[Vancomycin-resistant enterococci: prevalence and factors associated with intestinal colonization in oncology patients from Hospital de Niños de Córdoba]. / Enterococos resistentes a vancomicina: prevalencia y factores asociados a la colonización intestinal en pacientes oncológicos del Hospital de Niños de Córdoba.

Vancomycin-resistant enterococci (VRE) have an important impact on pediatric oncology population. The objectives of this study were: to know the prevalence of VRE intestinal colonization in oncology patients, to identify the risk factors that predispose hospitalized patients to VRE intestinal colonization, and to determine the VRE resistance profile to different antimicrobial agents. We studied all children with oncological disease aged 1 month to 16 years that had joined the protocol and had been hospitalized from October 2006 to April 2007. VRE intestinal colonization was analyzed when the patient was admitted to hospital, 72 hours later, and weekly during hospitalization. A total of 333 samples were taken from 67 patients. From these, VRE were isolated in 12 patients, with a prevalence of 17.9%. Of the 28 isolates studied, taking one per patient, 10 were Enterococcus faecium and 2 Enterococcus faecalis, both with resistance phenotype VanA (CIM90 512 microg/ml to vancomycin and CIM90 256 microg/ml to teicoplanin). The use of vancomycin (p = 0.02), duration of neutropenia greater than 7 days (p = 0.03) and prolonged hospitalization (42.8 days on average) (p = 0.0001) were risk factors significantly related to VRE colonization. We considered it necessary to carry out an epidemiological surveillance and to implement prevention and control measures.

Intraperitoneal photodynamic therapy.

Peritoneal carcinomatosis and sarcomatosis are generally incurable problems for which there are few good treatment options. Intraperitoneal PDT is potentially an ideal therapy for peritoneal carcinomatosis because of its relatively superficial treatment effect. A Phase II trial of IP PDT with the first generation photosensitizer, Photofrin, demonstrates that this treatment approach is tolerable clinically but is associated with substantial toxicity suggesting a narrow therapeutic index. Remarkably, responses were observed in heavily pre-treated patients suggesting clinical activity. Correlative studies of photosensitizer uptake in human tumour and normal tissues show little tumour selectivity. This lack of photosensitizer selectivity for tumour in combination with tumour hypoxia (as opposed to oxic normal tissues) is likely a major reason for the narrow therapeutic index of intraperitoneal PDT. However, the advent of novel and potentially molecularly targeted photosensitizers, combined with enhancement of PDT cancer cell cytotoxicity through inhibition of growth factor signaling should greatly improve the therapeutic index of intraperitoneal PDT. In addition, other approaches, including the use of nanotechnology, may allow the administration of fractionated PDT which may also improve the therapeutic index of this treatment. The clinical implementation of these technologies may allow for highly effective and well tolerated treatment of intraperitoneal carcinomatosis with PDT.

Prognostic value of FDG-PET scan imaging in lymphoma patients undergoing autologous stem cell transplantation.

We conducted a retrospective analysis of 50 lymphoma patients (Hodgkin's disease and non-Hodgkin's lymphoma) who had an 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET) scan after at least two cycles of salvage chemotherapy and before autologous stem cell transplantation (ASCT) at our institution. The patients were categorized into FDG-PET negative (N = 32) and positive (N = 18) groups. The median follow-up after ASCT was 19 months (range: 3-59). In the FDG-PET-negative group, the median progression-free survival (PFS) was 19 months (range: 2-59) with 15 (54%) patients without progression at 12 months after ASCT. The median overall survival (OS) for this group was not reached. In the FDG-PET-positive group, the median PFS was 5 months (range: 1-19) with only one (7%) patient without progression at 12 months after ASCT. The median OS was 19 months (range: 1-34). In the FDG-PET-negative group, chemotherapy-resistant patients by CT-based criteria had a comparable outcome to those with chemotherapy-sensitive disease. A positive FDG-PET scan after salvage chemotherapy and prior ASCT indicates an extremely poor chance of durable response after ASCT.

Effects of postoperative adjuvant chemotherapy and radiotherapy on ovarian function in women undergoing treatment for soft tissue sarcoma.

