Unresectable primary and recurrent head and neck tumors: effect of hyperthermia and carboplatin--preliminary experience.

PURPOSE: To perform a single-arm study to determine the effectiveness of and potential toxic reactions to local hyperthermia and systemic carboplatin (cis-diammine-1,1-cyclobutane dicarboxylate platinum II) for the treatment of advanced or recurrent squamous cell carcinomas of the head and neck. MATERIALS AND METHODS: Eight patients with squamous cell carcinoma of the head and neck and stage IV disease (N2 or N3 neck adenopathy) or recurrent local-regional disease and who were previously and definitively treated were included in the study. Thermochemotherapy was administered every 4 weeks. Recorded end points were tumor response, duration of response, incidence of distant metastases, survival, cause of death, and toxic reactions. RESULTS: One patient had a complete response to therapy, and two had a partial response. Five patients had no response or developed progressive disease during therapy. Six patients died after 4-13 months of progressive disease. Two long-term survivors received radiation therapy; one also underwent surgical resection for residual neck disease. Each thermochemotherapeutic session was well tolerated, with minimal discomfort. Toxic reactions included hypotension, vomiting, hyponatremia, anemia, thrombocytopenia, and infection at the site of administration. There were no life-threatening toxic reactions. CONCLUSION: The combined use of hyperthermia and carboplatin shows potential in the management of unresectable head and neck tumors and is safe and well tolerated. Further studies on thermochemotherapy are warranted to assess its potential.

A phase I/II study to evaluate radiation therapy and hyperthermia for deep-seated tumours: a report of RTOG 89-08.

The purpose of this paper is to evaluate the safety and efficacy of deep hyperthermia in conjunction with radiation therapy. This study employed 'second generation' electromagnetic devices which were felt to be better able to confine heating and spare normal tissue than the devices evaluated in a previous study (RTOG 84-01). Sixty six patients at six institutions were enrolled on a prospective Phase I/II study. Eligible deep seated tumours were treated with a combination of external hyperthermia and radiation therapy. Radiation consisted of 1.7-2 Gy per fraction, 4-5 fractions per week, to > 20 Gy (previously irradiated lesions) or > 50 Gy (no previous radiation). Deep hyperthermia was delivered with electromagnetic devices: BSD 2000 for 92% of cases, Thermotron for 5% of cases, other low frequency electromagnetic for 4% of cases. Hyperthermia was delivered < or = twice weekly. Overall complete and partial response rates were 34% and 16% respectively. Response was not correlated with maximum tumour temperature or disease site. There was, however, a strong association with radiation dose: 54% CR with > or = 45 Gy versus 7% with < 45 Gy (p < 0.0001). The achieved temperatures were less than ideal. Although the average maximum tumor temperature was 41.9 degrees C (range 35.7 degrees C-46.7 degrees C), the minimum tumour temperatures were low. The average minimum tumour temperature was 38.5 degrees C and was never > 41.8 degrees C. Treatment was well tolerated with no fatalities. There were four acute grade 3 or 4 toxicities (6% of patients). Patient discomfort resulted in interruption or discontinuation of sessions in 30% of the sessions. In 12 cases (18% of patients) the planned course of hyperthermia was discontinued due to acute discomfort. The devices used in this study were better tolerated than the devices used in the previous Phase I/II deep hyperthermia trial (RTOG 84-01) with less patient discomfort and no problems with severe systemic cardiovascular stress. In the previous study 68% of the hyperthermia courses were prematurely terminated primarily due to patient discomfort and toxicity; in the present study 18% were prematurely terminated. However, as indicated by the low minimum tumour temperature, fundamental problems with achieving acceptable temperature distributions remain.

Clinical hyperthermia in the 1990s: does the buck stop here?

Clinical hyperthermia in the USA is entering difficult times. To describe the present state of this art (1) all of the clinical manuscripts published in the International Journal of Hyperthermia and the International Journal of Radiation Oncology, Biology and Physics in the period from 1 January 1990 to 30 June 1993 were reviewed; (2) the Radiotherapy Research Division of the National Cancer Institute was queried as to existing extramural funding of clinical hyperthermia projects; and (3) individual institutions known to have active clinical research programmes in hyperthermia were surveyed as to the status of current studies. At the present time there are no hyperthermia trials being conducted by US cooperative groups. The majority of reports and active scientific protocols continue to deal with phase I and pilot studies. Many studies in several sites continue to suggest improvement in CR rate and local control over historical controls when hyperthermia is used as an adjunct to radiotherapy; however phase III proof of these hypotheses is still lacking. Extramural funding of clinical hyperthermia is limited and third party funding is decreasing. Details and future portents are discussed.

