Randomized neutron dose searching study for malignant gliomas of the brain: results of an RTOG study. Radiation Therapy Oncology Group

From September 1980 through January 1985, the Radiation Therapy Oncology Group (RTOG) conducted a randomized, dose-searching study testing the efficacy of a concomitant neutron boost along with whole brain photon irradiation in the treatment of malignant gliomas of the brain. Patients had to have biopsy-proven, supratentorial, anaplastic astrocytoma or glioblastoma multiforme (Nelson schema) to be eligible for the study. The whole brain photon irradiation was given at 1.5 Gy per treatment, 5 days-a-week to a total dose of 45 Gy. Two days-a-week the patients were to receive neutron boost irradiation to the tumor volume as determined on CT scans. The neutron irradiation was to be given prior to and within 3 hours of the photon irradiation on that day. The rationale for this particular treatment regime is discussed. A total of 190 evaluable patients were randomized among 6 different neutron dose levels: 3.6, 4.2, 4.8, 5.2, 5.6 and 6.0 Gyn gamma. There was no difference in overall survival among the 6 different dose levels, but for patients having less aggressive tumor histology (anaplastic astrocytoma), there was a suggestion that patients on the higher dose levels had poorer overall survival than patients on the lower dose levels and also did worse than historical photon controls. Important prognostic factors were identified using a Cox stepwise regression analysis. Tumor histology, Karnofsky performance status, and patient age were found to be related to survival while extent of surgery and neutron dose had no significant impact. Autopsies were performed on 35 patients and the results correlated with the actual neutron dose as determined by central-axis isodose calculations. At all dose levels there were some patients with both radiation damage to normal brain tissue and evidence of viable tumor. No evidence was found for a therapeutic window using this particular treatment regimen.     

A unique radiation scheme for the treatment of high-grade non-metastatic soft tissue sarcoma: the detroit medical center experience

Purpose:This is the initial report on the utilization of combined photon irradiation followed by a neutron boost irradiation for the initial management of patients with high-grade non-metastatic soft tissue sarcoma (STS). We present data on local control, complications, disease-free survival and overall survival in patients at high risk for local relapse.Methods and materials: Between 1/1/1995 and 10/31/02, twenty-three patients with high-grade non-metastatic soft tissue sarcoma were referred to the Department of Radiation Oncology at the Detroit Medical Center. These patients were referred for consultation due to surgical margin status (tumor within 3mm of surgical margin (n=11)), or gross residual disease (n=12). There were 14 males and nine females whose ages ranged from 12 to 75 at the time of diagnosis (med=44 years). The most common histology was malignant fibrous histiocytoma (n=6), followed by liposarcoma (n=5), synovial sarcoma (n=4), and angiosarcoma (n=2). Twenty-one of 23 patients also received multi-agent multi-cyclic cyto-reductive therapy. Treatment consisted of initial daily photon irradiation delivered either using twice daily fractions of 120 cGy (n=10) or once daily 200 cGy/fx (n=13).Total photon dose was 36-39.6 Gy. Neutron irradiation was initiated immediately following the photon irradiation and consisted of fraction sizes of 1.0-1.25NGy to a total dose of 6-10 NGy. The neutrons were given once daily. Follow-up is calculated from the day of last radiation treatment.Results: No patient has been lost to follow-up, which has ranged from 18 to 82 months (med=36 months). To date there have been two local relapses and three patients with distant disease development without local relapse. Each of the patients with distant disease has died. The local failures occurred at 9 and 12 months. The 36-month local control is 91%. Thirtysix month disease-free survival was 78%. Overall survival at 36 months was 87%. Three patients had unusual complications consisting of delayed wound healing, and in one of these patients a fracture of the tibia has been noted.Conclusion: The use of this unique radiation sequence post-surgically in patients at high risk for local relapse has resulted in an exciting 36-month local control rate of 91%. The 3-year disease-free survival of 78% and overall survival rate of 87% are exciting but need to mature. The low complication rate is similar to that reported in other large institutional series that have not utilized neutrons. We continue to evaluate the role of combined photon and once-off neutron irradiation in the treatment of patients with high-grade STS that are risk for local recurrence.     

