Five-year results of a phase II trial of hyperfractionated radiotherapy and concurrent daily cisplatin chemotherapy for stage III non-small-cell lung cancer

The purpose of this study was to evaluate the 5-year results for a phase II trial of hyperfractionated radiotherapy (RT) and concurrent daily cisplatin chemotherapy. Between August 1994 and December 1999, 63 patients with stage IIIA and stage IIIB non-small-cell lung cancer were treated with RT to a dose of 69.6 Gy at 1.2 Gy twice daily with daily cisplatin at 6 mg/m. Thirty-seven patients elected to receive consolidation carboplatin and paclitaxel chemotherapy. Recurrence and survival outcomes were evaluated by Kaplan-Meier analysis. Acute and late side effects were scored by the Radiation Therapy Oncology Group (RTOG) grading system. Radiographic complete or partial tumor response was achieved in 34 of 63 (54%) of cases. Median absolute survival was 20.1 months. Median time to local recurrence and distant metastases were 10.6 and 8.6 months, respectively. Overall survival rates were 57%, 35%, and 23% at 1, 3, and 5 years, respectively. Survival was significantly greater for patients receiving consolidation chemotherapy (50% versus 20% at 3 years). Only 5 patients (7%) experienced Grade 3 or 4 esophagitis. There were 16 cases of Grade 1 or 2 pneumonitis; steroid therapy resolved symptoms in 9 patients. This regimen of hyperfractionated RT and chemotherapy achieved significant response, and 5-year survival rates with acceptable toxicity.     

Late-course accelerated hyperfractionated radiotherapy for localized esophageal carcinoma

PURPOSE: To evaluate the long-term survival results and patterns of failure for localized carcinoma of the esophagus receiving late-course accelerated hyperfractionated (LCAF) radiotherapy (RT). METHODS AND MATERIALS: We studied 201 patients with histologically confirmed squamous cell carcinoma of the esophagus who were treated with LCAF RT between August 1994 and January 2000. The design of the radiation fields was based on the diagnosis by computed tomography and barium examination. All patients received conventionally fractionated RT at 1.8 Gy/d, five fractions weekly for the first two-thirds of treatment to a dose of about 41.4 Gy in 23 fractions within 4-5 weeks. This was followed by LCAF RT using reduced fields, 1.5 Gy/fraction twice daily with a 6-h interval between fractions, to a dose of about 27 Gy within 9 days. Thus, the total dose was 68.4 Gy in 41 fractions within 44 days. RESULTS: The incidence of Grade 3-5 acute radiation-induced bronchitis was 4.0% (8 cases), 3.0% (6 cases), and 0%, respectively. The incidence of Grade 3-5 acute radiation-induced esophagitis was 14.9% (30 cases), 0.5% (1 case), and 0%. Ten patients (5%) died of late complications. The 1-year, 3-year, and 5-year overall survival rate was 73%, 34%, and 26%, respectively. The 1-year, 3-year, and 5-year local control rate was 77%, 58%, and 56%, respectively. The main site of first failure was locoregional failure and distant metastasis (including lymph node metastasis from regional recurrence). Of 201 patients, 77 (38.4%) had local disease alone or with distant metastasis as the first failure, and 70 patients (34.9%) had distant metastasis and/or lymph node metastasis alone or with local failure as the first failure. CONCLUSION: The LCAF regimen offers similar local control and survival to standard chemotherapy plus RT, such as was delivered in the Radiation Therapy Oncology Group studies 85-01 and 94-05.     

Intravaginal high-dose-rate brachytherapy for Stage IB (FIGO Grade 1, 2) endometrial cancer

PURPOSE: To evaluate the outcome of patients with Stage IB Grades 1 and 2 endometrial cancer treated with adjuvant high-dose-rate intravaginal brachytherapy. METHODS AND MATERIALS: Between November 1987 and October 1999, 233 patients with Stage IB FIGO Grades 1 and 2 were treated with postoperative adjuvant high-dose-rate intravaginal brachytherapy. The median dose was 21 Gy in 7 Gy/fraction given at 2-week intervals. The mean age was 60 years. All patients underwent simple hysterectomy. Comprehensive surgical staging, defined as pelvic washing and pelvic and paraaortic lymph nodes sampling, was done in 9% of patients. Patients with FIGO Grade 3, papillary serous cancer, or clear-cell cancer were excluded from this analysis. Complications were assessed in terms of late Radiation Therapy Oncology Group toxicity (Grade > or =3) of the gastrointestinal tract, genitourinary tract, and vagina. RESULTS: With a median follow-up of 57 months, the 5-year vaginal/pelvic control, disease-free survival, and overall survival rate was 96% (95% confidence interval [CI] 94-99%), 94% (95% CI 91-98%), and 94% (95% CI 91-98%), respectively. The influence on outcome of age, grade (1 vs. 2), depth of invasion (one-third or less or greater than one-third), capillary space-like invasion, lower uterine segment involvement, and comprehensive surgical staging was evaluated. None of these factors significantly affected the rate of vaginal/pelvic control. Only age > or =60 years influenced the outcome for disease-free and overall survival. The 5-year rate for both disease-free and overall survival was 90% (95% CI 84-97%) for patients > or =60 years old compared with 99% (95% CI 96-100%) for those <60 years (p = 0.03 and 0.005, respectively). Of 233 patients, 3 (1%) developed Grade 3 or greater complications, with a 5-year actuarial rate of 2% (95% CI 0-5%). Two patients developed Grade 3 genitourinary toxicity, and 1 Grade 4 vaginal toxicity. CONCLUSION: On the basis of this retrospective study, adjuvant postoperative high-dose-rate intravaginal brachytherapy provides excellent outcomes and acceptable morbidity. These results compare very favorably with those reported in the literature using surgery alone or with pelvic radiation.     