Regional hyperthermia in patients with recurrent genitourinary cancer.

During a 6-year period, 53 patients with advanced tumors of the genitourinary tract were treated in Phase I protocols with deep regional hyperthermia in combination with irradiation (83%) or in combination with chemotherapy (11%). Primary tumors included those of bladder in 22 patients (41%), prostate in 20 patients (37%), kidney in 9 patients (17%), and ureter testicle or adrenal in 3 patients (5%). The majority (77%) had prior definitive therapy and had experienced treatment failure, and 11% had clinically important distant metastases. Treatment consisted of deep regional hyperthermia (mean of 4 sessions). In addition, 44 patients (83%) received irradiation (mean dose 39.2 Gy). The 1- and 3-year actuarial survival was 60% and 56%, respectively. Patients with carcinoma of the prostate had a 1- and 3-year survival of 82%. Complete response was observed in 7 patients (13%), partial response in 8 (15%), and nominal response in 13 (25%). Complete and partial response correlated well with histology of the tumor (adenocarcinoma), radiation dose (greater than 50 Gy), primary site (prostate, kidney), and treatment (hyperthermia-radiotherapy combination), (p = 0.02). There was no such correlation between response and thermal dose (p = 0.13). The treatment tolerance was good in 79% of patients. Treatment toxicity was limited to acute side effects, including pain during hyperthermia (47%), tachycardia greater than 140/min (7%), and blister formation in the treated area (4%). Phase II studies in previously untreated patients with locally advanced tumors of bladder, prostate, and kidney are needed for evaluation of the role of deep regional hyperthermia in the management of these cancers.

Treatment results of stereotactic interstitial brachytherapy for primary and metastatic brain tumors.

A total of 41 stereotactic interstitial brain implants in 39 patients were performed for recurrence after teletherapy (recurrence implant), or as part of initial treatment in conjunction with teletherapy (primary implant). Implanted tumors consisted of malignant gliomas (33), other primary brain tumors (3), and single metastatic lesions (3). All patients were temporarily implanted with Ir-192 using a coaxial catheter afterloading system; two patients were implanted twice. Survival post-implant for glioblastoma multiforme (GBM), 13 patients, was 10 months whether implanted primarily or for recurrence. Mean time to recurrence, measured from initiation of teletherapy to implantation, was 10 months. Twenty patients with anaplastic astrocytoma (AA) had a median survival post-implant of 23 months for primary implants (7 patients) and 11 months for recurrence implants (13 patients). Mean time to recurrence, measured from initiation of teletherapy to implantation, was 19 months. Three patients (9%) of the evaluable group required reoperation for symptomatic mass effect, all with initial diagnosis of AA. Survival for this subgroup was 14, 22, and 32 months post-implantation. Using stereotactic techniques, interstitial brachytherapy of brain tumors was technically feasible with negligible acute morbidity and mortality, and appeared to offer limited prolongation of control for a subset of patients with recurrent malignant gliomas. The role of this modality in primary treatment for malignant gliomas needs to be further defined by prospectively randomized trials.

RTOG quality assurance guidelines for clinical trials using hyperthermia for deep-seated malignancy.

Quality assurance has been vague or lacking in many previous hyperthermia trials. Recent publications by the Hyperthermia Physics Center, the Center for Devices and Regulatory Health, and the Radiation Therapy Oncology Group have described general guidelines for quality assurance in equipment reliability and reproducibility, superficial applications, and microwave techniques. The present report details quality assurance factors that are believed to be important for hyperthermia of deep clinical sites, defined as extending at least 3 cm beyond the skin surface. This document will discuss patient and physician factors, as well as thermometric accuracy, assessment of specific absorption rates (SAR), assurance of adequate coverage of tumors by the energy deposition pattern of the treatment device, and recommended documentation of the location, quantity, and frequency of treatment, specifically oriented to deep hyperthermia. The recommendations are structured to facilitate compliance in multiinstitutional trials.