Ovarian function was evaluated in 11 women 16 to 43 years of age at treatment who received doxorubicin, cyclophosphamide, and high doses of methotrexate with or without radiotherapy in adjuvant therapy of soft tissue sarcoma. Five women (16-33 yr old) who received chemotherapy alone or combined with radiotherapy only at sites distant from the ovaries (chest wall, thigh, and leg) had minimal menstrual irregularities or temporary cessation of menses during therapy; cyclic menses returned promptly after therapy. Gonadotropin levels (expressed as means +/- SD [follicle-stimulating hormone (FSH), 10 +/- 5 mlU/ml; luteinizing hormone (LH), 10 +/- 4 mlU/ml] and 17 beta-estradiol (E2) levels (means +/- SD, 208 +/- 147 pg/ml) were normal. By contrast, 4 older women (ages 36-43 yr) who received similar treatment developed persistent amenorrhea with postmenopausal levels of gonadotropin (FSH, 108 +/- 29 mlU/ml; LH, 72 +/- 19 mlU/ml) and E2 (19 +/- 8 pg/ml). Two additional women (ages 21 and 39 yr) who received radiation (7,000 rad) to the pelvis plus chemotherapy developed prompt cessation of menses and became functional castrates (FSH, 77 and 80 mlU/ml; LH, 40 and 58 mlU/ml; E2, 10 and 19 pg/ml). However, this result would be expected from the radiation dose alone. The data demonstrated that ovarian dysfunction may follow the use of doxorubicin, cyclophosphamide, and high doses of methotrexate and that the injury is age related.

Treatment of locally advanced cancer of the head and neck with 5'-iododeoxyuridine and hyperfractionated radiation therapy: measurement of cell labeling and thymidine replacement.

BACKGROUND: The halogenated pyrimidines 5'-iododeoxyuridine (IdUrd) and 5'-bromodeoxyuridine (BrdUrd) are under active study as radiation sensitizers for a variety of malignancies. Head and neck neoplasms may also be suitable for halogenated pyrimidine-mediated sensitization; previous regimens using intra-arterial BrdUrd delivery, however, were poorly tolerated. PURPOSE: A pilot study was undertaken with the use of intravenous IdUrd with hyperfractionated radiotherapy to assess tolerance. In addition, serial tumor biopsy specimens were obtained to determine the kinetics of IdUrd labeling and incorporation. METHODS: Twelve patients with squamous cell carcinomas of the head and neck (one patient had stage II cancer, one had stage III, and 10 had stage IV) were treated with hyperfractionated radiation therapy at a dose of 1.2 or 1.5 Gy twice a day, to a total dose in the range of 70-76 Gy. IdUrd (1000 mg/m2 per day) was infused for a maximum of 14 days at the beginning and then again during the middle of the radiotherapy. A tumor biopsy specimen was obtained from 11 patients following initiation of treatment with IdUrd. Eight patients consented to serial biopsy to allow the study of IdUrd-labeling indices and thymidine replacement over time. Incorporation of IdUrd into tumor DNA was determined by high-performance liquid chromatography, and cell labeling was determined with the use of an anti-BrdUrd/IdUrd monoclonal antibody in conjunction with flow cytometry. Patients continue to be followed to assess local control. RESULTS: A plot of corrected IdUrd replacement as a function of infusion time suggests the possibility of a plateau after 5-7 days of infusion at 7.5%-8%. The average rate of replacement from days 1 to 5 was 1.3% per day and was determined by linear regression analysis. Acute toxic effects, especially mucositis, were severe enough to require delays in the radiation therapy. Eleven of 12 patients treated had complete clinical remissions. Seven of these patients remain clinically free of local disease at the time of death or most recent follow-up. CONCLUSIONS: The level of IdUrd incorporation and cell labeling should be adequate to produce sensitization. However, the treatment as prescribed in this study (two 14-day infusions of IdUrd during radical radiotherapy with only one planned split) was not completed in a single patient because of either dose-limiting hematologic toxicity or severe mucositis necessitating treatment break. Since this particular regimen is not tolerable, future protocols will have shorter exposures to IdUrd. IMPLICATIONS: Previous regimens using halogenated pyrimidine radiosensitizers have generally used protracted drug delivery schedules. In this study, a high level of IdUrd labeling was measured after 5-7 days of drug infusion. The halogenated pyrimidines deserve further study with the use of repetitive short courses to reduce toxicity and possibly improve efficacy.

