Ibritumomab consolidation after 3 cycles of CHOP plus radiotherapy in high-risk limited-stage aggressive B-cell lymphoma: SWOG S0313.

In the S0313 trial, we evaluated the impact of adding ibritumomab tiuxetan consolidation to 3 cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy plus involved field radiotherapy (IFRT) in patients with limited-stage aggressive B-cell non-Hodgkin lymphoma (LD-NHL). Patients with at least 1 stage-modified adverse risk factor (nonbulky stage II, age >60 years, elevated lactate dehydrogenase, or World Health Organization performance status of 2) were treated with CHOP on days 1, 22, and 43, followed 3 weeks later by 40 to 50 Gy of IFRT. An ibritumomab tiuxetan regimen was initiated 3 to 6 weeks following IFRT. Forty-six patients were registered and eligible, with median follow-up of 7.3 years. The progression-free survival estimate is 89% at 2 years, 82% at 5 years, and 75% at 7 years. The overall survival estimate is 91% at 2 years, 87% at 5 years, and 82% at 7 years. Grade 4 adverse events occurring more than once included neutropenia (8), leukopenia (5), and lymphopenia (2). Febrile neutropenia was observed in 4 patients. No cases of treatment-related myeloid neoplasms were noted. In conclusion, patients with high-risk LD-NHL treated with 3 cycles of CHOP plus IFRT followed by ibritumomab tiuxetan consolidation had outcomes that compare favorably to our historical experience. The clinical trial was registered at www.clinicaltrials.gov as #NCT00070018.

Attitude towards genetic testing for breast cancer susceptibility: a comparison of affected and unaffected women.

The objective of this study is to evaluate women's awareness and interest in genetic testing for breast cancer risk, to identify socio-demographic factors, to analyse the reasons for wanting or not wanting to be tested and finally to determine whether breast cancer patients and healthy women have different attitudes towards genetic testing. Consecutive series of 879 women without and with breast cancer participated in a 20-item self-completing questionnaire. Among breast cancer patients, 57% answered that they would definitely or probably accept being tested, compared with 84% of women without breast cancer. At the multiple logistic regression analysis only to have a diagnosis of breast cancer conditioned significantly the interest to have genetic testing. Surprisingly, a family history of breast cancer was found to have no significant impact. The most frequently cited reason for being interested in genetic testing was 'to learn about your children's risk'. Although women's awareness about breast cancer genes is inadequate, the interest in genetic testing is substantial and higher both in healthy women and in women with breast cancer. These results provide important indications for the development of educational strategies.

Radioprotection from radiation-induced lymphedema without tumor protection.

Lymphedema or tissue swelling from impaired lymph drainage commonly occurs after regional nodal dissection and/or radiation therapy for cancer control. Treatment options for this disabling and life-altering complication involve long-term labor-intensive commitments. Sentinel node biopsy can forestall removal of negative regional nodes, offering some protection against lymphedema, however, most preventive measures are elusive, ineffective, or unproven. Our goal was to determine whether the radioprotectant amifostine could prevent or retard the development of lymphedema in a rodent radiation therapy-dependent model yet not offer tumor protection from the therapeutic effects of radiation therapy. We pre-treated rats after unilateral radical groin dissection with the organic thiophosphate radioprotectant amifostine or placebo prior to single dose post-operative groin radiation therapy and monitored hindlimb volumes, wound scores, and tissue lymphostasis. In addition, we determined whether amifostine protected human MCF7 breast cancer cells exposed to a range of radiation therapy doses in an in vitro clonogenic assay and an in vivo MCF7 tumor xenograft model. Our findings indicate that amifostine markedly reduced the volume of limb lymphedema and dramatically improved wound healing and tissue lymphostasis in the rodent lymphedema model. The in vivo and in vitro studies further demonstrated that amifostine offered no MCF7 tumor protection from radiation therapy. These pre-clinical findings provide proof-of-principle to further delineate specific mechanisms underlying amifostine's beneficial effects, determine optimal amifostine-radiation therapy dosing regimens, and thereby expedite translation into clinical trials to reduce lymphedema incidence and severity in cancer patients at high lymphedema risk in whom radiation therapy is the recommended therapy.

alpha6 integrin cleavage: sensitizing human prostate cancer to ionizing radiation.

