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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.

This analysis was performed to examine the outcome of adult and pediatric patients with brainstem tumors.Forty patients with brainstem glioma were evaluated retrospectively. Included were 24 females and 16 males ranging in age from 3 to 81 years (median, 29.5 years). These patients were treated with various combinations of surgery, chemotherapy, and radiotherapy (RT). The length of follow-up in survivors ranged from 0.6 to 20 years (median: 3.2 years, mean: 6 years). Survival rates were calculated with the Kaplan Meier method and differences between survival curves were calculated using the log-rank test.The overall 2 and 5-year survival rates were 44% and 34%, respectively. The median survival time was 19 months. The 5-year survival rate was 54% for patients with tumors outside the pons compared to 21% for those with tumors involving the pons (p = 0.04). The 5-year survival rate was 59% for patients with exophytic tumors as compared to 23% for those with intrinsic tumors (p = 0.05). Patients undergoing subtotal resection had a 5-year survival rate of 53% compared to 28% for those having only a biopsy or no surgical intervention (p = 0.04). None of the other potential prognostic or treatment related factors evaluated [patient age, tumor grade, tumor histology, radiotherapy parameters (including BID fractionation, 3-D treatment planning, or the use of doses55 Gy), or the administration of adjuvant chemotherapy] evaluated were associated with patient survival.Brainstem gliomas generally occur in younger individuals. The survival rates were better for patients with exophytic tumors, those involving sites other than the pons, and tumors amenable to subtotal resection. Improvements in the outcome of patients with brainstem gliomas will require new therapeutic approaches.

A three-arm Phase III randomized trial was performed to compare response rates, time to local or distant progression, and survival for patients with unresectable (Stage IIIA or IIIB) nonsmall cell lung carcinoma treated with standard fractionated thoracic radiotherapy (SFTRT) versus accelerated hyperfractionated thoracic radiotherapy (AHTRT) with or without combination etoposide and cisplatin chemotherapy.This trial was initiated in 1992 by the North Central Cancer Treatment Group. Patients with Stage IIIA or IIIB nonsmall cell lung carcinoma were eligible. They were randomly assigned to either SFTRT (6000 centigray [cGy] in 30 fractions) or AHTRT (150 cGy twice daily to a total dose of 6000 cGy, with a 2-week break after the initial 3000 cGy); the AHTRT was given alone or with concomitant cisplatin (30 mg/m2, Days 1-3 and 28-30) and etoposide (100 mg/m2, Days 1-3 and 28-30).A total of 110 patients were entered on study. Eleven patients were declared ineligible or off study on the day of study entry. This analysis was confined to the 99 eligible patients. This article reports mature follow-up, because more than 80% of the patients have died. The median follow-up of living patients was 2.5 years. There were suggestions of improvement in the rates of freedom from local recurrence and survival for patients treated with AHTRT (with or without chemotherapy) as opposed to SFTRT (P = 0.06 and P = 0.10, respectively). The improvement in survival associated with AHTRT (with or without chemotherapy) was statistically significant for the subgroup of patients with nonsquamous cell carcinoma after adjustment for other potentially confounding factors (P = 0.02). No differences in freedom from systemic progression or survival were found in a comparison of AHTRT with chemotherapy and AHTRT without chemotherapy.These results suggest that treatment of Stage IIIA or IIIB nonsmall cell lung carcinoma with AHTRT with or without chemotherapy may improve freedom from local progression and survival as compared with SFTRT, especially for patients with nonsquamous cell carcinoma. The statistical powers to detect the observed differences in median time to local progression and survival were approximately 55% and 35%, respectively. Therefore, further investigation comparing SFTRT with AHTRT is warranted.

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.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.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.Because of their substantially increased risk, survivors should stop smoking and may consider entering trials of secondary chemoprevention.

Previous nonsmall cell lung carcinoma studies have shown that patients with ipsilateral mediastinal (N2) lymph node involvement who underwent surgical resection have a greater local recurrence rate than those with less lymph node involvement (N0, N1). Therefore, it was hypothesized that complete surgical clearance of subclinical lymph node disease is difficult in N2 patients and that adjuvant postoperative thoracic radiotherapy (TRT) may be beneficial.A retrospective review was performed to determine the local recurrence and survival rates for patients with N2 disease undergoing complete surgical resection with or without adjuvant TRT. Between 1987 and 1993 at the Mayo Clinic, 224 patients underwent complete resection of N2 nonsmall cell lung carcinoma. More than one mediastinal lymph node station was sampled in 98% of patients; 39% then received adjuvant TRT (median dose, 50.4 grays).The median follow-up time was 3.5 years for the patients who were alive at the time of the analysis. The surgery alone versus surgery plus TRT groups were well balanced with respect to gender, age, histology, tumor grade, number of mediastinal lymph node stations dissected or involved, and involved N1 lymph node number. There were slightly more patients with right lower lobe lesions (compared with other lobes), patients with multiple lobe involvement, and patients with only one N2 lymph node involved in the surgery alone group. After treatment with surgery alone, the actuarial 4-year local recurrence rate was 60%, compared with 17% for treatment with adjuvant TRT (P0.0001). The actuarial 4-year survival rate was 22% for treatment with surgery alone, compared with 43% for treatment with adjuvant TRT (P = 0.005). On multivariate analysis, the addition of TRT (P = 0.0001), absence of superior mediastinal lymph node involvement (P = 0.005), and fewer N1 lymph nodes involved (P = 0.02) were independently associated with improved survival rate.This study, which to the authors' knowledge is the largest evaluating adjuvant TRT in N2 nonsmall cell lung carcinoma, suggests that adjuvant TRT may improve local control and survival.

