Ellen L. Jones

Randomized trial of hyperthermia and radiation for superficial tumors.

PURPOSE Randomized clinical trials have demonstrated hyperthermia (HT) enhances radiation response. These trials, however, generally lacked rigorous thermal dose prescription and administration. We report the final results of a prospective randomized trial of superficial tumors (</= 3 cm depth) comparing radiotherapy versus HT combined with radiotherapy, using the parameter describing the number of cumulative equivalent minutes at 43 degrees C exceeded by 90% of monitored points within the tumor (CEM 43 degrees C T(90)) as a measure of thermal dose. METHODS This trial was designed to test whether a thermal dose of more than 10 CEM 43 degrees C T(90) results in improved complete response and duration of local control compared with a thermal dose of </= 1 CEM 43 degrees C T(90). Patients received a test dose of HT </= 1 CEM 43 degrees C T(90) and tumors deemed heatable were randomly assigned to additional HT versus no additional HT. HT was given using microwave spiral strip applicators operating at 433 MHz. RESULTS One hundred twenty-two patients were enrolled; 109 (89%) were deemed heatable and were randomly assigned. The complete response rate was 66.1% in the HT arm and 42.3% in the no-HT arm. The odds ratio for complete response was 2.7 (95% CI, 1.2 to 5.8; P = .02). Previously irradiated patients had the greatest incremental gain in complete response: 23.5% in the no-HT arm versus 68.2% in the HT arm. No overall survival benefit was seen. CONCLUSION Adjuvant hyperthermia with a thermal dose more than 10 CEM 43 degrees C T(90) confers a significant local control benefit in patients with superficial tumors receiving radiation therapy.

Re-setting the biologic rationale for thermal therapy

This review takes a retrospective look at how hyperthermia biology, as defined from studies emerging from the late 1970s and into the 1980s, mis-directed the clinical field of hyperthermia, by placing too much emphasis on the necessity of killing cells with hyperthermia in order to define success. The requirement that cell killing be achieved led to sub-optimal hyperthermia fractionation goals for combinations with radiotherapy, inappropriate sequencing between radiation and hyperthermia and goals for hyperthermia equipment performance that were neither achievable nor necessary. The review then considers the importance of the biologic effects of hyperthermia that occur in the temperature range that lies between that necessary to kill substantial proportions of cells and normothermia (e.g. 39–42°C for 1 h). The effects that occur in this temperature range are compelling including—inhibition of radiation-induced damage repair, changes in perfusion, re-oxygenation, effects on macromolecular and nanoparticle delivery, induction of the heat shock response and immunological stimulation, all of which can be exploited to improve tumour response to radiation and chemotherapy. This new knowledge about the biology of hyperthermia compels one to continue to move the field forward, but with thermal goals that are eminently achievable and tolerable by patients. The fact that lower temperatures are incorporated into thermal goals does not lessen the need for non-invasive thermometry or more sophisticated hyperthermia delivery systems, however. If anything, it further compels one to move the field forward on an integrated biological, engineering and clinical level.

American Brachytherapy Society consensus guidelines for locally advanced carcinoma of the cervix. Part II: high-dose-rate brachytherapy.

PURPOSE This report presents an update to the American Brachytherapy Society (ABS) high-dose-rate (HDR) brachytherapy guidelines for locally advanced cervical cancer. METHODS Members of the ABS with expertise in cervical cancer formulated updated guidelines for HDR brachytherapy using tandem and ring, ovoids, cylinder, or interstitial applicators for locally advanced cervical cancer. These guidelines were written based on medical evidence in the literature and input of clinical experts in gynecologic brachytherapy. RESULTS The ABS affirms the essential curative role of tandem-based brachytherapy in the management of locally advanced cervical cancer. Proper applicator selection, insertion, and imaging are fundamental aspects of the procedure. Three-dimensional imaging with magnetic resonance or computed tomography or radiographic imaging may be used for treatment planning. Dosimetry must be performed after each insertion before treatment delivery. Applicator placement, dose specification, and dose fractionation must be documented, quality assurance measures must be performed, and followup information must be obtained. A variety of dose/fractionation schedules and methods for integrating brachytherapy with external-beam radiation exist. The recommended tumor dose in 2-Gray (Gy) per fraction radiobiologic equivalence (normalized therapy dose) is 80-90Gy, depending on tumor size at the time of brachytherapy. Dose limits for normal tissues are discussed. CONCLUSION These guidelines update those of 2000 and provide a comprehensive description of HDR cervical cancer brachytherapy in 2011.

