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OBJECT: The purpose of this study was to estimate the efficacy of gamma knife radiosurgery (GKS) in controlling tumor growth and endocrinopathy associated with prolactinomas. METHODS: Between 1993 and 1997, 164 of 469 patients with pituitary adenomas treated by GKS harbored prolactinomas. The dose to the tumor margin ranged from 9 to 35 Gy (mean 31.2 Gy), and the visual pathways were exposed to a dose of less than 10 Gy. The mean tumor diameter was 13.4 mm. The mean follow-up time for 128 cases was 33.2 months (range 6-72 months). Tumor control was observed in all but two patients who underwent surgery 18 and 36 months, respectively, after GKS. Clinical cure was achieved in 67 cases. Clinical improvement was noted with a decrease in the hyperprolactinemia after GKS. Nonetheless, in 31 (29%) of 108 patients who were followed for more than 2 years no improvement in serum prolactin levels was demonstrated, although this could be normalized by bromocriptine administration after treatment. Nine infertile women became pregnant 2 to 13 months after GKS and all gave birth to normal children. There was no visual deterioration related to GKS. Five women experienced premature menopause. In these patients there was subtotal disappearance of the tumor and an empty sella developed. CONCLUSIONS: Gamma knife radiosurgery as a primary treatment for prolactinomas can be safe and effective both for controlling tumor growth and for normalization of prolactin hypersecretion. A higher margin dose (> or = 30 Gy) seemed to be associated with a better clinical outcome. Gamma knife radiosurgery may make prolactinomas more sensitive to the bromocriptine.
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Estimates of genetic risks of radiation exposure of humans are traditionally expressed as expected increases in the frequencies of genetic diseases (single-gene, chromosomal and multifactorial) over and above those of naturally-occurring ones in the population. An important assumption in expressing risks in this manner is that gonadal radiation exposures can cause an increase in the frequency of mutations and that this would result in an increase in the frequency of genetic diseases under study. However, despite compelling evidence for radiation-induced mutations in experimental systems, no increases in the frequencies of genetic diseases of concern or other adverse effects (i.e., those which are not formally classified as genetic diseases), have been found in human studies involving parents who have sustained radiation exposures. The known differences between spontaneous mutations that underlie naturally-occurring single-gene diseases and radiation-induced mutations studied in experimental systems now permit us to address and resolve these issues to some extent. The fact that spontaneous mutations (among which are point mutations and DNA deletions generally restricted to the gene) originate through a number of different mechanisms and that the latter are intimately related to the DNA organization of the genes, are now well-documented. Further, spontaneous mutations include those that cause diseases through loss of function as well as gain of function of genes. In contrast, most radiation-induced mutations studied in experimental systems (although identified through the phenotypes of the marker genes) are predominantly multigene deletions which cause loss of function; the recoverability of an induced deletion in a livebirth seems dependent on whether the gene and the genomic region in which it is located can tolerate heterozygosity for the deletion and yet be compatible with viability. In retrospect, the successful mutation test systems (such as the mouse specific locus test) used in radiation studies have involved genes which are non-essential for survival and are also located in genomic regions, likewise non-essential for survival. In contrast, most of the human genes at which induced mutations have been looked for, do not seem to have these attributes. The inference therefore is that the failure to find induced germline mutations in humans is not due to the resistance of human genes to induced mutations but due to the structural and functional constraints associated with their recoverability in livebirths. Since the risk of inducible genetic diseases in humans is estimated using rates of "recovered" mutations in mice, there is a need to introduce appropriate correction factors to bridge the gap between these rates and the rates at which mutations causing diseases are potentially recoverable in humans. Since the whole genome is the "target" for radiation-induced genetic damage, the failure to find increases in the frequencies of specific single-gene diseases of societal concern does not imply that there are no genetic risks of radiation exposures: the problem lies in delineating the phenotypes of recoverable genetic damage that are recognizable in livebirths. Data from studies of naturally-occurring microdeletion syndromes in humans and those from mouse radiation studies are instructive in this regard. They (i) support the view that growth retardation, mental retardation and multisystem developmental abnormalities are likely to be among the quantitatively more important adverse effects of radiation-induced genetic damage than mutations in a few selected genes and (ii) underscore the need to expand the focus in risk estimation from known genetic diseases (as has been the case thus far) to include these induced adverse developmental effects although most of these are not formally classified as "genetic diseases". (ABSTRACT TRUNCATED)