To try and identify biologic differences based on tumor grade and histologic type between the major classes of glial tumors, including low-grade diffuse fibrillary and pilocytic astrocytomas, oligodendrogliomas, and mixed oligo-astrocytomas and high-grade diffuse fibrillary astrocytomas, oligodendrogliomas and mixed oligo-astrocytomas.Utilizing the St. Anne-Mayo (SAM) grading system, the incidence, patient characteristics, and survivals of 196 patients with low-grade (SAM grade 1 + 2) and 318 patients with high-grade (SAM 3 + 4) supratentorial tumors were compared.Among low-grade tumors, most favorable were 5- and 10-year survival rates for patients with pilocytic astrocytomas, which were 85% and 79%, respectively. Median survival and 5- and 10-year survival rates for the other low-grade tumors were lower, and were proportionately improved by the presence of an oligodendroglial component: diffuse fibrillary astrocytomas-4.7 years, 46%, and 17%, oligodendroglioma-9.8 years, 73%, and 49%; and mixed oligo-astrocytoma-7.1 years, 63%, and 33%, respectively. For high-grade tumors, patients with either oligodendrogliomas or mixed oligo-astrocytomas had comparable favorable survivals in comparison to diffuse fibrillary astrocytomas. Median survivals and 5- and 10-year survival rates were 4.5 years, 45%, and 15% for the oligodendrogliomas and mixed oligo-astrocytomas versus 0.8 years, 3%, and 0% for the diffuse fibrillary astrocytomas, respectively.These survival data suggest that both low-grade and high-grade supratentorial gliomas have outcomes which are highly dependent upon histologic type.

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.

A Phase I/II study of an aggressive six-drug chemotherapy regimen followed by the use of sequential hemibody radiation therapy as a possible non-cross-resistant systemic treatment was undertaken for patients with extensive stage small cell lung cancer.The 20 enrolled patients received 7 cycles of cyclophosphamide-based chemotherapy. The first cycle consisted of cyclophosphamide, doxorubicin, etoposide, vincristine, and lomustine. Subsequent cycles used a regimen of doxorubicin alternating with cisplatin. Thoracic radiation was delivered in a split-course fashion during the first week of chemotherapy cycles 5 and 6 (2000 cGy in five fractions during each week). Prophylactic cranial radiation was delivered in a split-course fashion during the first week of chemotherapy cycles 2 and 3 (1700 cGy in 5 fractions during each week). After the 7 cycles, patients received 600 cGy upper hemibody radiation followed by 800 cGy lower hemibody radiation.Nineteen of 20 patients were evaluable for toxicity and response to treatment. Hematologic toxicity accounted for treatment delays or decreased doses in 16 of 19 patients. Thirteen patients completed the initial 7 cycles; progressive disease was the only reason for discontinuing treatment. Two patients had fatal hematologic complications after lower hemibody radiation. Three patients had severe or greater peripheral neurologic toxicity, two had severe central neurologic toxicity, and one had severe cardiac toxicity. Of 19 patients, 9 achieved a complete response; median survival was 11.5 months. Five-year progression free survival and 5-year overall survival were 27% and 16%, respectively.This aggressive regimen is feasible for patients with extensive stage small cell lung cancer; however, hematologic-related mortality after lower hemibody radiation suggests that future investigations should be initiated at lower initial doses of lower hemibody radiation. Long term survival of the patients suggests that sequential hemibody radiation treatment warrants further investigation.

