Molecular and pharmacological characterization of recombinant rat/mice N-methyl-D-aspartate receptor subtypes in the yeast Saccharomyces cerevisiae

PURPOSE: To assess the local control and survival in patients who received pelvic irradiation for locally recurrent rectal carcinoma. METHODS AND MATERIALS: The records of 519 patients with locally recurrent rectal carcinoma treated principally with external-beam radiation therapy between 1975 to 1985 at a single institute were retrospectively reviewed. These included 326 patients who relapsed locally following previous abdominoperineal resection, 151 after previous low anterior resection, and 42 after previous local excision or electrocoagulation for the primary. No patients had received adjuvant radiation therapy or chemotherapy for the primary disease. Concurrent extrapelvic distant metastases were found in 164 (32%) patients at local recurrence and, in the remaining 355, the relapse was confined to the pelvis. There were 290 men and 229 women whose age ranged from 23 to 91 years (median = 65). Median time from initial surgery to radiation therapy for local recurrence was 18 months (3-138 months). Radiation therapy was given with varying dose-fractionation schedules, total doses ranging from 4.4 to 65.0 Gy (median = 30 Gy) over 1 to 92 days (median = 22 days). For 214 patients who received a total dose > or = 35 Gy, radiation therapy was given in 1.8 to 2.5 Gy daily fractions. RESULTS: The median survival was 14 months and the median time to local disease progression was 5 months from date of pelvic irradiation. The 5-year survival was 5%, and the pelvic disease progression-free rate was 7%. Twelve patients remained alive and free of disease at 5 years after pelvic irradiation. Upon multivariate analysis, overall survival was positively correlated with ECOG performance status (p = 0.0001), absence of extrapelvic metastases (p = 0.0001), long intervals from initial surgery to radiation therapy for local recurrence (p = 0.0001), total radiation dose (p = 0.0001), and absence of obstructive uropathy (p = 0.0013). Pelvic disease progression-free rates were positively correlated with ECOG performance status (p = 0.0001), total radiation dose (p = 0.0001), and previous conservative surgery for the primary (p = 0.02). CONCLUSIONS: Survival is poor for patients who develop local recurrence following previous surgery for rectal carcinoma. Pelvic radiation therapy provides only short-term palliation, and future efforts should be directed to the use of effective adjuvant therapy for patients with rectal carcinoma who are at high risk of local recurrence.     

Effect of adjuvant iridium-192 brachytherapy on the survival of patients with malignant gliomas

The effect of iridium-192 brachytherapy (BRTX) on the survival of patients with malignant gliomas was evaluated in 83 patients with malignant gliomas (42 astrocytoma grade III, 41 glioblastoma multiforme) over a period of 8.5 years. Fifty patients (Group 1) received only standard external beam radiotherapy (EBRT) (mean dose 51.5 +/- 12.4 Gy in 2.0 Gy fractions), and 33 patients (Group 2) received EBRT (mean dose 51.0 +/- 10.8 Gy) combined with BRTX (mean dose 50.2 +/- 13.2 Gy, dose rate of 0.3-0.4 Gy/hr). The median survival periods for patients in Groups 1 and 2 were 12.2 and 23.7 months, respectively (p = 0.0145). The median survival for 17 patients in Group 2 with glioblastoma multiforme was 21.9 months. Using BRTX as an adjuvant to EBRT appeared to confer survival benefits compared to only EBRT (p = 0.0284). Univariate and multivariate analysis identified the variables of histological diagnosis, location, Karnofsky performance status, and BRTX as relevant risk factors for survival time (p < 0.05 for each factor). Among these factors, BRTX was the most important for prolonging survival (p = 0.0015). Adjuvant iridium-192 BRTX and conventional EBRT appears to greatly improve the survival time of patients with malignant gliomas compared to only EBRT and may be the treatment of choice in selected patients with tumors located in deep-seated or eloquent areas.     

Inoperable non-small cell lung cancer: a retrospective analysis of 427 patients treated with high-dose radiotherapy

PURPOSE: The influence of patient and treatment characteristics on survival as well as normal tissue toxicity were retrospectively analyzed. METHODS AND MATERIALS: Four hundred twenty seven patients with unresectable non-small cell lung cancer received at least 60 Gy and two-thirds were treated with 70 Gy. RESULTS: Five-year survival rates and median survival time (95% confidence interval) were 2 +/- 2% (mean +/- s.e.) and 11.1 months (9.1-14.5) after 60-66 Gy (median 60 Gy); 8 +/- 2% and 14.9 months (13.3-16.5) after > or = 70 Gy (p = 0.0013). Stage I-II patients had significantly higher survival rates as compared to Stage III patients (p = 0.0015). Within the subgroup of Stage III patients those with Stage IIIA had significantly higher survival rates than Stage IIIB (p = 0.0167). Female patients achieved 5-year survival rates after 70 Gy of 15 +/- 7% as compared to only 7 +/- 2% of their male counterparts. Chemotherapy, histology, Karnofsky status, and age had no influence on survival after univariate and multivariate analysis. Nine percent and 11% of the patients suffered from moderate to severe pneumonitis and esophagitis. CONCLUSION: High-dose radiotherapy of unresectable non-small cell lung cancer with total doses > 60 Gy conventionally fractionated is feasible. With doses of > or = 70 Gy significantly higher survival rates were achieved as compared to 60-66 Gy. Normal tissue toxicity was acceptable. For Stage IIIB patients, however, treatment results are disappointingly low even after 70 Gy with no 5-year survivor.     

