Accelerated Fractionation Radiotherapy Research Articles

Phase II study of accelerated fractionation radiation therapy with carboplatin followed by PCV chemotherapy for the treatment of anaplastic gliomas

Purpose: To conduct a Phase II one-arm study to evaluate the long-term efficacy and safety of accelerated fractionated radiotherapy combined with i.v. carboplatin for patients with previously untreated anaplastic gliomas. Methods and Materials: Between 1988 and 1992, 90 patients received 1.9–2.0-Gy radiation 3 times a day with 2-h infusions of 33 g/m 2 carboplatin for two 5-day cycles separated by 2 weeks. After radiotherapy, patients received procarbazine, lomustine (CCNU), and vincristine (PCV) for 1 year or until the tumor progressed. Results: Ninety patients were evaluable for analysis. Histologically, 69 had anaplastic astrocytoma; 14, anaplastic oligoastrocytoma; and 7, anaplastic oligodendroglioma. Gross total resection was performed in 20 (22%), subtotal resection in 45 (50%), and biopsy in 25 (28%); reoperation (total or subtotal resection) was performed in 50 (56%) patients. A multivariate analysis showed that a younger age ( p = 0.026), Karnofsky performance score (KPS; p = 0.009), and brain necrosis ( p = 0.0002) were predictive of a better survival. Results from analysis of extent of surgery (biopsy, subtotal resection, gross total resection) approached significance ( p = 0.058). Radiation dose, irradiated tumor volume, and techniques used (boost and fields) were not significant variables. The median survival (MS) of all anaplastic glioma patients was 28.1 months; for anaplastic astrocytoma patients, MS was 28.7 months and 40.8 months for the combined anaplastic oligodendroglioma/oligoastrocytoma patients. Long-term survival occurred in 25% of anaplastic glioma patients who were alive 8.6 years after treatment was initiated. Treatment-induced necrosis was documented by surgery or autopsy in 19 (21%) patients; 21 (23%) had a mixed pattern of necrosis and tumor; and an additional 13 (14%) patients who did not have surgical or autopsy demonstration of predominant radiation necrosis had magnetic resonance imaging (MRI) evidence of radiation necrosis. Serious clinical neurologic deterioration and/or dementia requiring full-time caregiver attention were observed in 9 (10%) patients. Conclusion: When comparable selection criteria are applied, the rate of MS in this study is inferior to results attainable with current radiation and chemotherapy approaches, although the rates of long-term survival are comparable. Theoretically, patients failing therapy and dying earlier than anticipated may be because of excessive central nervous system (CNS) toxicity resulting from the combination of accelerated fractionated irradiation, intensive carboplatin chemotherapy before each radiation fraction, and postirradiation PCV chemotherapy. On the other hand, patients with treatment-induced necrosis survived significantly longer than patients who did not demonstrate MRI or histologic evidence of necrosis (MS, 106 months vs. 18–33 months).

Accelerated hyperfractionated radiation, concurrent paclitaxel/cisplatin chemotherapy and surgery for stage III non-small cell lung cancer

The low surgical cure rate in patients with stage III non-small cell lung cancer has prompted an exploration of multimodality treatment strategies. Mature results are presented from a phase II trial of accelerated hyperfractionated radiation therapy, concurrent paclitaxel/cisplatin chemotherapy and surgery for these patients. Between 1994 and 1997, 45 patients with surgically demonstrated stage III non-small cell lung cancer underwent induction treatment with a 96 h continuous cisplatin infusion (20 mg/m 2 per day) and a 24 h infusion of paclitaxel (175 mg/m 2) given concurrently with accelerated hyperfractionated radiation therapy (1.5 Gy twice daily) to a total dose of 30 Gy. Induction was completed in ten treatment (12 total) days. Surgical resection was scheduled 4 weeks later with a second identical course of chemoradiotherapy given 4–6 weeks post-operatively, to a total radiation dose of 60–63 Gy. Thirty-five patients had stage III A disease and ten had stage III B disease (eight with N 3 tumors). Induction toxicity included nausea in 89%, dysphagia in 89%, and neutropenia <1000/mm 3 in 84% which required hospitalization for fever in 40%. There were no toxic deaths during induction. About 40 of the 45 patients (89%) were operable and 32 (71%) were resectable for cure. A pathologic response was identified in 22 patients (49%); five patients (11%) had no residual disease. Fourteen patients (31%) were downstaged to mediastinal node negativity. With a median follow-up of 60 months, the Kaplan–Meier projected 5-year overall survival was 29%; locoregional control 79%; and distant metastatic disease control 38%. The projected 5-year survival for the 14 patients downstaged to mediastinal node negativity was 50%. For the 19 patients with residual ipsilateral mediastinal node involvement at surgery it was 32%. This short-course of paclitaxel and cisplatin chemotherapy and concurrent accelerated fractionation radiation is tolerable despite significant myelosuppression. Locoregional control is excellent and survival is better than historical expectations. Patients downstaged to mediastinal node negativity have a prognosis similar to those with de novo stage I B and II disease. Distant metastases are the major cause of treatment failure.