PURPOSE: The goal was to determine if prostate tumor cells containing a mutant alpha6 integrin would be defective in tumor re-population following clinically relevant fractionated ionizing radiation (IR) treatments. MATERIAL AND METHODS: Human prostate cancer cells derived from PC3N cells were used which conditionally expressed a cleavable, wild type form of alpha6 integrin (PC3N-alpha6-WT) or a mutated non-cleavable form of alpha6 integrin (PC3N-alpha6-RR). The resulting tumor growth before, during and after fractionated doses of IR (3 Gyx10 days) was analyzed using the endpoints of tumor growth inhibition (T/C), tumor growth delay (T-C), tumor doubling time (Td) and tumor cell kill (Log(10) cell kill). RESULTS: The T/C values were 36.1% and 39.5%, the T-C values were 20.5 days and 28.5 days and the Td values were 5.5 and 10.5 days for the irradiated PC3N-alpha6-WT and PC3N-alpha6-RR cells, respectively. The Log(10) was 1.1 for the PC3N-alpha6-WT cells and 0.8 for the PC3N-alpha6-RR cells. The tumor response to IR was altered in tumors expressing the mutant alpha6 integrin as indicated by a significant increase in tumor growth inhibition, an increase in tumor growth delay, an increase in tumor doubling time and an increase in tumor cell kill. CONCLUSIONS: Blocking integrin cleavage in vivo may be efficacious for increasing the IR responsiveness of slow growing, pro-metastatic human prostate cancer.

Folate and pterin metabolism by cancer cells in culture.

Malignant cells grown in culture excrete into their growth medium a folate catabolite that can be seen as a blue-fluorescent region on paper chromatograms of such media. This folate catabolite has now been identified by paper chromatography, thin-layer chromatography, and combined gas chromatography-mass spectrometry as 6- hydroxymethylpterin and not as pterin-6-carboxaldehyde as previously reported. Moreover, when pterin-6-carboxaldehyde was added to the growth medium of logarithmically growing malignant cells, it was primarily reduced to 6-hydroxymethylpterin. In contrast pterin-6-carboxylate was the principal product formed from added pterin-6-carboxaldehyde by normal established cell lines in culture. These results have been interpreted as indicative of a possible mechanism of folate catabolism in malignant cells. Folic acid or another folate derivative is oxidatively cleaved at the C-9-N-10 bond to yield pterin-6-carboxaldehyde as one of the products. This derivative is subsequently reduced to 6-hydroxymethylpterin, which is excreted into the growth medium.

Small-cell osteosarcoma: correlation of in vitro and clinical radiation response.

Small-cell osteosarcoma is an entity which shares some clinical and pathological features with both classic osteosarcoma and Ewing's sarcoma of bone. While noted to be "not radiosensitive" when first described, a retrospective review the National Cancer Institute experience of five patients with small-cell osteosarcoma treated with radiation therapy following biopsy (three pts) or limited excision (two pts) showed local control in all five patients with two long-term disease-free survivors (12, 18 years). This compares to three patients treated with surgery alone where one patient failed locally and one patient is a long-term disease-free survivor (7 years). We have studied the in vitro radiation response of a recently established small-cell osteosarcoma cell line (TC-252) and compared its response with that of a classic osteosarcoma cell line (U2-OS) and an Ewing's sarcoma cell line (5838). The small-cell osteosarcoma line responded with a similar Do and extent of PLDR compared to the Ewing's line and was different from the in vitro radiation response of classic osteosarcoma. Based on this small clinical series and the in vitro radiation studies, we conclude that small-cell osteosarcoma is a radioresponsive tumor. Definitive radiation therapy or conservative surgery plus radiation therapy are effective alternative therapeutic options, compared to ablative surgery, for the local treatment of this uncommon bone tumor of children and young adults.

Possible relationship between chromosome alterations and in vitro cellular radiosensitivity of human malignant melanoma.

