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BACKGROUND High-grade astrocytomas (HGA) carry a dismal prognosis and compose nearly 20% of all childhood brain tumors. The role of high-dose chemotherapy (HDCT) in the treatment of HGA remains unclear. METHODS In a nationwide study, The Children's Cancer Group (CCG) prospectively evaluated 102 children with HGA and postoperative residual disease for efficacy and toxicity of four courses of HDCT before radiotherapy (RT). Patients were randomly assigned to one of three couplets of drugs: carboplatin/etoposide (Regimen A), ifosfamide/etoposide (Regimen B), or cyclophosphamide/etoposide (Regimen C). After HDCT, all patients were to receive local RT followed by lomustine and vincristine. Twenty-six patients were excluded after central neuroradiographic review (n = 8) or pathology review (n = 18). RESULTS Of 76 evaluable patients (median age, 11.95 yrs; range, 3–20 yrs), 30 patients relapsed during HDCT, and 11 others did not complete HDCT because of toxicity. Nonhematologic serious toxicities were common (29%), and 21% of patients did not receive RT. Objective response rates were not associated with amount of residual disease and did not statistically differ between regimens: 27% (Regimen A), 8% (Regimen B), and 29% (Regimen C). Overall survival (OS) was 24% ± 5% at 5 years and did not differ between groups. Median time to an event was longest for Regimen A (283 days compared with 83 and 91 days for Regimens B and C, respectively). The five-year, event-free survival (EFS) rate for all patients was 8% ± 3% and 14% ± 7% for Regimen A (P = 0.07). CONCLUSIONS OS and EFS were not affected by histologic grade. Patients who responded to HDCT had a nominally higher survival rate (P = 0.03 for trend). The authors conclude that these commonly used HDCT regimens provide no additional clinical benefit to conventional treatment in HGA, regardless of the amount of measurable residual tumor. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND In the current study, the authors compared the incidence of subsequent primary lung carcinoma in patients with breast carcinoma who received radiotherapy as part of their treatment and in those patients who did not. The patients were participants in two large National Surgical Adjuvant Breast and Bowel Project (NSABP) breast carcinoma trials, B-04 and B-06, which prospectively randomized women to either undergo surgery alone or to undergo surgery and postoperative radiotherapy. METHODS The NSABP trial B-04 (1971–1974) randomized patients to undergo radical mastectomy versus total (simple) mastectomy and radiotherapy to the chest wall, axilla, and supraclavicular and internal mammary lymph node areas. For patients with a clinically uninvolved axilla, there was a third randomization arm: total mastectomy without radiotherapy. The B-06 trial (1976–1984) randomized patients between those undergoing total mastectomy versus lumpectomy versus those undergoing lumpectomy and breast irradiation, with all patients undergoing an axillary lymph node dissection. The records of all patients who developed a recurrence in the lung or a new primary lung tumor were reviewed to determine the incidence and laterality of confirmed and probable primary lung carcinoma. RESULTS For the 1665 evaluable patients on the NSABP B-04 trial (mean follow-up of 21.4 years), there was a total of 23 subsequent confirmed and probable ipsilateral or contralateral primary lung carcinomas. In those patients who had received comprehensive postmastectomy radiotherapy, there was a statistically significant increase in the incidence of these new primary tumors (P = 0.029). With regard to the development of confirmed new primary ipsilateral lung carcinoma alone, the incidence was statistically significantly increased (P = 0.013) in those patients who had received radiotherapy as part of their treatment, and when confirmed and probable ipsilateral lung carcinomas were analyzed, there was a strong trend toward a statistically significant increase in those patients who had received radiotherapy (P = 0.066). For the 1850 evaluable patients on the NSABP trial B-06 (mean follow-up of 19.0 years), there was a total of 30 second primary lung carcinomas but no increase in either ipsilateral or contralateral primary tumors of the lung in those patients who had received radiotherapy. CONCLUSIONS Extensive postmastectomy irradiation of the chest wall and regional lymphatic node areas, with consequent exposure of a greater volume of lung to higher doses as administered in the NSABP B-04 trial compared with postlumpectomy breast irradiation in the NSABP B-06 trial, was associated with an increased incidence of subsequent primary lung tumors, both ipsilateral and contralateral. Cancer 2003;98:1362–8. © 2003 American Cancer Society. DOI 10.1002/cncr.11655