Preliminary analysis of RTOG 9708: Adjuvant postoperative radiotherapy combined with cisplatin/paclitaxel chemotherapy after surgery for patients with high-risk endometrial cancer

PURPOSE: Patients with completely resected high-risk endometrial cancer have a risk of disease recurrence even with the addition of adjuvant pelvic radiotherapy (RT). A Phase II study was completed by the Radiation Therapy Oncology Group to assess the safety and toxicity of chemotherapy when combined with pelvic RT for these patients. METHODS AND MATERIALS: Eligibility requirements included a total abdominal hysterectomy and bilateral salpingo-oophorectomy with Grade 2 or 3 endometrial adenocarcinoma with >50% myometrial invasion, stromal invasion of the cervix, or pelvic-confined extrauterine disease. This study was designed to administer 4500 cGy in 25 fractions to the pelvis, along with cisplatin (50 mg/m(2)) on Days 1 and 28. Vaginal brachytherapy with a low-dose-rate applicator (1 x 20 Gy to the surface) or high-dose-rate applicator (3 x 6 Gy to the surface) was performed after external beam RT. Four courses of cisplatin (50 mg/m(2)) and paclitaxel (175 mg/m(2)) were given at 4-week intervals after RT completion. RESULTS: Forty-six patients were entered between October 1997 and April 1999. Two patients were ineligible (one with previous bladder cancer and one who had undergone surgery >8 weeks before the start of RT). Follow-up ranged from 6.9 to 48.8 months (median, 28.7 months). The disease was Stage III, II, and I in 66%, 16%, and 18% of patients, respectively. Two patients were not assessable because of incomplete treatment data. The protocol completion rate was 98% (41 of 42 assessable patients). Acute toxicity during RT/chemotherapy was Grade 1 in 27%, Grade 2 in 43%, Grade 3 in 27%, and Grade 4 in 2%. During adjuvant chemotherapy, the toxicity was Grade 1 in 7%, Grade 2 in 7%, Grade 3 in 21%, and Grade 4 in 62%. Severe toxicity was primarily hematologic. Chronic toxicity was Grade 1 in 20%, Grade 2 in 39%, Grade 3 in 16%, and Grade 4 in 2%, including 1 patient with a Grade 4 small bowel complication. At 24 months, the pelvic recurrence, regional recurrence, distant recurrence, disease-free survival, and overall survival rate was 2%, 3%, 17%, 83%, and 90%, respectively. CONCLUSION: This treatment protocol demonstrated an excellent treatment completion rate and expected toxicity. Longer follow-up is needed to assess the outcome. To assess the efficacy of this adjuvant treatment program, a Phase III trial (Radiation Therapy Oncology Group 9905) was designed with high-risk uterine-confined disease to be randomized between pelvic RT alone and pelvic RT with chemotherapy.     

An accelerated radiotherapy scheme using a concomitant boost technique for the treatment of unresectable stage III non-small cell lung cancer

BACKGROUND: We designed a phase II trial for evaluation of the efficacy and tolerability of an accelerated concomitant boost radiotherapy scheme for the treatment of the patients with non-small cell lung cancer (NSCLC). METHODS: Thirty patients with unresectable stage IIIA/IIIB NSCLC were prospectively enrolled in this protocol. All patients were scheduled to receive 15 fractions of conventional radiotherapy in doses of 1.8 Gy, to a total of 27 Gy. For the last 10 treatment days, an accelerated concomitant boost schedule was started that was composed of 1.8 Gy/fraction/day, 5 days/week to the large field and 1.8 Gy/fraction/day to the boost field 6 h apart, to a total dose of 63 Gy/35 fractions/5 weeks. RESULTS: Median follow-up time was 13 months (range, 5-50 months; 3-year overall, disease-free, loco-regional disease-free and metastasis-free survivals were 23%, 19%, 19% and 23%, respectively). The most common acute toxicity was esophagitis in 31% of patients with the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer (RTOG/EORTC) criteria grade 1, and in 54% with grade 2. Radiation pneumonitis developed in 16% of patients with RTOG/EORTC grade 1. Three-year actuarial rate of late pulmonary and skin-subcutaneous toxicity were 12% and 16%, respectively. No late radiotherapy complications of spinal cord or esophagus were recorded. CONCLUSION: Overall survival, local control and freedom from local progression were comparable with the results reported with pure hyperfractionated radiotherapy. The overall rate of acute and late toxicity was acceptable.     