In the present study, in vitro radiation survival analysis was performed on 8 human malignant melanoma cell lines with defined karyotypes. Exponentially growing cells were irradiated to doses of 0 to 8 Gy and examined for soft agar clonogenicity. Two groups emerged from this analysis: 4 cell lines with a small shoulder (extrapolation number, n less than 2) and 4 cell lines with a large shoulder (n greater than 2). Of possible significance, 4/4 cell lines with extrapolation numbers greater than 2 demonstrated clonal structural abnormalities of chromosome 7. In contrast, 3/4 cell lines with extrapolation numbers less than 2 had no structural abnormalities of chromosome 7. These very preliminary results suggest that structural alterations of chromosome 7 may be associated with melanoma tumors with high extrapolation numbers.

The effect of the number of computed tomographic slices on dose distributions and evaluation of treatment planning systems for radiation therapy of intact breast.

PURPOSE: This study was undertaken to answer the following questions in breast irradiation: (a) How many calculation planes are sufficient for three-dimensional (3-D) treatment planning? (b) Is pseudo-3-D planning system sufficiently accurate for 3-D treatment planning of a breast? METHODS AND MATERIALS: We carried out dose calculations and differential dose-volume analysis on three representative patients covering the range of breast size encountered in a clinic. The breast volumes were reconstructed from computed tomography (CT) scans using three slices, five slices and the full CT scan respectively. An established 3-D dose algorithm and two pseudo-3-D commercial systems were used in the calculations. Comparison of isodose distributions were made between the central axis plane, a cephalic and a caudal plane 6 cm above or below the central axis respectively. RESULTS: When comparing isodose distributions generated with conventional two-dimensional treatment planning with 3-D dose calculations, the former underestimated the size and magnitude of the hot spots in the medial and the lateral subcutaneous (SC) regions. When comparing the three-slice with the full CT model, while the three-slice model was found to be adequate for the "small" and the "medium" size patients, the full CT model provided a more accurate representation of dose distributions for the "large" patient. Comparison of a true 3-D algorithm with pseudo-3-D algorithms showed that while the latter systems were adequate for the "small" and the "medium" patients, significant differences were noted between the true 3-D and the pseudo-3-D algorithms for the "large" patient. CONCLUSION: For patients whose breast contours vary slowly within the tangential fields, a three-slice CT scan as well as a pseudo-3-D approach appears to be adequate for clinical decision. However, for patients with large variation of contours within the tangential fields, a full scale CT scan with a true 3-D dose algorithm is more accurate than either the three-slice or the five-slice model.

Treatment planning of template-guided stereotaxic brain implants.

We have initiated a Phase I clinical trial of interstitial hyperthermia induced with inductively heated ferromagnetic implants in combination with Ir-192 implants for glioblastomas and anaplastic astrocytomas of the brain. For speed and accuracy of the implant procedure, and to control the radiation and thermal dose, a stereotaxic frame is used to position a template. We have modified the Brown-Roberts-Wells frame to be used with a variety of templates which we designed. On the morning of the implant procedure, a CT scan is done, and a CT-based treatment plan is then completed before the patient goes to the operating room. We also describe the CT-based treatment planning system developed to accommodate the template-guided implant and illustrate its clinical use.

The use of stereotactic radiosurgical boost in the treatment of medulloblastomas.

PURPOSE: Starting in 1992, we began using a stereotactic radiosurgical (SRS) boost for the treatment of medulloblastomas. Four patients ranging in age from 7 to 42 years old have since been treated and are the subject of this retrospective study. METHODS AND MATERIALS: All patients were initially treated with a maximally debulking surgery and external beam radiotherapy, which were then followed by a stereotactic radiosurgical boost using a modified 6 MeV linear accelerator. Radiosurgical boost doses ranged from 4.50 to 10.0 Gy. Target volumes ranged from 1.1 to 8.1 cc. The procedure was well tolerated with minimal acute toxicities. RESULTS: All four patients are alive without evidence of recurrence (at 8 to 35 months). Acute nausea and vomiting was elicited during the radiosurgical procedure in the first patient treated. We have since begun premedicating patients with antiemetics or treating under general anesthesia. Late complications consisted of panhypopituitarism in one patient, which was thought to be attributable to the previous course of whole-brain radiotherapy. We have not observed any incidence of radionecrosis in this small cohort of patients. CONCLUSIONS: Our preliminary results with the use of radiosurgery for medulloblastomas are optimistic, and we would like to suggest the inclusion of a radiosurgery boost in future clinical trials for treatment of this disease.