Heating characteristics of a helical microwave applicator for transurethral hyperthermia of benign prostatic hyperplasia.

A new applicator for intraurethral hyperthermic treatment of benign prostatic hyperplasia is described. The applicator uses an insulated helical antenna wound on the outer surface of a silicone urological (Foley) balloon catheter. The balloon catheter assures rapid and reproducible localization of the antenna in the prostatic urethra. Two small cannulae are fixed to the exterior surface of the applicator. One holds a temperature control sensor at a fixed location, the other is used to map temperature along the applicator. Two-dimensional SAR and steady-state temperature distributions measured in a plane tangent to the applicator in a tissue-equivalent phantom are presented, as well as longitudinal temperature distributions measured in situ at the applicator-urethral interface. Prostatic temperatures were also measured intraoperatively. The applicator appears to be capable of elevating temperature to greater than 42 degrees C in a cylindrically symmetric volume of about 4 cm length and about 0.5 cm radial penetration surrounding the antenna. The heating characteristics of this applicator are similar to an earlier design that employed an array of three dipoles. The helical applicator is narrower, more flexible and simpler to use than the earlier design.

Thermochemotherapy in inoperable head and neck cancer.

A combined hyperthermia and chemotherapy approach was used to treat five patients with locally advanced or recurrent squamous cell carcinoma of the head and neck whose tumors had failed to respond to chemotherapy. In two patients, tumor had recurred after initial combined modality therapy (surgery/radiation) and had failed to respond to one course of cisplatin/5-fluorouracil (cisplatin/5-FU) chemotherapy. The three remaining patients were enrolled onto a phase II evaluation of induction chemotherapy with cisplatin/fluorouracil for advanced head and neck carcinomas and had failed to achieve a partial remission after one treatment cycle. Palpable cervical tumors were heated to 40 degrees to 42 degrees C for 30 to 40 minutes, during which time cisplatin (100 mg/m2) was infused intravenously. A 5-day infusion of 5-fluorouracil (1000 mg/m2/d) followed. Despite less than a partial response to previous cisplatin/fluorouracil chemotherapy alone, two patients had complete clinical resolution of the heated tumor volume with two cycles of the combined thermochemotherapy approach. One patient achieved a partial remission with this approach. The remaining two patients died shortly after the initial thermochemotherapy treatment, as a result of progressive tumor growth. The two complete responders were subsequently treated with radiation (1 patient) and radical neck dissection (1 patient) and remained without evidence of disease 2 and 26 months after the completion of therapy, respectively. The toxicity of this combined modality approach was acceptable and appeared to be no greater than had been experienced during earlier treatment with chemotherapy alone. Further studies using a combination of these treatment modalities for locally advanced head and neck carcinomas are warranted.

Adjuvant pelvic hyperthermia in advanced cervical carcinoma. I. Feasibility, thermometry and device comparison.

From 1981 to 1989, a total of 26 women with locally or regionally advanced carcinoma of the uterine cervix were treated with radiotherapy (RT) and pelvic regional hyperthermia (HT), in the Divisions of Radiation Oncology at the University of Utah Medical Center (UU) and the Kenneth Norris Jr Cancer Hospital of the University of Southern California (USC). HT was produced by the BSD-1000 HT system and the annular phased array (AA) applicator usually driven at 60-65 MHz, or the BSD-2000 HT system and the Sigma-60 (S60) applicator usually driven at 70-85 MHz. During the HT sessions acute toxicity was common, particularly because of pain within or outside the applicator, which was power-limiting in 43% of the patients overall. Pain was more easily manipulated, but more commonly power-limiting with the S60. Systemic stress was power-limiting in 22% of patients treated with the AA, but in no patients with the S60. Detailed thermal mapping and temperature analysis were performed on 26 patients. The mean overall average intratumour temperature achieved was 41 +/- 1.1 degrees C for 30 min; 5% and 35% of the monitored intratumour loci exceeded 43 degrees C and 42 degrees C, respectively. Temperatures recorded in the cervical os and proximal vagina appeared lower relative to the monitored normal structures in the region. Subacute treatment related toxicities occurred in five patients and included protracted pain (three) and superficial second degree burns (one), all of which resolved with supportive non-surgical therapy.