A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model

AbstractSalvage of patients with relapsed and refractory Hodgkin disease (HD) with high-dose chemoradiotherapy (HDT) and autologous stem cell transplantation (ASCT) results in event-free survival (EFS) rates from 30% to 50%. Unfortunately, the reduction in toxicity associated with modern supportive care has improved EFS by only 5% to 10% and has not reduced the relapse rate. Results of a comprehensive 2-step protocol encompassing dose-dense and dose-intense second-line chemotherapy, followed by HDT and ASCT, are reported. Sixty-five consecutive patients, 22 with primary refractory HD and 43 with relapsed HD, were treated with 2 biweekly cycles of ifosfamide, carboplatin, and etoposide (ICE). Peripheral blood progenitor cells from responding patients were collected, and the patients were given accelerated fractionation involved field radiotherapy (IFRT) followed by cyclophosphamide-etoposide and either intensive accelerated fractionation total lymphoid irradiation or carmustine and ASCT. The EFS rate at a median follow-up of 43 months, as analyzed by intent to treat, was 58%. The response rate to ICE was 88%, and the EFS rate for patients who underwent transplantation was 68%. Cox regression analysis identified 3 factors before the initiation of ICE that predicted for outcome: B symptoms, extranodal disease, and complete remission duration of less than 1 year. EFS rates were 83% for patients with 0 to 1 adverse factors, 27% for patients with 2 factors, and 10% for patients with 3 factors (P < .001). These results compare favorably with other series and document the feasibility and efficacy of giving uniform dose-dense and dose-intense cytoreductive chemotherapy and integrating accelerated fractionation radiotherapy into an ASCT treatment program. This prognostic model provides a basis for risk-adapted HDT.

328 poster Late morbidity of concomitant chemotherapy and accelerated fractionation radiotherapy in locally advanced unresectable head and neck cancer

328 poster Late morbidity of concomitant chemotherapy and accelerated fractionation radiotherapy in locally advanced unresectable head and neck cancer

A phase II trial of high-dose bromodeoxyuridine with accelerated fractionation radiotherapy followed by procarbazine, lomustine, and vincristine for glioblastoma multiforme

Purpose: To conduct a Phase II study to evaluate the long-term efficacy and safety of high-dose 5’-bromodeoxyuridine (BrdU) and accelerated radiotherapy followed by procarbazine, lomustine (CCNU), and vincristine (PCV) chemotherapy in patients with glioblastoma multiforme. Methods and Materials: Between 1994 and 1996, 88 patients were enrolled to receive 1.9 Gy of radiation three times a day for two 5-day cycles separated by 2 weeks; each 5-day cycle was preceded by a continuous 96-hour infusion of BrdU at a dose of 2.1 g/m 2/day. After radiotherapy, patients received PCV chemotherapy. Results: Median survival for all 88 patients was 50 weeks. Seventy (79.5%) received one or more courses of PCV; their median survival was 57 weeks. Covariates predictive of improved survival were gross total versus subtotal resection or biopsy ( p = 0.0048) and radiation dose ≥ 56 Gy ( p = 0.019). While receiving BrdU, 47 patients (53%) suffered grade 3 or 4 thrombocytopenia or leukopenia; 22 patients (25%) suffered grade 3 or 4 dermatologic toxicity. Conclusion: Survival was not extended in patients with glioblastoma or gliosarcoma who received BrdU at the dose and administration schedule used in this study. The BrdU dose used in this study resulted in substantial myelosuppressive and dermatologic toxicity.

