Randomized trial addressing risk features and time factors of surgery plus radiotherapy in advanced head-and-neck cancer.

PURPOSE: A multi-institutional, prospective, randomized trial was undertaken in patients with advanced head-and-neck squamous cell carcinoma to address (1) the validity of using pathologic risk features, established from a previous study, to determine the need for, and dose of, postoperative radiotherapy (PORT); (2) the impact of accelerating PORT using a concomitant boost schedule; and (3) the importance of the overall combined treatment duration on the treatment outcome. METHODS AND MATERIALS: Of 288 consecutive patients with advanced disease registered preoperatively, 213 fulfilled the trial criteria and went on to receive therapy predicated on a set of pathologic risk features: no PORT for the low-risk group (n = 31); 57.6 Gy during 6.5 weeks for the intermediate-risk group (n = 31); and, by random assignment, 63 Gy during 5 weeks (n = 76) or 7 weeks (n = 75) for the high-risk group. Patients were irradiated with standard techniques appropriate to the site of disease and likely areas of spread. The study end points were locoregional control (LRC), survival, and morbidity. RESULTS: Patients with low or intermediate risks had significantly higher LRC and survival rates than those with high-risk features (p = 0.003 and p = 0.0001, respectively), despite receiving no PORT or lower dose PORT, respectively. For high-risk patients, a trend toward higher LRC and survival rates was noted when PORT was delivered in 5 rather than 7 weeks. A prolonged interval between surgery and PORT in the 7-week schedule was associated with significantly lower LRC (p = 0.03) and survival (p = 0.01) rates. Consequently, the cumulative duration of combined therapy had a significant impact on the LRC (p = 0.005) and survival (p = 0.03) rates. A 2-week reduction in the PORT duration by using the concomitant boost technique did not increase the late treatment toxicity. CONCLUSIONS: This Phase III trial established the power of risk assessment using pathologic features in determining the need for, and dose of, PORT in patients with advanced head-and-neck squamous cell cancer in a prospective, multi-institutional setting. It also revealed the impact of the overall treatment time in the combination of surgery and PORT on the outcome in high-risk patients and showed that PORT acceleration without a reduction in dose by a concomitant boost regimen did not increase the late complication rate. These findings emphasize the importance of coordinated interdisciplinary care in the delivery of combined surgery and RT.

Local excision of T2 and T3 rectal cancers after downstaging chemoradiation.

OBJECTIVE: To evaluate the safety and efficacy of local excision in patients with T2 and T3 distal rectal cancers that have been downstaged by preoperative chemoradiation. SUMMARY BACKGROUND DATA: T2 and T3 cancers treated by local excision alone are associated with unacceptably high recurrence rates. The authors hypothesized that preoperative chemoradiation might downstage both T2 and T3 lesions and significantly expand the indications for local excision. METHODS: Local excision was performed after preoperative chemoradiation on patients with a complete clinical response or on patients who were either ineligible for or refused to undergo abdominoperineal resection. Local excision was approached transanally by removing full-thickness rectal wall and the underlying mesorectum. RESULTS: From 1994 to 2000, 95 patients with rectal cancers underwent preoperative chemoradiation and surgical resection for curative intent. Of these, 26 patients (28%), 19 men and 7 women, with a mean age of 63 years (range 44-90), underwent local excision. Pretreatment endoscopic ultrasound classifications included 5 T2N0, 13 T3N0, 7 T3N1, and 1 not done. Pathologic partial and complete responses were achieved in 9 of 26 (35%) and 17 of 26 (65%) patients, respectively. Two of nine partial responders underwent immediate abdominoperineal resection. The mean follow-up was 24 months (median 19, range 6-77). The only recurrence was in a patient who refused to undergo abdominoperineal resection after a partial response. There was one postoperative death from a stroke. This treatment was associated with a low rate of complications. CONCLUSION: Local excision appears to be an effective alternative treatment to radical surgical resection for a highly select subset of patients with T2 and T3 adenocarcinomas of the distal rectum who show a complete pathologic response to preoperative chemoradiation.