Results and prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma

PURPOSE: To review the results and evaluate the prognostic factors in the retreatment of locally recurrent nasopharyngeal carcinoma. METHODS AND MATERIALS: We reviewed the records of 74 patients with locally recurrent nasopharyngeal carcinoma treated at the University of California, San Francisco between 1957 and 1995. The histologic types included squamous cell carcinoma in 6 (8.1%), nonkeratinizing carcinoma in 48 (64.9%), and undifferentiated carcinoma in 20 (27%) cases. The site of recurrence was in the primary in 46 (62.2%), in the neck nodes in 20 (27%), and in both sites in 8 (10.8%) patients. The recurrent disease was Stage I in 10 (13.5%), Stage II in 16 (21.6%), Stage III in 20 (27%), and Stage IV in 28 (37.9%) patients. Thirty-seven (50%) patients developed recurrence within 2 years and 58 (78.4%) within 5 years after initial treatment. Radiotherapeutic techniques used in the retreatment of primary recurrence consisted of external beam radiotherapy (EBRT), intracavitary brachytherapy, heavy-charged particle beam, and gamma knife, alone or in combination. Reirradiation doses ranged from 18 to 108 Gy, with a median dose of 60 Gy. Treatment of recurrent neck nodes consisted of radical neck dissection (RND) +/- intraoperative radiotherapy (IORT), or EBRT +/- hyperthermia, or chemotherapy +/- hyperthermia. Chemotherapy was used in 22 (30%) patients. Median follow-up was 20 months (range: 2 to 308 months). RESULTS: The 3-, 5-, and 10-year actuarial overall survival following retreatment were 49, 37, 18%, respectively. Thirty-six patients (49%) were free of further local-regional recurrence after retreatment. The 3-, 5-, and 10-year local-regional progression-free rates were 52, 40, and 38%, respectively. On univariate analysis, histologic type (p < 0.0001), interval to recurrence (p = 0.034), and treatment modality for early-stage disease (p = 0.01) were significant prognostic factors for overall survival, with age being marginally significant (p = 0.053). For local-regional progression-free rate, only histology was significant (p = 0.035). On multivariate analysis, age (p = 0.026), histology (p = 0.015), and interval to recurrence (p = 0.030) were significant for overall survival, and only histology (p = 0.002) and presence of complications (p = 0.016) were significant for local-regional progression-free rate. Of the 64 reirradiated patients, late complications were documented in 29 (45%) patients. The late complications were permanent in 21 (33%) and severe in 15 (23%) patients. CONCLUSION: Retreatment using radiotherapy alone or in combination with other treatment modalities can achieve long-term local-regional control and survival in a substantial proportion of patients with locally recurrent nasopharyngeal carcinoma. Age, histology, and interval to recurrence were independent prognostic factors for overall survival, but only histology and presence of complications were significant for local-regional progression-free rate.     

Impact of radiation therapy fraction size on local control of early glottic carcinoma

PURPOSE: Different radiotherapy fractionation schedules were used over a 10-year period to treat patients with early squamous cell carcinoma of the vocal cords at McGill University. A retrospective analysis was performed to study the effect of fraction size on local control in this group of patients. METHODS AND MATERIALS: A total of 126 previously untreated patients with T1 invasive squamous cell carcinoma of the true vocal cords were irradiated between January 1978 and December 1988 in the Department of Radiation Oncology at McGill University. All patients received megavoltage irradiation, 94 patients received daily fractions > 2 Gy (64 patients received 50 Gy with once-daily 2.5-Gy fractions, and 30 received 65.25 Gy in 29 fractions of 2.25 Gy each), and 32 patients were treated to a dose of 66 Gy in 33 fractions with 2 Gy/fraction. Patients' characteristics of prognostic importance were equally distributed between the two fractionation groups. RESULTS: At a median follow-up of 84 months, the 10-year disease-free survival and overall survival were 76% and 93%, respectively. Local control for patients treated with > 2 Gy fraction was 84%, compared to 65.6% for those treated with 2-Gy fractions (p = 0.026). Among the prognostic factors tested, such as gender, age, stage, anterior and posterior commissure involvement, smoking history, and fraction size, the latter was the only significant predictor of local control for the whole group of patients in univariate (p = 0.041) and multivariate (p = 0.023) analysis. There was no observed difference in the incidence of complications between the two fractionation groups. CONCLUSIONS: From the results of this retrospective review of patients treated with radiotherapy for T1 true vocal cord cancer, and within the range of total doses and overall treatment times used in our patients, it was found that fractionation schedules using daily fraction size > 2 Gy are associated with a better local control than schedules delivering 2 Gy/fraction, with no increase in toxicity.     

The radiotherapy of inoperable non-small-cell bronchial carcinoma. A retrospective analysis of 427 cases

BACKGROUND: The influence of tumor and patient characteristics on survival as well as acute normal tissue toxicity was retrospectively analyzed. PATIENTS AND METHODS: 427 patients with inoperable non-small cell lung cancer were retrospectively analyzed. Two thirds received a total dose of at least 70 Gy, and one third was irradiated with 60 to 66 Gy (2.0 to 2.5 Gy per fraction; split-course technique). 92% had a Karnofsky performance index of > or = 80%. Kaplan-Meier survival curves were generated and comparisons were made by the log-rank test. Prognostic factors were adjusted for by a proportional hazards analysis. RESULTS: Five-year survival rates (+/- SE) and the median survival times (95% confidence interval) were 2 +/- 2% and 11.1 months (9.1 ... 14.5) after 60 to 66 Gy; 8 +/- 2% and 14.9 months (13.3 ... 16.5) after 70+ Gy. The difference was significant in univariate (p = 0.0013) and multivariate analysis (p = 0.0006). Tumor stage (p = 0.0029: I + II > III; IIIA > IIIB) and gender (p = 0.0387: female > male patients) reached significance in multivariate analysis. Acute pneumonitis and esophagitis were observed in 11% and 9% of cases. CONCLUSIONS: Inoperable non-small cell lung cancer stage I to IIIA should be treated in a curative intention with total doses of about 70 Gy. This is feasible with acceptable normal tissue toxicity. Stage IIIB patients have a particular bad prognosis and should only be treated palliatively.     