Transurethral hyperthermia for benign prostatic hyperplasia: preliminary clinical results.

A total of 21 patients with biopsy proved benign prostatic hyperplasia underwent treatment on a pilot protocol involving intracavitary transurethral radiating microwave (630 or 915 MHz.) antenna hyperthermia. Acute and subacute toxicity was mild and consisted primarily of bladder spasm (26% of the patients), hematuria (23%) and dysuria (9%), none of which significantly limited the achievement of desired temperatures during the treatment sessions. No chronic treatment-related morbidity or mortality was observed. Detailed thermal mapping, performed along the course of the prostatic urethra, recorded temperatures of 43C or more at greater than 75% of the loci. Highly significant increases in urine flow rate, decrease in post-void residual urine capacity and decrease in frequency of nocturia were observed. A marginally significant decrease in prostate volume was noted and, with a median followup of 12.5 months, only 3 patients have required subsequent prostatic resection. Transurethral hyperthermia represents a safe and promising outpatient approach to treatment of benign prostatic hyperplasia, particularly for patients who are not candidates for conventional surgical approaches because of medical or personal reasons. Further studies with the goal of optimizing the technique appear to be warranted, although long-term results would be best evaluated with prospective phase 3 trials.

An interactive treatment planning system for ophthalmic plaque radiotherapy.

Brachytherapy using removable episcleral plaques containing sealed radioisotope sources is being studied as an alternative to enucleation in the treatment of choroidal melanoma and other tumors of the eye. Encouraging early results have been reported, but late complications which lead to loss of vision continue to be a problem. A randomized national study, the Collaborative Ocular Melanoma Study (COMS) is currently in progress to evaluate the procedure. The COMS specified isotope is 125I. Precise dosimetric calculations near the plaque may correlate strongly with complications and could also be used to optimize isotope loading patterns in the plaques. A microcomputer based treatment planning system has been developed for ophthalmic plaque brachytherapy. The program incorporates an interactive, 3-dimensional, solid-surface, color-graphic interface. The program currently supports 125I and 192Ir seeds which are treated as anisotropic line sources. Collimation effects related to plaque structure are accounted for, permitting detailed study of shielding effectiveness near the lip of a plaque. A dose distribution matrix may be calculated in any subregion of a transverse, sagittal, or coronal planar cross section of the eye, in any plane transecting the plaque and crossing the eye diametrically, or on a spherical surface within or surrounding the eye. Spherical surfaces may be displayed as 3-dimensional perspective projections or as funduscopic diagrams. Isodose contours are interpolated from the dose matrix. A pointer is also available to explicitly calculate and display dose at any location on the dosimetry surface. An interactive editing capability allows new plaque designs to be rapidly added to the system.

Microwave applicator for transurethral hyperthermia of benign prostatic hyperplasia.

An applicator for heating the prostate gland using a transurethral approach is described. This technique uses three microwave antennas and a thermometry sensor attached to the outer surface of a balloon (Foley) type urological catheter. Each microwave antenna also includes a built-in thermistor to control temperature and balance power. The balloon catheter assures rapid and reproducible localization of the antennas in the prostatic urethra. The two-dimensional SAR and steady-state temperature distributions surrounding the applicator in tissue equivalent phantom are reported. Longitudinal temperature distributions measured in situ at the applicator-urethral interface and the longitudinal and radial temperature distributions measured in normal canine prostate are presented and discussed. The technique appears to be capable of elevating temperature to greater than 42 degrees C in a cylindrically symmetrical volume up to 5 cm length and 0.5 cm radial penetration surrounding the applicator.

Regional hyperthermia for advanced tumors: a clinical study of 353 patients.

