Simultaneous superficial hyperthermia and external radiotherapy: report of thermal dosimetry and tolerance to treatment.

BACKGROUND: In vitro and animal studies indicate that a moderate temperature of 41 degrees C maintained for approximately 1 h will provide radiosensitization if radiation (RT) and hyperthermia (HT) are delivered simultaneously, but not with sequential treatment. A minimum tumour temperature of 41 degrees C is a more feasible goal than the goal of >42 degrees C needed for sequential treatment. METHODS AND MATERIALS: Forty-four patients with 47 recurrent superficial cancers received simultaneous external beam radiotherapy and superficial hyperthermia on successive IRB approved phase I/II studies. All lesions had failed previous therapy, 35 were previously irradiated (mean dose 52.7 Gy). Hyperthermia was delivered with 915 MHz microwave or 1-3.5 MHz ultrasound using commercially available applicators. The average dimensions of 19 lesions treated with microwave were 4.7 x 3.6 x 1.7 cm and the average dimensions of 28 lesions treated with ultrasound were 8.0 x 6.1 x 2.9 cm. The most common sites were chest wall (15 cases) and head and neck (21 cases). Temperatures were monitored at an average of six intratumoral locations using multisensor probes. The median number of hyperthermia treatments was three and the median radiation dose 30 Gy. Radiation dose per fraction was 4 Gy with hyperthermia and 2 Gy or 4 Gy (depending on protocol) on non-hyperthermia days. RESULTS: Six different measures of minimum monitored temperature and duration were found to be highly correlated with each other. There was nearly a one-to-one correspondence between minimum tumour time at or above 41 degrees C (Min t41) and minimum tumour Sapareto Dewey equivalent time at 42 degrees C (Min teq42). After four sessions 63% of cases had a per session average Sapareto Dewey equivalent time at 41 degrees C which exceeded 60 min in all monitored tumour locations. The complete and partial response rate in evaluable lesions were respectively 21/41 (51%) and 7/41 (17%) and were best correlated with site (chest wall showing best response). Toxicity consisted of 10/47 (21%) slow healing soft tissue ulcers which healed in all cases but required a median of 7 months. The most important predictors for chronic ulceration were cumulative radiation dose >80 Gy and complete response to treatment. CONCLUSIONS: Minimum tumour temperatures maintained for durations compatible in vitro with thermal radiosensitization (if RT and HT are delivered simultaneously) are clinically feasible and tolerable for broad but superficial lesions amenable to externally applied ultrasound or microwave hyperthermia. The current in-house protocol is evaluating the impact of more than four hyperthermia sessions on the overall thermal dose distribution and toxicity.

Equilibrium temperature distributions in uniform phantoms for superficial microwave applicators: implications for temperature-based standards of applicator adequacy.

Equilibrium temperature distributions are computed using measured SAR distributions for five different superficial microwave (915 MHz) applicators. We assume a model with uniform conduction and blood flow. A Green's function approach is used to calculate equilibrium solutions which identically obey boundary conditions at the surface of the phantom and at infinite depth. The equilibrium solutions are categorized by surface temperature (TS), maximum allowed temperature (TM), and by a parameter (referred to as the diffusion length, lambda) which characterizes the contributions of thermal conduction relative to blood flow. The computed equilibrium temperature distribution at depths of 2 and 3 cm is strongly dependent on lambda and on TM. It is not strongly dependent on surface temperature for TS below 35 degrees C. In previous work we compared the SAR distribution with local control of 53 superficial tumours with over 1 year of follow-up. As an alternative to an SAR-based description of applicator adequacy we consider a temperature-based standard. Tumours are categorized by the minimum value of lambda that would allow full coverage of the tumour volume by the 42 degrees C contour, assuming a TM of 47.5 degrees C and a TS of 35 degrees C. Eighteen of 27 lesions (67%) were locally controlled for lambda less than 1 cm. The local control in 26 lesions with lambda greater than or equal to 1 cm was 31% (p = 0.016). The lesions with the best results were those with both good coverage in theory (lambda less than 1 cm) and with all monitored catheter tracks achieving at least one session with 30 min at or above 43 degrees C. We found that the temperature-based standard of applicator adequacy was not independent of an SAR-based standard, and in this cohort of patients either a minimum SAR criterion or a maximum diffusion length criterion would serve equally well as a screen for inappropriate applicators.

Postoperative radiotherapy for malignant fibrous histiocytoma.