Fractionated high dose rate intraluminal brachytherapy in palliation of advanced esophageal cancer

PURPOSE: To optimize the dose of fractionated brachytherapy for palliation of advanced esophageal cancer. METHODS AND MATERIALS: One hundred and seventy-two patients with advanced esophageal cancer were randomized to receive 12 Gy/2 fractions (group A); 16 Gy/2 fractions (group B), and 18 Gy/3 fractions (group C) by high dose rate intraluminal brachytherapy (HDRILBT). Treatment was given weekly and dose prescribed at 1 cm from the source axis. Patients were followed up monthly and assessed for dysphagia relief and development of complications. RESULTS: Twenty-two patients died before completing treatment due to advanced disease and poor general condition. The overall survival was 19.4% at the end of 12 months for the whole group (A--9.8%, B--22.46%, C--35.32%; p > 0.05). The dysphagia-free survival was 28.9% at 12 months for the whole group (A--10.8%, B--25.43%, C--38.95%; p > 0.05). Forty-three patients developed fibrotic strictures needing dilatation (A--5 of 35, B--15 of 60, C--23 of 55; p = 0.032). Twenty-seven patients had persistent luminal disease (A--11, B--6, C--10), 15 of which progressed to fistulae (A--7, B--2, C--6; p = 0.032). There was no effect of age, sex, race, histology, performance status, previous dilation, presenting dysphagia score, presenting weight, grade, tumor length, and stage on overall survival, dysphagia-free, and complication-free survival (p > 0.05). On a multivariate analysis, brachytherapy dose (p = 0.002) and tumor length (p = 0.0209) were found to have a significant effect on overall survival; brachytherapy dose was the only factor that had an impact on local tumor control (p = 0.0005), while tumor length was the only factor that had an effect on dysphagia-free survival (p = 0.0475). When compared to other forms of palliation currently available (bypass surgery, laser, chemotherapy, intubation, external radiotherapy), fractionated brachytherapy gave the best results with a median survival of 6.2 months. CONCLUSIONS: Fractionated brachytherapy is the best modality for palliation of advanced esophageal cancer. It offers the best palliation to patient when compared to all other modalities currently available. The optimal brachytherapy dose ranges between 16 Gy in two fractions and 18 Gy in three fractions given a week apart.     

Radiosurgery alone or in combination with whole-brain radiotherapy for brain metastases

PURPOSE: Evaluation of the treatment outcome after radiosurgery (RS) alone or in combination with whole-brain radiotherapy (WBRT) with special attention to prescribed dose and its influence on local control and survival. PATIENTS AND METHODS: Between September 1984 and January 1997, 236 patients with 311 brain metastases treated with radiosurgery met the following inclusion criteria: one to three brain metastases per patient; no previous WBRT; and Kamofsky performance status (KPS) > or = 50%. One hundred fifty-eight patients treated only with RS received a median dose of 20 Gy prescribed to the 80% isodose line; 78 patients received RS with a median dose of 15 Gy/80% and an additional course of WBRT. RESULTS: For the entire series, overall median survival was 5.5 months, with control of CNS disease achieved in 92% of the treated brain metastases; the results were not significantly different between patients treated by RS with or without WBRT. However, in patients without evidence of extracranial disease, median survival was increased for patients who received WBRT (15.4 vs 8.3 months; P=.08). Additionally, there was a suggestion that increased doses for patients treated with RS only resulted in improved outcome. Four lesions were suspicious for radiation necrosis by magnetic resonance imaging (MRI); in one of the four lesions, radiation necrosis was confirmed histologically. The incidence of transient low-grade toxicity was 18%; symptoms could be treated by the temporary administration of steroids. CONCLUSION: RS is an effective, noninvasive means of controlling brain metastases when used alone or in combination with WBRT. There is a trend for superior local control and especially in patients without extracranial disease for superior survival when RS is used in conjunction with WBRT. Randomized trials would seem to be warranted, comparing the benefit of RS with or without additional WBRT.     