Vulvar carcinoma.

PURPOSE: Controversies exist regarding the use of radiation therapy in the treatment of vulvar carcinoma. A retrospective review was performed to evaluate our institution's experience with surgery and radiation for this disease. METHODS AND MATERIALS: The medical records of 47 patients treated for squamous cell carcinoma of the vulva at our institution (1974-1992) were reviewed for TNM stage (AJCC criteria), treatment modality, and associated 5-year local control and survival based on Kaplan-Meier analysis. RESULTS: Twenty-eight patients (60%) presented with Stage I and II disease and their 5-year survival was 69%. Stage III patients accounted for 12 (25%) of the patients and their 5-year survival was 73%. Seven patients presented with Stage IV disease and five died within 13 months of diagnosis after predominantly palliative therapy. The 40 patients with Stages I, II, and III disease were treated aggressively and were further evaluated for treatment-modality-associated survival and local control. Radiation therapy was used as primary treatment in nine patients, of whom seven were treated with radiation alone and two were treated postoperatively after wide excision. Surgery alone was performed in 31 patients consisting of either radical vulvectomy (20 patients) or wide excision (11 patients). When comparing outcomes of radical vulvectomy vs. radiation therapy, we noted that the 5-year actuarial survivals were comparable (74% for either modality), despite the presence of more favorable prognostic factors in the group treated with radical vulvectomy. Patients treated with wide excision alone had a trend for a poorer 5-year actuarial survival (51%) and local control (50%). CONCLUSIONS: Radical vulvectomy offers good locoregional control and survival. This retrospective review further supports the use of radiation therapy with conservative surgery as an alternative treatment option for patients with vulvar carcinoma treated with curative intent. In contrast, the use of wide excision alone should be performed with caution due to a higher locoregional failure rate. The role of appropriately prescribed radiation therapy should be further investigated in prospective clinical trials.

Treatment of pelvic sarcomas in adolescents and young adults with intensive combined modality therapy.

Adolescent and young adult patients with pelvic sarcomas continue to have a poor prognosis with standard combination chemotherapy and local irradiation. In addition to a significant risk of local failure, these patients are at high risk for systemic relapse. Twenty-three consecutive patients with Ewing's sarcoma, alveolar rhabdomyosarcoma, undifferentiated sarcoma, or malignant peripheral neuroepithelioma originating in the pelvis were treated with short, intensive combined modality therapy. This approach integrates 5 cycles of VADRIAC chemotherapy (Vincristine, Adriamycin, Cyclophosphamide) with high dose irradiation to the primary lesion (55-60 Gy) and sites of gross metastatic disease (45-50 Gy). Following achievement of a complete response, intensification therapy consisting of total body irradiation (TBI) (8.0 Gy), high dose VADRIAC chemotherapy, and autologous bone marow transplantation is given. All therapy is completed within 6-7 months. No maintenance chemotherapy is given; no surgery is intended. Of the twenty-three patients with pelvic sarcomas treated on this combined modality protocol, 22 achieved a complete remission. Local control was achieved and maintained in all twenty-three patients. With a median follow-up of 21 months since initiation of treatment, there have been nine relapses (all systemic). Seven relapses occurred among the thirteen patients who presented with overt metastatic disease and the other two relapses were among the ten patients with localized disease at presentation. All seven metastatic patients who relapsed have died, whereas both of the relapsed localized patients remain alive. Acute and late toxicities have been acceptable using this aggressive combined modality approach. Induction chemotherapy had a significant impact on reduction of the typically large (greater than 10 cm diameter) soft tissue mass associated with these pelvic tumors, thus facilitating achievement of local control by high dose irradiation. Of 18 patients with measureable soft tissue tumor, all experienced a partial response (greater than 50% reduction in size) following the initial two cycles of chemotherapy given prior to local irradiation. In conclusion, this short, intensive chemoradiotherapeutic regimen is highly effective in controlling the primary lesion (100% local control) and inducing a complete response in a high proportion (96%) of these high risk pediatric and young adult patients with pelvic sarcomas. The role of TBI as "systemic" adjuvant therapy to control micrometastatic disease is discussed as still under investigation.