A Phase I study using deep regional hyperthermia (HT) with an annular phased array was conducted in 14 U.S. medical centers from 1980 through 1986. There were 353 patients whose average age was 57 years. All patients had advanced recurrent or persistent tumors. Prior frequently complex, multimodality anti-cancer therapy was received by 71% of the patients. Gastrointestinal adenocarcinoma was present in 146 (41%) patients, genitourinary tumors in 86 (24%), soft tissue sarcomas in 46 (13%), malignant melanoma in 21 (6%) and 15% had other tumors. The sites treated included: pelvis 55%, abdomen 21%, liver 14%, thorax 6%, and other sites 3%. All patients received deep regional HT with an average frequency of 55 MHz. A total of 1412 HT treatments was administered to these 353 patients with an aim to increase the temperature in the volume of interest to greater than 42 degrees C for greater than or equal to 30 minutes. Thermal dose (TD in equivalent minutes at 42.5 degrees C) was less than 50 in 104 (29%), greater than or equal to 50 less than 100 in 30 (11%), greater than or equal to 100 in 26 (7%), and greater than 200 in 34 (10%). The remaining 150 (42%) patients had TD = 0. In addition to HT, 260 (74%) received radiotherapy (RT). RT was given at 180 or 200 cGy daily with an average total dose of 33.4 Gy. A total of 42 (12%) patients were given chemotherapy (CT) with HT, and 15 (4%) CT + HT + RT/HT alone was given to 47 (13%) patients. Complete response (CR) was obtained in 35 (10%) and partial response (PR) in 59 (17%) patients. CR was 12% in patients who received RT, vs 2% in those who did not receive it, p = 0.003. Radiation dose was an important factor influencing response, p less than 0.001. Thermal dose was not an important parameter influencing tumor response. A duration of CR ranged from 4 to 73 weeks with an average duration of 31 weeks and the median duration of 28 weeks. The overall 2-year survival was 13% with the median survival of 42 weeks. Patients with CR and PR had a 2 year survival of 41%, and a median survival of 71 weeks. This compared with 8% 2-year survival and 24 weeks median survival in patients who did not have CR or PR, p less than 0.001. Of the patients presenting with significant pain, 62% had complete or partial pain relief.(ABSTRACT TRUNCATED AT 400 WORDS)

A technique for combining microwave hyperthermia with intraluminal brachytherapy of the oesophagus.

A technique for combining microwave hyperthermia with 192Ir brachytherapy for the treatment of oesophageal carcinoma is described. This approach uses an intraluminal afterloading applicator and up to six microwave antennae to deliver both hyperthermia and brachytherapy, with minimal modification of the existing procedure for brachytherapy alone. Each microwave antenna includes a built-in thermistor to control temperature and balance power. Longitudinal temperature distributions were measured in situ from within the applicator, and at the applicator-tissue interface in vivo. Two-dimensional SAR and steady-state temperature distributions measured in muscle-equivalent phantom are presented and discussed. The technique appears to be capable of elevating tissue temperature to greater than 42 degrees C in a radially symmetric volume of length greater than 5 cm, with radial penetration of 0.5 cm. The clinical technique is relatively simple and well tolerated.

The accuracy of temperature measurement from within an interstitial microwave antenna.

Temperature measurement from within microwave interstitial antennas is a promising new development for hyperthermia. These antennas could enable the development of multipoint temperature regulation, leading to improved control of temperature distributions and therefore more effective hyperthermia treatments. In the complex environment of an antenna within a plastic catheter, measured temperatures were found to differ from the estimated local tissue temperature by up to 8 degrees C. In the design evaluated in this report the primary source of this error appears to be self-heating distal to the antenna junction, particularly in the outer copper conductor. The magnitude of self-heating is directly proportional to applied microwave power. Catheter wall thickness, tissue perfusion, and longitudinal temperature gradient also influence the measured temperature.

Definitive radiation therapy in bile duct carcinoma.