Intravaginal brachytherapy alone for intermediate-risk endometrial cancer

PURPOSE: Despite the results of the Gynecologic Oncology Group trial No. 99 (GOG#99), some unanswered questions still remain about the role of adjuvant radiotherapy (RT) for intermediate-risk endometrial cancer. First, can intravaginal brachytherapy (IVRT) alone substitute for external beam RT but without added morbidity? Second, is the high-risk (HR) definition from GOG#99 a useful tool to predict pelvic recurrence specifically? The purpose of this study was to try to answer these questions in a group of patients with Stage IB-IIB endometrial carcinoma treated with high-dose-rate (HDR) IVRT alone. METHODS AND MATERIALS: Between November 1987 and December 2002, 382 patients with Stage IB-IIB endometrial carcinoma were treated with simple hysterectomy followed by HDR-IVRT alone at our institution. Comprehensive surgical staging (CSS), defined as pelvic washings and pelvic/paraaortic lymph node sampling, was performed in 20% of patients. The mean age was 60 years (range, 29-92 years). Lymphovascular invasion (LVI) was present in 14% of patients. The median HDR-IVRT dose was 21 Gy (range, 6-21 Gy), given in three fractions. Complications were assessed in terms of late Radiation Therapy Oncology Group (Grade 3 or worse) toxicity of the GI tract, genitourinary GU tract, and vagina. RESULTS: With a median follow-up of 48 months, the 5-year vaginal/pelvic control rate was 95% (95% confidence interval [CI], 93-98%). On multivariate analysis, a poor vaginal/pelvic control rate correlated with age > or =60 years old (relative risk [RR], 3, 95% CI, 1-12; p = 0.01), International Federation of Gynecology and Obstetrics (FIGO) Grade 3 (RR, 9, 95% CI, 2-35; p = 0.03), and LVI (RR, 4, 95% CI, 1-13; p = 0.051). The depth of myometrial invasion and CSS, however, were not significant. With regard to pelvic control specifically, the presence of GOG#99 HR features did not affect the pelvic control rate. The 5-year rate for HR patients was 96% (95% CI, 90-100%) vs. 96% (95% CI, 94-99%) for those without HR disease (p = 0.48). Even when the CSS effect was taken into account, the influence of HR features on pelvic control was still not significant (p = 0.51). In contrast, pelvic control was significantly influenced when patients were grouped according to CSS and stage/grade substages. For those with Stage IB Grade 3-IIB and no CSS, the 5-year pelvic control rate was 86% compared with 97% for those with Stage IB Grade 3-IIB and CSS, 97% for Stage IB, Grade 1-2 without CSS, and 100% for those with Stage IB, Grade 1-2 and CSS (p = 0.027). The 5-year disease-free survival rate was 93% (95% CI, 90-96%). On multivariate analysis, poor disease-free survival correlated with age > or =60 years (RR, 5; 95% CI, 1-18; p = 0.002), FIGO Grade 3 (RR 5, 95% CI 2-17; p = 0.013), and LVI (RR 3, 95% CI 1-8; p = 0.054). Unlike pelvic control, disease-free survival was significantly affected by GOG#99 HR features, with a 5-year rate of 87% (95% CI, 76-99%) vs. 94% (95% CI, 91-97%) for those without HR features (p = 0.027). The 5-year overall and disease-specific survival rate was 93% and 97%, respectively. The overall 5-year actuarial rate of Grade 3 or worse complications was 1% (95% CI, 0-2%). CONCLUSION: Tumor grade, depth of invasion, and the use of CSS were better predictors of pelvic control than the GOG#99 HR factors. IVRT alone seemed to provide adequate tumor control with very low morbidity. Therefore, it seems prudent to consider it for intermediate-risk patients because of its superior therapeutic ratio compared with that for surgery alone or pelvic RT. Additional follow-up, however, with a larger number of patients is needed, especially for those with LVI.     

Toxic cure: Hyperfractionated radiotherapy with concurrent cisplatin and fluorouracil for Stage III and IVA head-and-neck cancer in the community

PURPOSE: To evaluate efficacy and toxicity of the Duke University chemoirradiation regimen for locally advanced head-and-neck cancer in a regional community cancer center. METHODS AND MATERIALS: Between June 1998 and June 2002, 50 patients with Stage III or IVA squamous cell carcinoma of the head and neck were treated definitively with concurrent combined modality therapy (CMT). Patients received accelerated, hyperfractionated radiotherapy (AFRT), 1.2-1.25 Gy b.i.d., to a median prescribed dose of 70 Gy. Chemotherapy consisted of cisplatin 12 mg and fluorouracil 600 mg/m(2) daily for 5 consecutive days during Weeks 1 and 6, followed by two cycles after AFRT. Patients with N2-N3 neck disease (n = 21; 42%) were considered for neck dissection depending on their response to AFRT and chemotherapy. Twenty-nine patients with Stage III and IVA disease treated between 1991 and 1997 with definitive RT alone served as historical controls. RESULTS: Forty-nine patients (98%) in the CMT group completed the prescribed AFRT and 38 (76%) completed four cycles of chemotherapy. Three of 8 patients who underwent neck dissection had a pathologically complete response. The median follow-up for all patients was 23 months. The actuarial progression-free survival rate at 2 years was 75% for the CMT group vs. 40% (p <0.01) for the RT group. The overall survival rate was 80% and 43% (p <0.01), respectively, for the CMT and RT groups. Acute Radiation Therapy Oncology Group Grade 3 toxicities for the CMT group were mucosal (n = 50; 100%), skin (n = 9; 18%), and hematologic (n = 3; 6%). Late Grade 3-4 toxicities consisted of pharyngeal stricture (n = 7; 14%), laryngeal chondritis (n = 3; 6%), osteoradionecrosis (n = 2; 4%), and peripheral neuropathy (n = 1; 2%). CONCLUSION: This aggressive regimen of AFRT with concurrent cisplatin and fluorouracil with or without neck dissection is feasible in the community setting for patients with Stage III and IVA head-and-neck cancer. Early results indicated excellent survival, albeit with universal acute mucosal, and considerable, although acceptable, late toxicity.     

Results of radiotherapy for T2N0 glottic carcinoma: does the "2" stand for twice-daily treatment?