快中子放射治疗软组织肉瘤的疗效分析

目的回顾分析快中子与快中子、光子混合照射治疗软组织肉瘤的疗效及其影响因素.方法 52例患者共79个病灶,其中19例37个病灶采用35 MeV p→Be快中子治疗,33例42个病灶混合照射.单纯中子组剂量4.0～21.0 Gy(中位值11.7 Gy).混合照射组中子剂量3.9～16.0 Gy(中位值8.8 Gy),光子剂量9.0～62.0 Gy(中位值34.0 Gy),总剂量(16.5～69.4 Gy,中位值42.0 Gy).中子分次剂量0.8～1.5 Gy(中位值1.2 Gy),周二、五照射;光子为常规分割. 结果病灶局部控制率为48.7%,在治疗和随访中仅有24.1%的病灶出现进展.非转移性病灶、肿瘤较小以及放射治疗前手术切除是局部控制的有利因素(P< 0.05).混合照射总剂量与局部控制及无进展时间显著正相关(rs=0.453,r=0.288,P值分别为0.001和0.032).混合照射较单纯中子对病灶局部控制的改善接近于有显著性意义(57.1%∶35.5%,χ2=3.60,P=0.058).全组患者的1、3、5年生存率分别为57.3%、20.5%、13.7%,远地转移为主要死因.肿瘤组织学分级较低和接受混合照射的患者生存率较高.全组病灶3+4级近期放射反应发生率为2.7%,远期的为19.0%. 结论快中子治疗软组织肉瘤可以取得较好的局部控制,中子、光子混合照射有可能改善疗效,不能手术或术后残留的G1或G2级肿瘤适用于快中子治疗,放射反应的发生率可以接受.     

Photon irradiation of unresectable carcinomas of salivary glands.

This paper presents our experience and the local control rates of a group of patients with inoperable and unresectable lesions treated by photon irradiation from 1980 through 1989. The patient material consists of a total of 24 patients, 9 with carcinoma arising from the parotid gland and 15 with lesions in the minor salivary glands, mainly the oral cavity and oropharynx. The pathologic slides were reviewed and malignancy of various cell types confirmed. The 5-year actuarial local control of parotid gland lesions after photon irradiation was 100% and the survival rate was 65%. For the minor salivary gland lesions, the 5-year actuarial local control was 78% and the survival rate with or without disease was 93%. All lesions were irradiated by accelerated hyperfractionated photons (bid) with 1.6 Gy per fraction, intermixed with various boost techniques including electron beam, intraoral cone, interstitial implant, and/or submental photons for a total of 65-70 Gy. Most treatment failures of parotid cancer were due to distant metastases. The present series showed excellent local control and satisfactory survival of inoperable and unresectable salivary gland carcinomas after state-of-the-art photon irradiation, comparable to that achieved by neutron irradiation. The late complications were minimal. A controlled randomized trial may be indicated.     

Neutron therapy for head and neck cancer: II. Further follow-up on the M. D. Anderson TAMVEC randomized clinical trial

Between January 1977 and February 1980, 95 patients with inoperable squamous carcinomas of the head and neck were treated in a two-armed randomized clinical trial comparing 1) mixed schedule irradiation using two neutron and three photon fractions per week and 2) standard photon irradiation. Complete tumor regression was achieved in 80% of patients treated with mixed-schedule irradiation, and in 68% of patients treated with photons. The local control rate was 44% in patients treated with mixed-schedule irradiation and 41% in patients treated with photons. There were four complications of treatment in each treatment arm. Absolute survival was 20% with mixed-schedule treatment and 17% in photons. Actuarial analysis shows superior local control and survival rates with mixed-schedule irradiation over photons only in the first two years.     

Radiation Therapy Oncology Group (RTOG) survival data on anaplastic astrocytomas of the brain: does a more aggressive form of treatment adversely impact survival?