Clinical hyperthermia with a new device: the current sheet applicator.

PURPOSE: The current sheet applicator (CSA) is a newly developed microwave hyperthermia device. Advantages over commercial microwave applicators include its small size and high ratio of heating area to physical aperture area. These physical characteristics make the CSA excellent for heating constricted areas and allow the use of arrays of CSAs over large surfaces. This study examines the clinical efficacy of the CSA for heating superficial malignant tumors. METHODS AND MATERIALS: From December 1989 through October 1991, 19 patients with recurrent or metastatic superficial malignant tumors were treated once or twice weekly to 30 hyperthermia fields using one to four CSAs. Each field received from one to four hyperthermia treatments for a total of 74 treatments. The treatment objective was to elevate the tumor temperature to a minimum of 42.5 degrees C for 30 min (2 patients) or 60 min (17 patients). Intratumor temperatures were measured with percutaneous fiberoptic thermometry probes. All patients received concurrent fractionated radiation therapy with total dose ranging from 20 to 65 Gy (median 46 Gy). Seventeen of the 30 fields had been previously irradiated to a median dose of 50 Gy. RESULTS: Mean values for the maximum temperature, average temperature, and minimum temperature were 43.6 degrees C +/- 1.0, 42.2 degrees C +/- 1.4, and 41.0 degrees C +/- 1.5, respectively. Mean values for T50 and T90 were 42.2 degrees C +/- 1.1 and 41.0 degrees C +/- 1.3, respectively. The overall response rate for all assessable fields was 96%. Only Only three responding tumors have progressed with a median follow-up period of 6 months. Treatment related morbidity was generally mild and self-limited. CONCLUSION: The CSA is a promising new microwave hyperthermia device capable of heating superficial tumors to therapeutic temperatures. When used in combination with radiotherapy, response rates are excellent without excessive toxicity.

Interstitial irradiation versus interstitial thermoradiotherapy for supratentorial malignant gliomas: a comparative survival analysis.

PURPOSE: To compare the survival of two groups of patients with supratentorial malignant gliomas who were treated on two sequential protocols with either interstitial thermoradiotherapy or with interstitial irradiation without hyperthermia. METHODS AND MATERIALS: Between 1988-1992, patients with anaplastic astrocytoma or glioblastoma multiforme were treated at the University of Arizona on a Phase I/II protocol of interstitial thermoradiotherapy with ferro-magnetic seeds. The treatment protocol consisted of debulking surgery, a course of external beam radiotherapy and hyperthermia given immediately before and after brachytherapy. The survival of patients so treated was compared with that of a similar group of patients treated with interstitial brachytherapy alone at the Barrows Neurological Institute between 1982-1990. RESULTS: Twenty-five patients with primary tumors treated at the time of initial presentation with thermoradiotherapy were compared with a control group of 37 patients treated with interstitial brachytherapy alone. All primary patients were followed for a minimum of 34 months post implant. Multivariate analysis based on proportional hazards models showed that hyperthermia (p = 0.027), patient age (p < or = 0.00001) and histology (anaplastic astrocytoma vs. glioblastoma multiforme, p = 0.0017) were the only factors significantly associated with survival in this data set. From the fitted model, the hazard of dying when treated with hyperthermia was .53 times (95% confidence intervals 0.29-0.94) than that of the control group. In addition, we treated a small group of patients with recurrent tumors (13 with brachytherapy alone, and eight with thermoradiotherapy) and found no survival difference (p = 0.62). CONCLUSION: Within the constraints of the selection factors and the different treatment parameters used in these studies, we conclude that an interstitial thermoradiotherapy boost confers a statistically significant survival benefit to patients with primary high grade gliomas when compared to interstitial brachytherapy alone.

