostic and predictive factors in breast, colon, and prostate cancer, and to stratify these factors into categories reflecting the strength of published evidence. Because so little progress in prognostic factor clinical utility has been made in the last 5 years, the conference participants focused their attention on decreasing variation in methods, interpretation, and reporting of these factors so that greater clarity of value could be achieved. The conference was organized to promote discussion, broad input, and future planning. An initial plenary session provided an overview of the status of tumor marker research, the impact of variation in medicine and pathology, and statistical issues related to prognostic factor research. In working group sessions for each cancer type, participants interactively evaluated and refined the documents created by the expert panels. A second plenary session dealt with issues common to all 3 groups, including the problem of micrometastases in lymph nodes in these sites; statistical issues that arose during the breakout discussions; and issues of variation in methods, interpretation, and reporting of immunohistochemical assays. A faculty session brainstormed strategies that could be used to implement the changes recommended. This session included invited representatives of the Food and Drug Administration, Health Care Financing Administration, Centers for Disease Control and Prevention, National Cancer Institute, American Joint Committee on Cancer, and International Union Against Cancer. Cancer site and general recommendations were presented and discussed during a final session to achieve consensus of the conference participants and to address feasibility of implementation of these recommendations. A final discussion focused on future initiatives that might lead to implementation of the changes proposed in the conference by the various organizations represented. This report summarizes the general conference recommendations, cancer working group recommendations, and plans for implementation of the recommendations.

Prognostic factors in prostate cancer. College of American Pathologists Consensus Statement 1999.

BACKGROUND: Under the auspices of the College of American Pathologists, a multidisciplinary group of clinicians, pathologists, and statisticians considered prognostic and predictive factors in prostate cancer and stratified them into categories reflecting the strength of published evidence and taking into account the expert opinions of the Prostate Working Group members. MATERIALS AND METHODS: Factors were ranked according to the previous College of American Pathologists categorical rankings: category I, factors proven to be of prognostic importance and useful in clinical patient management; category II, factors that have been extensively studied biologically and clinically but whose importance remains to be validated in statistically robust studies; and category III, all other factors not sufficiently studied to demonstrate their prognostic value. Factors in categories I and II were considered with respect to variations in methods of analysis, interpretation of findings, reporting of data, and statistical evaluation. For each factor, detailed recommendations for improvement were made. Recommendations were based on the following aims: (1) increasing uniformity and completeness of pathologic evaluation of tumor specimens, (2) enhancing the quality of data collected pertaining to existing prognostic factors, and (3) improving patient care. RESULTS AND CONCLUSIONS: Factors ranked in category I included preoperative serum prostate-specific antigen level, TNM stage grouping, histologic grade as Gleason score, and surgical margin status. Category II factors included tumor volume, histologic type, and DNA ploidy. Factors in category III included perineural invasion, neuroendocrine differentiation, microvessel density, nuclear roundness, chromatin texture, other karyometric factors, proliferation markers, prostate-specific antigen derivatives, and other factors (oncogenes, tumor suppressor genes, apoptosis genes, etc).

Statistical issues in tumor marker studies.

CONTEXT: Inferences from tumor marker studies are complicated by a variety of statistical concerns, which can make proper interpretation of results difficult. This article focuses on important issues that should be addressed when designing, conducting, and analyzing tumor marker studies. OBJECTIVE: To highlight the importance of considering statistical significance, risk ratios, statistical power, reproducibility, multiple testing, confirmatory studies, and missing data in the design of marker studies used for prognosis. RESULTS: Suggestions are provided for more effectively conducting marker studies. These include more careful attention to adequacy of the number of subjects for a marker study and improved documentation and standardization of assay methods. The importance of complete reporting of study results and description of the statistical analysis methods used is also emphasized. CONCLUSION: Cooperation among clinicians, laboratory scientists, and statisticians will be required to conduct statistically sound tumor marker studies and to facilitate prioritizing markers for new and confirmatory studies in an environment of limited patient and specimen resources.

