Second primary cancers related to smoking and treatment of small-cell lung cancer. Lung Cancer Working Cadre.

BACKGROUND: An increased risk of second primary cancers has been reported in patients who survive small-cell carcinoma of the lung. The treatment's contribution to the development of second cancers is difficult to assess, in part because the number of long-term survivors seen at any one institution is small. We designed a multi-institution study to investigate the risk among survivors of developing second primary cancers other than small-cell lung carcinoma. METHODS: Demographic, smoking, and treatment information were obtained from the medical records of 611 patients who had been cancer free for more than 2 years after therapy for histologically proven small-cell lung cancer, and person-years of follow-up were cumulated. Population-based rates of cancer incidence and mortality were used to estimate the expected number of cancers or deaths. The actuarial risk of second cancers was estimated by the Kaplan-Meier method. RESULTS: Relative to the general population, the risk of all second cancers among these patients (mostly non-small-cell cancers of the lung) was increased 3.5-fold. Second lung cancer risk was increased 13-fold among those who received chest irradiation in comparison to a sevenfold increase among nonirradiated patients. It was higher in those who continued smoking, with evidence of an interaction between chest irradiation and continued smoking (relative risk = 21). Patients treated with various forms of combination chemotherapy had comparable increases in risk (9.4- to 13-fold, overall), except for a 19-fold risk increase among those treated with alkylating agents who continued smoking. IMPLICATIONS: Because of their substantially increased risk, survivors should stop smoking and may consider entering trials of secondary chemoprevention.

A study of donepezil in female breast cancer survivors with self-reported cognitive dysfunction 1 to 5 years following adjuvant chemotherapy.

PURPOSE: Some breast cancer survivors report cognitive difficulties greater than 1 year after chemotherapy. Acetylcholinesterase inhibitors (AChEI) may improve cognitive impairment. We conducted a randomized, placebo-controlled, pilot study to assess the feasibility of using the AChEI, donepezil, to improve subjective and objective measures of cognitive function in breast cancer survivors. METHODS: Women who received adjuvant chemotherapy 1-5 years prior with current cognitive dysfunction symptoms were randomized to 5 mg of donepezil/day vs placebo for 6 weeks and if tolerated 10 mg/day for 18 weeks for a total of 24 weeks. A battery of validated measures of attention, memory, language, visuomotor skills, processing speed, executive function, and motor dexterity and speed was administered at baseline and at 24 and 36 weeks. Subjective cognitive function, fatigue, sleep, mood, and health-related quality of life were evaluated at baseline and at 12, 24, and 36 weeks. RESULTS: Sixty-two patients were enrolled, 76 % completed the study, self-reported compliance was 98 %, and toxicities were minimal. At the end of treatment, the donepezil group performed significantly better than the control group on two parameters of memory-the Hopkins Verbal Learning Test -Revised (HVLT-R) Total Recall (p = 0.033) and HVLT-R Discrimination (p = 0.036). There were no significant differences on other cognitive variables or in subjective cognitive function or quality of life. CONCLUSION: Accrual to this feasibility trial was robust, retention was good, compliance was excellent, and toxicities were minimal. IMPLICATIONS FOR CANCER SURVIVORS: Randomized clinical trials in breast cancer survivors to improve cognitive dysfunction are feasible. A phase III trial testing the efficacy of donepezil is warranted given these pilot results.

Prophylactic cranial irradiation in complete responders with small-cell lung cancer: analysis of the Mayo Clinic and North Central Cancer Treatment Group data bases.