High-dose-rate postoperative vaginal cuff irradiation alone for stage IB and IC endometrial cancer.

PURPOSE: To evaluate the effectiveness of postoperative high-dose-rate (HDR) vaginal cuff irradiation alone (1500 cGy in 3 fractions) in patients with Stage Ib and Ic endometrial cancer. METHODS AND MATERIALS: This is a retrospective review of 102 patients with Stage Ib and Ic endometrial cancer treated with a hysterectomy and postoperative HDR intracavitary therapy alone during the period of 1/1/90-12/31/96. Each patient received 1500 cGy in 3 weekly treatments, dosed to a depth of 0.5 cm. Pathologic features such as depth of invasion, tumor grade, lower uterine segment (LUS) involvement, and lymphvascular invasion (LVI) were evaluated for their impact on recommended postoperative treatment. All survival curves were generated utilizing Kaplan-Meier methods and all statistical comparisons were via a Wilcoxon rank sum test. RESULTS: The 5-year actuarial overall survival (OS) is 84% and the 5-year disease-free survival (DFS) is 93%. Locoregional disease control (pelvic control) was excellent with 97% of the patients free of pelvic disease at 5 years. Of the three pelvic failures only one was in the vaginal cuff. LVI, LUS involvement, Grade 3 and/or outer third myometrial involvement were identified in 41 patients. Thirty-one of these patients underwent a lymphadenectomy and there were two regional failures within this increased-risk group. CONCLUSIONS: We obtained an excellent level of locoregional control with minimal morbidity and minimal time commitment for treatment with vaginal HDR brachytherapy alone. Our dose per fraction and total dose is lower than most reported series and there is no apparent loss in locoregional control. In addition, intermediate-risk patients and patients with an increased risk of recurrence (Grade 3, outer third myometrial involvement, LVI, LUS) may be treated with cuff irradiation alone, after surgical staging and a negative lymphadenectomy.

Stereotactic radiosurgery as an adjunct to surgery and external beam radiotherapy in the treatment of patients with malignant gliomas.

PURPOSE: To evaluate the efficacy and toxicity of a stereotactic radiosurgery boost as part of the primary management of a minimally selected population of patients with malignant gliomas. METHODS AND MATERIALS: Between June, 1991 and January, 1994 a stereotactic radiosurgery boost was given to 30 patients after completion of fractionated external beam radiotherapy. The study population consisted of 22 males and 8 females, with a range in age at treatment from 5 to 74 years (median: 54 years). Tumor volume ranged from 2.1 to 115.5 cubic centimeters (cc) (median: 24 cc). Histology included 17 with glioblastoma multiforme, 10 with anaplastic astrocytoma, 1 with a mixed anaplastic astrocytoma-oligodendroglioma, and 2 with a gliosarcoma. A complete resection was performed in 9 (30%) patients, while 18 (60%) underwent a subtotal resection, and 3 (10%) received a biopsy only. Fractionated radiation dose ranged from 44 to 62 Gy, with a median of 59.4 Gy. Prescribed stereotactic radiosurgery dose ranged from 0.5 to 18 Gy (median: 10 Gy), and the volume receiving the prescription dose ranged from 2.1 to 158.7 cc (median: 46 cc). The volume of tumor receiving the prescription dose ranged from 70-100% (median: 100%). One to four (median: 2) isocenters were used, and collimator size ranged from 12.5 to 50 mm (median size: 32.5 mm). The median minimum stereotactic radiosurgery dose was 70% of the prescription dose and the median maximum dose was 200% of the prescription dose. RESULTS: With a minimum follow-up of 1 year from radiosurgery, 7 (23%) of the patients are still living and 22 (73%) have died of progressive disease. One patient died of a myocardial infarction 5 months after stereotactic radiosurgery. Follow-up for living patients ranged from 12 to 45 months, with a median of 30 months. The 1- and 2-year disease-specific survival from the date of diagnosis is 57 [95% confidence interval (CI) 39 to 74%] and 25% (95% CI 9 to 41%), respectively (median survival: 13.9 months). No significant acute or late toxicity has been observed. CONCLUSION: Stereotactic radiosurgery provides a safe and feasible technique for dose escalation in the primary management of unselected malignant gliomas. Longer follow-up and a randomized prospective trial is required to more thoroughly evaluate the role of radiosurgery in the primary management of malignant gliomas.