Between 1980 and 1985, 24 patients with primary adenocarcinoma of the bile duct were treated with various combinations of surgery, biliary intubation, external irradiation, and transcatheter brachytherapy. Seventy-five percent of tumors were in the proximal bile ducts. Ten patients received no or only palliative radiation, Group 1, whereas 14 patients received definitive courses of radiation (4 by external beam irradiation, 2 by transcatheter irradiation, and 8 by both modalities), Group 2. Survival in Group 1 and Group 2 was significantly different (p less than 0.005) with median survivals of 2.0 and 12.8 months, respectively. This result may be in part due to differences in treatment and in part due to selection bias because the series is small, uncontrolled, and retrospective. Median survival of the 8 patients treated with combined modalities was 13.2 months (range 7.4-30.3) with 4 patients alive 8.7 to 16.2 months, 3 without cholangiographic evidence of disease. Complications of therapy were common, including bacterial sepsis (58%), cholangitis (38%), gastrointestinal bleeding (46%), intra or extrahepatic abscesses (33%), and recurrent biliary obstruction (25%). Cholangitis, hemorrhage, abscesses, and ulcers appeared more frequently in definitively treated patients, whereas recurrent biliary obstruction was absent in this group and frequent in Group 1. Differences in complication rates between groups were not statistically significant. Early diagnosis and management usually reversed a downhill clinical course in patients with abscess and hemorrhage. Both surgical and percutaneous techniques of biliary decompression, the usual initial form of therapy in bile duct cancer, are associated with frequent and serious complications. Although many of our complications may have derived from biliary decompression, it is possible that definitive treatment may have increased the frequency of serious complications.

Stereotactic interstitial brachytherapy of malignant astrocytomas with remarks on postimplantation computed tomographic appearance.

Seventeen patients were treated with stereotactically implanted high activity iodine-125 seeds, 12 patients for recurrent malignant astrocytomas (Protocol I) and 5 patients for newly diagnosed glioblastomas (Protocol II). Total radiation dosage to the recurrent tumors in Protocol I, including prior external beam irradiation, averaged 13,500 cGy. In the follow-up period of 6 to 50 months, the survival rate was 93% at 6 months, 60% at 12 months, 50% at 18 months, and 38% at 24 months after implantation. In Protocol II, brachytherapy was used as an interstitial radiation boost to the conventional treatment of newly diagnosed glioblastomas. External beam therapy and interstitial brachytherapy provided 11,000 cGy to these tumors. In the follow-up period of 15 to 27 months, there was a 100% survival at 12 months, 75% at 18 months, and 25% at 24 months after implantation. Eight of our 17 patients required reoperation for persistent or recurrent mass lesions at 6 to 15 months postimplantation; 7 were found to harbor masses of radionecrosis containing nests of anaplastic astrocytes; 1 had frank tumor recurrence. Median survival in this group of patients requiring reoperation was 18.7 months postimplantation. In a review of postimplantation computed tomographic scans, significant mass effect and crossover of hypodensity or enhancement into the corpus callosum or opposite hemisphere were found to have prognostic significance; persistent areas of contrast enhancement and excessive peritumoral hypodensity did not.

Myonecrosis following deep pelvic hyperthermia.

A case report is presented in which severe myonecrosis of the inferior anterior abdominal wall followed treatment of a recurrent pelvic tumour with an annular phased array (AA) deep heating device. This unusual complication has not been observed at this institution in 107 patients previously treated with deep pelvic or abdominal hyperthermia, who had undergone a total of 368 hyperthermia sessions. The injury was confirmed radiographically and histopathologically, and was associated with serum enzymatic elevations characteristic of muscular injury. The implications for clinical trials employing the AA or similar devices are discussed.

Phase I evaluation of hyperthermia equipment--University of Utah institutional report.

At the University of Utah Medical Center the thrusts of the effort with respect to the NCl Hyperthermia Equipment Evaluation Contract have been threefold. The first objective was the development of a reliable thermometry system for collecting temperature information as a function of space as well as time. The second objective was the evaluation and comparison of a number of hyperthermia devices, particularly with respect to deep-heating devices, and specifically as pertains to the BSD annular phased array system (AA) and its various configurations. The third objective was to develop methodology for analysing hyperthermia data which could be easily adapted toward device comparison. In the period from 10/81-1/86, a total of 137 patients were treated with one or more of 10 devices, totalling 199 device evaluations at the University of Utah Medical Center or the subcontracting institution, LDS Hospital. Of these, 132 device evaluations involved deep-seated tumours. The AA was found to be feasible for deep pelvic regional hyperthermia, although the frequency of reversible acute toxicity was high, and achievement of desired temperatures was frequently limited by one of several factors. The radiative electromagnetic wave applicators which were evaluated for treatment of superficial tumours were found to be mostly feasible for tumours of the thoracic and extremities regions, although the heating patterns were frequently too shallow or too small in area, when compared with the size of the lesion.