A total of 112 patients with the diagnosis of nonfunctional pituitary adenoma received radiation therapy at the University of Pittsburgh between 1964 and 1987. Postoperative radiation therapy was administered in 87 patients. Actuarial progression-free survival (tumor control) at 5, 10, 15, and 20 years was 97%, 89%, 87%, and 76%, respectively. Radiation prescribed to the 95% isodose ranged from 35.72 Gy to 62.32 Gy. Multivariate analysis showed decreased tumor control to be significantly associated with increasing field size (P = .036). No improvement in tumor control could be detected with increasing total radiation dose or nominal standard dose (NSD). One patient developed optic neuropathy and another developed a glioblastoma after doses in both patients of 4750 cGy in 25 fractions. External beam radiotherapy for nonfunctional pituitary adenomas was found to be effective and safe when doses less than 4750 cGy in 25 fractions were used.

Between 1971 and 1974, 1,665 women with primary operable breast cancer were entered into a prospective randomized clinical trial (NSABP Protocol No. B-04) in order to compare the worth of radical mastectomy with alternative treatments. Six-hundred forty-six of the women, 352 clinically nodenegative and 294 node-positive, were randomized so that they were to have been treated with total mastectomy and postoperative radiation. Due to a meticulous comprehensive program of radiation monitoring involving close cooperation between the NSABP Headquarters, the NSABP Radiation Monitoring Committee, the Radiological Physics Center at M. D. Anderson Cancer Center and participating institutions, it has been possible to determine protocol compliance of the radiation administered and to correlate any variation of radiation employed with treatment outcome. At the onset of the study and prior to any evaluation of treatment results, the Radiation Monitoring Committee defined minor variations from the protocol which were acceptable and those variations which were more major and unacceptable. While it was found that 53% of the 543 evaluable patients had been treated by radiation having some degree of variation from the protocol, it was ascertained that 77% of the 2.172 irradiated fields of those patients (82% in clinically node-negative and 71% in clinically node-positive patients) received radiation per protocol. Only 6.7% of all sites were the recipients of a major (unacceptabel) variation in radiation. Analysis of data demonstrated that there was a remarkable similarity in the incidence and rate of treatment failure (TF) or mortality between patients having some radiation variation, regardless of its degree or extent and those who were treated with no protocol variation. Results were similar when comparisons were made taking into consideration either the degree (minor or major low) or the extent (one or more than one field) of the radiation variation. A substantial number of clinically positive axillary node patients received only the radiation to the axillary field intended for those with clinically negative nodes, i.e., they failed to receive the specified radiation boost. Despite that deviation, there was no difference in TF or survival from those receiving the prescribed treatment. Moreover, findings were not different when the axilla was the only site of radiation deviation or there were deviations to other fields as well. Of singular importance was an inability to associate the localregional location of a recurrence with a low-dose radiation deviation at the site. Almost all recurrences in clinically node-negative patients were at sites treated per protocol. In positive-node patients, supraclavicular and chest wall recurrences occurred in patients having acceptable radiation to those sites and axillary recurrences were equivalent in patients treated with or without deviations at that site. The findings from these investigations are not presented in order to indicate that the quality and quantity of radiation may be unimportant. They have been obtained under careful monitoring and the variations are within a relatively narrow range. Consequently, more general extrapolations from these must be made with circumspection. The observations do suggest, however, that there is some acceptable leeway in the use of radiation, at least for treatment of the extent of disease present in patients in this study. Moreover, they refute any consideration that the failure to demonstrate a significant advantage following the use of postoperative radiation in Protocol No. B-04 could be related to the variation and inadequacy of radiation employed in a proportion of the patients. They tend to substantiate the contention that factors other than the type of operative procedure employed or the precision of administration of radiation are important in determining the survival of women with breast cancer. Finally, the mechanism whereby the radiation employed was quality controlled serves as a model for the mandatory monitoring of all modalities of therapy in cooperative clinical trials. Such monitoring, by providing more credible dat, will favorably affect the management of cancer patients. Cancer 46:1–13, 1980.