Nasopharyngeal carcinoma in childhood and adolescence

BACKGROUND: This study reviews the authors' experience from 1979 through 1996 in the management and outcome of 56 patients with nasopharyngeal carcinoma who were under 20 years of age. PROCEDURE: There were 33 males and 23 females, their ages ranging from 7 to 19 years (median: 16 years). Forty patients had World Health Organization type III carcinomas, 16 had T4 tumors, 41 had metastatic cervical lymph nodes, and 50 were at stage III or stage IV. Thirty-two patients were treated with radiation therapy alone and 24 with the addition of chemotherapy. Cumulative radiation dose to the primary tumor ranged from 18 to 70 Gy (median: 66 Gy) and radiation dose to metastatic cervical lymph nodes ranged from 18 to 70 Gy (median: 66 Gy). RESULTS: Follow-up ranged from 0.1 to 16.8 years (mean: 9 years). Locoregional tumoral complete response was achieved in 49 patients. Locoregional tumoral failure was observed in 12 patients and systemic failure in 11. Overall, locoregional failure-free, metastases-free, and disease-free survival rates at 5 years were 49%, 62%, 79%, and 47%, respectively, for the entire group of patients, 42%, 61%, 72%, and 42%, respectively, for patients treated with radiation therapy alone, and 58%, 63%, 87%, and 54%, respectively, for patients treated with the addition of chemotherapy. Advanced T-stage and lower radiation doses worsened locoregional failure-free survival, whereas advanced N-stage and exclusion of chemotherapy worsened metastases-free survival. CONCLUSIONS: In children and adolescents with nasopharyngeal carcinoma, radiation therapy alone results in an improved locoregional tumoral response rate and a reduced locoregional tumoral failure rate at higher radiation doses, while the addition of chemotherapy results in a reduced systemic failure rate.     

Chronic lymphocytic leukemia presenting as pyogenic arthritis of the proximal interphalangeal joint

PURPOSE: To evaluate the results of 125I brachytherapy in colorectal cancers recurrent in the pelvis and paraortics. METHODS AND MATERIALS: From September 1989 to January 1997, 29 patients with colorectal adenocarcinoma recurrent in the pelvis or the paraortic nodes were treated intraoperatively with permanent 125iodine seed implantation at the James Cancer Center of The Ohio State University (OSU). All patients had undergone prior surgery; 72% had prior EBRT. The implanted residual tumor volume was microscopic in 38% and gross in 62%. The implanted area (median 25 cc) received a median minimal peripheral dose of 140 Gy to total decay. An omental pedicle was used to minimize irradiation of the bowel. Five patients received additional postimplant EBRT (20-50 Gy; median 30 Gy). RESULTS: The 1-, 2-, and 4-year actuarial local-regional control rates were 38%, 17%, and 17%, respectively, with a median time to local failure of 11 months (95% CI 10-12 months). The first manifestation of disease progression in 52 % of the patients was local-regional. In addition, 22 patients (75%) developed distant metastases. The 1-, 2-, and 4-year actuarial overall survival rates were 70%, 35%, and 21%, (median = 18 months; 95% CI: 14-22 months). Overall survival was better for patients smaller volume implants (p = 0.007), with a lower total activity implanted (p = 0.0003), with a smaller number of implanted sites (p = 0.004), and with microscopic residual disease (p = 0.01). Patients receiving additional EBRT also had a better prognosis (p = 0.005). Local tumor progression was the cause of death in 34% of the patients who have died at the time of this report and 56% died of distant metastases. Of the patients, 13 (45%) experienced 15 toxic events, including 3 patients (10%) with enteric fistula. Neuropathy was not observed. CONCLUSIONS: 125I brachytherapy can be successfully used for salvage in patients with recurrent colorectal cancer. Patients with isolated, microscopic, or minimal gross residual disease requiring small-volume implants and those receiving additional EBRT have a better prognosis. Postimplant EBRT is now routinely added, even for previously irradiated patients, in an attempt to improve local control. Compared to IOERT and IOHDR, 125I brachytherapy is not associated with clinical neuropathy, probably due to the continuous low dose rate irradiation delivered by the 125I seeds.     

The activated clotting time loading dose response ratio (ACTLORR) as an indicator of heparin demand during cardiopulmonary bypass

PURPOSE: To develop a new technique, intraoperative high dose rate brachytherapy (IOHDR), to deliver localized radiation therapy intraoperatively to head and neck tumors at sites inaccessible to intraoperative electron beam radiotherapy (IOEBRT) in the skull base region. METHODS: After maximal surgical resection, afterloading catheters spaced 1 cm apart embedded in custom surface applicators made of foam or silicone were placed on resected tumor beds. IOHDR was delivered in a shielded operating room using preplanned dosimetry with a nominal 10 Ci iridium-192 source in an HDR micro-Selectron afterloader. Twenty-nine patients (20 males, 9 females) ranging in age from 9 to 80 years (median = 61) were irradiated intraoperatively for advanced head and neck tumors at sites inaccessible to IOEBRT. Six patients who had previously received external beam radiation (EBRT) ranging from 50 to 75 Gy, were given 15 Gy of IOHDR only. Twenty-three patients who had no prior radiation received 7.5 to 12.5 Gy IOHDR, and 45 to 50 Gy EBRT was planned post-operatively; however, six of these patients did not complete the planned EBRT. Doses to normal tissues were reduced whenever possible by shielding with lead or by displacement with gauze or retractors. Treatment time ranged from 3.8 to 23 min (median = 6.5 min). Five patients received concurrent cis-platinum based chemotherapy. RESULTS: Twenty-nine patients treated to 30 sites had local tumor control of 67% and crade survival of 72%, with the follow-up ranging from 3 to 33 months (median = 21 months). In the group of 17 previously unirradiated patients who had completed full treatment (IOHDR and EBRT) to 18 sites, the local tumor control was 89%, and all of these patients survived. Tumor control in the six previously unirradiated patients who did not complete EBRT was 50% with a crude survival of 50%. In the group of six previously irradiated patients treated by IOHDR only, the local tumor control was 17% with a crude survival of 17%. No intraoperative complications were noted. The delayed morbidity included cerebrospinal fluid (CSF) leak with bone exposure (1), chronic subdural hematoma (1), septicemia (1), otitis media (1), and severe xerostomia (1). We cannot comment on long-term morbidity due to the relatively short follow-up period of 21 months. CONCLUSIONS: It is feasible to deliver IOHDR, with acceptable toxicity, to skull base tumors at sites inaccessible to IOEBRT. The use of IOHDR as a pre-radiotherapy boost produced excellent local control and survival in the selected group of patients who had no previous radiation therapy. The use of exclusive IOHDR in the previously irradiated group resulted in poor outcome, possibly due to the limitations on re-irradiation doses and/or volumes determined by normal tissue tolerance or because these patients have inherently radioresistant tumors. Higher IOHDR doses, additional EBRT, and/or chemotherapy should be considered for this group. The use of IOHDR as a pre-EBRT boost to maximize local control has a promising future in the treatment of carefully selected patients with advanced skull base tumor.     