Gene Expression Profiles of Multiple Breast Cancer Phenotypes and Response to Neoadjuvant Chemotherapy

Purpose: Breast cancer is a heterogeneous disease, and markers for disease subtypes and therapy response remain poorly defined. For that reason, we employed a prospective neoadjuvant study in locally advanced breast cancer to identify molecular signatures of gene expression correlating with known prognostic clinical phenotypes, such as inflammatory breast cancer or the presence of hypoxia. In addition, we defined molecular signatures that correlate with response to neoadjuvant chemotherapy. Experimental Design: Tissue was collected under ultrasound guidance from patients with stage IIB/III breast cancer before four cycles of neoadjuvant liposomal doxorubicin paclitaxel chemotherapy combined with local whole breast hyperthermia. Gene expression analysis was done using Affymetrix U133 Plus 2.0 GeneChip arrays. Results: Gene expression patterns were identified that defined the phenotypes of inflammatory breast cancer as well as tumor hypoxia. In addition, molecular signatures were identified that predicted the persistence of malignancy in the axillary lymph nodes after neoadjuvant chemotherapy. This persistent lymph node signature significantly correlated with disease-free survival in two separate large populations of breast cancer patients. Conclusions: Gene expression signatures have the capacity to identify clinically significant features of breast cancer and can predict which individual patients are likely to be resistant to neoadjuvant therapy, thus providing the opportunity to guide treatment decisions.

The role of PET scanning in the detection of recurrent cervical cancer

OBJECTIVES [(18)F] Fluoro-2-deoxyglucose positron emission tomography (FDG PET) has recently been established as a sensitive and specific method of detecting lymph node metastases in newly diagnosed cervical cancer. Little is known about the efficacy of PET for detecting recurrent disease. We evaluated the potential role of FDG PET in the context of suspected recurrent cervical cancer. METHODS The records of patients undergoing PET scan to evaluate for cervical cancer recurrence between July 1998 and February 2002 were reviewed. Radiographic findings were classified as negative, suspicious, or equivocal. PET scan findings were compared to available clinical data to classify each PET result as a true positive, true negative, false positive, or false negative. Clinical proof of recurrence consisted of a tissue biopsy revealing recurrent cancer within 3 months of the PET scan. Clinical proof of no evidence of disease consisted of a negative tissue biopsy within 3 months or no clinical evidence of recurrence within 6 months after the PET scan. RESULTS Twenty-eight patients underwent 37 PET scans. Twenty-nine cases among 22 patients were clinically evaluable for recurrence status. Median age was 42, and stage distribution was IB 1 (n = 3), IB2 (n = 4), IIA (n = 1), IIB (n = 10), IIIB (n = 9), IVB (n = 1). Histologic types included squamous (n = 23) adenocarcinoma (n = 4) and unknown (n = 1). There were 12 true positive PET scans, 13 true negatives, 2 false positives, and 2 false negatives. The sensitivity and specificity of FDG PET for detecting recurrent cervical cancer were 85.7 and 86.7%, respectively. The positive and negative predictive values were 85.7 and 86.7%, respectively. CONCLUSIONS Whole-body FDG PET is a sensitive and specific tool for the detection of recurrent cervical cancer in patients who have clinical findings suspicious for recurrence. A larger prospective trial will determine whether this modality should be used routinely in conjunction with, or in lieu of, other imaging studies to detect recurrent disease in a broader population of cervical cancer patients.