PURPOSE: To determine whether prophylactic cranial irradiation (PCI) has an impact on brain failure and survival in patients with small-cell lung cancer (SCLC) who have achieved a complete response to chemotherapy with or without thoracic radiation therapy (TRT). METHODS: Between 1975 and 1990, the Mayo Clinic and North Central Cancer Treatment Group entered 1,617 patients on 15 phase II and III SCLC protocols of chemotherapy with or without TRT and PCI. RESULTS: Of 772 patients with limited disease, 457 (59%) achieved a complete response, compared with 200 of 845 patients (24%) with extensive disease. With follow-up durations of 2 to 17 years (median, 4), the median survival time and 2-, 5-, and 10-year survival rates for the 457 completely responding limited-disease (LD-CR) patients were 19.6 months, 41%, 17%, and 5%, compared with 13.9 months, 26%, 8%, and 5%, respectively, for the 200 completely responding extensive disease (ED-CR) patients (P = .0001). Multiple prognostic factors, including whether the patient did or did not receive PCI (30 to 38 Gy in 2- to 3.6-Gy fractions) were analyzed. In both univariate and multivariate analyses, PCI was not associated with improved (or worsened) survival. The brain relapse rate was 37% for LD-CR patients who did not receive PCI versus 9% for those who did (P = .0001). In ED-CR patients, the brain relapse rate was 31% without PCI and 8% with (P = .009). Essentially all patients who developed brain relapse died within 2 years, with a median survival time of 3.7 months following relapse. Severe, life-threatening, or fatal CNS toxicity occurred in approximately 3% of patients who received PCI. CONCLUSION: The use of PCI remains controversial outside the setting of a clinical trial.

Limited-stage small-cell lung cancer: patterns of intrathoracic recurrence and the implications for thoracic radiotherapy.

PURPOSE: This analysis was performed to determine the most appropriate volume that should be encompassed by thoracic radiation treatments (TRTs) for patients with limited-stage small-cell lung cancer (LSSCLC) who have responded to initial chemotherapy. PATIENTS AND METHODS: A retrospective review of all patients (N = 67) with LSSCLC who were not entered onto a research protocol and were treated at our institution between the years of 1982 and 1990 was performed. Fifty-nine of 67 patients had adequate information regarding the size of the tumor before the start of chemotherapy (computed tomographic [CT] scan of chest or chest x-ray), the size of the tumor before TRT, and the TRT field size based on a simulation radiography. All 59 patients were treated with cyclophosphamide-based chemotherapy, and TRT was generally delivered concomitantly with chemotherapy following two to three cycles of chemotherapy alone. RESULTS: Of 59 patients, 28 were treated with TRT field sizes that encompassed postchemotherapy tumor volumes, and 31 patients were treated with TRT field sizes that encompassed prechemotherapy tumor volumes (defined as a volume that included at least a 1.5-cm margin on the prechemotherapy tumor volume). Nineteen patients had an intrathoracic recurrence of disease as the first site of recurrent small-cell carcinoma: 10 of 31 patients treated with TRT fields that encompassed prechemotherapy tumor volumes and nine of 28 patients treated with TRT fields that encompassed postchemotherapy tumor volumes. For the 28 patients treated with TRT fields that encompassed postchemotherapy tumor volumes, the greatest distance that the prechemotherapy tumor volume (without margins) extended beyond the edge of the TRT field was 0.5 to 5.0 cm, with a median of 2.5 cm. All 19 of the intrathoracic recurrences were in-field failures, although two patients (one prechemotherapy volume and one postchemotherapy volume) did have concurrent pleural effusions. CONCLUSION: These results indicate that the use of TRT fields that encompass postchemotherapy tumor volumes does not increase the risk of marginal failures or intrathoracic failures outside the TRT field.

Phase II trial of primary chemotherapy followed by reduced-dose radiation for CNS germ cell tumors.