Between 1974 and 1989, 49 patients with histologically confirmed malignant fibrous histiocytoma received postoperative radiotherapy at the Mallinckrodt Institute of Radiology for primary (41) or recurrent (8) disease. Median age of the patients was 63 years, and the median follow-up period was 41 months. Patients were grouped according to the 1988 AJC staging classification: stage IA (one patient), stage IIA (4 patients), stage IIB (9 patients), stage IIIA (15 patients), stage IIIB (18 patients), and stage IVA (2 patients). Eight tumors (16%) were in the pelvis, 8 (16%) in the trunk, 4 (8%) in the head and neck, and 29 (60%) in the extremities. Primary surgical procedures included incisional biopsy (4 patients), excisional biopsy (19), narrow margin excision (14), wide local excision (9), and removal of the entire compartment (3). Based on pathology reports, the margins of resection were classified as positive in 23 (5 gross, 18 microscopic), 5 close, 11 negative, and 10 unknown. Patients were irradiated with shrinking field technique; the median radiation dose was 6000 cGy, with more than 95% of patients receiving at least 4500 cGy. In addition, seven patients received postoperative chemotherapy. The 5-year overall survival rate was 62%, disease-free survival 64%, local control 68%, and freedom-from-distant metastasis 85%. Thirteen patients had local recurrences, with greater than 75% recurring within 3 years. Sites of local recurrence were as follows: trunk (3), pelvis (3), lower extremities (4), and head and neck (3). There appears to be a correlation of local failure with positive surgical margin: of 23 patients with positive margins, 9 (39%) had local recurrences, whereas 1 of 11 patients (9%) with negative margins had local recurrence. Three of 13 patients with persistent or recurrent disease were salvaged by additional treatment, rendering ultimate local control in 80% (39/49). Thirty-four of 36 patients with local control obtained good to excellent function. Two patients were found to have grade 3 complications: 1 patient had edema of the extremity, and the other developed necrotic skin ulcer that was successfully treated with hyperbaric oxygen. Five patients developed distant metastases, with 80% occurring within 2 years. In summary, adequate but conservative surgery with postoperative radiotherapy for malignant fibrous histiocytoma can achieve local tumor control as well as preservation of functional limbs with acceptable morbidity in a large proportion of patients.

Three-dimensional photon treatment planning for Hodgkin's disease.

A multi-institutional study was undertaken using computerized planning systems to develop three-dimensional (3-D) radiotherapy plans for Hodgkin's disease (H.D.). Two patients, the first afflicted with bulky stage II disease and another one with early stage I H.D., were studied. Three main categories of plan were produced for each patient: a) a traditional plan which modelled a conventional mantle treatment on the 3-D system, b) a 3-D standard plan where anterior and posterior fields were designed to cover 3-D target volumes, and c) a 3-D unconstrained plan where innovational techniques were employed. Three-dimensional planning provides information about the dose distribution throughout the large volume irradiated in patients with H.D. that is not available with conventional mantle planning. The use of 3-D techniques resulted in improved tumor coverage, but by allowing for uncertainties such as motion, the doses to normal tissues tended to be higher. The use of unorthodox beam arrangements introduced added complexities, and further increased the lung doses. The most even dose distributions were obtained by incorporating compensating filters into anterior fields. Clinicians showed wide variations in their assessment of the plans, possible reasons for which are addressed in this paper. In addition, calculated probabilities from models of tumor control and normal tissue damage are also presented.

Theory and design of "shortened" multiantenna microwave applicators with controllable SAR patterns.

A "shortened" multiantenna hyperthermia applicator has been designed and tested at the Mallinckrodt Institute of Radiology at Washington University School of Medicine. By shortening the distance from antenna to aperture, an applicator is obtained that produces an SAR pattern that is essentially the same as produced by a monopole antenna. By placing several properly spaced probe antennas into the same "shortened" applicator, an applicator is obtained that produces a SAR distribution that is essentially a composite of small overlapping SAR patterns produced by weakly interacting incoherently driven antennas. Such a design significantly improves the applicator's lateral heating efficiency and allows the independent control of temperatures in certain tumor areas by changing the input power to the respective antennas.

Physical predictors of adequate hyperthermia with the annular phased array.