The use of gold foil wrapping for radiation protection of the spinal cord for recurrent tumor therapy.

PURPOSE: The development of a technique to provide sufficient radiation protection to previously irradiated spinal cord in such a manner that interstitial brachytherapy can be conducted after resection of a recurrent tumor and decompression of the cord. METHODS AND MATERIALS: A technique was developed that uses multiple layers of gold foil that are applied around the thecal sac and nerve root sleeves to produce an enveloping radiation shield after resection of recurrent tumor. Once the layers of gold foil are in place, interstitial I125 seeds are permanently placed in the bed of the tumor resection to prevent any recurrence from microcellular disease. The technique is described and its application in the case of a 28-year-old with a third recurrence of chondrosarcoma after external fractionated radiation therapy at the second to the fourth thoracic segments is reviewed. RESULTS: This technique has been used in this first patient. An additional tumor dose of 120.0 Gy was delivered to the tumor bed while the spinal cord was calculated to receive only 1% of the dose over the life span of the implant. To date, this dose of radiation has prevented tumor recurrence for more than 18 months of follow-up. CONCLUSION: This technique of multiple layers of gold foil shielding over the spinal cord and nerve roots has the potential to be a useful tool for the shielding of a previously irradiated spinal cord in the setting of resection of recurrent tumor. It may also have a wider application to a number of other radiosensitive tumors where interstitial brachytherapy may be useful to provide additional treatment after external fractionated radiation therapy.

Feasibility and toxicity of transrectal ultrasound hyperthermia in the treatment of locally advanced adenocarcinoma of the prostate.

PURPOSE: This Phase I trial tests the ability of a new hyperthermia device, the transrectal ultrasound probe, to heat the prostate gland, and evaluates the toxicity of transrectal ultrasound hyperthermia (TRUSH) given with concurrent standard external beam irradiation in the treatment of locally-advanced adenocarcinoma of the prostate. METHODS AND MATERIALS: Between June, 1990 and August, 1991, 14 patients with American Urological Society Stage C2 or D1 adenocarcinoma of the prostate were treated with TRUSH concurrently with standard external beam radiotherapy to the prostate. Twenty-two heat treatments were delivered in 14 patients; 8 patients received two TRUSH procedures, each separated by 1 week. Patient age ranged between 53-86 (mean: 72) years. Three patients had well-, 6 patients had moderately-, and 5 patients had poorly-differentiated adenocarcinoma of the prostate. Karnofsky status ranged from 70-90. Standard radiotherapy to the prostate and periprostatic tissues was delivered using a four-field approach with 1.8-2 Gy daily fractions delivered 5 x/week to a total dose of 67-70 Gy calculated to the minimum tumor volume. TRUSH was delivered after transperineal placement of multipoint thermometry probes by a urologist, under transrectal ultrasound guidance. Two to three thermocouple probes containing seven sensors each were placed in the prostate in an attempt to sample temperatures throughout the gland. The sensor depth from the rectal wall ranged from 5-25 mm. RESULTS: Thirty-six percent of all sensors were heated above 42.5 degrees C averaged over 30 min; and all patients had at least some sensors within the prostate heated to temperatures > or = 42.5 degrees C. The average temperature of all sensors of all sensors (T(ave) +/- s.d.) over all treatments, however, was only 41.9 degrees C +/- 0.9 degrees C over 30 min. The maximum temperature for normal tissues outside the gland was 41.1 degrees C +/- 1.3 degrees C. Treatments have been well-tolerated with few complications. Tolerance has been "good" in 17/22, "fair" in 3/22, and "treatment limiting" in 2/22 treatments secondary to position intolerance and/or pain. There has been one episode of hypotension related to narcotic administration and three episodes of rapidly resolving pain during hyperthermia treatment. Mild hematuria has occurred in 5/22, and moderate hematuria has occurred in 2/22 transperineal thermometer catheter placements. CONCLUSION: In conclusion, TRUSH is well-tolerated and has great potential for consistently heating the prostate gland. We anticipate that further equipment modifications will improve our ability to heat the entire prostate to temperatures > 42.5 degrees C.

