Intraoperative radiation therapy for high-risk pediatric neuroblastoma.

PURPOSE: To evaluate the efficacy of intraoperative radiation therapy (IORT) in the treatment of high-risk pediatric neuroblastoma. METHODS AND MATERIALS: Between 1986 and 1998, 23 children received IORT for pediatric neuroblastoma. Electron beam energies ranged from 4 MeV to 16 MeV and median dose was 10 Gy (7-16 Gy). RESULTS: Twenty-one of 23 patients were classified as high-risk. A gross total resection (GTR) was achieved in 18 patients, of whom 6 experienced disease recurrence, 2 of which included a locoregional relapse as a component of failure. Fourteen of 18 patients receiving IORT after a GTR are disease-free survivors. A second subset of 5 patients had a subtotal resection (STR), with gross residual disease remaining after surgery. All 5 patients recurred locally, and all died of their disease. IORT was extremely well-tolerated in our cohort. Surgical resection and IORT resulted in the narrowing of the abdominal aorta and an atrophic kidney in 1 patient. CONCLUSIONS: For high-risk neuroblastoma patients, IORT as the only radiotherapy to the primary, produced excellent local control after a GTR. However, IORT as the sole radiotherapy to the primary was inadequate for patients with extensive adenopathy or an STR. In this setting, we are exploring the use of IORT as a boost in conjunction with external beam radiation therapy.

Radiation therapy for malignancies in the setting of HIV disease.

With the introduction of increasingly effective antiretroviral agents for the management of AIDS, the life expectancy of appropriately treated patients will continue to lengthen as will the length of time during which infected patients amy develop malignancies, both HIV-related and non-HIV-related. The management of such patients will require careful consideration of the impact of all oncologic therapy on the immune system's ability to hold the virus at bay. Radiation therapy, with its recognized immunosuppressive effects, plays an important role in the management of the major AIDS-defining neoplasms, Kaposi's sarcoma, primary central nervous system lymphoma, and cervical carcinoma, and is used in approximately 50% of patients with non-HIV-related malignancies at some point in the disease course. The judicious use of radiation therapy and proper integration of aggressive antiretroviral therapy can result in control of malignancies without contributing to the rapid progression of HIV disease.

Pulsed low dose rate brachytherapy for pelvic malignancies.

PURPOSE: The pulsed low dose rate remote afterloading unit was designed to combine the radiation safety and isodose optimization advantages of high dose rate technology with the radiobiologic advantages of continuous low dose rate brachytherapy. This is the first report of a prospective clinical trial evaluating the relative incidence of acute toxicity and local control in patients with pelvic malignancies who underwent interstitial or intracavitary brachytherapy with the pulsed low dose rate remote afterloader. METHODS AND MATERIALS: From 5/11/92-6/21/95, 65 patients underwent 77 brachytherapy procedures as part of their treatment regimen for pelvic malignancies. Using the pulsed low dose rate Selectron, equipped with a single cable-driven 0.3-1.0 Ci Ir192 source, target volume doses of 0.40-0.85 Gy per pulse were prescribed to deliver the clinically determined dose. Forty-five intracavitary and 32 interstitial procedures were performed. Fifty-four patients had primary and 11 recurrent disease. Patients were followed closely to assess incidence of Grade 3-5 acute and delayed toxicity, local control, and survival. RESULTS: With a median follow-up of 16.1 months (range 1-29), 33 patients are NED, 10 alive with disease, 13 dead with disease, 4 dead of intercurrent disease, and 5 lost to follow-up. Local control was maintained until last follow-up or death in 48 cases, local failure occurred in 11, unknown in 5. Grade 3-5 acute toxicities (requiring medical or surgical intervention) occurred in 5 out of 77 procedures (6.5%), delayed complications in 10 patients (15% actuarial incidence at 2 years). In the 52 procedures performed for 42 patients with cervix cancer, the acute toxicity incidence was 5.8%, with a 14% 2-year actuarial incidence of delayed complications. Of 32 interstitial templates performed on 30 patients for pelvic malignancies, there were three incidences of acute toxicity and five delayed toxicities. CONCLUSION: Using the parameters described for this initial clinical study in patients treated for pelvic malignancies, pulsed low dose rate brachytherapy shows no significant increase in acute toxicity above that seen with the standard continuous low dose rate approach. Using the isodose optimization possible with pulsed brachytherapy, local control is excellent in patients treated at initial presentation, although longer follow-up is required for full assessment of local control and late toxicity. Further trials will need to be carried out to determine if larger doses per pulse and shorter total treatment times have comparable therapeutic ratios.