Combined chemo-radiotherapy for stage IV undifferentiated nasopharyngeal carcinoma.

Undifferentiated nasopharyngeal carcinoma is a chemosensitive lesion, but its role in the management of local advanced disease is under investigation. Twenty-seven untreated stage IV undifferentiated nasopharyngeal carcinoma patients were treated with radiotherapy (median dose, 66.6 Gy, 1.8 Gy/day) and concomitant cisplatin (100 mg/m2 days 1, 22 and 43). After 4 weeks, patients received, every 4 weeks, 3 cycles with cisplatin (80 mg/m2 day 1) + 5-fluorouracil (1,000 mg/m2/day continuous infusion for 96 h). After radiotherapy, we observed 74% complete responses and 26% partial responses; after adjuvant chemotherapy 96% had a complete and 4% a partial response. After a median follow-up of 36 months, 81% of the patients were alive (70% with no evidence of disease). Four-year overall and disease-free survival was 70% and 60%, respectively. Concomitant chemotherapy plus radiotherapy was well tolerated, whereas adjuvant chemotherapy was more toxic. Long-term results were significantly better than those observed with radiotherapy alone.

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.

Accelerated hyperfractionation for bronchogenic cancer: Radiation Therapy Oncology Group 9205.

RTOG 92-05 was a phase II trial developed to evaluate the feasibility, toxicity, and acceptance of a three times daily accelerated hyperfractionation radiation therapy schedule delivering 110 cGy, three times daily, to 79.2 Gy uncorrected tumor dose in 72 fractions, in 24 treatment days, in patients with bronchogenic cancer. The radiographically visible tumor received accelerated hyperfractionation and the other radiation volume received standard hyperfractionation. Three times a day, a dose of 110 cGy was delivered, with an interfractional interval of 4 hours; the middle fraction was a gross tumor boost. This schedule allowed treatment to be completed in approximately 4 1/2 weeks in an effort to minimize repopulation, to have a better biologically modeled therapeutic ratio than other schedules that have been completed in cooperative groups, and to use doses within cooperative group experience. In 33 months 35 patients were entered into the study; 15 of the patients had squamous cell carcinomas, 10 had adenocarcinomas, 8 had large-cell undifferentiated carcinomas, and 2 had unspecified non-small-cell cancers. Nineteen patients had AJCC stage IIIB; 13, IIIA; 14, T4; 10, T3; 13, N2; and 7, N3. Twenty-one patients (60%) had greater than 5% weight loss. The Karnofsky performance status was 90 to 100 in 12 patients and 70 to 80 in 23 patients. Treatment was completed in 91% of patients. Acute toxicity >RTOG grade II occurred in three patients: one skin, one lung, and two esophagus (one each III and IV, the only grade IV in the study). Overall late toxicity > or = grade III occurred in six patients: three lung, one thyroid, one esophagus, and one subcutaneous tissue (all grade III). The median survival was 10.5 months, 1-year survival was 42%, and 3-year survival was 18%. The outcome in this group of patients with many adverse prognostic variables compared favorably to prior RTOG radiation-alone studies.

Toxicity in head and neck cancer: a review of trends and issues.

The quest for improved fractionation and combined modality regimens in head and neck cancer has also yielded progressively higher rates of toxicity. Time compression of dose delivery in accelerated fractionation has produced high rates of severe mucositis including the early stoppage of two randomized trials. The addition of chemotherapy has introduced systemic toxicity and can exacerbate local tissue reactions when used concurrent with radiotherapy. Mucositis is recognized as the principal impediment to efforts at further treatment intensification. The development and utilization of standardized toxicity grading criteria and accepted reporting standards has lagged toxicity production, impeding a full appreciation of the true extent of both acute and late toxicity. Objective data regarding acute and chronic effects on organ function are also sorely lacking. A better characterization of the frequency, severity, and duration of the various toxicities encountered in head and neck cancer will also allow the rational development of toxicity interventions. New methods are needed to summarize the global or aggregate toxicity of a treatment program. Further research into the assessment and analysis of toxicity is not only crucial to improvements in quality of life (QOL), but perhaps, improved rates of disease control as well.