One hundred and fifty-two hyperthermia sessions in 36 consecutive patients treated with the BSD 1000 annular phased array system (APAS) are reviewed with regard to physical predictors of quality of hyperthermia. Although central tumour temperatures exceeding 42 degrees C were momentarily obtained in 62% of the sessions, it frequently proved difficult to maintain the patient at temperature for prolonged periods of time. The time to reach target temperature was negatively associated with quality of hyperthermia. Thus, of 25 sessions which required over 25 min to attain a temperature of 42 degrees C, only one was adequate (defined as central tumour temperature greater than or equal to 42 degrees C maintained for at least 30 min) as opposed to 28/69 adequate sessions when 42 degrees C was reached in less than 25 min. Physical parameters measured in the first 3 min of the session found to be associated with adequate hyperthermia include an initial rate of temperature rise at the tumour site exceeding 0.4 degrees C/min achieved with a net forward power less than 1500 W. Only three of 57 sessions not meeting these criteria were adequate. Treatment policy recommendations and recommendations for future research are made.

Primary tumors of the trachea. Results of radiation therapy.

From 1959 to 1986, 24 patients with primary malignant tumors of the trachea received radiotherapy as all or part of treatment. Common presentations included respiratory symptoms in 20 patients and hemoptysis in 15. Thirteen patients had squamous carcinomas with undifferentiated and adenoid cystic cancers in five and four patients, respectively. Overall actuarial survival was 45% at 1 year, 25% at 5 years, and 13% at 10 years. Survival was significantly correlated to histologic type (adenoid cystic versus squamous, P less than 0.03), but not to tumor extent or to patient age or sex. Local control was attained in 10 of 24 patients overall and was more frequent for patients with tumors localized to the trachea and for patients who were treated with combined surgery and radiotherapy. For the 18 patients treated with radiotherapy alone, complete response (CR) was seen to be significantly (P less than 0.001) related to dose: six of seven (86%) patients receiving greater than or equal to 6000 cGy attained CR versus one of 11 (9%) receiving less than 6000 cGy. Three patients developed complications related to radiotherapy. Radiotherapy can provide durable local control of localized tracheal tumors and should be considered for medically inoperable patients with localized tumors and for patients with high risk of recurrence after resection.

Prognostic factors and results of surgery and postoperative irradiation in the management of pituitary adenomas.

Prognostic factors and results of therapy were analyzed in a retrospective examination of 121 patients with pituitary adenomas treated with surgery and postoperative irradiation (RT) from January 1954 through December 1982 at the Radiation Oncology Center, Mallinckrodt Institute of Radiology. The 10-year overall and disease-free survival for all patients was 85.1 and 89.4%. The expected survival for an age-, gender-, and race-matched population was not significantly distinct at 85.3% (p = 0.72). Follow-up of 94 surviving patients ranged from 3.4 to 29.5 years (mean, 11.7). Statistical analysis was performed for multiple prognostic factors including age, race, gender, disease bulk, visual field symptoms, disease type, surgical approach, and irradiation dose and volume. The only prognostic variable identified by univariate analysis to significantly alter disease-free survival was irradiation dose. Patients receiving 5000-5400 cGy had a tumor control rate of 94.1% (64/68) compared to 85.0% (17/20) for 4000-4999 cGy, 75.0% (18/24) for 3000-3999 cGy, and 28.6% (2/7) for less than 3000 cGy (p = 0.000059). Factors evaluated but established to be insignificant were age, race, gender, disease bulk, visual field symptoms, disease type, surgical approach, and irradiated volume. The 10-year disease-free survival by classification was 93.3% for patients with amenorrhea/galactorrhea, 89.9% for non-functioning adenomas, and 76.4% for acromegaly (p = 0.21). Overall improvement in visual field defects subsequent to treatment occurred in 48.4% (44/91) of those with visual field defects before RT and was significantly correlated with RT dose. The median time to progression of disease was 10.2 years with the last failure occurring at 25 years following the fulfillment of RT. Severe complications related to RT were apparent in 1.7% (2/121). None were known to have endured brain radionecrosis. Serious surgical complications occurred in 9.9% (12/121).

Interaction of bleomycin and hyperthermia--results of a clinical pilot study.