The role of radiation therapy in the management of HIV-related Kaposi's sarcoma.

Radiation provides excellent palliation for symptomatic Kaposi's sarcoma in the settings of both limited and advanced disease. Integration of radiotherapy into the overall treatment strategy is critical to ensure that the benefits in terms of symptom reduction are not outweighed by a long-term increase in morbidity.

Anal neoplasia. Pathogenesis, diagnosis, and management.

Prolonged, severe immunodeficiency provides the necessary milieu for the emergence of anogenital neoplasia caused by human papillomaviruses. Anal neoplasia is likely to become a more common manifestation of HIV disease as patients with profound immunodeficiency, who would have succumbed to opportunistic infections earlier in the epidemic, are now surviving for extended periods of time because of increasingly effective antiretroviral, prophylactic, and antimicrobial therapies. The screening and treatment strategies described for use in HIV-infected patients with anal neoplasia are currently being investigated and refined.

Toxicities of total-body irradiation for pediatric bone marrow transplantation.

PURPOSE: To determine the acute and late effects, including cognitive function, of total body irradiation (TBI) and chemotherapy for bone transplant (BMT) in children with immunodeficiency or hematologic disorders. METHODS AND MATERIALS: At UCSF, 15 children with immunodeficiency disorders and 58 children with leukemia received chemoradiotherapy between July 1982 and November 1993 and were evaluated for toxicity. Patients with severe combined immunodeficiency disorder (SCID) received 7 Gy TBI while leukemia patients received 12 Gy TBI. RESULTS: Eight immunodeficient patients (53%) are alive at 4 months to 11 years posttransplant. Acute toxicity was limited and treatment well tolerated. Most patients developed mild nausea and vomiting, skin rash, or erythema. Transient fever/chills, oral mucositis, and alopecia were noted in approximately 50% of patients. Seventy-three percent of all patients demonstrated acute liver dysfunction, but only four (27%) developed veno-occlusive disease. All children had decreased growth velocity but normal growth hormone levels. Other endocrinologic evaluations including adrenocorticotropic hormone (ACTH), cortisol, and thyroid hormones were normal. Only one evaluable girl had delayed puberty with late onset of secondary sexual characteristics. Neuropsychological testing demonstrated an intelligence quotient (IQ) reduction between the baseline and 1 year post-BMT, with some recovery at 3 years. Only one patient developed a clinically significant cataract. Thirteen percent of patients had chronic interstitial lung disease. Four children developed exostosis. Only 1 of the 15 children developed a second malignancy (acute myelogenous leukemia) at age 5, 51 months posttransplant for SCID. For patients with leukemia, similar toxicities were observed. Twenty-nine percent disease-free survival was noted with a mean follow-up of 4.7 years. Twenty-two percent had chronic interstitial lung disease and two patients were diagnosed with cataracts. Graft-vs.-host-disease (GVHD), pubertal development arrest, and delayed puberty were seen. One child developed papillary thyroid carcinoma, 49 months post-BMT. Similar neuropsychological testing decrements were also observed. CONCLUSION: Our experience suggests that intensive chemoradiotherapy, even at a young age, does not cause severe, acute, or late toxicities but does result in a small IQ decrement and the risk of secondary malignancy in children with long-term follow-up.

Radiation pneumonitis following combined modality therapy for lung cancer: analysis of prognostic factors.

PURPOSE: To identify factors associated with radiation pneumonitis (RP) resulting from combined modality therapy (CMT) for lung cancer. MATERIALS AND METHODS: Series published before 1994 that used CMT for the treatment of lung cancer and explicitly reported the incidence of RP are the basis for this analysis. Factors evaluated included the radiation dose per fraction (Fx), total radiation dose, fractionation scheme (split v continuous), type of chemotherapy and intended dose-intensity, overall treatment time, histology (small-cell lung cancer [SCLC] v non-small-cell lung cancer [NSCLC]), and treatment schedule (concurrent v induction, sequential, or alternating CMT). RESULTS: Twenty-four series, including 27 treatment groups and 1,911 assessable patients, met our criteria for inclusion in this analysis. The median total dose of radiation used in the trials analyzed was 50 Gy (range, 25 to 63 Gy). The median daily Fx used was 2.0 Gy (range, 1.5 to 4.0 Gy). Nineteen series included 22 treatment groups and 1,745 patients treated with single daily fractions. Among these patients, 136 received a daily Fx greater than 2.67 Gy. Five series used twice-daily radiotherapy and included 166 patients (Fx, 1.5 to 1.7 Gy). The incidence of RP was 7.8%. In a multivariate analysis, only daily Fx, number of daily fractions, and total dose were associated with the risk of RP (P < .0001, P < .018, and P < .003, respectively). CONCLUSION: In this analysis, the use of Fx greater than 2.67 Gy was the most significant factor associated with an increased risk of RP. High total dose also appears to be associated with an increased risk, but twice-daily irradiation seems to reduce the risk expected if the same total daily dose is given as a single fraction. High-Fx radiotherapy should be avoided in patients who receive CMT with curative intent.