Common toxicity criteria: version 2.0. an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy.

In 1997, the National Cancer Institute (NCI) led an effort to revise and expand the Common Toxicity Criteria (CTC) with the goal of integrating systemic agent, radiation, and surgical criteria into a comprehensive and standardized system. Representatives from the Radiation Therapy Oncology Group (RTOG) participated in this process in an effort to improve acute radiation related criteria and to achieve better clarity and consistency among modalities. CTC v. 2.0 replaces the previous NCI CTC and the RTOG Acute Radiation Morbidity Scoring Criteria and includes more than 260 individual adverse events with more than 100 of these applicable to acute radiation effects. One of the advantages of the revised criteria for radiation oncology is the opportunity to grade acute radiation effects not adequately captured under the previous RTOG system. A pilot study conducted by the RTOG indicated the new criteria are indeed more comprehensive and were preferred by research associates. CTC v. 2.0 represents an improvement in the evaluation and grading of acute toxicity for all modalities.

Multimodality therapy of patients with locally advanced squamous cell cancer of the head and neck: preliminary results of two pilot trials using paclitaxel and cisplatin.

Chemotherapy has been integrated into the initial treatment of patients with locally advanced squamous cell cancer of the head and neck to improve locoregional control and survival. Two strategies for improving these outcomes are the use of new, potentially more effective drugs either with concurrent radiotherapy or as induction regimens. Because of its inherent activity against squamous cell cancer of the head and neck and its radiation-sensitizing properties, paclitaxel may be a valuable agent in the treatment of this patient population. We describe the preliminary results of two trials that evaluated the combination of paclitaxel and cisplatin in patients with locally advanced disease: a phase I trial of weekly paclitaxel and cisplatin with concurrent postoperative radiation therapy in patients with high-risk disease and a phase I/II trial of paclitaxel as a 96-hour infusion in combination with cisplatin as induction therapy. These studies identified tolerable doses of paclitaxel and cisplatin administered in these settings, with apparent clinical activity. These trials formed the basis for subsequent evaluation of induction paclitaxel and cisplatin followed by definitive radiotherapy and concurrent weekly paclitaxel and cisplatin plus radiotherapy.

Concurrent tirapazamine and radiotherapy for advanced head and neck carcinomas: a Phase II study.

PURPOSE: To evaluate the efficacy and toxicity of tirapazamine, a hypoxic cytotoxin, combined with conventional radiotherapy (RT) for advanced head and neck carcinomas. MATERIALS AND METHODS: From Oct. 1994 to Nov. 1996, 40 patients with stage III or IV carcinomas of the head and neck were enrolled in a Phase II trial to receive conventional RT (70 Gy in 7 weeks) with concurrent tirapazamine (159 mg/m2 intravenously, 3 times per week for 12 doses). One patient subsequently withdrew from the protocol treatment, and was excluded from analyses. Among the 39 cases, the primary sites were located in the oropharynx (n = 28), supraglottic larynx (n = 6), or hypopharynx (n = 5). Twenty-seven patients had T3 or T4, and 27 had N2 or N3 disease. RESULTS: Thirty-two (82%) patients received full 12 drug doses. Thirty-two patients (82%) received full 70 Gy of RT. The most frequent drug toxicities were muscle cramps (77%) and nausea/vomiting (62%), usually grade 1 or 2. Overall, 13 patients (33%) experienced grade 3 or 4 drug-related toxicities. No excessive RT-associated acute normal tissue reactions were observed. With a median follow-up of 13 months, the 1-year and 2-year local control rate was 64% and 59% respectively. CONCLUSION: The tirapazamine regimen was well tolerated with a compliance rate of 82%. The toxicity of RT with concurrent tirapazamine was acceptable in treating advanced head and neck carcinomas. The disease control trend was encouraging. Further clinical studies are warranted.