In vitro and animal studies indicate that concomitant administration of Bleomycin and hyperthermia result in a dramatic potentiation of cytotoxic (anti-tumor) activity. This effect takes place at temperatures above 42 degrees C. A Phase I/II pilot study has been conducted to assess the clinical feasibility of concomitant Bleomycin-hyperthermia application. Eligible patients were those with measurable tumors persistent or recurrent following treatment with conventional modalities including full dose radiotherapy. The protocol required placement of at least two interstitial catheters for continuous monitoring of temperature. Skin probes were also used and thermal mapping of all catheters was required. The therapeutic aim was minimal tumor temperature of 43 degrees C +/- .5 degrees C, the maximal normal tissue temperature was not to exceed 45 degrees C. Pretreatment evaluation included pulmonary function studies and arterial blood gases. Bleomycin was administered within 1 hour prior to initiation of hyperthermia at the dose of 15 units/m2. Twelve patients received therapy according to this protocol. Eight presented with carcinomas of the head and neck area, 4 with adenocarcinoma of the breast. Complete response was recorded in 4, partial in 6 patients. Rapid tumor lysis occurred in 2 patients. Reaction of the normal skin and subcutaneous tissues were mild in all cases and ranged from erythema to mild fibrosis. Three patients experienced pulmonary toxicity, only one of which was severe enough to cause cessation of therapy. Early clinical experience with thermochemotherapy using Bleomycin in heavily pretreated patients indicates a promising response rate and acceptable tolerance. Further studies of Bleomycin-hyperthermia alone and in combination with other modalities including radiotherapy appear warranted.

Thoracic irradiation with or without levamisole (NSC #177023) in unresectable non-small cell carcinoma of the lung: a phase III randomized trial of the RTOG.

A total of 285 patients with medically inoperable (RTOG Stage T1-2, N0-1) or unresectable (RTOG Stage T3, N0-1) non-small cell carcinoma of the lung were randomized by the Radiation Therapy Oncology Group (RTOG) to receive radiation therapy (6000 cGy total dose/6 weeks) plus levamisole (2.5 mg/kg twice weekly for 2 years or until tumor progression) or a placebo. One hundred twenty-nine evaluable patients were assigned to placebo and 131 to levamisole. This report is based on 260 (91%) eligible patients who started treatment and have adequate follow-up. Fifty percent of the patients in both treatment groups had Karnofsky scores of 90-100; 72% had squamous cell carcinoma, 12% adenocarcinoma, and 16% large cell undifferentiated carcinoma; 60% had RTOG Stage I or II primary tumors and 40% had Stage III (T3, N0-1) tumors. Complete regression of tumor was reported in 20% of the patients treated with levamisole and 36% of those receiving placebo. An additional 33% and 19%, respectively, had a partial response (trend test p = 0.08). Median survival was 9 months for patients treated with levamisole and 12 months for those on placebo (two-sided p less than 0.01); at 2 years, patients treated with levamisole had a 15% survival rate as compared to 24% in those receiving placebo. The cumulative proportion failing within the irradiated field with or without other sites of progression at 2 years was 30% in the levamisole group and 34% in the placebo patients. Median progression-free survival was 6 months for patients on levamisole and 7 months for those on placebo (overall two-sided p = 0.014); the estimated proportions progression-free at 2 years were 11% and 18%, respectively. The study showed no significant prolongation of survival, progression-free survival, or differences in patterns of failure in irradiated patients treated with levamisole compared with a placebo. Toxicity related to this immunoadjuvant was, in general, of moderate clinical importance. This study confirms a report by the Southeastern Cancer Study Group concluding that levamisole combined with definitive irradiation has no benefit in the treatment of unresectable non-small cell carcinoma of the lung.

Regional hyperthermia--assessment of tolerance to treatment.

To assess the patient's tolerance and the complications of treatment associated with delivery of regional hyperthermia using APAS BSD equipment, the data on 30 patients who received regional hyperthermia at the Radiation Oncology Center, Washington University School of Medicine, St. Louis, Missouri, has been reviewed. Most patients presented with advanced or recurrent tumors not amenable to conventional treatment modalities. Hyperthermia was administered in combination with either radiotherapy or chemotherapy. Cardiovascular evaluation was a standard part of pre-treatment work-up. Temperatures were obtained through interstitial probes, catheters inserted into the body cavities and (to record core temperature) esophagus. Local discomfort, anxiety, systemic temperature elevation, and tachycardia were the predominant factors limiting the number of sessions, the duration of sessions and the deposition of power, in 18, 6, 3, and 2 patients, respectively. The complications of treatment were rare. Significant injuries of the superficial tissues were recorded in two patients in whom this could be attributed to contact of urine and stool with the skin surface. Neuropathy was observed in two patients, both of whom had pelvic masses adjacent to or invading into the affected nerves. Both patients had received pelvic irradiation. Neuropathy developed within several days after the first hyperthermia session and proved reversible within several months. No injuries of the visceral organs that could be clearly attributed to hyperthermia have been recorded.