Thirty-eight patients with newly diagnosed medulloblastoma were studied with myelography and cerebrospinal fluid (CSF) cytology studies before radiotherapy. Seventeen (45%) patients had evidence of dissemination beyond the posterior fossa. Spinal cord lesions were demonstrated in ten patients (26%). Negative results of CSF cytology studies did not preclude demonstration of cord involvement. Children younger than 5 years were more likely than older patients to have spinal cord involvement at diagnosis. Patients who were truly M-0 did better in terms of absolute survival but not relapse-free survival when compared with patients with dissemination. Myelography and cytology studies are necessary in the evaluation of all newly diagnosed patients with medulloblastoma and may also be indicated for patients with other brain tumors with a known propensity for dissemination.

Sixteen children with newly diagnosed medulloblastomas underwent myelography prior to radiotherapy. None had clinical evidence suggesting spinal cord involvement. Seven patients (43%) were discovered to have unsuspected metastases involving the cord. Cerebrospinal fluid (CSF) cytology results were inaccurate in predicting spinal cord involvement. Additional radiation was administered to the demonstrated lesions. Thirteen children (81%) are alive and well 7-53 months (average 26) from completion of therapy. One of nine children with a normal myelogram initially, and two of seven with initial spinal cord involvement have relapsed.

In 1971, the National Surgical Adjuvant Breast Project (NSABP) implemented a prospective randomized clinical trial to compare the worth of alternative treatments with radical mastectomy in women with primary operable breast cancer. Information has been obtained from 1,665 patients eligible for follow-up from 34 NSABP member institutions in Canada and the United States. Results from that trial, at present in its sixth year with patients on study for an average of 36 months, (26 to 62 months), fail to demonstrate an advantage for those who had a radical mastectomy. No significant difference in the treatment failure or survival has as yet been observed in clinically negative node patients who have been randomly managed by conventional radical mastectomy, total mastectomy with postoperative regional radiation or total mastectomy followed by axillary dissection of those patients who subsequently develop positive nodes. Similarly, there presently exists no difference between patients with clinically positive nodes treated by radical mastectomy or by total mastectomy followed by radiation. Of particular interest is the observation that based upon findings from radical mastectomy patients, there may be as many as 40% of patients having a total mastectomy who had histologically positive nodes unremoved, to date only 15% have developed positive nodes requiring an axillary dissection. The persistence of such a difference in incidence would have profound biological significance. The discovery that leaving behind positive axillary nodes has as yet not been influential in enhancing the incidence of distant metastases or the overall proportion of treatment failures and that a disproportionate number of treatment failures in the total mastectomy group occurred in those patients who subsequently required axillary dissection provides reinforcement to the view that positive axillary lymph nodes are not the predecessor of distant tumor spread but are a manifestation of disseminated disease.

Ninety-one children younger than age five years have been treated with radiotherapy for primary intracranial tumors. Patients with cerebellar astrocytomas and optic chiasm gliomas did relatively well, whereas brain stem tumors, extensive posterior fossa tumors and cerebral gliomas had a poor prognosis. Medulloblastomas, ependymomas, and midbrain tumors were of intermediate prognosis. There was no definite correlation between age at diagnosis and survival, although patients over 24 months of age seemed to do slightly better. Tumor doses of at least 4000 rad seem necessary for any likelihood of control. Of 63 children diagnosed over five years ago, 27 (43%) survived at least five years. The majority of long-term survivors are leading normal lives, although many have mild impairments.