Radiation oncology: past achievements and ongoing controversies.

With the development of megavoltage treatment and computerized treatment planning the quality and precision of radiation oncology has steadily improved. Likewise, these developments have contributed to better local control for some cancers; however, micrometastatic lesions beyond the radiation treatment field and ineffective systemic treatments for many malignancies hamper efforts at the most important oncological end point, survival. Major advances in cancer therapy are therefore likely to come with improved combined modality treatment representing integration of local modalities with the systemic. These advances, in our opinion, will come from biological developments that address the problems that the modern oncologist faces at the cellular level. The biological developments will incorporate modern molecular biology, continued probing for biochemical mechanisms, and an intensified effort to learn more about the complexities of human tumor physiology.

Glutathione elevation during thermotolerance induction and thermosensitization by glutathione depletion.

Chinese hamster V79 cells were made thermotolerant by either continuous heating at 42.5 degrees or by fractionated 43 degrees exposures with interfraction incubation at 37 degrees. For both methods of thermotolerance induction, elevations in cellular glutathione (GSH) were observed. Additionally, GSH was also shown to be elevated following a 1-hr exposure to 6% ethanol, which also induces thermotolerance. These elevations in cellular GSH preceded thermotolerance induction in regard to cell survival. To determine if a reduction in cellular GSH prior to or during heating at 42.5 degrees would influence thermotolerance, GSH levels were reduced by either pretreatment with diethylmaleate, an agent that binds GSH, or treatment during heating with buthionine sulfoximine, an agent that inhibits GSH synthesis. Both depleting protocols resulted in thermosensitization. These data suggest that GSH may be important in the early cellular response to thermal stress.

Tempol, a stable free radical, is a novel murine radiation protector.

Nitroxide compounds are stable free radicals which were previously investigated as hypoxic cell radiosensitizers. The stable nitroxide 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (Tempol) has recently been shown to protect aerated cells in culture against superoxide generated from hypoxanthine/xanthine oxidase, hydrogen peroxide, and radiation-induced cytotoxicity and to modestly sensitive hypoxic cultured cells. To extend these observations from the cellular level to the whole animal, the toxicity, pharmacology, and in vivo radioprotective effects of Tempol were studied in C3H mice. The maximum tolerated dose of Tempol administered i.p. was found to be 275 mg/kg, which resulted in maximal Tempol levels in whole blood 5-10 min after injection. Mice were exposed to whole-body radiation in the absence or presence of injected Tempol (275 mg/kg) 5-10 min after administration. Tempol treatment provided significant radioprotection (P less than 0.0001); the dose of radiation at which 50% of Tempol-treated mice die at 30 days was 9.97 Gy, versus 7.84 Gy for control mice. Tempol represents a new class of in vivo, non-sulfur-containing radiation protectors. Given the potential for hypoxic radiosensitization and aerobic cell radioprotection, Temporal or other analogues may have potential therapeutic application.

Measurement of thymidine replacement in patients with high grade gliomas, head and neck tumors, and high grade sarcomas after continuous intravenous infusions of 5-iododeoxyuridine.

