Radiation therapy and ferromagnetic hyperthermia in the treatment of murine transgenic retinoblastoma.

BACKGROUND: Combined modality therapy for childhood retinoblastoma holds the potential of decreasing treatment-related morbidity while maintaining excellent tumor control rates. OBJECTIVE: To evaluate the efficacy of external beam radiation therapy (EBRT), ferromagnetic hyperthermia (FMH), and the combination of both modalities in the control of ocular tumors in a transgenic murine model of retinoblastoma. METHODS: One hundred sixty-six mouse eyes from 4-week-old animals transgenically positive for simian virus 40 large T antigen were treated with a total dose of 10, 15, 20, 30, 40, 45, or 50 Gy of EBRT in 5-Gy fractions twice daily, with 48 degrees C or 54 degrees C FMH for 20 minutes, or with combined EBRT at 10 or 30 Gy and 48 degrees C or 54 degrees C FMH for 20 minutes. Serial histologic sections, obtained 8 weeks after treatment, were examined for the presence of tumor. RESULTS: The tumor control dose for 50% of eyes (TCD50) treated with EBRT occurred at 27.6 Gy. Ferromagnetic hyperthermia at 48 degrees C cured 30% (6/20) of eyes, while 54 degrees C FMH resulted in a 100% (20/20) cure rate. Combined treatment with 48 degrees C FMH and EBRT exhibited a TCD50 at 3.3 Gy. The thermal enhancement ratio was 8.4. Ferromagnetic hyperthermia at 54 degrees C exhibited tumor cure in all animals, but 25% of eyes were lost owing to secondary treatment complications. CONCLUSIONS: This represents the first documentation of tumor control via EBRT, ocular FMH, and a combination of these treatment modalities in this murine transgenic retinoblastoma model. The extent of treatment synergy in this model suggests that combined treatment application may allow a reduction in total ocular and periocular radiation dose while maintaining excellent local tumor control.

External beam radiation for retinoblastoma: results, patterns of failure, and a proposal for treatment guidelines.

PURPOSE: To analyze treatment results and patterns of failure following external beam radiation for retinoblastoma and propose treatment guidelines according to specific clinical variables. METHODS AND MATERIALS: We analyzed 27 patients (34 eyes) with retinoblastoma who received external beam radiation as initial treatment at Hahnemann University Hospital from October 1980 to December 1991 and have been followed for at least 1 year. Of the 34 eyes, 14 were Groups I-II (Reese-Ellsworth classification), 7 were Group III, and 13 were Groups IV-V. Doses ranged from 34.5-49.5 Gy (mean 44.3 Gy, median 45 Gy) in 1.5-2.0 Gy fractions generally delivered through anterior and lateral wedged pair fields. RESULTS: At a mean follow up of 35.2 months (range 12-93 months), local tumor control was obtained in 44% (15 out of 34) of eyes with external beam radiation alone. Salvage therapy (plaque brachytherapy, cryotherapy, and/or photocoagulation) controlled an additional 10 eyes (29.5%), so that overall ocular survival has been 73.5%. Local tumor control with external beam radiotherapy alone was obtained in 78.5% (11 out of 14) of eyes in Groups I-II, but in only 20% (4 out of 20) of eyes in Groups III-V. A total of 67 existing tumors were identified prior to treatment in the 34 treated eyes and local control with external beam radiation alone was obtained in 87% (46 out of 53) of tumors measuring 15 mm or less and in 50% (7 out of 14) of tumors measuring more than 15 mm. When analyzing patterns of failure in the 19 eyes that relapsed, a total of 28 failure sites were identified and consisted of progression of vitreous seeds in seven instances (25% of failure sites) recurrences from previously existing tumors in 10 instances (36% of failure sites) and development of new tumors in previously uninvolved retina in 11 instances (39% of failure sites). CONCLUSIONS: 1) We find that external beam radiation to a dose of 45 Gy in fractions of 1.5 to 2.0 Gy provides adequate tumor control in retinoblastoma eyes Groups I-II (Reese-Ellsworth classification) or tumors measuring 15 mm in diameter or less. Eyes in more advanced group staging or containing tumors larger than the 15 mm seem to require higher radiation doses. We propose treatment guidelines for external beam radiation of retinoblastoma that specifically take into account the important clinical variables of tumor stage and patient age. 2) External beam radiation does not prevent the appearance of new tumors in clinically uninvolved retina. Therefore, the traditional belief that external beam radiation can treat the retina "prophylactically" should be seriously questioned. Due to this finding and their significant less morbidity, focal treatment modalities (plaque brachytherapy, photocoagulation, and/or cryotherapy), when clinically feasible, should be considered the treatment of choice for intraocular retinoblastoma. External beam radiation should be considered only when focal treatment modalities are not clinically indicated.