The RTOG has sponsored several studies for malignant gliomas of the brain that have included tumors classified as either glioblastoma multiforme (GBM) or anaplastic-atypical astrocytoma (AAF) under the Nelson schema. Glioblastoma multiforme, the more aggressive histology, has done poorly under all forms of treatment having a typical median survival of 8-11 months. The less common and less aggressive anaplastic-atypical astrocytoma seems to show a survival that worsens with treatment more aggressive than standard radiotherapy. All patients in this report have had their tumors centrally reviewed by a RTOG neuropathologist and have had the diagnosis of anaplastic-atypical astrocytoma confirmed. We compare three patient groups: standard photon radiotherapy from the 60 and 70 Gy arms of RTOG 74-01/ECOG 1374 and from the 65 Gy control arm of RTOG 76-11; radiation therapy and chemotherapy from RTOG 74-01/ECOG 1374 (60 Gy + BCNU and 60 Gy + MeCCNU + DTIC) and from RTOG 79-18 (60 Gy + BCNU); and photon irradiation plus a neutron boost from RTOG 76-11 and RTOG 80-07. There are 47 analyzable cases treated with photons alone, 78 analyzable cases treated with photons + chemotherapy, and 38 analyzable cases treated with photons + neutron boost. Median survival for the three groups of patients is, respectively, 3.0 years, 2.3 years, and 1.7 years. Actuarial survival curves are presented for each subgroup of patients and then for the patient subgroups further broken down by major prognostic variables--age and Karnofsky performance status. In each "better prognostic category," the median survival decreased as the "aggressiveness" of the treatment increased. The implications of these findings for future clinical trials is discussed.     

RTOG Phase I study on fast neutron teletherapy for squamous cell carcinoma of the esophagus

From August, 1977, through January, 1981, the Radiation Therapy Oncology Group sponsored a Phase I study (RTOG 77-09) on the use of fast neutrons for treating inoperable squamous cell carcinomas of the esophagus. A total of 39 evaluable patients were treated with curative intent using either fast neutrons alone or in combination with low LET irradiation as part of a mixed beam fractionation scheme. Actuarial survival curves are presented for both the "neutrons alone" and the "mixed beam" treatment groups. There was no significant survival difference between these groups of patients. The projected survival at two years is less than 10%, which is comparable with megavoltage photon results for an unselected series of patients. The size of the primary lesion and the initial Karnofsky performance status were found to be the most important prognostic indications for prolonged survival. Sixteen of 39 patients were felt to have achieved local clearance of their tumor at some time during their follow-up with the median time until a local recurrence being 17 months. Treatment related complications and patterns of metastatic spread are discussed. In general, it appeared that the response of large tumors to neutron irradiation resulted in necrosis and fistula formation. In many cases this was accompanied by persistent/recurrent tumor within the high dose radiation volume.     

Radiotherapeutic management of brain metastases from breast cancer

We have reviewed the medical records of 28 breast cancer patients with brain metastases who were treated with radiotherapy at our clinic from 1980 through 1994 (4 patients, postoperatively; 24 patients, radiotherapy alone). Radiotherapy was delivered as whole brain irradiation using lateral opposed 10 MV X-rays. Ten patients received an additional boost to a reduced field. One patient was treated with localized stereotactic irradiation alone. The radiation dose for tumors ranged from 32 Gy to 60 Gy (mean, 49 Gy) in 2 or 3 Gy daily fractionated doses. The brain was the first site of metastatic involvement in only two patients. In the 26 evaluable patients, neurologic functional improvement was achieved in 24 patients (92%) with complete response (CR) in 1 2 patients (46%) and partial response (PR) in 1 2 patients (46%). The survival rates from the initial treatment were 39% at 5 years and 16% at 10 years (median survival time, 50 months), and those after treatment of brain metastases were 29% at one year and 18% at 2 years (median survival time, 6 months). Performance status tended to be associated with survival (p=0.10), and the presence of liver metastasis was the most important risk factor concerning survival (p=0.056). Two patients suffered severe chronic complications. One patient developed severe dementia after whole brain irradiation with a total dose of 45 Gy in 3 Gy daily fractionated dose, and another patient developed widespread brain necrosis after combined radiotherapy with intrathecal local infusion of methotrexate. Radiotherapeutic management is useful for breast cancer patients with brain metastasis, and long-term survival may also be possible even if patients have preexisting extracranial metastases, except for hepatic involvement. Radiation-related complications should therefore be avoided in these patients.     