Tolerance of patients with human immunodeficiency virus and anal carcinoma to treatment with combined chemotherapy and radiation therapy.

PURPOSE: To evaluate treatment tolerance in patients with and without the human immunodeficiency virus (HIV) who were undergoing treatment of anal cancer. MATERIALS AND METHODS: The authors retrospectively reviewed the medical records of 62 patients with anal cancer who received radiation treatment. Seven patients had HIV, four of whom had acquired immunodeficiency syndrome. Fifty-five patients were HIV negative, including 11 patients identified as being at high risk for HIV infection whose status was unknown. RESULTS: Thirty of the 55 (55%) patients who were HIV negative required treatment breaks of a mean duration of 16.7 days. Four of those 55 (7%) patients required hospitalization. Three of 42 (7%) patients who were HIV negative receiving chemotherapy required chemotherapy dose reduction. All seven patients with HIV required treatment breaks of a mean duration of 21.7 days. Three of the seven (43%) patients required hospitalization. Four of the seven (57%) patients required chemotherapy dose reduction. CONCLUSION: Patients with HIV undergoing treatment of anal cancer have increased toxic reactions to chemoradiation. Treatment must be individually tailored on the basis of extent of disease and degree of compromise of the immune system.

Irradiation of the cervix uteri: value of unenhanced and contrast-enhanced MR imaging.

PURPOSE: To analyze the value of magnetic resonance (MR) imaging after radiation therapy for cancer of the cervix. MATERIALS AND METHODS: Eighty-nine MR images were retrospectively studied in 69 patients aged 46.3 years +/- 11.5. MR findings of tumor recurrence and irradiation changes were correlated with time after radiation therapy; paracentral radiation dose (dose to point A); and in patients with pretreatment images, primary tumor size and stage. RESULTS: Overall accuracy of MR in diagnosis of tumor recurrence was 78% (positive predictive value, 65%; negative predictive value, 97%). In MR examinations less than 6 months after the beginning of radiation therapy, accuracy (69%) and specificity (46%) were significantly lower than in examinations more than 6 months later (88%, P = .0032; 81%, P = .0166, respectively). Comparison of pre- and posttreatment MR findings and knowledge of stage or initial tumor size did not affect MR results. CONCLUSION: Overall, diagnosis was best with unenhanced T2-weighted images, but in patients with adnexal or pelvic sidewall recurrence and in patients with treatment complications (eg, fistula formation), contrast enhancement did help.

Interstitial thermoradiotherapy with ferromagnetic implants for locally advanced and recurrent neoplasms.

PURPOSE: The University of Arizona, University of California at San Francisco, City of Hope Medical Center, and University of Wisconsin participated in a Phase I/II protocol to assess the heating ability and the toxicity of interstitial thermoradiotherapy using ferromagnetic implantation. METHODS AND MATERIALS: Forty-four patients with advanced primary or recurrent extra-cranial solid malignancies were enrolled in this study. Fourteen gauge catheters were implanted into tumors and, once in the department of Radiation Oncology, loaded with ferromagnetic seeds to deliver a 60 min hyperthermia treatment. Multi-point thermometry was continuously used throughout the heating sessions for all patients, sampling the periphery as well as the core of the tumor. After 192Iridium brachytherapy, 18 patients then had an additional treatment. The mean radiation dose while on protocol was 50.0 Gy, with total doses (including prior radiotherapy) ranging from 20.3-151.8 Gy (median = 88.7 Gy). Response and toxicity were assessed by inspection, palpation, and/or radiologic studies. Forty-one patients were evaluable for response, and there were 55 analyzable hyperthermia treatment sessions. RESULTS: The complete response rate was 61% (25/41). The partial response rate was 31.7% and only 7.3% failed to respond. Median duration of local control has not yet been reached. The mean maximum, minimum, and mean time-averaged temperatures for all in-tissue sensors were 43.7 degrees C, 38.7 degrees C, and 41.0 degrees C, respectively. Tumor size was the only factor significantly correlated with temperatures or with complete response rate; larger tumors attained higher temperatures but smaller tumors had a higher response probability. Nineteen patients (43%) experienced toxicities, however there was only a 7% (3/44) rate of serious complications (Grade 3 or 4). Prior treatment with hyperthermia was the only factor significantly correlated with serious toxicity. CONCLUSION: These results, a 93% total response with only 7% serious toxicity, are encouraging especially in the context of the patient population treated. Phase II/III studies involving ferromagnetic implantation are warranted.