Based upon the radiation sensitization properties of the halogenated pyrimidines, 5-iododeoxyuridine (IdUrd) and 5-bromodeoxyuridine, long term i.v. infusions of halogenated pyrimidines in conjunction with fractionated radiation therapy have been evaluated in the treatment of a variety of human malignancies. While clinical studies have attempted to measure the halogenated pyrimidine incorporation, few have successfully related tumor response to the incorporation of IdUrd by the tumor. The present study reports the continuous IdUrd labeling index (number of cells labeled) and the IdUrd corrected replacement (percentage of thymidine replacement in the labeled cells of the population) from the tumors of 17 patients who received continuous infusions of IdUrd (1000 mg/m2/24 h). The tumors treated included four high grade gliomas, five head and neck tumors, four high grade sarcomas, and five other tumors of varying types. Less than 25% of the cells in three of four gliomas incorporated IdUrd after 5-7-day IdUrd infusion time. Corrected replacement for the gliomas ranged from 0 to 4%. In contrast, 63-85% of the cells in the head and neck biopsies were labeled with IdUrd after 3-7-day IdUrd infusions suggesting that these large tumors (3-12 cm diameter) have a high fraction of dividing cells. Corrected replacements values for the head and neck tumor patients ranged from 2.9 to 26.3%. The high grade sarcomas also demonstrated a high percentage of IdUrd labeled cells (57-79%) with three patients having corrected replacements of 7.5-14.2%. The continuous labeling and thymidine replacement data for four patients from whom serial biopsies were taken during IdUrd infusion demonstrated both an increasing IdUrd replacement and continuous labeling index with an increasing duration of IdUrd infusion. The clinical response of both the high grade glioma and head and neck tumor patients indicate that the IdUrd replacement and labeling data may provide some important predictive information with regard to the successful use of the halogenated pyrimidines in clinical radiation trials.

Pharmacological evaluation of intravenous delivery of 5-bromodeoxyuridine to patients with brain tumors.

Previously, 5-bromodeoxyuridine (BrdUrd) has been shown to be an effective radiosensitizing agent in rapidly dividing cells. As part of a Phase I/II study to evaluate BrdUrd as a radiosensitizer in gliomas, the pharmacology was studied in eight patients. BrdUrd was infused using an i.v. route as a 12-hr constant infusion each day for as long as 14 days. BrdUrd steady-state arterial levels are described for three different infusional rates: 1.6 mumol/sq m/min (350 mg/sq m/12 hr) produced a steady-state arterial level of 0.7 microM; 3.2 mumol/sq m/min (700 mg/sq m/12 hr) resulted in 2.1 microM; 5.9 mumol/sq m/min (650 mg/sq m/6 hr) showed a level of 3.9 microM. Because of myelosuppression, the highest tolerable dose for this intermittent long-term infusional therapy with BrdUrd appears to be 700 mg/sq m/12 hr. Contrary to the nonlinear pharmacokinetics of thymidine, 5-fluorouracil, and 5-fluorodeoxyuridine described previously, BrdUrd shows linear behavior in the range studied. BrdUrd still has promise as a radiosensitizer for gliomas in humans, but an alternative means of safe delivery into the carotid artery is needed. Because of an estimated 11- to 16-fold-higher local concentration, use of the intraarterial route could deliver optimum levels of BrdUrd to the tumor with minimal systemic toxicity.

Illusion and reality: practical pitfalls in interpreting clinical trials.

This paper has attempted to review for the reader some of the common problem areas in the interpretation of results of cancer treatment. The intention has been to point out potential pitfalls in interpretation so that the reader can comprehend the literature with more insight and criticalness . The plethora of journals and ongoing investigations indicates a greater need for critical understanding on the part of readers. This understanding stretches from the definitions of success and failure used in generating survival curves, to the accumulation and analysis of data and presentation of the results. We hope this paper will help the reader to achieve a greater degree of that understanding.

Treatment of non-small-cell lung cancer.

The treatment of non-small-cell lung cancer (NSCLC; including squamous, large-cell anaplastic, and adenocarcinoma) is one of the most frustrating areas in oncology. With the exception of the high cure rates for surgical treatment of truly localized disease, the prognosis for patients with NSCLC is grim. Often rancorous debate has ensued about the best means of exploiting the currently available modalities of radiation therapy and chemotherapy. Recognizing that the effectiveness of the current therapeutic modalities is limited, we will review the treatment results from the past few years that help define where specific treatment options should be used or suggest areas in which to focus future trials. We will also review the implications of current findings in the cell biology of lung cancer as they pertain to the therapy of NSCLC.