Trends in surgical management of astrocytomas and other brain gliomas

PURPOSE: Retrospective analysis of the influence of clinical and technical factors on local control and survival after radiosurgery for brain metastasis. PATIENTS AND METHODS: From January 1994 to December 1996, 42 patients presenting with 71 metastases underwent radiosurgery for brain metastasis. The median age was 56 years and the median Karnofsky index 80. Primary sites included: lung (20 patients), kidney (seven), breast (five), colon (two), melanoma (three), osteosarcoma (one) and it was unknown for three patients. Seventeen patients had extracranial metastasis. Twenty-four patients were treated at recurrence which occurred after whole brain irradiation (12 patients), surgical excision (four) or after both treatments (eight). Thirty-six sessions of radiosurgery have been realized for one metastasis and 13 for two, three or four lesions. The median metastasis diameter was 21 mm and the median volume 1.7 cm3. The median peripheral dose to the lesion was 14 Gy, and the median dose at the isocenter 20 Gy. RESULTS: Sixty-five metastases were evaluable for response analysis. The overall local control rate was 82% and the 1-year actuarial rate was 72%. In univariate analysis, theoretical radioresistance (P = 0.001), diameter less than 3 cm (P = 0.039) and initial treatment with radiosurgery (P = 0.041) were significantly associated with increased local control. Only the first two factors remained significant in multivariate analysis. No prognostic factor of overall survival was identified. The median survival was 12 months. Six patients had a symptomatic oedema (RTOG grade 2), only one of which requiring a surgical excision. CONCLUSION: In conclusion, 14 Gy delivered at the periphery of metastasis seems to be a sufficient dose to control most brain metastases, with a minimal toxicity. Better results were obtained for lesions initially treated with radiosurgery, theoretically radioresistant and with a diameter less than 3 cm.     

Carcinoma of the nasopharynx in young patients

PURPOSE: To provide an analysis of eighteen cases of adolescent nasopharyngeal carcinoma treated between 1971 and 1989. METHODS AND MATERIALS: Between 1971 and 1989, 48 cases of nasopharyngeal carcinoma were evaluated at the Medical College of Georgia Hospital and Clinics. Eighteen patients between the ages of 9 and 29 years were treated at the Georgia Radiation Therapy Center. All patients presented for treatment with (AJCC) Stage IV disease. Fifteen patients with lymphoepithelioma and three with squamous cell carcinoma histologies received definitive radiation therapy to a median dose of 64.8 Gy. Males outnumbered females by more than 2:1 and the majority of patients (67%) were black. Nine patients received multiagent adjuvant chemotherapy. RESULTS: Thirteen patients are alive from 7 to 166 months (median 32 months) including three with disease at 17, 24, and 132 months. Overall and disease-free survival at 5 and 10 years were 63% and 54%, respectively. Five patients died from disease; four patients had pulmonary metastases while one had CNS metastasis. Eighty percent of relapses occurred within the first 2 years following treatment. Acute and chronic toxicities were limited, consisting primarily of mucositis and xerostomia. Radiation doses of 65 Gy or more (p = 0.049) and age greater than 20 years (p = 0.005) were positive prognosticators for survival. Adjuvant chemotherapy, race, and sex were not found to be of prognostic value. Disparities in the distribution of patients with lymphoepithelioma and squamous cell histologies and the presentation of advanced regional disease precluded analysis for prognostic significance of histology and nodal status in this series. CONCLUSION: The results of the present series compare favorably with those published from other institutions. High doses of radiation and a high systemic failure rate continue to be the fundamental obstacles to effective management and enhanced survival for patients with nasopharyngeal carcinoma.     

Treatment of intracranial ependymomas of children: review of a 15-year experience

PURPOSE: There are still major controversies in the optimal management of children with intracranial ependymomas. To assess the impact of tumor site, histology, and treatment, the outcome of children treated at the Institut Gustave Roussy was reviewed retrospectively. METHODS AND MATERIALS: Between 1975 and 1989, 80 children aged 4 months to 15.8 years were seen at the Institut Gustave Roussy for postoperative management of an intracranial ependymoma. Location of tumor was infratentorial in 63 cases and supratentorial in 17. Surgical treatment consisted of complete resection in 38, incomplete resection in 38 and biopsy only in 4. Postoperative irradiation was done in 65 patients and chemotherapy in 33. Surviving patients have been followed from 12-197 months with a median of 54 months. RESULTS: The 5-year actuarial survival and event-free survival are 56% and 38%, respectively. Thirty-four patients relapsed from 3-72 months after diagnosis (median 25 months). In 20 patients, the only site of failure was the original tumor site. Three patients failed locally and at distance, while 10 others failed only at distance. Survival at 5 years was significantly better for patients who had complete resection of the tumor (75% vs. 41%, p = 0.001) and for those who received radiation therapy (63% vs. 23%, p = 0.003). Event-free survival at 5 years was superior in patients with complete resection of the tumor (51% vs. 26%, p = 0.002) and in patients who received radiation therapy (45% vs. 0%, p < 0.001). Sex and tumor site had no impact on survival or event-free survival. There was no difference in survival, event-free survival, or pattern of failure between patients treated with local field, whole brain or craniospinal irradiation, while severe longterm sequelae were noted predominantly in the latter two groups. CONCLUSION: Considering that failures were predominantly local and that there was no apparent benefit from prophylactic irradiation, we recommend local field irradiation with doses above 50.0 Gy for all children with intracranial ependymomas, without meningeal dissemination at diagnosis. Special considerations are necessary for children < 3 years of age.     