PURPOSE: Radiotherapy (RT) is often the therapy of choice for patients with Stage T2 glottic carcinoma. This retrospective study updated the results of RT for patients treated at our center. The primary focus of this study was whether a policy of using hyperfractionated RT for these patients resulted in a therapeutic gain.METHODS AND MATERIALS: A search of the database of patients treated in the Department of Radiation Oncology at The University of Texas M. D. Anderson Cancer Center was performed to identify patients with Stage T2 glottic carcinoma treated with RT alone between 1970 and 1998. A total of 230 patients formed the study cohort.RESULTS: The median follow-up for all patients was 82 months. Of the 230 patients, 180 were treated with parallel-opposed fields, and the median field size was 30 cm(2). Eighty-one patients (36%) were treated with twice-daily fractionation to 74-80 Gy. Eighty-nine patients (38%) were treated with 32-75 Gy at 2-Gy per fraction once daily, and 57 patients (25%) were treated with 2.06-2.26 Gy, once daily, to 66-70 Gy. The 2- and 5-year actuarial local control rate was 75% and 72%, respectively. After salvage therapy, the ultimate 5-year local control and disease-specific survival rate was 91% and 92%, respectively. The presence of subglottic extension and treatment with a daily dose of < or =2 Gy were associated with poorer local control (p <0.01) on both univariate and multivariate analyses. The 5-year local control rate for patients treated with twice-daily and once-daily RT was 79% and 67%, respectively (p = 0.06).CONCLUSION: The 5-year local control rates with hyperfractionated RT for Stage T2 glottic carcinoma approach 80%. Patients treated with twice-daily fractionation to a median dose of 77 Gy had an improvement in local control compared with patients treated with 70 Gy in 35 fractions. The Radiation Therapy Oncology Group is testing these two fractionation schedules in a randomized study. High control rates were also seen in selected patients treated with hypofractionated schedules, leaving the question of the optimal schedule for patients with Stage T2 disease unanswered.     

High-dose whole abdominal and pelvic irradiation for treatment of ovarian carcinoma: long-term toxicity and outcomes

PURPOSE: To evaluate the role of high-dose whole abdominal and pelvic irradiation (WART) in the treatment of epithelial ovarian carcinoma. METHODS AND MATERIALS: A retrospective review was performed on 71 patients with Stage I-III ovarian carcinoma who were treated with WART using an open field technique after total abdominal hysterectomy and bilateral oophorectomy with or without omentectomy. Whole abdominal doses greater than typically recommended were used in a series of patients to enhance local control and to decrease abdominal recurrence. None of the patients had received chemotherapy before RT. Thirty-one patients received Alkeran or cyclophosphamide and two received cisplatin-based chemotherapy after WART. The median whole abdominal dose was 36 Gy (range 9-45.5), delivered in a median of 30 fractions (range 8-46). A pelvic boost was delivered using AP-PA fields during whole abdominal RT to a total midline pelvic dose of 200 cGy/d. The median pelvic dose was 51 Gy (range 16-59). The right lobe and a portion of the left lobe of the liver were shielded with custom blocks at a median dose of 25 Gy (range 9-41). The kidneys were shielded either AP-PA or PA from the first day of RT. The median dose to the kidneys was 19 Gy (range 4-30). RESULTS: The 5-year overall survival rate was 93%, 48%, and 29% for Stage I, II, and III patients, respectively. On multivariate analysis, stage and the extent of residual disease were independent prognostic factors. The 5- and 10-year overall survival rate for the 46 patients in the intermediate-risk group was 61% and 54%, respectively. For this group, a total abdominal dose of > or /=36 Gy was associated with a longer overall survival independent of stage, grade, and the amount of residual disease. This was most likely due to a significant reduction in the incidence of abdominal recurrence in patients receiving >36 Gy to the whole abdomen (18% vs. 49%, p = 0.006). Multivariate analysis revealed that grade (p = 0.023) and abdominal dose (p = 0.018) were independent factors influencing the rate of abdominal recurrence. Pelvic recurrence was rare as a first site of failure (6%). Twenty-one percent (n = 15) of the patients developed Grade 3 or 4 (Radiation Therapy Oncology Group [RTOG] criteria) chronic small or large bowel toxicity. Eleven percent of all patients had a small bowel obstruction requiring surgery. A whole abdominal dose >30 Gy and a pelvic dose >50 Gy were associated with a significant increase in small bowel obstruction (p = 0.01) independent of other factors. Chronic Grade 3 or 4 (Common Toxicity Criteria) anemia, thrombocytopenia, and leukopenia were seen in 7%, 1%, and 4% of the patients, respectively. Transient liver enzyme elevation was common (62%). Two patients had Grade 3 (RTOG) hepatic toxicity. Grade 3 or 4 renal toxicity (RTOG) was observed in 4%, and 2 patients (3%) were diagnosed with pelvic insufficiency fractures that were managed conservatively. CONCLUSION: Survival after RT for ovarian carcinoma rivals that achieved with systemic chemotherapy. The results of this study suggest a possible dose-control relationship between the whole abdominal dose and the risk of abdominal recurrence; however, a higher rate of small bowel obstruction was observed when greater abdominal doses and greater pelvic doses were combined. Careful attention to balancing toxicity and efficacy is imperative if RT is to have a future role in the treatment of this disease.     