PURPOSE: A prospective phase II study was initiated to assess the response rate, survival, and late effects of treatment in patients with newly diagnosed CNS germ cell tumors (GCT), using etoposide plus cisplatin followed by radiation therapy prescribed by extent of disease, histology, and response to chemotherapy. PATIENTS AND METHODS: Seventeen patients aged 8 to 24 years with histologically proven CNS GCT received etoposide (100 mg/m2/d) plus cisplatin (20 mg/m2/d) daily for 5 days every 3 weeks for four cycles, followed by radiation therapy. Nine patients had germinomas; eight had mixed GCT. Four patients (three with germinomas and one with mixed GCT) presented with leptomeningeal dissemination. RESULTS: Radiographically, 14 of 17 patients were assessable for response; 11 patients experienced complete regression, and three had major partial regression before radiation. Six of seven assessable patients with elevated CSF levels of alpha-fetoprotein or betahuman chorionic gonadotropin had normalization with chemotherapy alone; all normalized with combined chemotherapy and radiation therapy. All 17 patients are alive without evidence of disease (median follow-up, 51 months). One patient developed a relapse in the spinal leptomeninges and was rendered free of disease with spinal radiation more than 5 years ago. One patient developed carotid stenosis requiring surgery. Thus far, only minimal long-term deterioration in neurocognitive function has been detected as a consequence of protocol treatment. CONCLUSION: Conventional-dose intravenous chemotherapy with etoposide and cisplatin can effect tumor regression in a high proportion of patients with CNS GCT, including those with leptomeningeal metastases. Acute and long-term toxicities are acceptable. Progression-free survival and overall survival are excellent.

Randomized double-blind placebo-controlled trial of cisplatin and etoposide plus megestrol acetate/placebo in extensive-stage small-cell lung cancer: a North Central Cancer Treatment Group study.

PURPOSE: Megestrol acetate has been reported to improve appetite and quality of life and to decrease nausea and vomiting in patients with cancer anorexia/cachexia. The present trial was formulated to evaluate the impact of megestrol acetate on quality of life, toxicity, response, and survival in individuals with extensive-stage small-cell lung cancer who received concomitant chemotherapy. PATIENTS AND METHODS: Patients were randomized to receive megestrol acetate 800 mg/d orally or placebo. In addition, all patients were scheduled to receive a maximum of four cycles of cisplatin and etoposide chemotherapy. Quality of life was self-assessed at entry onto study, with every cycle of chemotherapy, and 4 months thereafter with a linear visual analog scale. Toxicity was evaluated by patient questionnaire and investigator reports. RESULTS: A total of 243 eligible patients were randomized. Those who received megestrol acetate had increased nonfluid weight gain (P = .004) and significantly less nausea (P = .0002) and vomiting (P = .02). Significant thromboembolic phenomena occurred more often in patients who received megestrol acetate versus placebo (9% v 2%, P = .01). Patients who received megestrol acetate had more edema (30% v 20%, P = .002), an inferior response rate to chemotherapy (68% v 80%, P = .03), and a trend for inferior survival duration (median, 8.2 v 10.0 months, P = .49). These findings may have been influenced by a poorer quality of life of the megestrol acetate group at study initiation. There were no significant changes in quality of life scores over time between either of the study arms. CONCLUSION: Megestrol acetate cannot be routinely recommended for all patients with small-cell lung cancer at the time of chemotherapy initiation. Rather, its therapeutic ratio may be more favorable for patients with problematic cancer anorexia/cachexia.

Genetic analysis of second primary lung cancers in patients surviving small cell lung cancer.

We performed genetic analysis on 12 second primary non-small cell lung cancers in patients surviving small cell lung cancer to assess the potential contribution of smoking to the development of these tumors. Mutations of TP53 were found in three (25%) tumors, KRAS2 in three (25%) tumors, and CDKN2 in two (18%) tumors. Four (50%) mutations (one each in TP53 and CDKN2 and two in KRAS2) were G:C to T:A transversions on the coding strand, a mutation accounting for approximately one-third of mutations in smoking-related tumors but uncommonly found in lung cancers not associated with smoking. The genetic changes in these second lung cancers are more representative of smoking-associated malignancies than lung cancers arising in patients occupationally exposed to irradiation and atomic bomb survivors.

Significance of neuron-specific enolase levels before and during therapy for small cell lung cancer.