Repair of congenital tracheal stenosis with a free tracheal autograft

PURPOSE: This retrospective review was conducted to determine if delay in the start of radiotherapy after definitive breast surgery had any detrimental effect on local recurrence or disease-free survival in node-negative breast cancer patients. METHODS AND MATERIALS: A total of 568 patients with T1-T2, N0 breast cancer were treated with breast-conserving surgery and breast irradiation, without adjuvant systemic therapy between January 1, 1985 and December 31, 1992, at the London Regional Cancer Centre. Adjuvant breast irradiation consisted either of 50 Gy in 25 fractions or 40 Gy in 15 or 16 fractions, followed by a boost of 10 Gy or 12.5 Gy to the lumpectomy site. The time intervals from definitive breast surgery to breast irradiation used for analysis were 0-8 weeks (201 patients), > 8-12 weeks (235 patients), > 1216 weeks (91 patients), and > 16 weeks (41 patients). The time intervals of 0-12 weeks (436 patients) and > 12 weeks (132 patients) were also analyzed. Kaplan-Meier estimates of time to local recurrence and disease-free survival rates were calculated. The association between surgery-radiotherapy interval, age (< or = 40, > 40 years), tumor size (< or = 2, > 2cm), Scharf-Bloom-Richardson (SBR) grade, resection margins, lymphatic vessel invasion, extensive intraductal component, and local recurrence and disease-free survival were investigated using Cox regression techniques. RESULTS: Median follow-up was 63.5 months. Patients in all 4 time intervals were similar in terms of age and pathologic features. There was no statistically significant difference between the 4 groups in local recurrence or disease-free survival with surgery-radiotherapy interval (p = 0.189 and p = 0.413, respectively). The 5-year freedom from local relapse was 95.4%. The crude local recurrence rate was 6.9% (7.8% for 436 patients treated within 12 weeks (median follow-up 67 months) and 3.8% for 132 patients treated > 12 weeks from surgery (median follow-up 52 months). In a stepwise multivariable Cox regression model for disease-free survival, allowing for entry of known risk factors, tumour size (p < 0.001), grade (p < 0.001), and age (p = 0.048) entered the model, but the surgery-radiotherapy interval did not enter the model. CONCLUSION: This retrospective study suggests that delay in start of breast irradiation beyond 12 and up to 16 weeks does not increase the risk of recurrence in node-negative breast cancer patients. The certainty of these results are limited by the retrospective nature of this analysis and the lack of information concerning the late local failure rate.     

Local recurrences and distant metastases after breast-conserving surgery and radiation therapy for early breast cancer

PURPOSE: To identify predicting factors for local failure and increased risk of distant metastases by statistical analysis of the data after breast-conserving treatment for early breast cancer. METHODS AND MATERIALS: Between January 1976 and December 1993, 528 patients with nonmetastatic T1 (tumors < or = 1 cm [n = 197], >1 cm [n = 220]) or T2 (tumors < or = 3 cm [n = 111]) carcinoma of the breast underwent wide excision (n = 435) or quadrantectomy (n = 93) with axillary dissection (negative nodal status [n-]: 396; 1-3 involved nodes: 100; >3 involved nodes: 32). Radiotherapy consisted of 45 Gy to the entire breast via tangential fields. Patients with positive axillary lymph nodes received 45 Gy to the axillary and supraclavicular area. Patients with positive axillary nodes and/or inner or central tumor locations received 50 Gy to the internal mammary lymph node area. A boost dose was delivered to the primary site by iridium 192 Implant in 298 patients (mean total dose: 15.2+/-0.07 Gy, range: 15-25 Gy) or by electrons in 225 patients (mean total dose: 14.8+/-0.09 Gy, range: 5-20 Gy). The mean age was 52.5+/-0.5 years (range: 26-86 years) and 267 patient were postmenopausal. Histologic types were as follows: 463 infiltrating ductal carcinomas, 39 infiltrating lobular carcinomas, and 26 other histotypes. Grade distribution according to the Scarff, Bloom, and Richardson (SBR) classification was as follows: 149 grade 1, 271 grade 2, 73 grade 3, and 35 nonclassified. The mean tumor size was 1.6+/-0.3 cm (range: 0.3-3 cm). The intraductal component of the primary tumor was extensive (EIC = IC > or = 25%) in 39 patients. Tumors were microscopically bifocal in 33 cases. Margins were assessed in the majority of cases by inking of the resection margins and were classified as positive in 13 cases, close (< or = 2 mm) in 21, negative (>2 mm tumor-free margin) in 417, and indeterminate in 77. Peritumoral vascular invasion was observed in 40 patients. Tamoxifen was administered for at least 2 years in 176 patients. At least six cycles of adjuvant systemic chemotherapy were administered in 116 patients. The mean follow-up period from the beginning of the treatment was 84.5+/-1.7 months. RESULTS: First events included 44 isolated local recurrences, 8 isolated axillary node recurrences, 44 isolated distant metastases, 1 local recurrence with synchronous axillary node recurrence, 7 local recurrences with synchronous metastases, and 2 local recurrences with synchronous axillary node recurrences and distant metastases. Of 39 pathologically evaluable local recurrences, 33 were classified as true local recurrences and 6 as ipsilateral new primary carcinomas. Seventy patients died (47 of breast carcinoma, 4 of other neoplastic diseases, 10 of other diseases and 9 of unknown causes). The 5- and 10-year rates were, respectively: specific survival 93% and 86%, disease-free survival 85% and 75%, distant metastasis 8.5% and 14%, and local recurrence 7% and 14%. Mean intervals from the beginning of treatment for local recurrence or distant metastases were, respectively, 60+/-6 months (median: 47 months, range: 6-217 months) and 49.5+/-5.4 months (median: 33 months, range: 6-217 months). After local recurrence, salvage mastectomy was performed in 46 patients (85%) and systemic hormonal therapy and/or chemotherapy was administered to 43 patients. The 5-year specific survival rate after treatment for local recurrence was 78+/-8.2%. Multivariate analysis (multivariate generalization of the proportional hazards model) showed that the probability of local control was decreased by the following four independent factors: young age (< or = 40 yr vs. >40 yr; relative risk [RR]: 3.15, 95% confidence interval [CI]: 1.7-5.8, p = 0.0002), premenopausal status (pre vs. post; RR: 2.9, 95% CI: 1.4-6, p = 0.0048), bifocality (uni- vs. bifocal; RR: 2.7, 95% CI: 2.6-2.8,p = 0.018), and extensive intraductal component (IC <25% vs. IC > or = 25%; RR: 2.6, 95% CI: 13-5.2, p = 0     