Neurobehavioral sequelae of cranial irradiation in adults: a review of radiation-induced encephalopathy.

PURPOSE: To examine behavioral dimensions of treatment outcomes for patients receiving cranial irradiation. Radiation encephalopathy is one of these and refers to significant cognitive and emotional dysfunction following radiation therapy to the brain. Issues of definition, estimated incidence, pathophysiologic mechanisms, and recommended research designs are reviewed in relationship to functional neurobehavioral outcomes. PATIENTS AND METHODS: Twenty-nine studies of adults receiving therapeutic cranial irradiation (TCI) involving 748 patients and 18 studies of prophylactic cranial irradiation (PCI) involving 368 patients are reviewed. Assessment of patient outcomes are summarized for research published since 1980, with specific attention to adverse changes in cognitive and emotional functioning. RESULTS: Analyses revealed that 213 TCI patients and 100 PCI patients showed encephalopathy attributed to radiation. Manifestations of the late delayed effects of radiotherapy on brain function are related to patient age, total dose of irradiation, fraction sizes, and timing of chemotherapy. Radiation encephalopathy appears to be more common than the pathologic tissue injury of radiation necrosis. Accurate diagnosis of these neurobehavioral sequelae can require follow-up over a period of years with sensitive assessment procedures. CONCLUSIONS: It is likely that the true incidence of treatment-related side effects of cranial irradiation in adults who survive more than 6 months without brain tumor growth or recurrence has been significantly underestimated. Research designs that include formal neuropsychologic assessment in conjunction with other neurodiagnostic tests can provide more comprehensive evaluation of long-term neurobehavioral outcomes.

Photodynamic therapy.

Photodynamic therapy (PDT) is an experimental cancer treatment modality that selectively destroys cancer cells by an interaction between absorbed light and a retained photosensitizing agent. This review discusses the basic components of photodynamic activity and examines the clinical applications of photodynamic therapy in cancer treatment. Treatment of superficial and early-stage malignancies is encouraging. Technologic advancement and further elucidation of the fundamental basis of photodynamic action should permit treatment of more advanced malignancies.

Preliminary results of a randomized study of adjuvant radiation therapy in resectable adult retroperitoneal soft tissue sarcomas.

Between January 1980 and September 1985, 35 adult patients with resectable retroperitoneal soft tissue sarcomas were entered on a randomized trial comparing two forms of adjuvant radiation therapy. Fifteen patients received the experimental therapy consisting of intraoperative radiotherapy (IORT) to 20 Gy using high-energy electrons followed by low-dose (35 to 40 Gy) postoperative external beam irradiation. Twenty patients received standard therapy consisting of high-dose (50 to 55 Gy) postoperative external beam irradiation. With a minimum follow-up of 15 months, there is no significant difference in the actuarial disease-free survival (DFS) and overall survival (OS) comparing the two groups (median DFS, 34 months; median OS, 38 months). At 5 years follow-up, approximately 40% of patients are alive and 20% of patients remain disease-free. Although there is a trend towards an improvement in in-field local control in the experimental arm, the predominant pattern of failure in both groups was locoregional within the retroperitoneum and/or peritoneal cavity. Acute and late radiation enteritis were significantly reduced in the experimental group. However, four experimental patients developed late (greater than 6 months following treatment) peripheral neuropathy believed related to the use of IORT; all four recovered. We conclude that there is no difference in the therapeutic effectiveness of the combination of IORT and low-dose external beam radiation compared with conventional high-dose radiation as adjuvant treatment in retroperitoneal sarcomas, although the former appears to be less toxic. Newer combined modality treatment strategies are discussed to improve the prognosis in these patients.

Dose-intensive induction therapy with cyclophosphamide, cisplatin, and consolidative abdominal radiation in advanced-stage epithelial ovarian cancer.