Short-course induction chemoradiotherapy with paclitaxel for stage III non-small-cell lung cancer

Background. This study assessed toxicity, tumor response, disease control, and survival after short-course induction chemoradiotherapy and surgical resection in patients with stage III non-small-cell lung carcinoma.Methods. Forty-five patients with stage III non-small-cell lung carcinoma received 12-day induction therapy of a 96-hour continuous infusion of cisplatin (20 mg/m2 per day), 24-hour infusion of paclitaxel (175 mg/m2), and concurrent accelerated fractionation radiation therapy (1.5 Gy twice daily) to a dose of 30 Gy. Surgical resection was scheduled for 4 weeks later. Postoperatively, a second identical course of chemotherapy and concurrent radiation therapy (30 to 33 Gy) was given.Results. Induction toxicity resulted in hospitalization of 18 (40%) patients for neutropenic fever. No induction deaths occurred. Of 40 (89%) patients who underwent thoracotomy, resection for cure was possible in 32 (71%) patients. Pathologic response was noted in 21 (47%) patients, and 14 (31%) were downstaged to mediastinal node negative (stage 0, I, or II). At a median follow-up of 19 months, 24 patients were alive, 10 with recurrent disease. Of 21 deaths, 16 were from recurrent disease, three were from treatment, and two were unrelated. Recurrent disease was distant in 21 patients, distant and locoregional in 2, and locoregional in 3. The Kaplan-Meier projected 24-month survival is 49%. Projected 24-month survival is 61% for stage IIIA, 17% for stage IIIB (p = 0.035); 84% for pathologic responders, 22% for nonresponders (p < 0.001); 83% for downstaged patients (stage 0, I, or II), 33% for those not downstaged (p = 0.005); and 63% for resectable patients, 14% for unresectable patients (p = 0.007).Conclusions. We conclude that short-course neoadjuvant therapy with paclitaxel (1) has manageable toxicity and a low treatment mortality, (2) results in good tumor response and downstaging, (3) provides excellent locoregional control with most recurrences being distant, and (4) has improved the median survival compared with historical controls. Survival was better in stage IIIA patients, resectable patients, pathologic responders, and patients downstaged to mediastinal node negative disease (stage 0, I, or II).

Survival Results from a Phase I Study of Etanidazole (SR2508) and Radiotherapy in Patients with Malignant Glioma

Purpose: To report the survival results from a previous Phase I study of etanidazole (ETA) and radiotherapy in patients with glioblastoma multiforme (GBM n = 50) or anaplastic astrocytoma (AA n = 19) and examine survival according to age, Karnofsky performance status (KPS), and implant status. Patients and Methods: In a previous Phase I study, 70 previously untreated patients (median age 49) with malignant gliomas were accrued. One patient was excluded from analysis because pathology was unverifiable. All had KPS ≥ 70. Prior to initiation of treatment, patients were stratified according to whether they were candidates for interstitial implantation. The implant patients (IMP n = 14) received accelerated fractionation radiotherapy (XRT) 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m 2 × 6 doses, a 2 week break, and then interstitial implant for an additional 50 Gy (4–7 days) with a continuous infusion of ETA over 90–96 hours. There were 55 patients treated on two sequentially conducted non-implant arms. These patients started with accelerated fractionation XRT 2 Gy BID (6 hours apart) to 40 Gy in 2 weeks with ETA 2 gm/m 2 × 4–5 doses/week. Non-IMP1 arm (n = 41) received a 2-week break before standard fractionated boost XRT of 2 Gy/day for 2 weeks to a total dose of 60 Gy with ETA. Non-IMP2 arm (n = 14) did not have the 2-week break. All patients had plasma pharmacokinetic monitoring of ETA. Subsequent follow-up study provided information regarding long-term survival status of this group of patients. The Phase I toxicity evaluation was conducted according to the RTOG toxicity scale and was found well tolerated in both groups. Overall actuarial survival was plotted for all patients, by histologic group, and by implant status. Subset analyses of GBM patients by age (≤ 49 or > 49 years), KPS (≤ 80 or > 80) and implant versus non-implant were also performed. Results: Median survival of GBM patients was 1.1 years and that of anaplastic astrocytoma patients was 3.1 years ( p = 0.0001). In GBM patients, KPS > 80, implanted patients, and age ≤ 49 were factors found not to be associated with a statistically improved survival. Conclusion: The results of survival in this Phase I etanidazole study of patients with anaplastic astrocytoma are comparable to the results from other studies using bromodeoxyuridine, iododeoxyuridine, or procarbazine, lomustine (CCNU), and vincristine. The use of etanidazole with accelerated radiotherapy does not appear to improve survival in patients with glioblastoma multiforme compared to those treated with conventional therapies.