American Brachytherapy Society consensus guidelines for adjuvant vaginal cuff brachytherapy after hysterectomy

PURPOSE To develop recommendations for the use of adjuvant vaginal cuff brachytherapy after hysterectomy and update previous American Brachytherapy Society (ABS) guidelines. METHODS AND MATERIALS A panel of members of the ABS performed a literature review, supplemented their clinical experience, and formulated recommendations for adjuvant vaginal cuff brachytherapy. RESULTS The ABS endorses the National Comprehensive Cancer Network guidelines for indications for radiation therapy for patients with endometrial cancer and cervical cancer and the guidelines on quality assurance of the American Association on Physicists in Medicine. The ABS made specific recommendations for applicator selection, insertion techniques, target volume definition, dose fractionation, and specifications for postoperative adjuvant vaginal cuff therapy. The ABS recommends that applicator selection should be based on patient anatomy, target volume geometry, and physician judgment. The dose prescription point should be clearly specified. Suggested doses were tabulated for treatment with brachytherapy alone, and in combination with external beam radiation therapy, when applicable. A properly fitted brachytherapy applicator should be selected that conforms to the vaginal apex and achieves mucosal contact with optimal tumor and normal tissue dosimetry. Dose prescription points may be individually selected but doses should be reported at the vaginal surface and at 0.5-cm depth. CONCLUSIONS Recommendations are made for adjuvant vaginal cuff brachytherapy. Practitioners and cooperative groups are encouraged to use these recommendations to formulate their treatment and dose reporting policies. These recommendations will permit meaningful comparisons of reports from different institutions and lead to better and more appropriate use of vaginal brachytherapy.

Thermochemoradiotherapy Improves Oxygenation in Locally Advanced Breast Cancer

Purpose: The purpose of this research was to evaluate toxicity, response, and changes in oxygenation (pO2) in patients with locally advanced breast cancer (LABC) treated with concurrent taxol, hyperthermia (HT), and radiation therapy (RT) followed by mastectomy. Experimental Design: Eighteen patients with LABC were enrolled from October 1995 through February 1999. Treatment consisted of taxol (175 mg/m2) given every 3 weeks for three cycles. Radiation therapy included the breast and regional nodes with a dose of 50 Gy, followed by a boost to 60–65 Gy for those not undergoing surgery. Mastectomy was performed for patients deemed resectable after this neoadjuvant program. HT was administered twice per week. Oxygenation was measured before the first HT treatment and 24 h after the first HT treatment. Results: Fifteen of 18 patients responded, 6 with a clinical complete response, 9 with a partial clinical response, and 3 nonresponders. Thirteen underwent mastectomy with 3 pathological complete responses. Tumor hypoxia was present in 8 of 13 patients (pO2 = 4.7 ± 1.2 mmHg). Five patients had well-oxygenated tumors (pO2 = 27.6 ± 7.8 mmHg). Patients with well-oxygenated tumors before treatment as well as those with significant reoxygenation had a favorable clinical response. Tumor reoxygenation appeared to be temperature dependent and associated with the lower thermal doses. Conclusions: This novel therapeutic program resulted in a high response rate in patients with LABC. Hyperthermia may offer a strategy for improving tumor reoxygenation with consequent treatment response. However, the effect of hyperthermia on tumor reoxygenation appears to depend on thermal dose and requires additional investigation.

American Brachytherapy Society consensus guidelines for interstitial brachytherapy for vaginal cancer

PURPOSE To present recommendations for the use of interstitial brachytherapy in patients with vaginal cancer or recurrent endometrial cancer in the vagina. METHODS A panel of members of the American Brachytherapy Society reviewed the literature, supplemented that with their clinical experience, and formulated recommendations for interstitial brachytherapy for primary or recurrent cancers in the vagina. RESULTS Patients with bulky disease (approximately >0.5cm thick) should be considered for treatment with interstitial brachytherapy. The American Brachytherapy Society reports specific recommendations for techniques, target volume definition, and dose-fractionation schemes. Three-dimensional treatment planning is recommended with CT scan and/or MRI. The treatment plan should be optimized to conform to the clinical target volume and should reduce the dose to critical organs, including the rectum, bladder, urethra, and sigmoid colon. Suggested doses in combination with external beam radiation therapy and summated equivalent doses in 2Gy fractions are tabulated. CONCLUSION Recommendations are made for interstitial brachytherapy for vaginal cancer and recurrent disease in the vagina. Practitioners and cooperative groups are encouraged to use these recommendations to formulate treatment and dose-reporting policies. Such a process will result in meaningful outcome comparisons, promote technical advances, and lead to appropriate utilization of these techniques.