Development of a head and neck companion module for the quality of life-radiation therapy instrument (QOL-RTI)

PURPOSE/OBJECTIVE: A review of available head and neck quality of life (QOL) instruments reveals them to inadequately address important radiation related side effects, or to be too cumbersome for routine use. The purpose of this study was to develop a head and neck disease specific module as a companion to the previously developed quality of life - radiation therapy instrument (QOL-RTI). The goal was to create a more complete, yet concise, head and neck site-specific module geared toward patients receiving radiation therapy for head and neck cancer. METHODS AND MATERIALS: This exploratory study included 34 consecutive patients undergoing definitive radiotherapy over a 6-7 week course (60-79.8 Gy). We developed and administered a 14-item questionnaire to all eligible patients treated with radiotherapy for head and neck cancer who were not already registered in another research study assessing quality of life (e.g., RTOG). During the treatment period, the QOL-RTI general tool and the head and neck (H&N) module were administered as follows: at baseline, at week four (for test-retest), and at the end of the treatment period. For validation purposes the QOL-RTI/H&N was compared to the functional assessment cancer tool head and neck (FACT-H&N) questionnaire. The FACT-H&N was administered one time at week 4, on the same day as the QOL-RTI/H&N. This report includes the treatment phase of the study (during the course of radiation). RESULTS: Mean age was 62 years (range 40-75). Internal consistency of the module was satisfactory (Chronbach's alpha = 0.85). Test-retest yielded a correlation coefficient of 0.90 (p < 0.001). Concurrent validity, established by comparing the module to the FACT/H&N , yielded a correlation coefficient of 0.85. Significant changes in quality of life scores during a course of radiation was noted for both general quality of life tool and the site specific module. For the head and neck module, the difference in the mean baseline (7.17) and end of treatment scores (4.20) was 2.94, or 42% change (p < 0.0001). A smaller, yet still significant, difference in scores was seen in the general QOL tool (22 % change, p = 0.001). Item analysis of the module revealed statistically significant (p < 0.05) worsening in quality of life scores in the following areas: pain in throat, swallowing difficulty (meat/bread and liquids), changes in mucous and saliva, changes in taste, difficulty chewing, trouble with coughing, and speech difficulties. Items that were not significant were pain in the mouth, and appearance. CONCLUSION: These initial results suggest that the H&N companion module to the QOL-RTI is a valid and reliable tool that is responsive to changes in QOL during a course of H&N radiation therapy. This tool differs from existing H&N tools by including specific assessments of mucous, saliva, taste, cough, and local pain in a concise format. Significant changes in QOL scores were noted in all of these items. Evaluation of the tool in the post-treatment period (follow-up) is ongoing.

Suppression of fibroblast cell cycle progression in G1 phase by N-acetylcysteine.

The antioxidant N-acetyl-L-cysteine (NAC) has been increasingly used as an experimental tool to assess involvement of reactive oxygen species in cell signaling and is being evaluated as a preventive and therapeutic agent for cancer and pulmonary diseases related to inflammation and oxidative stress. However, a detailed characterization of the effect of NAC on cell cycle progression has not been reported. In the present study, modulation of cell cycle progression by NAC was analyzed in mouse fibroblast NIH3T3 cells grown in 10% fetal bovine serum. Complete inhibition of NIH3T3 cell proliferation was obtained with 20 mM NAC. Inhibition of cell proliferation by NAC (at or below 20 mM) was not due to cell death, and the antiproliferative effect of NAC was reversible. Flow cytometric analysis of cell cycle phase distribution indicated that NAC blocked the cell cycle in the G1 phase. Consistent with this observation, NAC inhibited DNA synthesis. After releasing the G1-block by NAC, S phase re-entry occurred between 8 and 12 h, suggesting that NAC blocked the cell cycle in early to mid-G1 phase. NAC prevented activation of mitogen-activated protein (MAP) kinases p42MAPK and p44MAPK and inhibited expression of cyclin D1, but had no effect on the levels of proliferating cell nuclear antigen. Incubation of cells with PD98059, a specific inhibitor of MAP kinase kinase 1, partially arrested the cell cycle in the G1 phase. These results indicate that the antiproliferative effect of NAC is linked in part to inhibition of the MAP kinase pathway.