PURPOSE: The primary goal of this trial was to evaluate the clinical activity of a high-dose cisplatin-based induction regimen for women with advanced-stage ovarian cancer. A secondary goal was to assess the use of whole-abdominal radiation as consolidative therapy in the subset of women left with less than 5 mm residual disease after completion of chemotherapy. PATIENTS AND METHODS: Fifty consecutive patients with newly diagnosed, advanced-stage ovarian cancer received cisplatin 40 mg/m2/d and cyclophosphamide 200 mg/m2/d intravenously (IV) for 5 days, every 4 to 6 weeks. After three to four cycles of chemotherapy, patients who still had residual disease less than 5 mm in greatest diameter at second-look surgery were given whole-abdominal radiotherapy. RESULTS: The overall response rate in 49 patients assessable for response was 61.3% (24.5% pathologic complete responses [pCRs], 32.7% pathologic partial responses [pPRs], and 4.1% clinical partial responses [cPRs]). Median survival for all patients was 23.4 months, and actuarial 4-year survival was 33.7% (95% confidence interval [CI], 21.8% to 48.1%). Multivariate analysis showed stage III and serous histology as independent favorable prognostic factors for survival. Median survival for stage III patients was 36.5 months, with an actuarial 4-year survival of 41.6% (95% CI, 25.5% to 59.6%). Median survival for stage IV patients was 12.0 months, with actuarial 4-year survival of 22.9% (95% CI, 9.5% to 45.5%). The major acute toxicities encountered were myelosuppression and peripheral neuropathy. Patients who received consolidative radiotherapy were at increased risk of developing late-onset enteropathy. CONCLUSIONS: This regimen is active against advanced-stage ovarian cancer, but the associated toxicity is severe. Consolidative whole-abdominal radiation did not appear to prolong survival in the subset of women left with less than 5 mm residual disease after chemotherapy.

Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non-small-cell lung carcinoma.

PURPOSE: Some studies report a high risk of death from intercurrent disease (DID) after postoperative radiotherapy (XRT) for non-small-cell lung cancer (NSCLC). This study determines the risk of DID after modern-technique postoperative XRT. PATIENTS AND METHODS: A total of 202 patients were treated with surgery and postoperative XRT for NSCLC. Most patients (97%) had pathologic stage II or III disease. Many patients (41%) had positive/close/uncertain resection margins. The median XRT dose was 55 Gy with fraction size of 1.8 to 2 Gy. The risk of DID was calculated actuarially and included patients who died of unknown/uncertain causes. Median follow-up was 24 months for all patients and 62 months for survivors. RESULTS: A total of 25 patients (12.5%) died from intercurrent disease, 16 from confirmed noncancer causes and nine from unknown causes. The 4-year actuarial rate of DID was 13.5%. This is minimally increased compared with the expected rate for a matched population (approximately 10% at 4 years). On multivariate analysis, age and radiotherapy dose were borderline significant factors associated with a higher risk of DID (P =.06). The crude risk of DID for patients receiving less than 54 Gy was 2% (4-year actuarial risk 0%) versus 17% for XRT dose > or = 54 Gy. The 4-year actuarial overall survival was 34%; local control was 84%; and freedom from distant metastases was 37%. CONCLUSION: Modern postoperative XRT for NSCLC does not excessively increase the risk of intercurrent deaths. Further study of postoperative XRT, particularly when using more sophisticated treatment planning and reasonable total doses, for carefully selected high-risk resected NSCLC is warranted.

Treatment of advanced-stage massive mediastinal Hodgkin's disease: the case for combined modality treatment.

In the initial series of 198 patients treated at the National Cancer Institute (NCI) with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy for Hodgkin's disease, a review of presenting chest radiographs available on 192 of these patients showed 49 patients with mediastinal masses greater than one third the greatest posteroanterior chest diameter. Five patients had stage IIB disease, and 44 had stage III or IV disease. Thirty-five (71%) patients achieved a complete remission with MOPP chemotherapy. Fourteen (40%) of the complete responders relapsed, but four of these achieved durable remissions in response to subsequent therapy. Thirty (61%) patients have died (14 induction failures, nine relapsed patients, seven complete responders in remission). Thus, with a median follow-up of 20 years (range, 15 to 23), the overall survival for the group is 39%, and the disease-free survival for the complete responders is 60%. A subset of 10 patients received mantle radiation therapy after maximal response to MOPP. One of these patients failed to achieve complete remission, but among the nine complete responders only one has relapsed. In contrast, 13 of 26 (50%) patients achieving a complete response to MOPP alone have relapsed (P2 = .0536). Although MOPP alone was not prospectively compared with MOPP plus radiation therapy in the treatment of advanced-stage massive mediastinal Hodgkin's disease in this series, the retrospective analysis shows a nearly significant difference in disease-free survival favoring combined modality treatment. The difference in tumor mortality between MOPP-treated (44%) and combined modality-treated patients (80%) was also nearly significant (P2 = .055). However, overall survival differences between patients treated with MOPP alone and those treated with combined modality therapy were not significantly different (P2 = 0.23) because of the mortality related to late complications of combined modality treatment.