Use of concurrent chemotherapy, accelerated fractionation radiation, and surgery for patients with esophageal carcinoma

The results of a Phase II study of concurrent chemotherapy and accelerated fractionation radiation therapy followed by surgical resection for patients with both adenocarcinoma and squamous cell carcinoma of the esophagus are presented. Pretreatment and postinduction staging were correlated with pathologic findings at surgery to assess the role of surgical resection and the predictive value of noninvasive staging techniques. Patients received 2 induction courses with 4-day continuous intravenous infusions of cisplatin (20 mg/m2/day) and 5-fluorouracil (1000 mg/m2/day) beginning on Day 1 and Day 21, concurrent with a split course of accelerated fractionation radiation (1.5 grays [Gy] twice daily, to a total dose of 45 Gy). All patients were subsequently referred for surgical resection. A single, identical postoperative course of chemotherapy and 24 Gy accelerated fractionation radiation was planned for patients with residual tumor at surgery. Seventy-four patients were entered on this study; 72 patients were considered eligible and evaluable. Induction toxicity included nausea (85%), increased dysphagia (90%), neutropenia (<1000/mm3) (43%), thrombocytopenia (<20,000/mm3) (10%), and reversible nephrotoxicity (8%). Sixty-seven patients (93%) underwent surgery, and 65 (90%) were found to have resectable tumors. Twelve of these patients (18%) died perioperatively, and 18 (27%) had no residual pathologic evidence of disease. Resolution of symptoms and normalization of radiographic studies, endoscopy, or esophageal ultrasound did not identify pathologic complete responders accurately. No patient completing induction therapy and surgery experienced a locoregional recurrence. The Kaplan-Meier 4-year projected recurrence free and overall survival rates were 49% and 44%, respectively. Although this regimen is feasible, there was significant preoperative toxicity and perioperative mortality. Nonetheless, the recurrence free and overall survival rates were encouraging. However, no staging tool can predict a pathologic complete response after induction therapy accurately, suggesting a continued need for surgical resection.

Use of concurrent chemotherapy, accelerated fractionation radiation, and surgery for patients with esophageal carcinoma

Use of concurrent chemotherapy, accelerated fractionation radiation, and surgery for patients with esophageal carcinoma

245 Stage III non-small cell lung cancer (NSCLC): Short course multimodality treatment with accelerated fractionation radiation (AFR), concurrent cisplatin (DDP)/paclitaxel (TAX) chemotherapy (CT) and surgery

245 Stage III non-small cell lung cancer (NSCLC): Short course multimodality treatment with accelerated fractionation radiation (AFR), concurrent cisplatin (DDP)/paclitaxel (TAX) chemotherapy (CT) and surgery

Status of accelerated fractionation radiotherapy in head and neck squamous cell carcinomas.

Considerable interest has been shown in recent years about hyperfractionated and accelerated radiation therapy for head and neck squamous cell carcinomas. The first randomized trial showing an advantage for hyperfractionation in terms of tumor control was the European Organization for Research and Treatment of Cancer 22791 trial. More recently, accelerated radiotherapy has been tested in many studies showing that high total doses of radiation could be delivered in overall treatment time shorter than conventional radiation therapy. The benefit of accelerated radiation therapy has been reported in some recently completed randomized trials, which suggests that rapid repopulation of surviving tumor cells during radiation therapy is a major determinant to obtain cure in this type of cancer.

2058 Accelerated fractionation radiotherapy for high-grade gliomas

2058 Accelerated fractionation radiotherapy for high-grade gliomas

Retrospective DNA ploidy analysis by image and flow cytometry in head and neck cancer.