Although tumors are a known complication of von Recklinghausen's neurofibromatosis (NF), they often develop after the second decade and their characteristics in the pediatric population are unclear. To define the frequency and distribution of tumor types in children with NF, the authors reviewed the experience at Children's Hospital of Pittsburgh between 1953 and 1984. During that time, 121 children younger than 18 years with documented NF were seen. Three patients (2.5%) developed locally extensive, unresectable sarcomas, two of which were clearly neural in origin. Two other children died from complications of highly cellular but not histologically malignant neurofibromas. Seventeen patients (14%) had brain tumors, of which 3 (2.5%) were malignant astrocytomas and 9 were optic gliomas. Two children had acute myelogenous leukemia. Although it has been said that patients with NF are particularly susceptible to the oncogenic effects of radiation, 12 children were treated with a median of 5000 rad to their tumor bed. Follow-up after radiation in that small cohort of patients ranged from 6 months to 12 years (mean, 6 years). Eleven of 12 patients experienced adequate local control. During the follow-up period, none developed a second tumor outside or within the radiation port that could be related to radiation. The authors conclude that clinically significant tumors in children with NF, not all of which are histologically malignant, are not rare. Although more prospective information is needed on response to and sequelae from therapy, the data in this report suggest no contraindication to aggressive therapy.

Thirty-six patients were evaluated between 1965 and 1983 for glioma of the optic nerves and/or chiasm. Median follow-up was 10.2 years. Pathologic verification was obtained in 32 patients. Tumor initially confined to the optic nerve recurred in one of five patients after complete resection. The actuarial survival for 25 patients irradiated for biopsy-proven glioma of the optic chiasm was 96%, 90%, and 90% at 5, 10, and 15 years, respectively, and the progression-free survival was 87% at 5, 10, and 15 years. Vision stabilized or improved in 86% of patients after radiotherapy. Patients irradiated to a dose greater than a NSD of 1385 ret had a significantly improved progression-free survival (P = 0.015). One serious complication occurred after a dose of 1533 ret. The recommended radiation dose for optic glioma is 45 to 50 Gy with 1.8 Gy fractions.

The authors present 15 children with cancer of the nasopharynx. Of seven patients with primary epidermoid carcinomas, only two are alive and well. Only one of four patients with a primary soft tissue sarcoma is alive and well. Two of four patients with lymphoma of the nasopharynx are alive and well. All deaths were due to uncontrolled distant metastases. Only one patient (rhabdomyosarcoma) died with uncontrolled local disease. Radiotherapy to the primary and neck is recommended for all children with primary malignancy of the nasopharynx. Adjuvant chemotherapy may also be of value for all patients regardless of histopathology.

Findings from 1665 women with primary breast cancer, treated at 34 NSABP institutions in Canada and the United States, have failed to demonstrate that patients with medial-central tumors had a greater probability of developing distant metastases or dying than did those with lateral tumors despite the greater incidence of internal mammary (IM) node involvement when tumors are medial-central in location. A comparison of patients with similar clinical nodal status and tumor location who were treated either by radical mastectomy (RM) or by total mastectomy plus radiation therapy (TM + RT) failed to indicate that radiation of IM nodes reduced the probability of distant treatment failure (TF) or mortality. When findings from patients having equivalent clinical nodal status and tumor location treated by TM alone or TM + RT were compared, it was found that the addition of RT failed to alter the probability of the occurrence of a distant TF or of death. This was despite the fact that in the nonradiated group two putative sources of further tumor spread, i.e., positive axillary and IM nodes, were left unremoved and untreated. The findings provide further insight into the biologic significance of the positive lymph node and confirm our prior contention that positive regional lymph nodes are indicators of a host-tumor relationship which permits the development of metastases and that they are not important investigators of distant disease.