Neoadjuvant radiochemotherapy for locally advanced gastric cancer: long-term results of a phase I trial

PURPOSE: To assess the long-term results of radiation therapy (RT) when added preoperatively to systemic chemotherapy in patients with locally advanced gastric cancer. METHODS AND MATERIALS: Patients presenting with T3-4 or N+ gastric cancer received two cycles of cisplatin 100 mg/m2 d1, 5FU 800 mg/m2 d1-4, and Leucovorin 60 mg twice daily d1-4; one cycle before and one concomitantly with hyperfractionated RT (median dose, 38.4; range, 31.2-45.6 Gy). All patients underwent a total or subtotal gastrectomy with D2 lymph node resection. RESULTS: Nineteen patients were accrued and 18 completed the neoadjuvant therapeutic program. All patients were subsequently operated and no fatality occurred. At a mean follow-up of 8 years for the surviving patients, no severe late toxicity was observed. The 5-year locoregional control, disease-free, and overall survival were of 85%, 41%, and 35%, respectively. The peritoneum was the most frequent site of relapse. Among long terms survivors, no severe (Radiation Therapy Oncology Group Grade 3-4) late complication was reported. CONCLUSIONS: The present neoadjuvant treatment does not seem to increase the operative risk, nor the late side effects. The encouraging locoregional control rate suggests that the neoadjuvant approach should be considered for future trials in locally advanced gastric cancer. Also, the frequency of peritoneal recurrence stresses the need for a more efficient systemic or intraperitoneal treatment.     

Can concomitant-boost accelerated radiotherapy be adopted as routine treatment for head-and-neck cancers? A 10-year single-institution experience

PURPOSE: Accelerated schedules are effective in overcoming repopulation during radiotherapy (RT) for head-and-neck cancers, but their feasibility is compromised by increased toxicity. The therapeutic ratio may be particularly favorable for 5-week regimens. This study reports the 10-year experience of a single institution in the routine use of concomitant boost RT as standard radical treatment in all but the most favorable stage patients. METHODS AND MATERIALS: Between February 1991 and June 2001, 296 patients (mean age, 59 years) were treated with concomitant boost RT either alone (67%) or combined with cisplatin-based chemotherapy (33%), with a median tumor dose of 69.9 Gy. Tumors were located in the oropharynx in 52%, hypopharynx in 20%, larynx in 15%, nasopharynx in 7%, and oral cavity in 6%. International Union Against Cancer Stage III-IV disease represented 77% of tumors. The median follow-up for surviving patients was 55 months (range, 10-138 months). RESULTS: The RT schedule was completed to the prescribed dose in all but 1 patient. Twenty patients (7%) had a treatment interruption (median, 5 days; range, 2-35 days). Grade 3-4 Radiation Therapy Oncology Group acute toxicity was observed in 77% of patients, and nutritional support was required in 110 patients (37%). For all patients, the 5-year actuarial locoregional control and disease-free survival rate was 72% and 61%, respectively. In a multivariate analysis, only T and N stage was significantly associated with locoregional control and disease-free survival. Grade 3-4 late toxicity occurred in 14%, mostly bone and cartilage necrosis. CONCLUSIONS: The present, moderately accelerated, concomitant boost regimen is logistically feasible, causing minimal inconvenience to the technical staff and yielding a high rate of patient compliance. Concomitant chemotherapy administration is feasible provided that patients are carefully selected and supportive care is introduced in a timely fashion. Considering the manageable toxicity and the satisfactory tumor control obtained, this regimen represents a good choice when considering implementation of an altered RT fractionation schedule as standard treatment for head-and-neck cancers.     

Postoperative radiotherapy for Stage 1 endometrial carcinoma: long-term outcome of the randomized PORTEC trial with central pathology review

PURPOSE: In 2000, the results of the multicenter Post Operative Radiation Therapy in Endometrial Carcinoma (PORTEC) trial were published. This trial included 714 Stage I endometrial carcinoma patients randomly assigned to postoperative pelvic radiotherapy (RT) or no further treatment, excluding those with Stage IC, Grade 3, or Stage IB, Grade 1 lesions. Radiotherapy significantly decreased the risk of locoregional recurrence (4% vs. 14%), without affecting overall survival. In this report the long-term outcome and results with central pathology review are presented. METHODS AND MATERIALS: The slides of 569 patients (80%) could be obtained for pathology review. Median follow-up for patients alive was 97 months. Analysis was done according to the intention-to-treat principle. The primary study endpoints were locoregional recurrence and death. RESULTS: Ten-year locoregional relapse rates were 5% (RT) and 14% (controls; p < 0.0001), and 10-year overall survival was 66% and 73%, respectively (p = 0.09). Endometrial cancer related death rates were 11% (RT) and 9% (controls; p = 0.47). Pathology review showed a substantial shift from Grade 2 to Grade 1, but no significant difference for Grade 3. When cases diagnosed at review as Grade 1 with superficial myometrial invasion were excluded from the analysis, the results remained essentially the same, with 10-year locoregional recurrence rates of 5% (RT) and 17% (controls; p < 0.0001). CONCLUSIONS: In view of the significant locoregional control benefit, radiotherapy remains indicated in Stage I endometrial carcinoma patients with high-risk features for locoregional relapse.     