A retrospective analysis of DNA content (DNA ploidy) was conducted in formalin-fixed specimens from patients with advanced, unresectable head and neck cancer who were treated on a single defined protocol with accelerated fractionation radiation therapy and concomitant cisplatin (Platinol) chemotherapy. Specimens from 31 tumor sites were analyzed by image cytometry using the Feulgen staining method. Fifteen specimens were analyzed by flow cytometry after deparaffinization, nuclear disaggregation, and staining with propidium iodide. By image analysis, 10 (32%) of 31 specimens contained only diploid tumor cells, while 21 (68%) specimens exhibited at least one aneuploid tumor component. Seven of the eight tumors with a single G0/G1 peak by image analysis had a single peak by flow analysis. Five of the seven tumors with multiple peaks by image analysis had multiple peaks by flow analysis. Histology was also reevaluated, and tumor grade was determined, reflecting tumor cell differentiation based on keratinization, mitotic activity and the degree of nuclear polymorphism. For this well-defined patient population managed according to a uniform therapeutic approach, DNA ploidy status and histology provided a suggestion of prognostic separation; however, statistical significance was not obtained, most likely due to the small number of patients.

Accelerated fractionation radiotherapy and concomitant chemotherapy in patients with stage IV inoperable head and neck cancer: J. Dragovic, T. Doyle, E. J. Tilchen, R. D. Nichols, M. S. Benninger, E. R. Carlson, S. B. Boyd, G. R. Jacobsen Cancer 1995: 76: 1655–61

Background. Stage IV inoperable head and neck cancer has a 2-year mortality rate of greater than 70% when treated with conventional radiotherapy. A Phase II study was undertaken to evaluate the effects of concomitant chemotherapy and accelerated, interrupted, twice-a-day radiotherapy on tumor response, locoregional control, survival, and morbidity. Methods. Thirty-four patients with Stage IV inoperable squamous cell carcinoma of the head and neck and a minimum follow-up of 36 months were evaluated. Concomitant chemoradiotherapy was administered during weeks 1, 3, and 5 (with planned breaks during weeks 2 and 4), consisting of cisplatin 60 mg/m 2 on Day 1, continuous 5-day infusion of 5-fluorouracil, 750 mg/m 2 per day, and radiotherapy, 2 Gy twice a day, more than 6 hours apart, followed by 3 days of radiation therapy alone (final boost) in week 6, for a total dose of 70 Gy and treatment duration of 51/2 weeks (38 days). Results. Twenty-seven patients achieved a clinical complete response (82%). Actuarial locoregional control at 3 years was 73% and the actuarial 3-year survival probability, including all deaths, was 38%. All locoregional recurrences were manifested within 12 months. Of the 20 deaths, 12 were tumor related (locoregional and/or metastatic), 3 were treatment related, and 5 were due to other causes. Acute toxicity consisted of grade 3 mucositis and dysphagia and grade 2-3 leukopenia, not requiring treatment interruption or cessation. Conclusion. Concomitant accelerated radiation therapy and chemotherapy is a feasible treatment approach in this prognostically poor patient population, yielding dramatic tumor responses and impressive locoregional control at the cost of somewhat increased acute toxicity. Although serious late complications have not been observed, caution should be exercised in view of the relatively short follow up.

Accelerated induction therapy and resection for poor prognosis stage III non-small cell lung cancer

Induction therapy and resection may improve the survival of patients with poor prognosis stage III non-small cell lung cancer, at the cost of significant treatment prolongation. The purpose of this study was to assess toxicity, response, and survival of an accelerated induction regimen and resection in poor prognosis stage III non-small cell lung cancer. Forty-two surgically staged patients with poor prognosis stage III non-small cell lung cancer received 11 days of induction treatment consisting of 96 hours of continuous chemotherapy infusions of cisplatin (20 mg.m-2.day-2), 5 fluorouracil (1,000 mg.m-2.day-2), and etoposide (75 mg.m-2.day-2) concurrent with accelerated fractionation radiation therapy (1.5 Gy twice a day, to a dose of 27 Gy). Induction was followed in 4 weeks by resection. Postoperatively, a second course of continuous chemotherapy and concurrent accelerated fractionation radiation therapy (postoperative dose 13 to 36 Gy) was given. Despite some degree of induction toxicity in all patients there was only one induction death (2.4%). A clinical partial response was seen in 24 patients (57%). Thirty-six patients (86%) underwent thoracotomy, and resection was possible in 33 (79%). Pathologic downstaging was seen in 17 patients (40%), and 2 patients (5%) had no residual carcinoma at operation. There were 11 postoperative complications (31%) and 4 postoperative deaths (11%). Thirteen patients (31%) are alive and disease-free, 24 (57%) have persistent disease or have recurred (15 distant, 5 locoregional, 4 both), and 9 patients are alive with disease. The median survival is 21 months and the 2-year Kaplan-Meier survival is 43%, with no differences identified between stages IIIA and IIIB patients (p = 0.63). We conclude that accelerated induction therapy and resection in poor prognosis stage III non-small cell lung cancer (1) is toxic, with a 12% treatment mortality; (2) is effective with a 79% resection rate and 40% pathologic downstaging rate; (3) provides excellent local control; (4) may prolong survival; and (5) is of value in stage IIIB as well as stage IIIA patients.