Long-term follow-up of testicular function following radiation therapy for early-stage Hodgkin's disease.

Seventeen male patients with pathological staged I-IIIA1 Hodgkin's disease were followed prospectively for radiation damage to the testes from low-dose scattered irradiation. During conventionally fractionated radiation therapy, the testicular dose ranged from 6 to 70 cGy. Testicular function was measured in a prospective fashion by repeated analyses (every 6 to 12 months) of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. Patients were also followed by serial semen analyses and by a questionnaire on fertility. The follow-up period ranged from 3 to 7 years after completion of radiation therapy. In patients receiving greater than or equal to 20 cGy, there was a dose-dependent increase in serum FSH values following irradiation, with the maximum difference at 6 months compared with pretreatment levels. All patients showed a return to normal FSH values within 12 to 24 months following irradiation. No significant changes in LH and testosterone were observed in this patient group. Eight patients with a normal pretreatment semen analysis provided serial semen samples and two patients showed transient oligospermia with complete recovery by 18 months following treatment. Four patients have fathered normal offspring following radiation therapy. We conclude that low doses (greater than 20 cGy) of scatter irradiation during treatment for Hodgkin's disease can result in transient injury to the seminiferous tubule as manifested by elevations of FSH for 6 to 24 months following treatment. Below 20 cGy, FSH values remained in the normal range. No evidence of Leydig cell injury (using LH and testosterone) was seen in this dose range (up to 70 cGy). Thus, patients with early-stage Hodgkin's disease can be treated with radiation therapy with little to no risk of irreversible testicular injury. Radiation treatment techniques to shield the testes are discussed.

Long-term follow-up on National Cancer Institute Phase I/II study of glioblastoma multiforme treated with iododeoxyuridine and hyperfractionated irradiation.

PURPOSE: We report the results of the final phase I/II program in glioblastoma (GBM) multiforme patients using only hyperfractionated irradiation and intravenous iododeoxyuridine (IdUrd). METHODS: For a decade we investigated halogenated pyrimidine radiosensitizers in an effort to exploit the potential for differential uptake of thymidine analogs between proliferating tumor and normal brain tissues. Trials began with bromodeoxyuridine (BrdUrd) but were changed to IdUrd when the latter proved less photosensitizing. A series of dose-escalating pilot trials led to treatment at a maximum-tolerated dose (MTD) of IdUrd of 1,000 mg/m2/d for two separate 14-day courses, one during the initial radiation field and one during the cone down. The radiotherapy also evolved over time and was hyperfractionated in all cases reported. Over 5 years we accrued 45 patients into the final hyperfractionated, 1,000 mg/m2/d scheme. We report here results on only the patients with minimum follow-up of 1 year (90% had at least 2 years of follow-up) or until death. RESULTS: The results do not indicate a significant benefit for use of sensitizers, as compared with other contemporary and aggressive types of radiation treatment. The median survival has been 11 months, with a 2-year actuarial survival of 9%. As yet, there are no survivors at 3 years. Tumor biopsies at craniotomy showed relatively low sensitizer incorporation. CONCLUSION: The failure of radiosensitizers combined with radiation therapy to show major benefit may be due to patient selection but appears also to be related to the combined problems of poor drug penetration/uptake into tumor, tumor-cell heterogeneity, and a high inherent cellular radioresistance of GBM.