TREATMENT OF INFLAMMATORY BREAST CANCER

Thermoradiotherapy is well established as a primary or adjunct treatment of mammary adenocarcinoma. Results in our series since 1984, encompassing 142 treated patients show a 90% response rate of which 72% are complete responses. However, when local treatment is done in the face of disseminated disease, the response rate is markedly reduced. Response rate increases with the number of hyperthermia treatments.
Localized inflammatory breast cancer, usually extending from the affected breast or mastectomy site to the chest wall is a rapidly lymphatic spreading form for cancer, usually resistant to radiation or chemotherapy, and prone to rapid dissemination.
This presentation reports on a phase 1 clinical trial involving 62 fields in 22 patients. Each field received 2000-4000cGy of external beam bolused radiation combined with 25 or more hyperthermia treatments given within one hour of the radiation.
Response rate was gratifying. 90% of the fields responded to the combined treatment, with complete disappearance of the inflammatory process in 81% of the treated areas. There were only 4 recurrences in the areas of complete response while areas that responded partially showed regrowth within 3 months of treatment. Side effects were minimal, in the form of 6 first degree superficial burns. There was no correlation between the response rate and the radiation dose.
These preliminary results show that thermoradiotherapy should be considered as a treatment modality for inflammatory breast cancer.

Introduction
That hyperthermia potentiates radiation therapy has been proven in malignant cancers, metastatic nodes in the head and neck region [1-6] and several other locations [7-9]. Due to these early findings, clinical applications were limited to recurrent advanced or metastatic cancers [10-12]. However, prospective randomized trials in the 1990's demonstrated the effectiveness of thermoradiotherapy not only in superficial tumors but also when deeper structures are affected [13-14] provided these tumors can be effectively heated. The addition of heat roughly doubles the effectiveness of radiation, but also the fact that hyperthermia increases tumor oxygenation [15-16, 41] makes hypoxic tumors such as sarcomas or glioblastomas more susceptible to thermoradiotherapy [17].
In previous publications [18] we described a treatment regimen based on protraction of the radiation fractionation combined with daily hyperthermia treatments coinciding with each radiation dose. This regimen is effective in eradicating tumors with diminished toxicity.
Based on our early experience as well as the vast literature available, we undertook to treat accessible tumors "de novo" with curative intent in a subgroup of patients that explicitly refused other accepted cancer treatment modalities, including classic radiation therapy, surgery and chemotherapy. The areas chosen were breast, head and neck and prostate cancer.

Material and Methods

1.Hyperthermia Equipment and Technique - Hyperthermia treatments were delivered using either microwave or ultrasound FDA approved equipment. Microwaves were delivered using a BSD-1000 machine with an MA-100 applicator at 600 MHz (BSD Medical Corporation, Salt Lake City, Utah) or a Cheung Laboratories Machine (Columbia, MD) operating at 915 MHz using its air cooled applicators. Temperature measurements were done using disposable micro thermocouple pairs (150 micron size sensors) (DANBI, Inc., Los Angeles, CA) inserted through a 20 gauge plastic catheter placed in the tumor region, providing at least 3 different measuring points. Another probe is placed on the skin above. Temperatures were recorded using P.C. computers connected to the thermocouples through an Omega Engineering temperature acquisition board. Ultrasound hyperthermia was induced using a Labthermics machine (Labthermics, Champagne, IL) using appropriate applicators (large - 15 cm x 15 cm, 3MHz and 1 MHz; small-7.5 cm x 7.5 cm,3Mhz and 1 MHz), and the same thermometry devices as described above. Breast and head and neck tumors were treated either with microwave or ultrasound. Prostate tumors using ultrasound only.
2.Hyperthermia Fractionation and Treatment Plan - Hyperthermia treatments of one hour each were delivered daily, 5 days/week for 16 to 20 weeks, to the tumor and involved nodal areas, within one hour of each radiation fraction. Hyperthermia was given either before or after radiation. The treated area was divided into 2 or more adjacent fields sequentially treated. Most patients received 2 daily heat treatment, one to each field. The target temperature was 41.5o C, usually achieved at least in 2 of the measurement points. Temperatures were heterogenous within the tumors. The hyperthermia part of the protocol extends the number of heat treatments to correspond to the number of radiation fractions, as each hyperthermia treatment preceeds or follows each radiation treatment. The number of hyperthermia treatments therefore varies from 25-50 per course for each treatment field.
3.Radiation Therapy Technique - Radiation therapy was delivered using a Mevatron 12 Siemens machine (Siemens Medical Solutions USA, Inc., Malvern, PA) operating at 10 MeV. Tumors were treated to primary and lymph drainage areas using standard treatment plans for each of the treated tumors; and accepted quality assurance procedures.
4.Radiation Therapy Fractionation - The radiation protocol consists of progressively decreasing daily doses of radiation therapy combined with the daily hyperthermia treatments. Typically the treatment is started at a daily dose of 180 cGy gradually reduced to 100 cGy protracting a typical radiation therapy treatment course from 5000 cGy in five weeks to 5000 cGy given in over eight weeks or 7000 cGy in seven weeks to 7000 cGy in 14 weeks. (See Table 1) According to the ELLIS TDF formula ([19] this results in a 15% or 25% reduction of the effective radiation dose. The total dose is of course adapted to the clinical situation. To this effect, the use of objective end result parameters is introduced, including MRI, MR Spectroscopy [20], PET Scanning.
Tumor Markers and PSA levels. Typically, the treatment is continued with further reduced doses until all the objective parameters confirm a complete response or failure is determined. Therefore, as opposed to classic radiation therapy, patients are treated to effect as objectively demonstrated, instead of to a pre-determined radiation dose or number of fractions.
5.Patient Population - Tumors Treated. - Patients included in this study belong to a subpopulation that refuses all standard medical treatments, including clinical radiation therapy, surgery and chemotherapy . All signed appropriate consent forms. Only patients with early stage III or below with a potential for eradication of localized disease were included. The tumors chosen were breast, head and neck or prostate cancer confined to an anatomical location allowing for accessible technically feasible heat delivery.

Statistics
All tests were done with Graph Pad Prism 4 software (Graph Pad Software Inc., San Diego, USA) using the method of Kaplan and Meier.

Results
Complete response rates were gratifying when compared with published results of thermoradiotherapy or our previous experience [6, 13, 21-26]. Breast tumors showed a complete response rate (CR) of 82% with 7% partial responders (PR). (See Table 2) The CR rate for head and neck tumors was 88% (See Table 3) and for prostate tumors 93% (See Table 4)

Recurrence rate was low when complete response was achieved. For breast cancer it stood at 6% (Table 2), for head and neck tumors 13% (Table 3) and at 14% for prostate tumors (Table 4).
Dissemination rates were comparable. They were 23% for breast tumors (Table 2)13% for head and neck (Table 3) and 14% for prostate tumors (Table 4)
Pojected 5 year survival rates are depicted in Tables 5 and 6. They are 80% for breast patients, 88% for head and neck and 87% for prostate patients. Side effects were commensurable with the biological equivalent of radiation doses given. Dermatitis and occasional thermal burns (61% of treatments in breast patients). Nausea, vomiting and occasional diarrhea and cystitis when treating pelvic fields in prostate patients; mucositis, thickness of saliva and altered taste during head and neck treatment. Hyperthermia did not seem to add to the radiation early effects. In all, the treatment was well tolerated on the vast majority of the patients.

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