CT characteristics of patients with brain metastases treated in RTOG study 79-16.

The search continues for a favorable subgroup of patients with brain metastases in whom testing of new modalities might show a benefit in overall survival. Complete pre- and post-treatment CT evaluation of the brain was performed in 779 of the 859 patients entered into RTOG protocol 7916, a phase III study of the role of misonidazole combined with radiation therapy in the treatment of brain metastases. Pretreatment scan findings of mass effect, midline shift, massive edema, central necrosis, location of sentinel lesion, and number of lesions were correlated with length of survival for all patients as well as for each treatment group. The only characteristics that showed a statistically significant difference in survival in the overall group were the presence of < or = 3 lesions and the presence of a midline shift. The actual benefit in overall survival, however, was found to be only 3 weeks. The volume of the largest lesion prior to treatment did not correlate well with survival, nor did location of lesions. The time to response, number of responders and absolute decrease in number of lesions were similar for the four treatment arms. Patients who responded to cranial treatment had a significantly prolonged survival over those who did not respond. No CT characteristic evaluated in this study showed value as a clinically relevant prognosticator for patients with brain metastases for the overall group. Patients who fulfilled three of the four favorable clinical characteristics previously described by Diener-West (age < or = 60, KPS > or = 70, primary lesion absent or controlled and brain as sole site of metastasis), were analyzed separately. Those with < or = three lesions had a statistically significantly prolonged survival over those with four or more lesions.

31P magnetic resonance spectroscopy of animal uveal melanoma.

Scleral surface coils were used to obtain in vivo magnetic resonance spectra (MRS) of Greene melanoma implanted in the rabbit uvea. Well-localized tumor spectra (4.7 Tesla) with good signal-to-noise ratios (S/N) were obtained from the tumor with a "single-pulse" sequence in less than 1 hour. Tumor localization was confirmed with one-dimensional spectroscopic imaging studies. Serial 31P spectra were obtained during tumor growth and after both optimal and suboptimal hyperthermia. Early 31P MRS change is correlated with tumor treatment response and preceded histologic evidence of cell destruction. Twenty-four to 48 hours after successful treatment, the inorganic phosphate/nucleoside triphosphate (NTP), and phosphomonoester/NTP ratios were significantly increased from 1.2 +/- 0.1 to 1.7 +/- 0.1 and 1.3 +/- 0.1 to 1.8 +/- 0.2, respectively. In contrast, untreated or ineffectively treated tumors showed little change. Interpretation of 31P MRS data in this animal uveal melanoma model after the first week was complicated by decreased S/N, increased contamination from contiguous tissues, ingrowth of fibroblasts, macrophages, and intratumor hemorrhage.

Microwave hyperthermia for choroidal melanoma in rabbits.

Radiation has provided excellent local control rates in choroidal melanoma, but significant impairment in visual acuity has occurred in 30-60% of patients due in part to the development of radiation vasculopathy in the fovea and optic disc. Hyperthermia has been shown to have a synergistic effect when added to radiation therapy in human malignancies. The use of hyperthermia in ocular melanoma may allow a reduction in the total radiation dose necessary to achieve local control. A 2450-MHz microwave plaque applicator with integral surface cooling was used to deliver hyperthermia treatments to rabbit eyes containing choroidal melanomas. Extensive thermal mapping was done in acute eyes. In 18 survival animals, a single 23-G needle thermocouple probe with three sensors was inserted into the tumor. Target temperatures of 41.0-46.0 degrees C were maintained for 1 hour. All tumor-bearing eyes were followed for 1 month after treatment, or until tumor growth was noted, with serial ultrasound measurements and visual examinations. A 92% response rate was obtained in tumors treated at temperatures greater than 43.0 degrees C for 1 hour with no significant toxicity. Heat alone has significant tumoricidal properties in this animal model.