High-dose-rate brachytherapy in uterine cervical carcinoma

PURPOSE: High-dose-rate (HDR) brachytherapy is in wide use for curative treatment of cervical cancer. The American Brachytherapy Society has recommended that the individual fraction size be <7.5 Gy and the range of fractions should be four to eight; however, many fractionation schedules, varying from institution to institution, are in use. We use 9 Gy/fraction of HDR in two to five fractions in patients with carcinoma of the uterine cervix. We found that our results and toxicity were comparable to those reported in the literature and hereby present our experience with this fractionation schedule. METHODS AND MATERIALS: A total of 121 patients with Stage I-III carcinoma of the uterine cervix were treated with HDR brachytherapy between 1996 and 2000. The total number of patients analyzed was 113. The median patient age was 53 years, and the histopathologic type was squamous cell carcinoma in 93% of patients. The patients were subdivided into Groups 1 and 2. In Group 1, 18 patients with Stage Ib-IIb disease, tumor size <4 cm, and preserved cervical anatomy underwent simultaneous external beam radiotherapy to the pelvis to a dose of 40 Gy in 20 fractions within 4 weeks with central shielding and HDR brachytherapy of 9 Gy/fraction, given weekly, and interdigitated with external beam radiotherapy. The 95 patients in Group 2, who had Stage IIb-IIIb disease underwent external beam radiotherapy to the pelvis to a dose of 46 Gy in 23 fractions within 4.5 weeks followed by two sessions of HDR intracavitary brachytherapy of 9 Gy each given 1 week apart. The follow-up range was 3-7 years (median, 36.4 months). Late toxicity was graded according to the Radiation Therapy Oncology Group criteria. RESULTS: The 5-year actuarial local control and disease-free survival rate was 74.5% and 62.0%, respectively. The actuarial local control rate at 5 years was 100% for Stage I, 80% for Stage II, and 67.2% for Stage III patients. The 5-year actuarial disease-free survival rate was 88.8% for Stage I, 76.52% for Stage II, and 50.4% for Stage III patients. Local failure occurred in 2 (11.1%) of the 18 Group 1 patients and in 20 (21.0%) of the 95 Group 2 patients. Distant failure occurred in none of the Group 1 patients and in 8 (8.4%) of the 95 Group 2 patients. None of the patients developed Grade 3 rectal toxicity. Grade 3 bladder toxicity was observed in 2 patients. The actuarial risk of Grade 3 or worse late toxicity was 3.31%. CONCLUSION: The results of our study indicate that HDR brachytherapy at 9 Gy/fraction is both safe and effective in the management of carcinoma of the cervix, with good local control and a minimum of normal tissue toxicity.     

Feasibility and early results of accelerated radiotherapy for head and neck carcinoma in the elderly

BACKGROUND: Accelerated radiotherapy (RT) represents a promising method with which to improve the treatment outcome in patients with head and neck carcinoma. However, its applicability to elderly patients has not been well established. This study assessed treatment toxicities, patient compliance, and oncologic results in patients age >/= 70 years who were treated with an accelerated concomitant boost RT schedule. METHODS: Between 1991 and 1997, 39 patients aged >/= 70 years (mean, 75 +/- 6 years) presenting with carcinomas of the oral cavity, pharynx, or larynx were treated radically with a modified concomitant boost RT schedule (planned dose of 69.9 grays [Gy] over 38 days). Based on American Joint Committee on Cancer staging, there were 14 patients with Stage I-II disease and 25 patients with Stage III-IV disease. Eighty-one patients age < 70 years who were treated with the same RT schedule served as a comparative group. The median follow-up for the surviving patients was 19 months (range, 3-65 months) and 23 months (range, 2-76 months), respectively, for the elderly and younger patient groups. RESULTS: The planned RT schedule was completed in all cases. Three patients (8%) in the elderly group and none in the younger group had an unplanned treatment interruption because of acute toxicity or lack of compliance (P = 0.03). The median tumor dose (69.9 Gy; range, 67-73 Gy) and the median overall treatment time (41 days; range, 36-60 days) were identical in both groups. According to the Radiation Therapy Oncology Group grading system, Grade 3-4 acute reactions were observed in 66% of elderly patients and in 71% of younger patients. Ten elderly patients (26%) and 19 younger patients (23%) required a nasogastric tube or a percutaneous gastrostomy for feeding, with a median weight loss of 4.1 kg and 4.4 kg, respectively, in the 2 groups. Grade 3-4 late complications were observed in 3% of the elderly patients and 10% of the younger patients (P = 0.43). Both elderly and younger patients had similar results with regard to 3-year actuarial overall survival (68% vs. 62%; P = 0.48) and locoregional control (73% vs. 68%; P = 0.31). CONCLUSIONS: The current study suggests that an accelerated concomitant boost RT schedule is feasible in elderly patients who are physically healthy enough to undergo curative treatment. The acute and late toxicities appear to be similar to those observed in younger patients, and treatment outcomes appear to be comparable.     

Tolerance of pelvic normal tissues to hyperfractionated radiation therapy: results of Protocol 83-08 of the Radiation Therapy Oncology Group