Radiotherapy and chemotherapy for invasive thymomas: a multicentric retrospective review of 90 cases. The FNCLCC trialists. Fédération Nationale des Centres de Lutte Contre le Cancer

PURPOSE: Thymoma is a rare disease. The treatment of patients with invasive thymoma remains controversial. The prognosis of such patients is poor, even with the use of postoperative radiation therapy and chemotherapy. We retrospectively reviewed the outcome and prognostic factors in a series of 90 patients presenting with an invasive thymoma treated by partial resection or biopsy and radiation therapy. METHODS AND MATERIALS: From 1979-1990, 163 patients with the diagnosis of lymphoepithelial thymoma were treated in 10 French cancer centers. Patients were staged using the postoperative "GETT" classification derived from that of Masaoka. Ninety patients who presented with an invasive thymoma, 58 Stage III (21 IIIA: partial resection and 37 IIIB: biopsy) and 32 Stage IVA (intrathoracic thymoma spread), are the subject of this report. Treatment combined surgery and radiation therapy (+/- chemotherapy), with curative intent. Surgery consisted of partial resection in 31 patients (21 Stage III), and biopsy in 55 patients (37 Stage III). The median radiation dose to the tumor was 50 Gy (30-70 Gy). Supraclavicular radiation was performed in 59 patients (median dose 40 Gy). Chemotherapy, combined with radiation in 59 patients, consisted of multidrug regimens, mainly platinum based. RESULTS: The median follow-up is 105 months (20-165 months). The 5- and 10-year overall survival rates are 51 and 39%, respectively. There is a great impact of the extent of surgery on survival: the 5- and 10-year survival rates were 64% and 43%, respectively, after partial resection, compared to 39% and 31% after biopsy (p < 0.02). Local control at 8.5 years was obtained in 59 of 90 patients (66%): 40 Stage III, 19 Stage IVA. There is a significant relationship between the extent of surgery and the local control (16% of relapse after partial resection vs. 45% after biopsy, p < 0.05). Seven patients developed significant (grades 3-4 WHO grading system) treatment-induced side effects. Stage, histologic type, and chemotherapy were not prognostic factors. CONCLUSION: In this large multicentric retrospective study of invasive thymomas (Stage III-IVA) treated by surgery and radiation, results show the importance of loco-regional treatments, such as surgery and radiation therapy. There is also a great impact of radiation on local control. However, the rate of local recurrence (34%) justifies recommending a higher dose of radiation (> 50 Gy) than doses used in this study, for incompletely resected patients. The role of chemotherapy needs to be further assessed.     

External irradiation of macroinvasive pituitary adenomas with telecobalt: a retrospective study with long-term follow-up in patients irradiated with doses mostly of between 40-45 Gy