The treatment of high-grade soft tissue sarcomas with preoperative thermoradiotherapy.

PURPOSE To explore the use of a novel program of preoperative radiation and hyperthermia in the management of high-grade soft tissue sarcomas (STS). METHODS AND MATERIALS Eligible patients were adults over 18 with Grade 2 or 3 STS, surgically resectable without a local excision prior to referral to Duke University Medical Center and without distant metastases. Patients were staged generally with CT and/or MR imaging. The diagnosis was established with fine needle aspiration or incisional biopsy. Patients were then treated with 5000 to 5040 cGy, 180-200 cGy per fraction. Chemotherapy was usually not employed. Generally two hyperthermia treatments per week were given with a planned thermal dose of 10-100 CEM 43 degrees T90. Invasive thermometry and thermal mapping were done in all patients. Surgical resection was planned 4-6 weeks after the completion of radiation and hyperthermia. RESULTS Ninety-seven patients were treated on study between 1984 and 1996. Follow-up ranged from 12 to 155 months (median 32). All tumors were high-grade in nature, 44 greater than 10 cm in size (maximum tumor diameter), 43 5-10 cm in size, 10 less than 5 cm. Seventy-eight of the 97 tumors were located in an extremity. Of the 97 patients, 48 remain alive and continually free of disease following initial therapy. Of the remaining 49 patients, 44 have relapsed (34 dead, 10 living with disease), 3 have died secondary to complications of therapy, and 2 have died of unrelated causes. Ten-year actuarial overall survival, cause-specific survival, and relapse-free survival are 50, 47, and 47% respectively. The predominant pattern of failure has been distant metastases with only 2 patients developing local failure alone. Ten-year actuarial local control for extremity tumors is 94%, 63% for the 19 patients with tumors at sites other than the extremity. Of the 78 patients with extremity lesions, 63 have had limb preservation and remain locally controlled. Overall 38 patients experienced 57 major complications. There were 3 deaths, one due to adriamycin cardiomyopathy and two secondary to wound infections. Four patients required amputation secondary to postoperative wound healing problems. Complications directly attributable to hyperthermia occurred in 15 patients with 11 instances of second- or third-degree burns and two instances of subcutaneous fat necrosis. The hyperthermia complications were generally not severe and either healed readily or were excised at the time of surgical resection of the primary tumor. CONCLUSIONS For these aggressive high-grade soft tissue sarcomas, this treatment program of preoperative thermoradiotherapy provided excellent local regional control for extremity lesions (95%) and satisfactory local regional control (63%) of nonextremity sarcomas, but did not appear to influence the rate of distant metastases or survival. Complications were frequent but apart from the direct thermal burns, not too different from those reported for preoperative radiotherapy alone. More effective adjuvant systemic therapy is necessary to impact favorably on survival.

Hyperthermia combined with radiation therapy for superficial breast cancer and chest wall recurrence: A review of the randomised data

Hyperthermia has long been used in combination with radiation for the treatment of superficial malignancies, in part due to its radiosensitising capabilities. Patients who suffer superficial recurrences of breast cancer, be it in their chest wall following mastectomy, or in their breast after breast conservation, typically have poor clinical outcomes. They often develop distant metastatic disease, but one must not overlook the problems associated with an uncontrolled local failure. Morbidity is enormous, and can significantly impair quality of life. There is no accepted standard of care in treating superficial recurrences of breast cancer, particularly in patients that have previously been irradiated. There is a substantial literature regarding the combined use of hyperthermia and radiotherapy for these superficial recurrences. Most of it is retrospective in nature, but there are several larger phase III randomised trials that show an improved rate of clinical complete response in patients treated with both modalities. In this review article, we will highlight the important prospective data that has been published regarding the combined use of hyperthermia and radiation.