The level of serum neuron-specific enolase (NSE) has been implicated as a prognostic factor for patients with small cell lung cancer (SCLC). A prospective evaluation was undertaken to assess the prognostic significance of pretreatment NSE and treatment-induced minimum NSE values in patients with SCLC. Patients from two Phase III North Central Cancer Treatment Group trials [one for patients with extensive stage SCLC and one for patients with limited stage SCLC] were asked to enter this laboratory correlational trial. Both trials included treatment with four to six cycles of etoposide and cisplatin, and 121 patients (71 extensive stage SCLC and 50 limited stage SCLC) were entered into the present study of NSE. Pretreatment NSE values and treatment-induced minimum NSE values were independent predictors of time to progression and survival in multivariate analysis. Hazard rate modeling allowed the formulation of specific relationships of NSE to time to progression and survival. Pretreatment NSE levels inversely correlated with time to progression and survival in these patients with SCLC. Pretreatment NSE accounted for 28% of the variance in survival. Both pretreatment NSE and treatment-induced minimum NSE were independent prognostic predictors of time to progression and survival.

Randomized trials of radiation therapy in adult low-grade gliomas.

There are two central questions in the radiotherapeutic management of the adult patient with a supratentorial low-grade (WHO grade II) astrocytoma, oligo-astrocytoma, or oligodendroglioma. The first question is one of timing. Following tissue diagnosis with or without maximum surgical resection, should immediate postoperative radiation therapy (RT) be given, or should RT be deferred to the time of local recurrence? The second question is one of dose. Assuming RT is given, should lower doses (ie, approximately 45-50 Gray (Gy)) or higher doses (ie, approximately 60-65 Gy) be administered? One Phase III prospective randomized clinical trial addressing the first question and two addressing the second question have been performed. Their results suggest that delayed (versus immediate) RT and low-dose (versus high-dose) RT are both acceptable treatment strategies despite the bias amongst radiation oncologists (primarily based on retrospective data) that immediate and high-dose RT would result in better outcome. The schema of the ongoing Radiation Therapy Oncology Group study is presented.

Three-dimensional conformal radiation treatment planning and delivery for low- and intermediate-grade gliomas.

Three-Dimensional conformal radiation treatment (3D-CRT) planning and delivery is an external beam radiation therapy modality that has the general goal of conforming the shape of a prescribed dose volume to the shape of a 3-dimensional target volume, simultaneously limiting dose to critical normal structures. 3-Dimensional conformal therapy should include at least one volumetric imaging study of the patient. This image should be obtained in the treatment position for visualizing the target and normal anatomic structures that are potentially within the irradiated volume. Most often, computed tomography (CT) and/or magnetic resonance imaging (MRI) are used; however, recently, other imaging modalities such as functional MRI, MR spectroscopy, and positron emission tomography (PET) scans have been used to visualize the clinically relevant volumes. This article will address the clinically relevant issues with regard to low- and intermediate-grade gliomas and the role of 3D-CRT planning. Specific issues that will be addressed will include normal tissue tolerance, target definition, treatment field design in regard to isodose curves and dose-volume histograms, and immobilization.

Sarcomas of calvarial bones: rare remote effect of radiation therapy for brain tumors.

After latent periods lasting from 7 to 23 years, sarcomas of the calvaria developed in four patients who had received radiation therapy for a brain tumor. There was no evidence of bony disease before radiation therapy, and the sarcoma (two fibrosarcomas and two osteosarcomas) developed in the field of radiation in all four patients. One of these four died during resection of the tumor, two survived for either 7 or 21 months after diagnosis of the sarcoma, and one was alive at 23 months after the clinical appearance of the sarcoma. The latter patient has had two resections and extensive chemotherapy. Distant metastases were not present in any of the patients. Sarcoma of the calvarial bones is a serious but rare remote effect of radiation therapy for brain tumors.

Analysis of outcome in patients reirradiated for brain metastases.