Statistical power for a long-term survival trial with a time-dependent treatment effect.

A time-dependent treatment effect is often observed in cancer clinical trials with survival endpoints, especially in long-term studies. This article evaluates the statistical power of the log-rank test when change point(s) in treatment effect are given. Following the work of Schoenfeld, we derive the asymptotic properties of the log-rank test statistics with time-dependent step-function alternatives. We show that the statistical power for such an alternative hypothesis is determined by the distribution of the number of events for given time intervals. Then, the relationship between the statistical power and the sample size, accrual, and minimum follow-up period can be established. Aided by the examples of two prostate cancer trials conducted by the Radiation Therapy Oncology Group, we demonstrate the changes in statistical power under various alternative hypotheses such as prolonged lag time and a declining treatment effect in long-term studies. Having examined the loss in statistical power by the interim analyses under the alternative hypothesis with a lag time, we recommend that the lower sequential boundary not be used in a long-term survival clinical trial. Control Clin Trials 2000;21:561-573

Methodology and research by the Radiation Therapy Oncology Group (RTOG).

The studies of the Radiation Therapy Oncology Group have contributed important evidence to improve the outcome of patients with cancer. The evidence has been compelling both to the scientific community and to practicing physicians a very large number of whom participated in the investigations. It is a tribute to the hard work of these many hundred volunteers that the studies mentioned above, and many other clinical investigations were completed, and patients throughout the world had improved outcomes.

Radiation Therapy Oncology Group (RTOG) trials for head and neck cancer.

Clinical investigations for cancer of the head and neck, primarily tumors of the upper respiratory and digestive tracts, have been one of the most important components of the Radiation Therapy Oncology Group (RTOG) since its inception 30 years ago. Emphasis from the very beginning to the present time has been on altered fractionation. Studies of hypoxic cell sensitizers were also explored for many years. More recently, combinations of radiation therapy with cytotoxic chemotherapeutic agents, either sequentially or concurrently, have been a major focus. Although the majority of the trials have been for unresectable tumors, surgical adjuvant radiation therapy alone or combined with chemotherapy has also been an important activity. Combined modality trials emphasizing organ conservation have been carried out within the last decade. The RTOG represents a national and international resource for studies of cancer of the head and neck. Its results influence the care of patients and the clinical research environment.

Failure of cricopharyngeal myotomy to improve dysphagia following head and neck cancer surgery.

OBJECTIVE: To determine whether cricopharyngeal myotomy can improve dysphagia associated with head and neck cancer surgery. DESIGN: Prospective, randomized, multicenter trial. SETTING: Twelve clinical sites across the United States. PATIENTS: Between 1989 and 1994, 125 patients undergoing combined modality therapy for head and neck cancer, including resection of the tongue base or supraglottic larynx, were prospectively entered into the trial. INTERVENTION: Cricopharyngeal myotomy on a randomized basis. MAIN OUTCOME MEASURES: Videofluoroscopic examination to determine oropharyngeal swallowing efficiency, which is defined as the ratio of percentage of the bolus swallowed to total swallowing time using 3 different bolus consistencies. RESULTS: No significant difference in oropharyngeal swallowing efficiency between myotomy vs no myotomy was seen at 6 months of follow-up regardless of bolus consistency. CONCLUSIONS: In this prospective test of cricopharyngeal myotomy, the procedure fails to significantly improve dysphagia associated with head and neck cancer surgery. The efficacy of this surgical procedure in other disease entities should also be rigorously explored.

Overexpression of p53 protein and outcome of patients treated with chemoradiation for carcinoma of the anal canal: a report of randomized trial RTOG 87-04. Radiation Therapy Oncology Group.