A prospective, centrally randomized Phase I/II trial of hyperfractionation in definitive radiation therapy for locally advanced squamous and transitional cell carcinoma of the bladder was conducted by the Radiation Therapy Oncology Group (RTOG) from April 1983 through June 1986. Patients with T3-4 and T2 N+ (AJC) histologically-confirmed cancer of the bladder received twice daily radiation therapy with 1.2 Gy per fraction and a minimum of 4 hr between fractions. All patients received a whole pelvic total dose of 50.4 Gy: Total doses to reduced volumes were 60.0 Gy, 64.8 Gy, or 69.6 Gy. Of 54 patients entered, 50 were eligible. An unbalanced treatment assignment was used: Nine patients received 60.0 Gy, 15 patients received 64.8 Gy and 26 received 69.6 Gy. Performance status (Karnofsky) was 90-100 in 72% of patients and 92% had transitional carcinoma. Eighty percent of tumors were T3 or T4. Observation of at least 18 months was available for 26 patients. Grade 3 acute reactions (within 90 days) were reported in eight patients (one at 60.0 Gy, three at 64.8 Gy and four at 69.6 Gy). Five patients experienced a total of seven major late effects--four Grade 3 and three Grade 4. The cumulative probability of Grade 3 and 4 late complications of treatment for the 46 patients at risk for late complications was 5% +/- 3% at 6 months, 7% +/- 4% at 12 months, and 10% +/- 5% at 18 and 24 months. The cumulative probability of Grade 3 or 4 late complications for patients who received a total dose of 69.6 Gy was 5% +/- 4% at 6 and 12 months and 11% +/- 8% at 18 and 24 months. Only one patient who experienced major late effects was also reported to have major acute reactions. Comparisons of survival of patients treated in the current study with those who received 60 Gy in 30 fractions in 6 weeks in RTOG Protocol 71-04, did not suggest any deleterious effects from hyperfractionated radiation therapy to the pelvis. The normal pelvic tissues tolerated hyperfractionated radiation therapy sufficiently well to justify exploring it, alone and with brachytherapy, in other pelvic tumors.     

Accelerated hyperfractionated radiotherapy for locally advanced cervix cancer.

PURPOSE: A phase II trial was designed to evaluate the toxicity and outcome of patients with locally advanced cervix cancer treated with accelerated hyperfractionated radiotherapy (AHFX). METHODS AND MATERIALS: In this prospective trial, AHFX doses of 1.25 Gy were administered twice daily at least 6 hours apart to a total pelvic dose of 57.5 Gy. A booster dose was then administered via either low-dose rate brachytherapy or external beam therapy to a smaller volume. All patients were accrued and treated at Peter MacCallum Cancer Institute (PMCI) between 1986 until April 1991. RESULTS: Sixty-one eligible patients were enrolled in this protocol; 2 (3.2%) had Stage IIB; 42 (68.9%) had Stage III; 8 (13.1%) had Stage IV and 9 (14.8%) had recurrent cervical cancer. Fifty-two patients (85%) completed the planned external beam without a treatment break. Thirty patients had acute toxicity that required regular medication. One patient died of acute treatment related toxicity. Fifty-five patients received booster therapy: 45 with intrauterine brachytherapy, 6 with interstitial brachtherapy, and 4 with external beam. The median follow-up of surviving patients was 6 years. Overall 5-year survival is 27% and 5-year relapse free survival is 36%. Nineteen patients died with pelvic disease and the actuarial local control rate was 66%. There were 8 severe late complications observed in 7 patients. Seven required surgical intervention (an actuarial rate of 27%). Five patients also required total hip replacement. CONCLUSIONS: The local control rate was favorable compared with other series that have used standard fractionation, although overall survival remained similar. The severe late complication rate was high for this protocol and higher than similar protocols reported in the literature.     

Complications from radiotherapy dose escalation in prostate cancer: preliminary results of a randomized trial

OBJECTIVE: To compare early and late side effects in prostate cancer patients with Stage T1b-T3 disease randomized to receive 70 Gy or 78 Gy. METHODS: There were 189 patients randomized with a minimum follow-up of 2 years, that were available for this analysis. All patients were initially treated with a 4-field box to an isocenter dose of 46 Gy at 2 Gy per fraction. In the 70-Gy arm, treatment was continued to a reduced volume using a 4-field box technique. In the 78-Gy arm, treatment was continued to a reduced volume using a conformal 6-field arrangement. Side effects were graded on a 1-4 scale, adapted from Radiation Therapy Oncology Group and Late Effects Normal Tissue Task Force criteria. RESULTS: No significant differences in acute rectal or bladder toxicity were seen between the two treatment techniques (p > 0.6 for all comparisons). The 5-year Kaplan-Meier risks of Grade 2 or higher late bladder toxicity were 20% and 9% for 70-Gy and 78-Gy groups, respectively (log rank, p = 0.8). The 5-year risks of Grade 2 or higher late rectal toxicity were 14% and 21% for 70 Gy and 78 Gy, respectively (p = 0.4). Dose-volume histogram analysis of the 78-Gy patients showed a significant correlation between the percentage of rectum irradiated to 70 Gy or greater and the likelihood of developing late rectal complications. Patients with more than 25% of the rectum receiving 70 Gy or greater had a 5-year risk of Grade 2 or higher complications of 37% compared to 13% for patients with 25% or less (p = 0.05). All three Grade 3 complications occurred when greater than 30% of the rectum received 70 Gy or more. CONCLUSION: The overall rate of complications was similar in both treatment arms. However, there is evidence for a significant increase in late rectal complications when more than 25% of the rectum received 70 Gy or greater. This parameter may serve as a benchmark for the design of future three-dimensional conformal trials.     