PURPOSE: Patients with newly diagnosed brain metastases generally benefit from whole brain radiation therapy (WBRT). However, the role of reirradiation for patients who develop progressive brain metastases has been controversial. This retrospective study examines our experience with reirradiation of patients for progressive brain metastases after an initial+ course of WBRT. METHODS AND MATERIALS: From 1975-1993, 2658 patients received WBRT for brain metastases at our institution. Eighty-six patients were subsequently reirradiated for progressive brain metastases. The median age of these patients was 58 (range: 31-81). The most common primary sites were breast and lung. Fifty patients had metastatic disease at other sites. Most patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 (40 patients) or 3 (38 patients). The median dose of the first course of irradiation was 30 Gy (range: 1.5-50.6 Gy). The median dose of the second course of irradiation was 20 Gy (range: 8.0-30.6 Gy). RESULTS: Twenty-three patients (27%) had resolution of neurologic symptoms, 37 patients (43%) had partial improvement of neurologic symptoms, and 25 patients (29%) had either no change or worsened after reirradiation. The median survival following reirradiation was 4 months (range: 0.25-72 months). The majority of patients had no significant toxicity secondary to reirradiation. Five patients had radiographic abnormalities of their brain consistent with radiation-related changes. One patient had symptoms of dementia that was thought to be caused by radiotherapy. Various potential prognostic factors were evaluated for possible associations with survival, including age, sex, primary site, ECOG performance status, RTOG neurologic functional class, absence of extracranial metastases, and dose of irradiation. Absence of extracranial metastasis, solitary brain metastasis, and retreatment dose > 20 Gy were associated with improved survival in univariate analysis (p=0.025, 0.033, and 0.061, respectively). The absence of extracranial disease was the only significant factor in multivariate analysis (p=0.05). CONCLUSION: The majority of patients in our series had favorable symptomatic responses. Clinically significant complications were minimal. Reirradiation should be offered to patients who develop progressive brain metastases.

Postoperative radiotherapy of intracranial ependymoma in pediatric and adult patients.

In 33 patients undergoing operation and postoperative irradiation for intracranial ependymomas between January 1963 and December 1983, the tumor was grade 1 or 2 in 26 (79%) patients and grade 3 or 4 in 7 (21%). Operation consisted of only biopsy in 1 (3%), subtotal removal of tumor in 28 (85%), and gross total resection in 4 (12%). All patients received brain irradiation with a median dose of 4800 cGy. Seventeen (52%) patients also received spinal axis irradiation (median dose, 3000 cGy) which included 5 with high-grade tumors and 12 with low-grade infratentorial tumors. The relapse-free and overall survival rates at 5 years were 61% and 62%, respectively. Prognostic factors analyzed for statistically significant survival differences included age, sex, hydrocephalus, site, grade, extent of operation, extent of brain field, spinal axis irradiation, and brain dose. Grade was the only significant factor found: the 5-year survival of patients with low-grade ependymomas, 71%, was significantly better (p less than 0.04) than that of patients with high-grade ependymomas, 29%. Among the 31 patients evaluable for patterns of failure, treatment failed in 12 (39%) (10 only in the brain, 1 in the brain and spinal cord, and 1 only in the spine). All but one of the brain failures were at the site of the original primary lesion. Treatment failed in 4 of the 6 (67%) patients with high-grade tumor but in only 8 of the 25 (32%) with low grade tumor. Among the 7 low-grade infratentorial ependymomas treated with brain irradiation only, there was 1 treatment failure (in the spine; salvaged with further irradiation). Among the 12 patients with low-grade infratentorial tumors who received spinal axis irradiation, treatment failed in 1 (8%) (in the spine and also in the brain; patient subsequently died of disease). Nineteen (58%) patients remain alive; all but 2 of the patients who had recurrence died of their disease. This retrospective study suggests that: (a) patients with high-grade tumors have significantly poorer survival compared with those with low-grade tumors; (b) the main cause of death in ependymoma patients is intracranial failure at the primary site; and (c) craniospinal axis irradiation may not be necessary for patients with low-grade infratentorial ependymoma (localized irradiation alone may be adequate).

Doses to radiation sensitive organs and structures located outside the radiotherapeutic target volume for four treatment situations.