BACKGROUND: Despite encouraging results with chemoradiation as the primary means of managing carcinoma of the anal canal, approximately 20% of patients will develop a local recurrence. This study examined the prognostic significance of p53 nuclear protein overexpression in the pretreatment biopsies of patients treated with chemoradiation for epidermoid carcinoma of the anal canal. METHODS: All patients were treated in a prospective, randomized Radiation Therapy Oncology Group trial (RTOG 87-04) in which radiotherapy to the pelvis was compared with concurrent 5-fluorouracil (5-FU) or 5-FU and mitomycin-C. Formalin fixed, paraffin embedded blocks or unstained slides from the pretreatment biopsies of 64 patients were obtained from referring institutions and evaluated immunohistochemically with the polyclonal p53 antibody CM-1. A multivariate analysis was conducted to analyze overexpression of p53 in terms of locoregional control, no evidence of disease (NED), and overall survival. RESULTS: p53 protein was overexpressed in 48.4% of the cases. Although not statistically significant, there was a trend for patients whose tumors overexpressed p53 to have inferior locoregional control (52% vs. 72%, P = 0.13), NED survival (52% vs. 68%, P = 0.27), and absolute survival (58% vs. 78%, P = 0.14). Of all the pretreatment factors analyzed, only International Union Against Cancer stage was predictive of outcome in multivariate analysis. Among those patients whose tumors overexpressed p53, there was a trend toward improved outcome in the arm that received 5-FU and mitomycin-C compared with the arm that received 5-FU only. CONCLUSIONS: Overexpression of the p53 protein may be associated with inferior outcome for patients managed with definitive chemoradiation for epidermoid carcinoma of the anal canal.

Metastatic nonresectable fibrolamellar hepatoma: prognostic features and natural history.

Fibrolamellar hepatoma has a clinical course distinct from that of typical histologic hepatocellular carcinoma. The clinical behavior and prognostic features of nonresectable metastatic fibrolamellar hepatoma have not previously been fully addressed and are the focus of this report. Retrospective chart review of all patients (n = 17) with nonresectable metastatic fibrolamellar hepatoma referred to the Johns Hopkins Oncology Center from 1985 through 1990 was carried out. All patients had hepatic parenchymal involvement and regional node metastases at the time of referral. Metastases were limited to regional nodes in four patients. The remaining patients had lung metastases (n = 4), peritoneal metastases (n = 5), or both (n = 4). To assess the impact of the fibrolamellar variant, characteristic-matched control patients with typical histologic hepatocellular carcinoma were obtained from the Radiation Therapy Oncology Group database. Actuarial median survival from treatment was 14 months in the patients with fibrolamellar hepatoma and 7.7 months in the patients with hepatocellular carcinoma (p < 0.001). Karnofsky performance status and hepatic tumor volume at time of referral were important prognostic features. Multimodality treatment included radiation therapy and radiolabelled antibody, cisplatin-based chemotherapy, or both; results are discussed. Thirteen patients died, nine of liver failure, three of metastatic disease, and one of sepsis. Fibrolamellar histologic type, liver function tests, tumor volume, and patient performance status were significant predictors of survival. The cause of death in fibrolamellar hepatoma differs considerably from that observed in typical histologic hepatocellular carcinoma in the United States. The techniques of treatment of this uncommon disease were modeled after advances in the multimodality treatment of hepatocellular carcinoma and are discussed. Median survival was 14 months in patients with metastatic nonresectable fibrolamellar hepatoma.

Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer.

BACKGROUND: We performed a multi-institutional randomized trial comparing preoperative chemotherapy followed by surgery with surgery alone for patients with local and operable esophageal cancer. METHODS: Preoperative chemotherapy for patients randomly assigned to the chemotherapy group included three cycles of cisplatin and fluorouracil. Surgery was performed two to four weeks after the completion of the third cycle; patients also received two additional cycles of chemotherapy after the operation. Patients randomly assigned to the immediate-surgery group underwent the same surgical procedure. The main end point was overall survival. RESULTS: Of the 440 eligible patients with adequate data , 213 were assigned to receive preoperative chemotherapy and 227 to undergo immediate surgery. After a median possible study time of 55.4 months, there were no significant differences between the two groups in median survival: 14.9 months for the patients who received preoperative chemotherapy and 16.1 months for those who underwent immediate surgery (P=0.53). At one year, the survival rate was 59 percent for those who received chemotherapy and 60 percent for those who had surgery alone; at two years, survival was 35 percent and 37 percent, respectively. The toxic effects of chemotherapy were tolerable, and the addition of chemotherapy did not appear to increase the morbidity or mortality associated with surgery. There were no differences in survival between patients with squamous-cell carcinoma and those with adenocarcinoma. Weight loss was a significant predictor of poor outcome (P=0.03). With the addition of chemotherapy, there was no change in the rate of recurrence at locoregional or distant sites. CONCLUSIONS: Preoperative chemotherapy with a combination of cisplatin and fluorouracil did not improve overall survival among patients with epidermoid cancer or adenocarcinoma of the esophagus.