Regional hyperthermia: a feasibility analysis.

Thirty patients received regional hyperthermia using the annular phased array system (APAS) in conjunction with either radiotherapy or chemotherapy. A total of 139 treatment sessions were available for analysis, averaging 4.6 per patient. The number of hyperthermia sessions per patient varied from 1 to 9 and was dependent on the patients' tolerance. The duration of the sessions also varied considerably. Although the goal of each session was to attain temperatures of 42 degrees C or higher for 1 h, minimally one-half hour, this was rarely achieved. Temperatures of 42 degrees C or higher were achieved in 95 (68.8 per cent) sessions. The time span at that level ranged between 1 and 40 min, median 8.5 min. The predominant limiting factor in 18 (60 per cent) of patients was local discomfort. Generalized discomfort (anxiety) as a predominantly limiting factor in 5 (16.6 per cent), systemic temperature elevation in 3 (10 per cent), and tachycardia in two (6.6 per cent) patients. Careful attention to technical details and patient preparation may ameliorate or eliminate some of the limiting factors and improve the efficacy of heat delivery.

Correlation of radiotherapeutic parameters and treatment related morbidity--analysis of RTOG Study 77-06.

The current report is an updated and detailed analysis of treatment related morbidity in RTOG 77-06, a Phase III randomized study comparing prostatic irradiation versus pelvic irradiation followed by a prostatic boost, in patients with Stage A2 and B carcinoma of the prostate without evidence of nodal involvement. A total of 453 analyzable cases were accrued from 1978 to 1983, when the study was closed. All cases of treatment related morbidity were classified as to severity (using a clinical severity grading system). The data were then correlated with a number of radiotherapeutic parameters including treatment volumes (fields), doses, and techniques. Overall, pelvic irradiation, compared to prostate irradiation only, was not associated with a significantly increased incidence of treatment related morbidity. Within the range of pelvic doses used in this study a significant dose effect could not be detected. Total doses to the prostate of more than 7000 cGy were associated with an increased risk of rectal bleeding. Certain treatment techniques, (AP/PA irradiation of the pelvic lymphatics) were associated with an increased incidence of bowel complications.

Radical prostatectomy or radiotherapy in carcinoma of prostate. The dilemma continues.

Evaluation of the efficacy of radical prostatectomy versus radiotherapy in carcinoma of the prostate has been compromised by the scarcity of data in comparable populations. A nationwide search was conducted to compile the available data on the use of radiotherapy in lymphadenectomy-staged patients. The assessed population consists of patients with tumor confined to the gland (Stages A2 and B), negative staging lymphadenectomy, negative bone scan, and normal serum acid phosphatase level who received external beam radiotherapy with curative intent. To provide a broad spectrum of experiences, the search included patients from a large number of institutions including Stanford University, Washington University (St. Louis), those participating in the Radiation Therapy Oncology Group, and a broad range of radiotherapy practices surveyed by the PCS (Patterns of Care Study). A total of 209 patients were identified. No selection criteria other than the aforementioned were applied. The patients were treated consecutively during the survey period. In sharp contradistinction to the reported results of the VA Uro-Oncology Group the analysis indicates a less than 10 per cent probability of progression within the first five years after completion of treatment. Nationwide, the outcome of radiotherapy-treated patients appears to be equivalent to the comparable surgically treated population.

Definitive radiotherapy in resectable (stage A2 and B) carcinoma of the prostate--results of a nationwide overview.

To evaluate the efficacy of definitive radiotherapy in a population of patients with carcinoma of the prostate who satisfy the customary selection criteria for radical prostatectomy, a nation-wide search was conducted. The assessed population consists of patients with clinical Stage A2 and B carcinoma of the prostate, negative staging lymphadenectomy, negative bone scan, and normal serum acid phosphatase. The search included patients from Stanford University, Washington University in St. Louis, those participating in the Radiation Therapy Oncology Group and a broad range of radiotherapy practices surveyed by the PCS (Patterns of Care Study). A total of 209 patients satisfying the selection criteria received definitive radiotherapy during the surveyed period. The end-point of analysis was the time to progression (distant metastases). The results of the analysis indicate a very low (less than 10%) probability of progression within the first 5 years after completion of treatment. Contrary to the recent report from the VA Uro-Oncology Group the study demonstrates a comparable outcome in radiotherapeutically and surgically treated patients.