Phase II study of accelerated fractionation radiation therapy with carboplatin followed by vincristine chemotherapy for the treatment of glioblastoma multiforme

Purpose : To conduct a Phase II one-arm study to evaluate the long-term efficacy and safety of accelerated fractionated radiotherapy combined with intravenous carboplatin for patients with previously untreated glioblastoma multiforme tumors. Methods and Materials : Between 1988 and 1992, 83 patients received 1.9 – 2.0 Gy radiation three times a day with 2-h infusions of 33 mg/m 3 carboplatin for two 5-day cycles separated by 2 weeks; following radiotherapy, patients received procarbazine, lomustine (CCNU), and vincristine (PCV) for 1 year or until tumor progressed. Results : Eighty-three patients were evaluable for analysis. Seventy-four of the 83 patients (89%) received one or more courses of PCV; their median survival was 55 weeks. Total resection was performed in 20% (15 of 74), subtotal resection in 69% (51 of 74), and biopsy in 11% (8 of 74); reoperation (total or subtotal resection) was performed in 28 patients (37%). Survival was worst for those ≥ 61 year old (median 35 weeks). Fits of the Cox proportional hazards regression model showed covariates individually predictive of improved survival were younger age ( p < 0.01), smaller log of radiation volume ( p = 0.008), total or subtotal resection vs. biopsy ( p = 0.056), and higher Karnofsky performance status ( p = 0.055) A. multivariate analysis showed that age ( p = 0.013) and extent of initial surgery ( p = 0.003) together were predictive of a better survival with no other variables providing additional significance. Only 8.4% (7 of 83) of patients had clinically documented therapy-associated neurotoxicity (“radiation necrosis”). Conclusion: When comparable selection criteria were applied, the survival in this study is similar to the results currently attainable with other chemoradiation approaches. The relative safety of accelerated fractionated radiotherapy, as used in this study with carboplatin, enables concomitant full-dose administration of chemotherapy or radiosensitizing agents in glioblastoma multiforme patients.

Randomized phase [formula omitted] trial of two variants of accelerated fractionated radiotherapy regimens for advanced head and neck cancer: Results of RTOG 88-09

To establish the feasibility of performing split-course accelerated hyperfractionation (AHFX-S) and concomitant boost accelerated fractionation radiotherapy (AFX-C) for advanced head and neck cancer in a multi-institutional cooperative trial setting and to evaluate the tumor clearance rate and acute and late toxicity of these fractionation schedules. Between February 1989 and January 1990, 75 patients with Stage III or IV squamous cell carcinoma of the head and neck were randomized to receive: (a) AHFX-S: 1.6 Gy/fraction, twice daily (6-h interval), 5 days/week, to a total dose of 67.2 Gy/42 fractions/6 weeks, with a 2-week rest after 38.4 Gy; or (b) AFX-C: 1.8 Gy/fraction/day, 5 daily fractions/week to 54 Gy/30 fractions/6 weeks to a large field and 1.5 Gy/fraction/day to a boost field, 6 h after large field treatment during the last 11 treatment days, to a total dose of 70.5 Gy/41 fractions/6 weeks. Acute and late toxicities were scored according to the RTOG normal tissue reaction scales and tumor clearance was evaluated at completion of therapy and at regular intervals thereafter. Of the 70 analyzable patients, 38 received AHFX-S and 32 received AFX-C. The two arms were balanced with respect to sex, age, T-stage, and Karnofsky Performance Status (KPS). However, the AHFX-S arm had a higher proportion of oropharyngeal primaries (63% vs. 44%), and Stage IV disease (82% vs. 50%) and lower proportion of oral cavity lesions (3% vs. 22%) and N0 disease (16% vs. 31%) than the AFX-C arm. The median follow-up was 2 years (range: 0.03-4.87 years). Tolerance of both variants of accelerated fractionated radiotherapy was satisfactory. There was no significant difference in local-regional control, disease-free survival, or survival between the two arms. The 2-year local-regional failure rate, survival, and disease-free survival was 50, 50, and 40%, respectively, for the entire group of patients. Acute radiation mucositis was increased in both arms. There was no significant difference in the incidence of grade 3 acute toxicities (63% vs. 56%) and grade 3 (14% vs. 14%) or grade 4 (6% vs. 17%) late toxicities. Permanent grade 4 late toxicity was observed in 6 and 7% of the patients, respectively. Results of this randomized Phase I/II trial showed that the two accelerated fractionated schedules studied can be successfully given in a multi-institutional cooperative trial. There was no significant difference in acute or late toxicities, local-regional control, disease-free survival, or survival in this small scale study. Therefore, a Phase III trial comparing the relative efficacy of these two accelerated fractionation schedules against standard fractionation and hyperfractionation has been activated.