Precisely defining high-risk operable head and neck tumors based on RTOG #85-03 and #88-24: targets for postoperative radiochemotherapy?

BACKGROUND: Local-regional recurrence of disease remains the major obstacle to cure of advanced head and neck cancers. METHODS: This investigation reviewed data derived from Radiation Therapy Oncology Group (RTOG) protocols #85-03 and #88-24 to identify characteristics of tumors that predicted local-regional recurrence of disease following surgery and postoperative radiotherapy (RT). RESULTS: The presence of tumor in two or more lymph nodes, and/or extracapsular spread of nodal disease, and/or microscopic-size tumor involvement of the surgical margins of resection imparts a high risk of local-regional (L-R) relapse. Our data also support the hypothesis that, following surgery, the concurrent addition of chemotherapy (CT) to RT may increase the likelihood of L-R control of disease for patients who have these high-risk characteristics. CONCLUSION: A prospective trial of surgery followed by concurrent RT and CT is warranted for patients who have high-risk characteristics found at surgery.

Survival results among patients with alpha-fetoprotein-positive, unresectable hepatocellular carcinoma: analysis of three sequential treatments of the RTOG and Johns Hopkins Oncology Center.

PURPOSE: To analyze the observed therapeutic impact of the post-induction components of three treatment programs utilized sequentially between 1983 and 1991 for patients with unresectable alpha-fetoprotein-positive hepatoma. METHODS: Over a 7.5-year period, three treatment regimens were sequentially utilized: (1) RTOG 83-19, (2) a Johns Hopkins Oncology Center Institutional Pilot Program, and (3) RTOG 88-23. Each treatment program began with an induction phase of external-beam hepatic irradiation (2100 cGy/7 fractions), with concurrent doses of intravenous chemotherapy intended to be radiosensitizing. After induction, patients received cycles of one of the following: (1) intravenous doxorubicin and 5-fluorouracil (5-FU) with or without 131I-polyclonal antiferritin (RTOG 83-19); (2) intrahepatic artery cisplatin (Hopkins Institutional Pilot); or (3) intrahepatic artery cisplatin with or without 131I-polyclonal antiferritin (RTOG 88-23). Analysis of survival results was performed with multivariate and Cox regression methods. RESULTS: The addition of intravenous 131I-polyclonal antiferritin to post-induction cycles of either intravenous doxorubicin and 5-FU or intrahepatic artery cisplatin did not enhance survival. Intrahepatic artery cisplatin treatment yielded median survival duration of 9.1 months and survival at 12 and 24 months of 37% and 9%, respectively. These results were significantly superior to those resulting from use of intravenous doxorubicin and 5-FU (P = 0.0001; median survival duration 3.6 months; 12- and 24-month survival results 17% and 4%, respectively). A significant survival difference for the cisplatin regimen remained even when patients were stratified by previously identified prognostic factors and the results were appropriately adjusted. CONCLUSION: Patients with unresectable alpha-fetoprotein-positive hepatocellular carcinoma experienced improved survival and decreased toxicity when managed with post-induction cycles of intra-arterial cisplatin as compared with intravenous doxorubicin and 5-FU. Intravenous 131I-polyclonal antiferritin did not improve survival when added to either post-induction regimen but dramatically increased hematologic toxicities.