"Instant-mix" whole brain photon with neutron boost radiotherapy for malignant gliomas

From July 1985 through March 1987, 44 consecutive patients with supratentorial, nonmetastatic anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were treated with whole brain photon irradiation with concomitant neutron boost at the University of Chicago. All patients had biopsy proven disease and surgery ranged from biopsy to total gross excision. Whole brain photon radiation was given at 1.5 Gy per fraction, 5 days weekly for a total dose of 45 Gy in 6 weeks. Neutron boost radiation was prescribed to a target minimum dose that included the pre-surgical CT tumor volume plus 1 cm margin. Neutrons were administered 5-20 minutes prior to photon radiation twice weekly and a total dose of 5.2 Gyn gamma was administered over 6 weeks. Median follow-up was 36 months. The median survival was 40.3 months for anaplastic astrocytoma (10 patients) and 11 months for glioblastoma multiforme (34 patients) and 12 months for the overall group. Variables that predicted longer median survival included histology (AA vs. GBM), age (less than or equal to 39 years vs. older), and extent of surgery (total gross or partial excision vs. biopsy) whereas tumor size and Karnofsky performance status did not have a significant influence. The median survival of the anaplastic astrocytoma group was better than expected compared to the RTOG 80-07 study (a dose-finding study of similar design to this study) and historical data. Reasons for this are discussed.     

Concomitant Chemoradiotherapy, Neutron Boost, and Adjuvant Chemotherapy for Anaplastic Astrocytoma and Glioblastoma Multiforme

The survival rate for patients with malignant gliomas is poor. We describe the results of a prospective study using concomitant chemoradiotherapy, neutron boost, and adjuvant chemotherapy for patients with malignant gliomas. Forty-two patients with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were treated with postoperative photon radiation 45 Gy/25 fraction (fxs) with concomitant continuous intravenous infusion of 5-fluorouracil at 300 mg/m²/day × 5 days and hydroxyurea 0.5 g orally every 12 hr for 6 days for 5 consecutive weeks, followed by a neutron boost of 450 N cGy/6 fxs delivered twice weekly. Adjuvant chemotherapy with procarbazine, CCNU, and vincristine (PCV) was given up to 1 year or until tumor progression. Thirty-four patients (81%) had GBM and 8 patients (19%) had AA. Sixteen patients (38%) were ineligible for the neutron boost because of large tumors or poor performance status and instead received a photon boost with concomitant chemotherapy for a total dose of 60-65 Gy to the tumor. The overall median survival is 68 weeks at a median follow-up of 203 weeks (range 166-302 weeks for the 11 patients remaining alive); 7/8 patients with AA are alive, 2 of these with progressive disease. For AA the median survival is not reached at a median follow-up of 203 weeks (range 166-302 weeks for the 7 patients alive with AA). Time to tumor progression for the 1 dead patient with AA was 35 weeks and the other 2 patients failed at 171 weeks and 179 weeks following treatment. The median survival for the 34 patients with GBM was 62 weeks; 4/34 patients with GBM are alive at 285, 238, 216, and 206 weeks. Multivariate survival analysis in the 34 patients with GBM revealed age and Karnofsky performance status as important prognostic factors. Extent of surgery and neutrons did not affect survival. Concomitant chemoradiotherapy was well tolerated by all patients. The only toxicities observed were mucositis × grade II in 3 patients (7%) and mild myelosuppression in 1 patient (2.4%). Adjuvant PCV was well tolerated. Continuous concomitant chemoradiotherapy was well tolerated by all patients with acceptable side effects. The survival rate for the patients with GBM suggests no significant impact on the prognosis for these patients. Patients with AA did well; however, the patient numbers are small.     