Aggressive concurrent chemoradiotherapy and surgical resection for proximal esophageal squamous cell carcinoma

Proximal esophageal cancer has been a disease associated with relatively poor treatment success, partly due to advanced disease at presentation and the morbidity of the surgery required. Therefore, most patients receive palliative radiation therapy, and disease control is poor. Between July 1990 and December 1992, nine consecutive patients with proximal esophageal squamous cell carcinoma were treated with aggressive concurrent chemoradiotherapy followed by surgical resection. Treatment consisted of cisplatin (20 mg/m2/day) and 5-fluorouracil (1000 mg/m2/day), both given as continuous intravenous infusions over 4 days concurrent with accelerated fractionation external beam radiation therapy (150 cGy twice a day to a dose of 2400 cGy). Three weeks after beginning treatment, a second course of chemotherapy and accelerated fractionation radiation therapy was administered to a total preoperative radiation therapy dose of 4500 cGy. After restaging of their disease, patients next underwent surgical resection. A single postoperative course of chemotherapy and 2400 cGy of concurrent accelerated fractionation radiation therapy was administered to those patients with residual tumor in the resection specimen. Two of these nine patients also were given 4-day etoposide infusions (75 mg/m2/day) as part of their chemotherapy and received lower induction radiation therapy doses. Although significant toxicity was experienced, there were no deaths attributable to the chemoradiotherapy and only one perioperative death. All nine patients underwent surgery; five required pharyngolaryngoesophagectomy. No residual tumor was found in the resection specimen in three of the nine patients. Continuous locoregional tumor control was achieved in all patients. Only two developed distant metastases. These results, using aggressive multimodality treatment, suggest that excellent locoregional control and long term, disease free survival can be achieved in selected patients with proximal esophageal cancer.

Randomized phase i/ii trial of two variants of accelerated fractionation radiotherapy regimens for advanced head and neck cancer: Results of RTOG 88-09

Randomized phase i/ii trial of two variants of accelerated fractionation radiotherapy regimens for advanced head and neck cancer: Results of RTOG 88-09

Accelerated fractionation radiotherapy for laryngeal cancer, acute, and late toxicity

The acute toxicity of an accelerated radiotherapy scheme was compared with a conventional schedule. Eighteen patients with squamous cell carcinoma of the larynx were treated with accelerated fractionation radiotherapy. An average reduction of overall treatment time of 11 days was accomplished by giving 2 fractions a day during the last part of the treatment. Total dose and fraction dose were left unchanged. Acute reactions of skin and mucosa in these patients were compared with those in 40 patients treated with a conventional fractionation scheme, that is, 2 Gy per fraction, 5 fractions per week, to a total dose of 64–70 Gy. Acute reactions were maximal between 5 and 7 weeks after the start of treatment. Complete healing occurred within 3 months in all patients. Mucosal reactions and, as a consequence, dysphagia were clearly increased in those patients treated with accelerated fractionation. For confluent mucositis an ED50 of 66 Gy was calculated compared to 69 Gy for conventional fractionation. To a lesser degree, skin toxicity was also enhanced in the patients treated with the accelerated schedule. Severe edema of the laryngeal mucosa occurred only in patients treated to a total dose of 68 or 70 Gy and was somewhat more frequent with accelerated fractionation ( 4 10 ) than with conventional fractionation (4/24). One patient in the accelerated fractionation group underwent laryngectomy for persistent edema and laryngeal necrosis. No severe late skin reactions were observed. It can be concluded that the fractionation schedule tested in this study is feasible. Further shortening of overall treatment time without reduction of total dose will likely lead to unacceptable acute and, possibly, also late toxicity.