This study documents dosage to radiation sensitive organs/structures located outside the radiotherapeutic target volume for four treatment situations: (a) head and neck, (b) brain (pituitary and temporal lobe), (c) breast and (d) pelvis. Clinically relevant treatment fields were simulated on a tissue-equivalent anthropomorphic phantom and subsequently irradiated with Cobalt-60 gamma rays, 6- and 18-MV x-ray beams. Thermoluminescent dosimeters and diodes were used to measure absorbed dose. The head and neck treatment resulted in significant doses of radiation to the lens and thyroid gland. The total treatment lens dose (300-400 cGy) could be cataractogenic while measured thyroid doses (1000-8000 cGy) have the potential of causing chemical hypothyroidism, thyroid neoplasms, Graves' disease and hyperparathyroidism. Total treatment retinal (400-700cGy) and pituitary (460-1000 cGy) doses are below that considered capable of producing chronic disease. The pituitary treatment studied consisted of various size parallel opposed lateral and vertex fields (4 x 4 through 8 x 8 cm). The lens dose (40-200 cGy) with all field sizes is below those of clinical concern. Parotid doses (130-1200 cGy) and thyroid doses (350-600 cGy) are in a range where temporary xerostomia (parotid) and thyroid neoplasia development are a reasonable possibility. The retinal dose (4000 cGy) from the largest field size (8 x 8 cm2) is in the range where retinopathy has been reported. The left temporal lobe treatment also used parallel opposed lateral and vertex fields (7 x 7 and 10 x 10 cm). Doses to the pituitary gland (5200-6200 cGy), both parotids (200-6900 cGy), left lens (200-300 cGy) and left retina (1700-4500 cGy) are capable of causing significant future clinical problems. Right-sided structures received insignificant doses. Secondary malignancies could result from measured total treatment thyroid doses (670-980 cGy). Analysis of three breast/chest wall and regional nodal irradiation techniques demonstrated a 25-50% decrease in secondary lung dose with use of independent collimation compared to use of custom alloy blocking material. However, it is unlikely that a reduction in secondary dose of this magnitude would reduce the risk of treatment sequellae. In four-field "box" pelvic irradiation, secondary testes dose may result in temporary (clamshell shield) or permanent azoospermia, but is unlikely to impair androgen production.

Matching intraoperative electron-beam fields: dosimetric and clinical considerations.

In the setting of a large or irregularly shaped tumor, adjacent or intentionally overlapped intraoperative electron fields may be required to give adequate coverage of the intraoperative target volume. The matching of such intraoperative electron fields present special dosimetric problems because of the divergence of electron isodose curves with depth. In the intraoperative setting, where large, single-fraction doses are delivered, the low- and high dose areas which result from gaps or overlaps between the diverging isodose curves of electron fields matched at depth or the surface may translate into decreased local tumor control or excessive normal tissue toxicity. This study examines the dosimetry of gapped, adjacent, and overlapped 8 X 9 cm2 rectangular intraoperative fields, for 9 to 18 MeV electrons, using film densitometry. "Ideal" methods of matching rectangular intraoperative electron fields are presented, and include: 1) a 2-mm gap plus surface bolus for adjacent fields, and 2) placing a tenth-value layer shaped lead cutout in the overlap region for intentionally overlapped fields.

Radiotherapeutic management of adult intraspinal ependymomas.

Twenty-two adults with ependymomas of the spinal cord were treated with surgery and postoperative radiation between January 1963 and December 1983. The median age was 47 years. Nineteen patients had grade 1 lesions, two had grade 2 and one grade 3. Ten patients had the myxopapillary histologic subtype (all grade 1) and 12 had the cellular variant. There were 15 distal cord lesions originating from the conus medullaris, filum terminale and/or cauda equina. The remaining seven lesions arose more proximally. Fourteen patients had localized lesions involving one to three vertebral segments, while the remaining eight had extensive ependymomas spanning six to thirteen vertebral segments. The median time from onset of symptoms to diagnosis was 3 years. Surgical treatment consisted of biopsy only in three patients, subtotal removal in eleven patients and total removal in eight patients. Radiation was given to the spine only in all cases. Five patients received whole spine radiation; seventeen received partial spine treatment, appropriate for the length of the primary lesion. The median dose was 5000 cGy (range 3600-5700 cGy). The disease free survival at 5 and 10 years was 81 and 71%, respectively. Overall survival at 5 and 10 years was 95%. Seven of twenty-two (32%) patients failed. Factors analyzed for prognostic significance included age, sex, histology, extent of primary, location of primary within the cord, extent of surgical resection and dose. Too few grade 2 and 3 patients precluded meaningful statistical analysis of grade as a prognostic factor. Neither age, sex, histology, extent of primary, location of primary, nor extent of surgical removal significantly affected disease free or overall survival (p greater than 0.05). Four of nineteen (21%) patients with grade 1 lesions failed, while all three patients with grade 2 and 3 lesions did so. Half of the eight patients with extensive ependymomas failed compared to three of fourteen (21%) with limited ones. Six of seventeen (35%) patients failed at doses less than or equal to 5000 cGy while only one of five (20%) failed at doses greater than 5000 cGy. Patterns of failure were analyzed for the seven patients who failed. Six of the seven failures (86% of the failure group, 27% of the overall group) were local, that is, within the initial radiation field at the site of the original tumor. A single patient (grade 2) failed in the posterior fossa while remaining NED in the spinal cord (a head CT scan at initial work-up was negative).(ABSTRACT TRUNCATED AT 400 WORDS)