Dose rate effect of 125I irradiation on normal rabbit eyes and experimental choroidal melanoma.

The dose rate effect of radiation by 125I plaque on choroidal melanoma and normal intraocular tissue was studied. In the first part of the experiment, high activity plaques (HAP) and low activity plaques (LAP) were implanted on rabbit eyes with experimental Greene choroidal melanoma to deliver a total dose of 10,000 cGy to the tumor apex. The mean dose rate calculated at 0.5 mm from the inner sclera in eight eyes with high activity plaques was 3341.5 cGy hr-1 (1 cGy = 1 rad) while that in ten eyes with low activity plaques was 239.9 cGy hr-1. For tumors less than 1.0 mm in height, both groups showed complete tumor regression at the tumor implantation site after plaque treatment. For tumors more than 1.0 mm in height, two out of two eyes in the low activity plaque group and one of four eyes in the high activity plaque group failed to show complete tumor regression. Both LAP and HAP were effective in eradicating tumors, but logistic regression analysis demonstrates that HAP was more effective than LAP when adjustment was made for initial tumor height (P = 0.032). Nine tumor control eyes without 125I plaque implantation demonstrated marked tumor growth within 3 weeks. In the second part of the experiment, 125I plaques were implanted on the sclera of 12 normal rabbits' eyes. Six received high dose rate plaque treatment, while the other six received low dose rate plaque treatment. Clinical and histologic examinations demonstrated more damaging effects to the normal chorioretinal tissues at the plaque implantation site in the high dose rate plaque group at 24 weeks of follow-up. These results suggest that high dose rate plaques are more effective than low dose rate plaques when tumor height is statistically controlled. However, high dose rate delivery increases the damaging effects on normal intraocular tissue.

Multidisciplinary approach to the treatment of locally and regionally advanced non-small cell lung cancer: University of Miami experience.

An intensive multimodality therapy protocol incorporating neoadjuvant chemotherapy was initiated in July 1985 for patients with either borderline resectable or unresectable non-small cell carcinoma of the lung. Thirty-five patients, 21 men and 14 women were entered till March 1991. The median age was 58 years (27-74). Histology was squamous in 15, adenocarcinoma in 11, large cell in 6, and adenosquamous carcinoma in 3. Initial stages were IIIA in 19 patients, IIIB in 14 and II in 2. All patients tolerated preoperative chemotherapy with 5-FU, etoposide and cisplatin (FED). The response to chemotherapy was complete response in 2 (6%), and partial response in 22 (63%). Thirty-two patients underwent surgery. 26 patients were rendered disease free including two found disease free at surgery. Fifteen underwent pneumonectomy, 14 lobectomy and 3 biopsy only. Interstitial radiation therapy was used in 7 patients. The median survival of all patients was 19 months, those who underwent incomplete surgical resection was 12 months and patients rendered disease free at operation 21 months. Thirteen patients are alive and free of disease, including 6 patients alive longer than 5 years. Only patients who responded to chemotherapy and also had complete resection survived more than 2 years. Aggressive neoadjuvant therapy with FED, followed by resection, brachytherapy, postoperative radiation therapy, and adjuvant chemotherapy can be safely accomplished with encouraging survival in stage III patients.

Hyperfractionated radiation therapy and concurrent 5-fluorouracil, cisplatin and mitomycin-C in head and neck carcinoma. A pilot study.