Radiation Therapy Oncology Group Phase I-II study on fast neutron teletherapy for carcinoma of the bladder

From June 1977 through March 1981, the Radiation Therapy Oncology Group sponsored a Phase I-II study (RTOG 77-05) on the use of fast neutrons for treating carcinomas of the urinary bladder. Patients entered on the study had Stage B1 (grade III or IV histology) or Stage B2, C, or D1 (any grade histology) disease. Thirteen patients received preoperative mixed-beam (neutron/photon) irradiation to 50 photon Gy-equivalent, and in 12 of these a cystectomy was performed in 4 to 6 weeks. The incidence of pathologic downstaging to Po was 58% in the cystectomy specimens. The projected survival at 30 months is 32%. Twenty-six patients were treated definitively with mixed-beam irradiation consisting of 50 photon Gy-equivalent to the pelvis followed by a 20 photon Gy-equivalent boost to the bladder itself. Eighteen of 26 patients (69%) achieved tumor clearance at some time during their follow-up but 8/18 (44%) of these ultimately exhibited some component of local failure. The projected survival at 30 months for this group of patients is 34%. However, the subset of patients with Stage B or C disease had a projected survival at 30 months of 60%. Four patients received definitive neutron irradiation alone and 3/4 achieved tumor clearance at some time during their follow-up. Actuarial curves are presented for patient survival and duration of local control, and results are compared with comparably staged patients treated with megavoltage photon irradiation. Treatment-related morbidity is also discussed.     

Symptoms Related to Brachial Plexus Neuropathy After Supraclavicular Irradiation and Boost in Breast Cancer

PurposeTo evaluate the incidence of symptoms related to brachial plexus neuropathy (BPN) and the dose distribution to the brachial plexus (BP) in patients with breast cancertreated with supraclavicular (SCV) irradiation and boost.Methods and MaterialsIn this study, 117 patients with initial ipsilateral supraclavicular lymph node (SLN) metastasis and 39 with recurrent SLN metastasis between 2008 and 2018 in our cancer center were retrospectively analyzed. All patients were treated with 50 Gy of SCV irradiation in 25 fractions and a boost (median dose, 10 Gy; range, 10-16 Gy) to involved nodes in the SCV area. Symptoms related to BPN (including ipsilateral arm numbness, pain, and weakness) were recorded and graded according to the Common Terminology Criteria for Adverse Events, version 5.0. The BP was delineated on simulation computed tomography, and the dose distributions to the BP were evaluated. Meanwhile, 297 patients treated with SCV irradiation without boost during the same period were identified as a control group to compare the incidences of BPN-related symptoms and dosimetric data with patients who received an SCV boost.ResultsThe 5-year overall survival rate was 80.3% for patients with initial SLN metastasis and 51.0% for patients with recurrent SLN metastasis. For patients who received an SCV boost, incidence rates of ipsilateral arm numbness, pain, and weakness were 23.9%, 18.3%, and 34.3%, respectively. Four patients (5.6%) developed grade 2 numbness and 3 (4.3%) developed grade 2 arm weakness. In the control group, incidence rates of arm numbness, pain, and weakness were 31.6%, 21.9%, and 36.0%, respectively. The incidence of BPN-related symptoms was not significantly different between the 2 groups. Symptoms of grade 3 were not observed in either cohort. The mean doses to the BP in patients who received boost and who did not were 56.8 and 46.8 Gy, respectively (P < .001). The maximum doses to the BP in patients who received boost and who did not were 64.5 and 53.5 Gy, respectively (P < .001). The BP volumes receiving at least 50 Gy, 60 Gy, 61 Gy, and 62 Gy were also significantly higher in the boosted group compared with the control group (P < .001).ConclusionsThis study found that an SCV boost of 10 Gy did not increase the incidence of BPN-related symptoms and that the toxicity to the BP was acceptable. Comprehensive treatment including SCV irradiation and boost led to satisfactory survival outcomes in patients with breast cancer who had SLN metastasis.     