The role of prophylactic cranial irradiation (PCI) for patients with limited-stage small cell lung cancer (LSSCLC) remains a controversial issue. This study evaluated PCI in patients with LSSCLC who achieved a complete response to initial chemotherapy.A retrospective case study of all nonprotocol patients with LSSCLC examined at our institution from 1982 to 1990 was performed. Of the 67 nonprotocol patients who were treated with combination chemotherapy (cyclophosphamide-based) and thoracic radiotherapy during those years, 43 achieved a complete response. Twenty-four patients received prophylactic cranial irradiation (PCI+) (25-36 Gy in 10-16 fractions), and 19 did not (PCI-) at the physician's or patient's discretion.The distribution of prognostic factors between the PCI+ and PCI- groups was well balanced. Of the PCI+ patients, the 2-year actuarial freedom from relapse in the central nervous system was 93% versus 47% for the PCI- patients (log rank analysis, P = 0.001). An initial central nervous system relapse developed in 2 of the 24 PCI+ patients as the only site of failure versus 7 of 19 PCI- patients (P = 0.003). The 2-year actuarial overall survival was 50% for the PCI+ patients versus 21% for the PCI- patients (P = 0.01). The addition of prophylactic cranial irradiation was the only significant factor contributing to an improvement in time to central nervous system relapse and survival for the PCI+ patients. There were five patients alive at the time of this report, and all received prophylactic cranial irradiation. None had cognitive or neurologic impairment.Prophylactic cranial irradiation may contribute to improved survival in patients with LSSCLC who achieve a complete response after chemotherapy and thoracic radiation therapy.

To assess the role of clinical factors, size of lesion, site of involvement, and radiation dose in patients with cerebral arteriovenous malformations (AVMs) who underwent stereotactic radiosurgical treatment.We reviewed the results in 121 patients with cerebral AVMs treated with the Leksell "Gamma Knife" between January 1990 and December 1993 at the Mayo Clinic in Rochester, Minnesota.The following strict dose-volume protocol was used: AVMs 2.0 cm or smaller in diameter (volume, 4.2 cm3 or less) received 20 Gy to the margin of the nidus, those between 2.1 and 3.0 cm in diameter (4.3 to 14.1 cm3) received 18 Gy to the margin, and those that exceeded 3.0 cm in diameter (more than 14.1 cm3) received 16 Gy to the margin. Lesions that involved the brain stem received a radiosurgical dose of 18 Gy or less to the margin. Patients participated in regular follow-up clinical and imaging studies for up to 55 months.Follow-up cerebral angiography in 43 patients demonstrated total obliteration of the AVM nidus in 31 (72.1%), including 5 of 7 (71.4%) who had AVMs with a volume larger than 10 cm3. Clinical follow-up revealed that 111 patients (91.7%) had a stable or improved outcome, 3 had a nonfatal AVM hemorrhage, 2 suffered a fatal hemorrhage, and 2 died of causes not directly attributed to the AVM or radiosurgical treatment. Two patients had new or increased, nondisabling neurologic deficits as a result of treatment, and one patient had a temporary partial eyelid ptosis.Our findings suggest that previous theories about the relationship between AVM size and rate of obliteration after radiosurgical treatment may need revision. Our experience confirms that radiosurgical treatment for cerebral AVMs is safe and effective, even in cases for which the latency period before obliteration is longer than 2 years.

Patients with esophageal cancer and a malignant tracheoesophageal fistula (TEF) have an extremely poor prognosis. Additionally, these patients often are denied treatment with radiation therapy because there is concern that these treatments may increase the size and associated problems of the TEF.To determine the appropriate treatment (use of radiation therapy) for patients with esophageal cancer and malignant TEF, a review was performed of all such cases seen at the Mayo Clinic between 1971 and 1991.Between 1971 and 1991, 41 patients with malignant TEF arising as a result of esophageal cancer were seen at the Mayo Clinic in Rochester. Twenty-eight of these cancers were locally recurrent, and this group of patients had a uniformly poor outcome (median survival time, 1.4 months). Thirteen patients had a malignant TEF and had not received previous treatment for their esophageal cancer. The median survival length was 4 months for this group of patients. Of the 41 patients in this study, 10 received radiation therapy for their malignant TEF (30-66 Gy). The median survival length of this group of patients was 4.8 months. Six of these 10 patients died of metastatic disease (median survival length, 9 months), and there was no evidence of progression of the local tumor. Four of these 10 patients died of local progression of the malignancy (median survival length, 3 months).Radiation therapy did not increase the severity of the TEF. The authors conclude that radiation therapy can be administered safely in patients with TEF resulting from esophageal cancer. In some patients, radiation treatment may contribute to stabilization of the local tumor process (60% of patients treated with radiation therapy died of metastatic disease without local progression of tumor); however, all patients in this study eventually died of esophageal cancer.