Between May 1980 and July 1983, the RTOG conducted a randomized prospective study comparing external radiation therapy and misonidazole to radiation therapy alone for patients with hepatic metastases. Two hundred fourteen patients were accessioned to this study of whom 187 were evaluable. Radiation therapy was delivered to the whole liver to a dose of 21.0 Gy in 7 fractions. Misonidazole was administered orally, 1.5 gm/m2 daily 4-6 hr before each treatment. Patients in the two treatment groups were evenly distributed with respect to stratification variables including primary site, extent of metastatic disease, and Karnofsky Performance Score (KPS). End points examined included amelioration of hepatic pain, improvement of KPS and alkaline phosphatase, decrease in liver and tumor size, and survival. The addition of misonidazole did not significantly improve the therapeutic response to radiation therapy in any of the parameters studied. Hepatic irradiation was effective in relieving abdominal pain with 80% of the symptomatic patients achieving improvement following therapy. Pain was completely relieved in 54% of these patients. Patients with liver metastases from colon carcinoma improved more frequently than those with metastases from other primary tumor sites (p = 0.02). Relief of pain occurred more frequently in patients treated with radiation therapy and misonidazole (87%) compared with radiation therapy alone (74%) (p = 0.08). Palliation of pain was prompt, occurring within a median of 1.7 weeks from the initiation of treatment, and 94% of patients who improved did so within 6 weeks of treatment. The median duration of response was 13.0 weeks in the symptomatic patients; 52% of those surviving 3 months remained improved. KPS improved in 28% of patients. Serial CT scans revealed a partial response in 7% and a marginal response in 13% of patients. One patient had a complete response to treatment. The median survival of patients treated in this series was 4.2 months with no difference between the two treatment groups. Patients with metastases from colon carcinoma and an initial KPS of 80 or more (48% of the patient population) had a median survival of 5.8 months with radiation therapy alone compared with 6.6 months with radiation therapy and misonidazole (p = 0.36). There was no significant treatment related morbidity. Radiation therapy remains an excellent palliative tool for the management of patients with symptomatic hepatic metastases. Further research must continue to identify new methods of selectivity enhancing the tumor response to radiation therapy.
One hundred and ten patients with base of tongue tumors less than or equal to 4 cm in diameter (T1 and T2 by the UICC staging system) were treated according to three different methods; surgery followed by external radiation in 27 cases, external radiation followed by interstitial implantation in 29 cases, and external radiation alone in 54 cases. The median follow-up is 8 years with a minimum of 4 years. Local failure occurred twice as often in patients treated by external radiation alone (43%) compared to the other two therapeutic modalities (20.5% for external radiation plus implantation and 18.5% for surgery plus radiation). Ninety per cent of recurrences occurred within the first 2 years. The 5-year survival rate for N0 and N1 nodal disease is 30.5% for patients treated by external radiation alone and 50% for the other two methods. This survival difference is related to poorer local control. Surgery plus external radiation gives identical results to those of external radiation and interstitial implantation, but surgery is only practical for peripheral base of tongue tumors and it has poorer functional results. External radiation followed by interstitial implantation is, in our opinion, the best of the three therapeutic techniques for T1 and T2 base of tongue tumors.
PURPOSE: To evaluate the effect of immediate androgen suppression in conjunction with standard external beam irradiation vs. radiation alone on a group of pathologically staged lymph node-positive patients with adenocarcinoma of the prostate. METHODS AND MATERIALS: A national prospective randomized trial (RTOG 85-31) of standard external beam irradiation plus immediate androgen suppression vs. external beam irradiation alone was initiated in 1985 for patients with locally advanced adenocarcinoma of the prostate. One hundred seventy-three of the patients in this trial had biopsy-proven pathologically involved lymph nodes. Ninety-eight of these patients received radiation plus the immediate androgen suppression (LHRH agonist), while 75 received radiation alone with hormonal manipulation instituted at the time of relapse. RESULTS: With a median followup of 4.9 years, estimated progression-free survival with PSA < 1.5 ng/ml at 5 years was 55% for the patients who received radiation plus immediate LHRH agonist vs. 11% of the patients who received radiation alone with hormonal manipulation at relapse (p = 0.0001). Because all of these patients had locally advanced disease (i.e., pathologically positive lymph nodes), stage does not explain this difference in outcome, and Gleason grade was not statistically different between the two groups. Estimated absolute survival at 5 years for the radiation and LHRH group was 73 vs. 65% for the radiation alone group who received androgen suppression at relapse. Estimated disease-specific survival at 5 years was 82% for the radiation and immediate LHRH agonist group and 77% for the radiation-alone group. CONCLUSION: Patients with adenocarcinoma of the prostate and pathologically involved pelvic lymph nodes (pN+ or clinical stage D1) should be seriously considered for external beam irradiation plus immediate hormonal manipulation over radiation alone with hormonal manipulation at the time of relapse.