Concomitant boost radiotherapy in oropharynx carcinomas

Fifty-five patients with resectable and unresectable oropharynx carcinomas were treated with concomitant boost radiotherapy. Forty-two of the patients (76%) had stages III-IV disease. Although none of the patients had undergone major surgery to the primary tumor, 11 had neck dissections prior to radiotherapy, and 19 (35%) received chemotherapy. The planned total tumor dose was 69.9 Gy, delivered over 5.5 weeks. During the last 3.5 weeks, a boost to the initial gross disease was delivered in 13 fractions of 1.5 Gy each, as a second daily fraction in a progressively accelerated schedule; the prescribed dose outside the boost volume thus was 50.4 Gy. Median follow-up for surviving patients was 31.5 months (range: 16-65 months). All patients but one completed the planned radiotherapy schedule. According to the RTOG scoring system, 48 patients (88%) presented with grades 3-4 acute toxicity. The rate of grades 3-4 late complications was 12%. At three years the actuarial locoregional control rate was 69.5% and overall survival was 60%. We conclude that this concomitant boost schedule is feasible and does not seem to be associated with an excess risk of late complications. Acute toxicity was higher in association with chemotherapy, but remained manageable. Although the oncological results appear encouraging, evaluation of the efficacy of concomitant boost schedules compared with conventionally fractionated irradiation with or without concomitant chemotherapy requires prospective randomized trials.     

Concomitant Boost Radiotherapy in Oropharynx Carcinomas

Fifty-five patients with resectable and unresectable oropharynx carcinomas were treated with concomitant boost radiotherapy. Forty-two of the patients (76%) had stages III-IV disease. Although none of the patients had undergone major surgery to the primary tumor, 11 had neck dissections prior to radiotherapy, and 19 (35%) received chemotherapy. The planned total tumor dose was 69.9 Gy, delivered over 5.5 weeks. During the last 3.5 weeks, a boost to the initial gross disease was delivered in 13 fractions of 1.5 Gy each, as a second daily fraction in a progressively accelerated schedule; the prescribed dose outside the boost volume thus was 50.4 Gy. Median follow-up for surviving patients was 31.5 months (range: 16-65 months). All patients but one completed the planned radiotherapy schedule. According to the RTOG scoring system, 48 patients (88%) presented with grades 3-4 acute toxicity. The rate of grades 3-4 late complications was 12%. At three years the actuarial locoregional control rate was 69.5% and overall survival was 60%. We conclude that this concomitant boost schedule is feasible and does not seem to be associated with an excess risk of late complications. Acute toxicity was higher in association with chemotherapy, but remained manageable. Although the oncological results appear encouraging, evaluation of the efficacy of concomitant boost schedules compared with conventionally fractionated irradiation with or without concomitant chemotherapy requires prospective randomized trials.     

Fast neutron and mixed beam radiotherapy for inoperable non-small cell carcinoma of the lung. Results of an RTOG randomized study

From July 1979 through March 1984 the Radiation Therapy Oncology Group conducted a randomized study comparing fast neutron radiotherapy versus mixed beam (neutron/photon) radiotherapy versus conventional radiotherapy for patients with non-small cell carcinoma of the lung. Patients were either medically or technically inoperable. One hundred two evaluable patients were placed on the study. The radiation doses were approximately 60 Gy-equivalent on each arm. Patients were stratified according to size of primary, histology, Karnofsky performance status, and age distribution. Overall local response rates as measured by serial radiographs were the same on the three arms, and an actuarial analysis showed no significant differences in either median or long-term survival. However, for the subgroup of patients exhibiting a complete or partial tumor response at 6 months there was a suggestion of improved 3-year survival on the two experimental arms (mixed beam, 37%; neutrons, 25%; photons, 12%). The p value for the difference between the mixed beam and photon curves is 0.14 (two-sided test). The incidence of major complications was higher on the neutron and mixed beam arms. These complications included four cases of myelitis which are analyzed in detail. The results are placed in the context of other published work on the use of neutrons in the treatment of lung cancer.     