Clinical radiobiology of stage T2-T3 bladder cancer

PURPOSE: To evaluate the relationship between total radiation dose and overall treatment time (OTT) with the treatment outcome, with adjustment for selected clinical factors, in patients with Stage T2-T3 bladder cancer treated with curative radiotherapy (RT). METHODS AND MATERIALS: The analysis was based on 480 patients with Stage T2-T3 bladder cancer who were treated at the Center of Oncology in Gliwice between 1975 and 1995. The mean total radiation dose was 65.5 Gy, and the mean OTT was 51 days. In 261 patients (54%), planned and unplanned gaps occurred during RT. Four fractionation schedules were used: (1) conventional fractionation (once daily, 1.8-2.5 Gy/fraction); (2) protracted fractionation (pelvic RT, once daily, 1.6-1.7 Gy/fraction, boost RT, once daily, 2.0 Gy/fraction); (3) accelerated hyperfractionated boost (pelvic RT, once daily, 2.0 Gy/fraction; boost RT, twice daily, 1.3-1.4 Gy/fraction); and (4) accelerated hyperfractionation (pelvic and boost RT, twice daily, 1.2-1.5 Gy/fraction). In all fractionation schedules, the total radiation dose was similar (average 65.5 Gy), but the OTT was different (mean 53 days for conventional fractionation, 62 days for protracted fractionation, 45 days for accelerated hyperfractionated boost, and 41 days for accelerated hyperfractionation). A Cox proportional hazard model and maximum likelihood logistic model were used to evaluate the relationship between the treatment-related parameters (total radiation dose, dose per fraction, and OTT) and clinical factors (clinical T stage, hemoglobin level and bladder capacity before RT) and treatment outcome. RESULTS: With a median follow-up of 76 months, the actuarial 5-year local control rate was 47%, and the overall survival rate was 40%. The logistic analysis, which included the total dose, OTT, and T stage, revealed that all of these factors were significantly related to tumor control probability (p = 0.021 for total radiation dose, p = 0.038 for OTT, and p = 0.00068 for T stage). A multivariate Cox model, which included the treatment-related parameters and other clinical factors, revealed that the hemoglobin level and bladder capacity before RT and T-stage were statistically significant factors determining local control and overall survival. The total radiation dose was of borderline statistical significance for overall survival (p = 0.087), and OTT did not reach statistical significance. CONCLUSION: The results of our study showed that the treatment outcome after RT for bladder cancer depends mainly on clinical factors: hemoglobin level and bladder capacity before RT, and clinical T stage. An increase in the total radiation dose seemed to be associated with a better treatment outcome. The effect of the OTT was difficult to define, because it was influenced by other prognostic factors.     

Efficacy of orgotein in prevention of late side effects of pelvic irradiation: a randomized study

PURPOSE: To study whether orgotein is effective in preventing late radiation-induced effects. METHODS AND MATERIALS: Patients >18 years old who were diagnosed with rectal cancer, had an indication for pelvic irradiation (RT) after surgery, and complied with the selection criteria were randomly assigned at the end of RT to receive orgotein for 7 weeks or no treatment (control). The Radiation Therapy Oncology Group toxicity scale was used to evaluate the RT-induced side effects for up to 2 years. Interruptions due to toxicity, concomitant medication, and non-RT adverse events were also recorded. RESULTS: A total of 100 patients were included, with 50 in each group. The groups were comparable in terms of the demographic and baseline characteristics. The orgotein group had statistically significant less late toxicity than the control group (p = 0.036) and nontreated patients had a 66% greater chance of developing late toxicity at 2 years. Grouping toxicity as nonrelevant (Radiation Therapy Oncology Group Grade 0-1) and relevant (Grade 2 or worse), patients given orgotein had a lower incidence of late relevant toxicity than did controls, with statistical significance reached at all follow-up visits. After 2 years, patients not treated with orgotein had, in general, a 37% greater chance of developing late relevant toxicity; this risk was 26% when referring specifically to GI toxicity. No adverse events attributable to orgotein were recorded at any time during the study. CONCLUSION: Orgotein is a safe treatment that significantly prevents the overall occurrence of late toxicity, with toxicity reduction particularly evident in the lower GI tract.     

Accelerated superfractionated radiotherapy with concomitant boost for invasive bladder cancer

PURPOSE: To determine the toxicity and clinical effectiveness of accelerated superfractionated radiotherapy with delayed concomitant boost (ASCBRT) in locally invasive carcinoma of the bladder. METHODS AND MATERIALS: Between July 1997 and December 2001, 87 patients (unsuitable or refusing cystectomy) with invasive bladder cancer underwent ASCBRT. The mean patient age was 66 years (range 40-90). The stage distribution was as follows: 2 T1, 51 T2, 13 T3, and 21 T4. Initially, the whole pelvis was treated by 1.8-Gy conventional daily fractions up to a total dose of 45 Gy. A small field boost covering gross disease was added as a second daily fraction (1.5 Gy) during the last 3 weeks of the 5-week schedule up to a total dose of 67.5 Gy. The interfraction interval was a minimum of 6 h. The patients were evaluated in follow-up for toxicity, local control, and survival. RESULTS: All but 2 patients completed the study protocol. Grade 3 acute urinary toxicity was observed in 2 patients. Grade 2 and 3 late bladder toxicity was observed in 12 patients and 1 patient, respectively. Grade 2 and 3 late bowel toxicity was observed in 5 and 3 patients, respectively. The 3-year actuarial local control, distant disease control, cause-specific survival, and overall survival rate was 64%, 78%, 58%, and 46%, respectively. Multivariate analysis revealed T stage as independent predictor of complete response. For Stage T2 and T3, the 3-year local control rate was 77% and 48%, respectively. At the last follow-up, 53 patients (61%) were still alive with a survival time between 6 and 62 months. CONCLUSION: ASCBRT is feasible with acceptable tolerance even in relatively old patients with Stage T3 or greater tumor. The encouraging locoregional control and survival results of this institutional experience, favorable compared with conventional radical and other accelerated fractionated (with or without a concomitant boost) RT series, make ASCBRT worthy of further study in a Phase III trial.