Pilot study of human recombinant interferon gamma and accelerated hyperfractionated thoracic radiation therapy in patients with unresectable stage IIIA/B nonsmall cell lung cancer.

PURPOSE: Gamma interferon has a wide range of properties, including the ability to sensitize solid tumor cells to the effects of ionizing radiation. The North Central Cancer Treatment Group has previously completed pilot studies of accelerated hyperfractionated thoracic radiation therapy (AHTRT) in patients with unresectable Stage IIIA/B nonsmall cell lung cancer (NSCLC). This Phase I study was designed to assess the toxicity of concomitant gamma interferon and AHTRT in a similar patient population. METHODS AND MATERIALS: Between December 1991 and May 1992, 18 patients with unresectable Stage IIIA/B NSCLC were treated with daily gamma interferon (0.2 mg subcutaneously) concomitant with AHTRT (60 Gy given in 1.5 Gy twice daily fractions). All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1 with weight loss < 5%. Eight patients had Stage IIIA and 10 had Stage IIIB disease. RESULTS: Nine patients (50%) experienced severe, life-threatening, or fatal toxicities. Eight of the patients (44%) developed significant radiation pneumonitis, which was severe in six patients and fatal in two patients (11% treatment-related mortality). Two patients (11%) developed severe radiation esophagitis. With follow-up of 15-21 months, 2 patients are alive, and 16 have died. The median survival time and 1-year survival rate is 7.8 months and 38%, respectively. CONCLUSION: Gamma interferon appeared to sensitize normal lung tissue to the effects of radiation, as demonstrated by the high incidence of severe or fatal radiation pneumonitis. We do not recommend pursuing gamma interferon as a radiosensitizer in this setting.

Radiation therapy for diabetes insipidus caused by Langerhans cell histiocytosis.

Hypothalamic-pituitary radiation therapy has been the standard treatment for the diabetes insipidus of Langerhans cell histiocytosis. The goal of this study was to assess the role of radiation therapy in Langerhans cell histiocytosis-associated diabetes insipidus and to compare the results with nonirradiated controls. Forty-seven patients with pathologically confirmed Langerhans cell histiocytosis were diagnosed with diabetes insipidus between 1950 and 1989 and were treated at the Mayo Clinic. These patients were divided into two groups on the basis of treatment for the diabetes insipidus: The first group (radiation group) included 30 patients (28 of whom were evaluable for response) who received hypothalamic-pituitary radiation therapy, and the second group (control group) included 17 patients who did not. A partial response to treatment was defined as a reduction in vasopressin dosage or improvement in computed tomography (CT) or magnetic resonance imaging (MRI). A complete response was defined as no further need for vasopressin therapy or normalization of CT or MRI. End points analyzed included treatment response, patient characteristics, morbidity, dose-response relationship, and survival. Patient characteristics of the two groups were similar except for age and lung involvement, both of which were significantly less in the radiation group. Thirty-six percent of patients (10 of 28) in the radiation group responded to hypothalamic-pituitary radiation therapy (22% complete response and 14% partial response), whereas none in the control group responded. Five of the six complete responders were irradiated within 14 days of the diagnosis of diabetes insipidus. The mean dose used in the responding and nonresponding patients was 11.2 and 10 Gy, respectively. Three of five patients (60%) treated with more than 15 Gy responded compared to seven of 23 (30%) treated with less than 15 Gy. Eight of the 10 responders (80%), compared to 16 of 35 nonresponders (46%), were female. Only one in 20 patients with concomitant lung histiocytosis responded. Complications of therapy may include insufficiency in other hypothalamic-pituitary axes in the treated patients. Actuarial survivals at 5, 10, 20, and 40 years for the entire group were 80%, 78%, 75%, and 65%, respectively, with a median follow-up in living patients of 14.7 years.