Supratentorial pilocytic astrocytomas are uncommon tumors, the prognosis and management of which have been controversial.The authors retrospectively studied the clinical and pathologic aspects of 51 patients with supratentorial pilocytic astrocytomas, with particular reference to their response to treatment.The study group consisted of 25 male and 26 female patients (median age, 15 years). The extent of surgical removal was gross total or radical subtotal in 16 patients and subtotal removal or biopsy in 35. At a median follow-up of 14.9 years, 41 patients were alive. Overall survival was 82% at 10 and 20 years; 89% of surviving patients were fully active. Survival at 10 years was 100% for the 16 patients who underwent gross total or radical subtotal removal and 74% for the 35 who had subtotal tumor removal or biopsy. No association was found between pathologic features such as histologic grade or flow cytometric characteristics and patient survival.Supratentorial pilocytic astrocytomas behave differently from low-grade astrocytomas of the diffuse or fibrillary type in that they have a favorable prognosis. Radiation therapy appears not to be needed for patients undergoing gross total removal. In patients undergoing subtotal resection, close follow-up with additional surgery or radiation therapy at the time of tumor progression is recommended. Patients who have biopsy only should receive radiation therapy. Histologic grading and flow cytometric analysis add little to clinical decision making with regard to patients with pilocytic astrocytoma.

The majority of patients with astrocytomas of the cerebellum have an excellent prognosis; however, a small percentage of patients continue to do poorly. To clarify the clinical, pathologic, and treatment characteristics that determine prognosis and therapeutic recommendations, a large group of patients with astrocytic tumors of the cerebellum was reviewed and analyzed.A clinicopathologic analysis was performed of all patients undergoing initial operation for astrocytomas in the cerebellum between 1960 and 1984. Of the 132 patients, 105 patients had pilocytic astrocytomas and 27 had diffuse astrocytomas.Multivariate analysis revealed that the division of pilocytic and diffuse histologic type was the most significant prognostic factor influencing survival. The 5-year, 10-year, and 20-year survival rates were 85%, 81%, and 79%, respectively, for patients with pilocytic astrocytomas and 7%, 7%, and 7%, respectively, for patients with diffuse astrocytomas (P0.001). Pilocytic astrocytomas occurred in a younger age group and were more commonly cystic and completely resected.Astrocytomas of the cerebellum can be divided into two principal groups, the pilocytic and the diffuse astrocytomas, each of which has distinct clinical, pathologic, and prognostic characteristics.

The primary goal of this study was to determine the incidence of severe or greater acute radiation toxicity, and secondarily, response, survival, and local control in patients with unresectable Stage IIIA or B non-small cell lung cancer treated with accelerated hyperfractionated thoracic radiation therapy (AHTRT).From September, 1989 through March, 1990, 21 evaluable patients with unresectable Stage IIIA or B non-small cell lung cancer were treated with AHTRT, using 6000 cGy in 40 fractions of 150 cGy twice daily, 6 hours between fractions, with a 2-week break midway through treatment.Two patients (9.5%) had acute Grade 3 radiation esophagitis requiring intravenous hydration, and two patients (9.5%) had acute Grade 3 radiation pneumonitis requiring oxygen and steroids. Only one patient had chronic toxicity, a Grade 3 radiation pneumonitis. Five patients (24%) achieved a complete response, whereas eight (38%) had a partial response or regression. With minimum follow-up of nearly 3 years, 3 patients are alive and 18 are dead. The median survival time and 1-, 2-, and 3-year survival rates were 10.8 months, 48%, 29%, and 14%, respectively. Local control was achieved in 11 of 21 (52%) patients.This AHTRT regimen can be given with an acceptable incidence of acute radiation toxicity. Response, survival, and local control rates in this unfavorable group of patients are encouraging. A North Central Cancer Treatment Group Phase III study of standard thoracic radiation therapy (6000 cGy in 30 fractions of 200 cGy daily) versus AHTRT (+/- chemotherapy) is now open.

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.

Forty-four cases of meningeal hemangiopericytoma that were treated between 1938 and 1987 are reviewed. Fifty-five percent of these tumors occurred in men. The average age of the patients at diagnosis was 42 years. The average duration of preoperative symptoms was 11 months. Symptoms were related to tumor location, which was similar to that of meningioma. The operative mortality was 9% overall, and has been zero since 1974 (18 patients). The average time before the first recurrence was 47 months, with the recurrence rates at 1, 5, and 10 years after surgery being 15, 65, and 76%, respectively. Ten patients have developed extraneural metastasis, mostly to lung and bone, at an average of 99 months after the first operation. The 10- and 15-year rates of metastasis were 33 and 64%, respectively. The average survival period has been 84 months, with survival rates at 5, 10, and 15 years after surgery of 67, 40, and 23%, respectively. The histological diagnosis of the tumor was not related to survival or recurrence and did not change with recurrence. Tentorial and posterior fossa tumors tended to be more lethal. Total tumor resection favorably affected recurrence and survival, as opposed to subtotal resection. Metastasis adversely affected survival, and was followed by death at an average of 24 months after its diagnosis. Radiation therapy after the first operation extended the average time before first recurrence from 34 to 75 months, and extended survival from 62 to 92 months.