Radiation sensitizers are agents which can increase the lethal properties of ionizing radiation when administered in conjunction with radiation therapy. They increase radiosensitivity without being innately toxic and give rise to significant increase in the radiation sensitivity of neoplasm over normal tissues. Much laboratory work, mostly in vitro, has shown that many chemical compounds can act as radiation sensitizers. The practicality depends upon the exploitation of the differences between normal and malignant cells when radiation sensitizers are used. Many tumors contain hypoxic cells which are relatively resistant to the lethal effects of ionizing radiation. In human tumors, these hypoxic cells present a potential barrier to successful treatment. The application of chemical radiosensitizers active against hypoxic cells offers great potential for improvement in cancer management using radiation therapy. Data is presented to illustrate the usefulness of these agents in gynecologic cancer.
Between February 1983 and January 1986, 77 evaluable patients with non-small cell lung cancer were randomized to receive radiotherapy with or without nimustine hydrochloride (ACNU) according to a centralized resistration system using a telephone call. The randomization was for radiation 50 to 60 Gy/5 to 6 weeks with or without ACNU (30 mg/m2 x 4 times) during irradiation. There were no significant differences in the patient characteristics of either group. The complete response rates to both regimens were statistically significantly different: 55% in radiation plus ACNU and 13.6% in radiation alone for squamous cell carcinoma. In addition, there were statistically significant differences in Stage III. The median survival time for radiation plus ACNU was 47.7 weeks, compared with 41.9 weeks for radiation alone. Overall survival did not significantly differ in either group. There was a significant decrease in the incidence of leukocyte nadirs below 2000/ml (5.7%) and platelet 50,000/ml (14.3%) with ACNU. This study confirmed that radiation with ACNU in the treatment of non-small cell lung cancer was effective and superior as compared to radiation alone.
One-hundred-ninety-four eligible and evaluable patients with histologically confirmed locally unresectable adenocarcinoma of the pancreas were randomly assigned to therapy with high-dose (6000 rads) radiation therapy alone, to moderate-dose (4000 rads) radiation + 5-fluorouracil (5-FU), and to high-dose radiation plus 5-FU. Median survival with radiation alone was only 51/2 months from date of diagnosis. Both 5-FU-containing treatment regimens produced a highly significant survival improvement when compared with radiation alone. Forty percent of patients treated with the combined regimens were still living at one year compared with 10% of patients treated with radiation only. Survival differences between 4000 rads plus 5-FU and 6000 rads plus 5-FU were not significant with an overall median survival of ten months. Significant prognostic variables, in addition to treatment, were pretreatment performance status and pretreatment CEA level.
PURPOSE: To develop evidence-based guidelines for (1) prostate re-biopsy after radiation and (2) radiation therapy with rising prostate-specific antigen (PSA) levels after radical prostatectomy in the management of patients with localized prostatic cancer. DESIGN: The American Society of Therapeutic Radiology and Oncology (ASTRO) challenged a multidisciplinary consensus panel to address consensus on specific issues in each of the two topics. Four well-analyzed patient data sets were presented for review and questioning by the panel. The panel sought criteria that would be valid for patients in standard clinical practice as well as for patients enrolled in clinical trials. Subsequent to an executive session that followed these presentations, the panel presented its consensus guidelines. RESULTS AND CONCLUSIONS: Based on the data presented, the prostate re-biopsy negative rates ranged from 62% to 80% for patients with stage T1-2 tumors. The panel judged that prostate re-biopsy is not necessary as standard follow-up care and that the absence of a rising PSA level after radiation therapy is the most rigorous end point of total tumor eradication. Further, the panel judged that re-biopsy may be an important research tool. Based on the data presented, the long-term (5 years or more) PSA remission rate after salvage radiation therapy ranges from 27% to 45%. The panel requested results from prospective randomized trials to evaluate optimally this information. The panel judged that the total dose of radiation should be 64 Gy or slightly higher and that, in patients with or without radiation therapy, there is no standard role for androgen suppressant therapy for rising PSA values after prostatectomy.
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Radiation sickness manifestations have been studied in two species (Macaca fascicularis and Papio hamadryas) exposed to electron and gamma-neutron radiations in a wide supralethal doses range. Dose-response relationships have been calculated for mortality and some clinical manifestations of the intestinal and cerebral forms of radiation sickness. Higher radiosensitivity of baboons in comparison with Macaca fascicularis and clinically more dangerous damage due to electrons as compared to gamma-neutron radiation have been demonstrated.