The results of radiotherapy for ependymomas: the Mayo Clinic experience.

PURPOSE: This analysis was performed to examine the outcome of patients with histologically confirmed ependymomas of the brain or spinal cord who received postoperative radiotherapy. METHODS AND MATERIALS: Eighty patients with histologically confirmed ependymomas were evaluated retrospectively. All were treated with various combinations of surgery, radiotherapy (RT), and chemotherapy. Follow-up ranged from 5 to 30 years (median 10.4 years). RESULTS: The 5- and 10-year survival rates for the entire study group were 79% and 73%, respectively. Patients with low-grade (1 and 2 of 4) tumors had a 5-year survival rate of 87% as compared to 27% for those with high-grade (3 and 4 of 4) tumors (p < 0.0001). Patients with tumors of the spine had a 5-year survival rate of 97% as compared to 68% for those with infratentorial tumors, and 62% for those with supratentorial tumors (p = 0.03). Patients with myxopapillary ependymomas of the spine had a 5-year survival rate of 100% as compared with 76% for patients with other histological subtypes of ependymoma (p = 0.02). Multivariate analysis revealed that the survival rate was independently associated with tumor grade (p = 0.0007) and histological subtype (p = 0.02). Twenty-eight patients (35%) experienced local failure and 10 patients (13%) developed leptomeningeal seeding. The 5-year leptomeningeal failure rate was 10% in patients with low-grade tumors as compared to 41% for patients with high grade tumors (p = 0.01). CONCLUSION: Patients with low-grade tumors, especially those with myxopapillary subtypes, have high 5-year survival rates when treated with post-operative radiotherapy. High grade ependymomas are associated with a much poorer outcome. New forms of therapy are required to improve the outcome of patients with high-grade ependymomas.

Spinal cord localization in the treatment of lung cancer: use of radiographic landmarks.

PURPOSE: In the treatment of thoracic malignancies with radiotherapy, the critical dose-limiting structure is the spinal cord. Oblique fields typically are designed to exclude the spinal cord, and by convention, the field edge that shields the spinal cord is placed at the anterior border of the vertebral pedicles. Thus, the purpose of our study was to estimate the distance between the field edge and spinal cord in oblique fields that were designed by using the vertebral pedicle as a radiographic landmark. METHODS AND MATERIALS: The spinal cord of a cadaver was wrapped in wire, and oblique fields were simulated at 15 degree intervals. The distance from the spinal cord to a field edge placed at the anterior border of the pedicle was measured. In the second investigation, a three-dimensional treatment planning system was used to simulate hypothetical fields using actual patient data from computed tomography (n = 10), and measurements identical to those in the anatomical model were made (n = 1,100). RESULTS: The results of the anatomical and computed tomographic models were in close agreement (mean difference, 0.6 mm). The computed tomographic model predicted a mean field edge to spinal cord distance of 8.7 mm (95% confidence interval, 5.6-11.8 mm) for 30 degree/150 degree oblique fields and 8.0 mm (95% confidence interval, 4.7-11.7 mm) for 45 degree/135 degree oblique fields. This distance was greatest at levels T-1, T-2, and T-11 (8 to 20% greater). CONCLUSIONS: The mean distance from a field edge placed at the anterior border of a vertebral pedicle to the spinal cord for commonly used oblique angles constitutes a sufficient margin to account for expected differences in daily positional variations and mechanical uncertainties.