Seventeen patients were entered into a Phase I/II trial of concurrent hyperfractionated radiation therapy (7,440 cGy total dose; 120 cGy b.i.d.) combined with constant infusion of 5-fluorouracil (5-FU) (1,000 mg/m2/24 hours for 72 hours) and cisplatin (DDP) (50 mg/m2) for a total of three cycles. Thirteen patients had Stage IV disease; three, Stage III disease; and one, Stage II hypopharyngeal disease. Thirteen of 17 patients had positive cervical lymph nodes, and the mean size of the largest lymph node was 5.5 x 5.1 cm. The patients were not treated with planned adjunctive surgery except for one patient who had a radical neck dissection for massive, rapidly growing cervical adenopathy, which recurred promptly within 1 month before the initiation of protocol therapy. After the initial six patients were entered, mitomycin-C (Mito 8 mg/m2) was added during the second cycle. All the patients completed the planned course of radiotherapy with a median dose of 7,440 cGy and a mean dose of 7,248 cGy except for two patients who died--one from toxicity and the other, suicide. The predominant toxicity was mucositis, which was grade 3/4 in 11 of 15 patients, resulting in an average interruption of radiation therapy of 12 days. Weight loss was significant and was on the average 12% of baseline weight. Hematological toxicity was mild in the 5-FU/DDP group (only one grade 3 toxicity of six) and severe in the 5-FU/DDP/Mito-treated patients (five of eight patients having grade 3/4 toxicity including one leukopenic pneumonitis death). Additional toxicity included one parapharyngeal cellulitis, which responded to antibiotics. Noncompliance with the complex regimen was only seen in three patients. One patient refused b.i.d. radiation therapy, and one patient refused further chemotherapy after the first cycle. Additionally, one patient who had a severe ethanol withdrawal reaction during the first cycle of 5-FU/DDP did not receive further chemotherapy. The complete response rate of both primary site and neck by the protocol regimen alone was 71%. However, two patients, one from each group, did undergo salvage neck dissection, and the locoregional control is currently 73%, with a mean follow-up time of 18.4 months. The feasibility of combining hyperfractionated radiation therapy with aggressive concurrent chemotherapy was demonstrated. The response and local control rate justifies the added toxicity of concurrent chemotherapy and radiation therapy.

Radiation therapy for adjunctive treatment of adrenal cortical carcinoma.

Adrenocortical carcinoma is a rare disease which is primarily approached surgically. There have been few reports of the efficacy of radiation therapy and, for the most part, these have been anecdotal. This paper reports on the potential adjuvant role of radiation therapy after surgical excision of primary adrenal cortical carcinoma and also comments about the efficacy of palliative radiation therapy for metastases. We have identified eight patients treated for adrenal cortical carcinomas at Hahnemann University Hospital (HUH) from 1962 until the present and have also identified five patients with the same diagnosis at Philadelphia General Hospital (PGH) from 1962 until its close in 1975. These two groups are examined separately. In the PGH group, in which two patients were diagnosed at autopsy and only one patient was treated by radiation therapy, the median survival was between 0 and 1 month for Stage IV disease with the only patient surviving to 6 months being that patient receiving radiation therapy. In the HUH group, five of eight patients were treated adjunctively after diagnosis, one was not and two received palliative therapy. The median survival for treated Stage III patients was between 34 months and 7 years. The suggestion, based on a limited patient series, is that patients treated postoperatively to the tumor bed and nodal areas in Stage III disease may have improved survival over historic series and improved local control.

Innovative techniques in radiation oncology. Clinical research programs to improve local and regional control in cancer.

There is a growing importance in failure analysis in cancer management. In these analyses locoregional failure as the cause of death emerges as a significant problem in many tumor sites, e.g., head and neck cancer, gynecologic cancer, genitourinary cancer. Because of these data, the radiation oncology community has attributed high priority to research efforts to improve locoregional control. These efforts include the following: (1) brachytherapy alone or with external beam radiation therapy or surgery; (2) intraoperative radiation therapy; (3) hyperthermia with radiation therapy; (4) particle irradiation (protons, neutrons, stripped nuclei, and pions); and (5) routes of administration of the treatment, including infusional (intravenous) chemotherapy with radiation therapy, intraarterial monoclonal antibodies with radionuclides, and intraarterial chemotherapy with radiation therapy. Each area of investigation is discussed.

Superficial chest wall recurrences of breast cancer: prognostic treatment factors for combined radiation therapy and hyperthermia.

Forty-nine patients with chest wall recurrences of breast carcinoma received radiation therapy and 915-MHz microwave hyperthermia for 95 lesions. Follow-up ranged from 3 to 39 months, with five patients dying before 6 months follow-up. At 1 month follow-up, 49 (52%) of 95 lesions showed complete response; 28 (29%), partial response; and 18 (19%), no change. At 6 or more months follow-up, 54 (67%) of 81 lesions demonstrated local control; 10 (12%), partial response; six (7%), no change; and 11 (14%), local-regional recurrences. Superficial blisters occurred in 24 (25%) of 95 lesions, whereas long-term complications (deep necrosis, subcutaneous burns) occurred in seven (7%) lesions. Relapse occurred in 16 (17%) lesions, seven after initial complete response and nine after partial response. Several prognostic treatment factors were identified: applied radiation dose (greater than 30 Gy, P less than .01), size of tumor (less than 6 cm diameter, P less than .001), minimum tumor temperature (greater than 41 degrees C, P less than .001), and status of disease (M0 or M1 vs M2, P less than .001). Treatment complications were correlated with maximum temperatures (greater than 45 degrees C, P less than .001). In summary the palliative treatment concept proved to be safe and effective.