PURPOSE: Published dose recommendations for radiotherapy in patients with pituitary macroadenomas vary. Therefore, we retrospectively analyzed the results in our patients from the treatment period 1973-1992. METHODS AND MATERIALS: From a total of 89 patients with macroinvasive adenomas, 66 received radiation therapy immediately following subtotal surgical removal (combined treatment modality), and 22 were irradiated as primary treatment or after surgical recurrence. Only one patient was reirradiated. The surgical interventions have been performed by the same surgeon. For the majority of patients (79 out of 89) with a mean follow-up of 8.1 years (0.5-19 years) the total tumor dose ranged between 40-45 Gy at a dose per fraction of 1.8-2.25 Gy. All patients had bilateral opposed fields with telecobalt. Eleven patients had an additional arc rotation. RESULTS: The 10-year progression-free survival for all 89 patients independent of treatment modality was 88.1%. The 10-year progression-free survival for patients treated by surgery and adjuvant radiation therapy (40-45 Gy at 1.8-2.25 Gy, 60 out of 79) was 90.3%, and for radiation therapy alone (40-45 Gy at 1.8-2.25 Gy, 19 out of 79), 100% (p = 0.32). The prognostic factors for progression-free survival were the subtype of adenoma, the presence of visual symptoms at the time of diagnosis, the suprasellar extension, and the initial hormone levels. The presence of infiltration of adenoma cells in the basal dura or in the mucosa of the sinus sphenoidalis do not represent prognostic factors showing the special biological behavior of pituitary adenomas. Signs of x-ray-induced cerebral necrosis have not been observed in any patient. Long-term visual complications developed in four patients. This could be due to scar formation in the treated region, which can compress the optic nerve and provoke disturbance similar to an empty-sella syndrome. The latter occurred prevalently years after treatment, even though surgical methods of sellar plugging were used. The incidence of hypopituitarism after combined treatment modality at time of last follow-up (irradiated between 40-45 Gy at 1.8-2.25 Gy) was low (36%, 21 out of 60). CONCLUSION: In patients with pituitary macroadenomas, radiotherapy with a total dose of 40-45 Gy at 1.8-2.25 Gy per fraction resulted in a high local tumor control without serious morbidity.     

Induction cisplatin/vinblastine and irradiation vs. irradiation in unresectable squamous cell lung cancer: failure patterns by cell type in RTOG 88-08/ECOG 4588. Radiation Therapy Oncology Group. Eastern Cooperative Oncology Group

PURPOSE: To analyze disease failure patterns by pretreatment characteristics and treatment groups in a prospective randomized trial. METHODS AND MATERIALS: Patients with medically inoperable Stage II, unresectable IIIA and IIIB nonsmall cell lung cancer with KPS > or =70 and weight loss < or =5% were randomized to one of three treatment groups: standard radiation therapy with 60 Gy at 2.0 Gy per day (STD RT), induction chemotherapy with cisplatin 100 mg/m2 days 1 and 29 with vinblastine 5 mg/m2 weekly for 5 weeks followed by 60 Gy at 2.0 Gy per day (CT + RT), or hyperfractionated radiation therapy with 69.6 Gy at 1.2 Gy b.i.d. (HFX RT). Of 490 patients enrolled, 458 were evaluable. Minimum and median periods of observation for this analysis were 4 years and 6 years, respectively. RESULTS: Pretreatment characteristics were equally distributed. Toxicities were previously reported. Median survival rates were 11.4, 13.6, and 12.3 months for STD RT, CT + RT, and HFX RT, respectively (log rank p = 0.05, Wilcoxon p = 0.04). Survivals were 20, 31, and 24% at 2 years, and 4, 11, and 9% at 4 years in the STD RT, CT + RT, and HFX RT groups, respectively. There were no differences in local tumor control rates among the treatments. Patterns of first failure showed less distant metastasis (DM) (other than brain) for CT + RT compared to the RT alone arms (p = 0.04). Within squamous cell carcinoma (SCC), DM (other than brain) rates were 43%, 16%, and 38% in SCC for STD RT, CT + RT, and HFX RT, respectively (p = 0.0015). Patients with peripheral/chest wall lesions were significantly more likely to fail first in the thorax when treated on STD RT compared to CT + RT and HFX RT (p = 0.009). Survival rates were similar among the treatment arms for patients with squamous cell carcinoma. Among patients with nonsquamous cell carcinoma, failure patterns did not differ by treatment group, but survival was significantly better in those who were treated by induction chemotherapy (p = 0.04). CONCLUSION: Patients with squamous cell carcinoma treated on the CT + RT arm had a significant reduction of first DM other than brain, but there was difference in survival. Survival favored CT + RT in nonsquamous carcinoma despite similar failure patterns. Reasons for improved survival with CT + RT in NSCLC are not yet available.     

Changes with age in the modulation of natural killer activity of murine leukocytes by gastrin-releasing peptide, neuropeptide Y and sulfated cholecystokinin octapeptide

From Jan. 1993 to Sept. 1995 23 patients suffering from brain metastases from renal cell carcinoma were treated with the Leksell Gamma Knife at the University of Vienna. At the time of diagnosis 13 patients had single and 10 patients presented with multiple metastatic lesions with a total of 44 metastases in MRI scans. Median tumour volume was 5500 cmm (range 100-24000 cmm). Predominant neurological symptoms and signs were different forms of hemiparesis, focal and generalized seizures, cognitive deficit, headache, dizziness, ataxia and CN XII paresis. Fourteen patients received Gamma Knife Radiosurgery (GKRS) with a median dose of 22 Gy (range 8-30 Gy) at the tumour margin. Nine patients underwent a combined treatment of a radiosurgical boost with a median dose of 18 Gy (range 10-22 Gy) at the tumour margin followed by Whole Brain Radiotherapy (total dose 30 Gy/2 weeks). In 20 patients tumour volume reduction up to 30% of the primary tumour volume was found after 4 weeks, evaluated on CT or MRI. A total remission was seen in 4 cases 3 months after GKRS. We achieved a local tumour control of 96%. Rapid neurological improvement after GKRS was seen in 17 patients. The median survival time was 11 months; the one-year actual survival in this unselected group was 48%. Five long term survivors were still alive, 18 patients had subsequently died, 15 of them of general tumour progression. GKRS induces a significant tumour remission accompanied by rapid neurological improvement and therefore provides the opportunity for extended high quality survival. Neither local tumour control was improved nor CNS relapse free survival was prolonged significantly by additional WBRT.