Interstitial thermoradiotherapy of brain tumors: preliminary results of a phase I clinical trial.

A Phase I clinical trial has been initiated to determine the feasibility, tolerance, and toxicity of interstitial thermoradiotherapy in the treatment of high-grade supratentorial brain gliomas. Hyperthermia was delivered by means of thermally-regulating ferromagnetic implants afterloaded into stereotactically placed plastic catheters. Heat treatments were given immediately before interstitial irradiation; in addition, five patients received a second heat treatment at the completion of brachytherapy. The desired target temperature for the 60-minute hyperthermia session was between 42 degrees C and 45 degrees C. Following hyperthermia, the catheters were afterloaded with Ir-192, which delivered a variable radiation dose of 14-50 Gy depending on the clinical situation. Interstitial irradiation was supplemented with external beam radiotherapy (40-41.4 Gy) in patients with previously untreated tumors. A total of 14 patients (4 males, 10 females) have been treated to date on this protocol. Eleven of the patients had a diagnosis of glioblastoma multiforme, whereas three had anaplastic astrocytoma. The mean implant volume was 61.5 cm3 (range: 9-119 cm3); the median number of interstitial treatment catheters implanted was 19 (range: 7-33). Continuous temperature monitoring was performed by means of multisensor thermocouple probes inserted in the center as well as in the periphery of the tumor. Of the 175 monitored intratumoral points, 83 (47%) had time-averaged mean temperatures of greater than 42 degrees C, and only 12 sensors (7%) exceeded a temperature of 45 degrees C. Among the 19 heat treatments attempted, there have been four minor acute toxicities, all of which resolved with conservative medical management and one major complication resulting in the demise of a patient. These preliminary results indicate that ferromagnetic implants offer a promising new approach to treating brain tumors with hyperthermia.

Treatment of malignant gliomas with interstitial irradiation and hyperthermia.

A Phase I study of interstitial thermoradiotherapy for high-grade supratentorial gliomas has been completed. The objective of this trial was to test the feasibility and toxicity of hyperthermia induced by ferromagnetic implants in the treatment of intracranial tumors. The patient population consisted of 16 males and 12 females, with a median age of 44 years and a median Karnofsky score of 90. Nine patients had anaplastic astrocytoma while 19 had glioblastoma multiforme. Twenty two patients were treated at the time of their initial diagnosis with a course of external beam radiotherapy (median dose 48.4 Gy) followed by an interstitial implant with Ir-192 (median dose 32.7 Gy). Six patients with recurrent tumors received only an interstitial implant (median dose 40 Gy). Median implant volume for all patients was 55.8 cc and median number of treatment catheters implanted per tumor was eighteen. A 60-minute hyperthermia treatment was given through these catheters just before and right after completion of brachytherapy. Time-averaged temperatures of all treatments were computed for sensors located within the core of (> 5 mm from edge of implant), and at the periphery of the implant (outer 5 mm). The percentage of sensors achieving an average temperature > 42 degrees C was 61% and 35%, respectively. Hyperthermia was generally well tolerated; however, there have been 11 minor toxicities, which resolved with conservative management, and one episode of massive edema resulting in the death of a patient. In addition, there were three major complications associated with the surgical implantation of the catheters. Preliminary survival analysis shows that 16 of the 28 patients have died, with a median survival of 20.6 months from diagnosis. We conclude that interstitial hyperthermia of brain tumors with ferromagnetic implants is feasible and carries significant but acceptable morbidity given the extremely poor prognosis of this patient population.