Analysis of treatment results in 36 children with retinoblastoma treated by scleral plaque irradiation.

This is a retrospective analysis of treatment results in 36 patients with retinoblastoma treated by the Radiation Oncology Department of Hahnemann University Hospital and the Division of Oncology of Wills Eye Hospital between January 1975 and December 1986. There were 14 females and 22 males; ages ranged from 2 months to 4 1/2 years of age at presentation. Leukocoria was the most common clinical sign of presentation. These patients were treated with external beam radiation therapy in combination with scleral plaque irradiation in 20 patients and with scleral plaque alone in 16 patients. Cobalt-60, Iodine-125, Iridium-192, and Ruthenium-106, scleral plaques were used. The dose delivered to the mid plane of the globe was 40 Gy and the scleral dose adjacent to the plaque was in the range of 180-200 Gy. The treatment was successful in 30 of 36 patients. Complications of radiation therapy were minimal in patients treated by scleral plaque alone. The advantages of this treatment modality are discussed.

Episcleral plaque radiotherapy for retinoblastoma.

The authors report their preliminary results of episcleral plaque radiotherapy (cobalt 60, iridium 192, ruthenium 106, and iodine 125 plaques) in 50 selected patients with retinoblastoma. There were 97 plaque applications to 51 affected eyes in these 50 patients. The plaque was used as primary treatment in 15 eyes and as secondary treatment after failure of external beam radiotherapy, photocoagulation, and/or cryotherapy in 36 eyes. Vitreous seeding of tumor cells was evident ophthalmoscopically in 49 of the 51 eyes, negating the possibility of ultimate success by further photocoagulation or cryotherapy. In 18 patients, the contralateral eye had been enucleated and the remaining eye was being considered for enucleation because all other treatment modalities had failed. In 2 of these 18 patients (11%), the remaining eye was salvaged with plaque radiotherapy and some vision was preserved. In 33 eyes with less advanced tumors, 31 had some degree of vitreous seeding by tumor cells. The eye has been retained in all 33 of these patients and useful vision preserved in most. On the basis of these preliminary observations, the authors conclude that plaque radiotherapy can be used successfully as a primary treatment for selected cases of unilateral or bilateral retinoblastoma or as a supplemental treatment after other treatment methods have failed. The current indications for plaque radiotherapy and its advantages over other therapeutic modalities are discussed.

The treatment of primary intraocular malignancy.

This paper will summarize much of the information derived in an association between The Department of Radiation Oncology of Hahnemann University Hospital and the Oncology Service of Wills Eye Hospital of Thomas Jefferson University, a collaborative effort for the treatment of primary intraocular malignancies that has spanned the last dozen years. In that time we have treated malignant intraocular melanoma by radioactive eyeplaque brachytherapy and have begun to develop a similar program for treatment of recurring retinoblastoma. These experiences will be described.

Treatment of orbital pseudotumors and lymphoma.

Thirty-seven patients were identified in a retrospective review at Hahnemann University and Wills Eye Hospital; they had been treated for pseudotumor or lymphoma of the orbit and had adequate follow-up (x = 61.5 months). Overall, 31 of 37 patients (83.8%) were cleared of their orbital disease. Of the nine patients treated for lymphoma, all were cleared of disease in the orbit. Twenty-two of 28 patients (78.6%) with benign disease were likewise cleared of orbital disease. Ten of 10 patients who received radiation as their initial therapy were cleared. Overall, 17 of 20 (85%) of patients who received radiation as part of their therapy were cleared of orbital disease, with mean dosages of 2,166 cGy (1 cGy = 1 rad) for benign disease and 3,547 cGy for lymphoma. Brief representative case studies and a review of the literature are presented. Two patients with benign disease were cured of disease in the orbit but went on to develop systemic lymphoma. Radiation therapy plays an essential role in the management of patients with orbital lymphomatous diseases.