Locally advanced breast cancer treated with neutron beams: long-term follow-up in 28 patients

Between 1972 and 1978, 28 patients with locally advanced breast cancer were treated, 15 with neutron beams only and 13 with mixed neutron and photon beams. Half the patients had inflammatory cancer. For neutrons only, doses ranged between 13.35-25.34 nGy. In mixed-beam regimens, the prescribed total dose ranged between 62 and 76 Gy photon equivalent. Nine patients (32%) had a complete response without local recurrence for the duration of their survival ranging from 1 to 14+ years; 18 patients had a partial response (64%); and one patient had no change. Late toxicity was high: of 24 patients who received tangential breast irradiation, 5 (21%) had ulceration of the breast or chest wall, or both. In four patients, mastectomy and skin grafts were necessary for repair. In only one patient did the skin necrosis heal without corrective surgery. Twelve patients received axillary neutron irradiation, resulting in severe edema in four patients, and brachial plexopathy in six patients. Radiation-induced complications progressed steadily for the duration of the patients' survival after the neutron irradiation. The high complication rate encountered is attributed to high doses resulting from an under estimation of the relative biological effect of the neutron beam for late effects, and to the poor physical and geometrical characteristics of the neutron beam.     

Randomized trial of initial chemotherapy in 151 locally advanced carcinoma of the cervix (T2b-N1, T3b, MO)

From 1982 to 1987, a randomized phase III trial was performed in order to determine the long-term effect of induction chemotherapy before standard pelvic irradiation in stage IIb-N1, III squamous cell carcinomas of the cervix. Patients were randomized to either chemotherapy and radiotherapy (C + R group) vs radiotherapy alone (R group). Radiotherapy for all patients consisted of 50 Gy in the pelvis with a boost by external irradiation or by brachytherapy (cumulative dose of 68 Gy). The chemotherapy regimen was an association of methotrexate (10 mg/m2, D2-4), chlorambucil (4 mg/m2, D1-5), vincristine (0,7 mg/m2, D1), cisplatin (80 mg/m2, D5), given every 3 wks; at least 2 courses were to be given before assessing efficacy and 2 more courses were given to patients who responded. One hundred and fifty-one patients were fully evaluable, after a mean follow-up of 38 mths (range 2-7 years), 76 in the R arm and 75 in the C + R arm. The response rate (greater than 50%) to chemotherapy was 42.5%. After completion of treatment, the complete response rate was 86.8% in the R arm and 86.3% in the C + R arm. The 3 year disease-free survival was 58.7% in the C + R group and 54.5% in the R group, and the median survival was 39.5% and 47 months respectively (NS). The survival of patients with a complete response at the end of radiotherapy was significantly better in the C + R group (when chemotherapy had been active) than in the R group (p = 0.04). Although radiotherapy was not modified whether patients had initial chemotherapy or not, tolerance was not significantly different between the 2 groups. The data collected in this study indicate that: 1) efficacy of induction chemotherapy is the only available predictive test for long-term results, 2) tolerance to treatment is crucial for optimal chemotherapy delivery, 3) higher dose intensity of chemotherapy in cervical carcinoma is associated with a better tumor reduction, and probably a better survival.     

Clinical report on external irradiation combined with californium-252 neutron intraluminal brachytherapy for cervical carcinoma treatment

AIMS AND BACKGROUND: Neutron rays produce high linear energy transfer radiation, which has particular radiobiological characteristics. The aim of the study was to observe the curative effects and complications of external irradiation combined with californium-252 (252Cf) neutron intraluminal brachytherapy for treatment of cervical carcinoma. METHODS AND STUDY DESIGN: From December 2000 to December 2004, 128 cases of cervical carcinoma staged IIA to IIIB were treated with 252Cf neutron intraluminal brachytherapy using 8-10 Gy-eq per fraction, once a week. The total dose at reference point A was 36-40 Gy-eq in 4 to 5 fractions. From the second day after 252Cf neutron intraluminal brachytherapy, the whole pelvic cavity was treated with 6 MV X-ray external irradiation, applying 2 Gy per fraction 4 times per week. After 20-24 Gy of external irradiation, the center of the whole pelvic field was blocked with a 4-cm-wide lead shield; the total dose of external irradiation was 44-50 Gy. RESULTS: The short-term curative effects were 95.3% complete remissions and 4.7% partial remissions. The 3-year and 5-year local control rates were 93.5% and 87.9%, respectively. The 3-year and 5-year survival rates were 87.5% and 70%, respectively. The rates of radiation complications were 4.7% for radiation cystitis, 7.8% for radiation proctitis, 6.3% for vaginal contracture and adhesion, and 5.5% for protracted radiation proctitis. The results of univariate and multivariate analysis indicated that differentiation of tumor cells and lymphatic metastasis are the main factors related to the clinical prognosis of cervical carcinoma. CONCLUSIONS: A combination of external irradiation with 252Cf neutron intraluminal brachytherapy for treatment of cervical carcinoma can be well tolerated by patients. The rate of local tumor control is high and radiation complications are few.     

立体适形推量放射治疗在鼻咽癌首程放疗中的应用

目的：探索立体适形推量放射治疗在鼻咽癌首程放疗中的临床应用价值。方法：2000年5月～2002年9月，31例初治鼻咽癌患者，常规外照射至40～49天总量59～70Gy／30～35次后行立体适形推量放射治疗，以90％等剂量覆盖靶区，每次3～4Gy，每周3次，共治疗3～5次。其中15例每次3Gy，16例每次4Gy。结果：随访时间11～40月，中位随访时间23月，一、二年局控率分别为100％、90．81％，一、二年生存率分别为100％、94．44％，无严重放疗反应发生。结论：三维适形放射治疗作为推量技术应用于鼻咽癌首程放疗是可行的，并显示较好的局控和生存结果，远期疗效尚待进一步观察。     

Radiotherapy for advanced adenoid cystic carcinoma: neutrons, photons or mixed beam?

PURPOSE: To compare retrospectively radiotherapy with neutrons, photons, and a photon/neutron mixed beam in patients with advanced adenoid cystic carcinoma of the head and neck. Local control, survival, distant failure, and complications were analyzed. MATERIALS AND METHODS: Between 1983 and 1995, 75 patients with inoperable, recurrent, or incompletely resected adenoid cystic carcinoma of the head and neck received radiotherapy that consisted of either fast 14.1 MV DT neutrons (median dose 16 neutron Gy), linac-based photon irradiation (median dose 64 photon Gy), or both (median dose 8 neutron Gy and 32 photon Gy). Follow-up ranged from 1 to 160 months (median 51 months), and the surviving patients had a minimum follow-up of 3 years at the time of analysis. RESULTS: The actuarial 5-year local control was 75% for neutrons, and 32% for both mixed beam and photons (P = 0.015, log-rank). This advantage for neutrons in local control was not transferred to significant differences in survival (P > 0.1). The survival is dictated by the tumor diseases due to distant metastases occurring in 29 (39%) of the 75 patients. Positive lymph nodes were the only significant factor (P = 0.001) associated with the development of distant metastases although negative lymph nodes did not predict absence of distant metastases, but predicted a delay of occurrence. In multivariate analysis postoperative radiotherapy (P = 0.003) and small tumor size (P = 0.01) were associated with high local control, while primary therapy (P = 0.006) and negative lymph nodes (P = 0.01) were associated with longer survival. While acute toxicity was similar in all three radiotherapy groups, severe late grade 3 and 4 toxicity tended to be more prevalent (P > 0.1) with neutrons (19%) than with mixed beam (10%) and photons (4%). CONCLUSION: Fast neutron radiotherapy provides higher local control rates than a mixed beam and photons in advanced, recurrent or not completely resected adenoid cystic carcinoma of the major and minor salivary glands. Neutron radiotherapy can be recommended in patients with bad prognosis with gross residual disease (R2), with unresectable tumors, or inoperable tumors. The type of radiation does not impact survival, which is dominated by the high number of distant metastases.