Autophagy is an ancient cell survival pathway that is induced by metabolic stress and that helps prevent bioenergetic failure. This pathway has emerged as a promising new target in cancer treatment, ...where agents that inhibit autophagic degradation have efficacy in preventing cancer and in treating resistant disease when combined with conventional chemotherapeutics, which generally activate the pathway. However, agents that specifically target the autophagy pathway are currently lacking, and monitoring the effects of therapeutics on the autophagy pathway raises several challenges. Here we review the potential roles of the autophagy pathway in tumor progression and in maintenance of the malignant state, and introduce novel methods that we have developed that allow one to monitor autophagic activity ex vivo and in vivo.
Patients with brain metastases in disseminated non-seminomatous germ cell cancer of the testis are treated by combined modality, e.g., cisplatin-containing chemotherapy, whole brain irradiation ...and/or surgical excision. However, cure rates of patients refractory to that standard treatment are low (5-year survival rate <30%). Preclinical data on the use of hyperthermia combined with selected cytotoxic drugs clearly show increased tumor cell killing compared to chemotherapy alone with no increase in toxicity to normal tissue. These results are consistent with the concept that whole body hyperthermia (WBH) at 41.8 degrees C is non-myelosuppressive and can potentiate the tumoricidal effects of specific chemotherapeutic agents, thus improving the therapeutic index. We report on a patient with embryonal testicular cancer presenting with lung, liver and brain metastases who initially underwent orchiectomy, whole brain irradiation and cisplatin-containing chemotherapy. Restaging revealed minor regression of brain and lung metastases and no change of liver metastases. However, beta-HCG values dropped from initial 400000 mIU/ml to 12 mIU/ml with a normal alpha-fetoprotein all the time. Then, two cycles of whole body hyperthermia (WBH) plus chemotherapy were performed, followed by one cycle of chemotherapy without WBH. Radiotherapy, WBH and chemotherapy were well tolerated, especially no neurologic sequelae occurred. After more than 5 years of follow-up, the patient is still alive and disease-free. WBH plus chemotherapy seems to be feasible and may contribute to long-term survival in patients with advanced stages of non-seminomatous germ cell cancer refractory to standard treatment.
Tumor size is a significant prognostic variable for attaining complete regression (CR) with local hyperthermia (HT) and radiation therapy (RT). The addition of weekly chemotherapy was evaluated to ...improve the efficacy of thermoradiotherapy in poor-prognosis lesions (i.e. > or = 7 cm2 or > or = 14 cm3) which have an expected CR rate of approximately 30 +/- 8%. Patients were entered into a two-arm phase-II study: arm 1 = breast cancer (10 patients), ifosfamide (1.5 g/m2) + epirubicin (20 mg/m2) + HT + RT; arm 2 = sarcoma (7 patients) and head and neck cancer (9 patients), cisplatin (40 mg/m2) + HT + RT. Therapy encompassing 106 triple-modality sessions was generally well tolerated for both arms; 2 instances of grade-3 and 1 of grade-4 (arm 2) local toxicity (WHO criteria) were observed. There were 4 instances of grade-3 myelosuppression (arm 1). The CR rates for arms 1 and 2 were 70 and 19%, respectively, suggesting that the combination of ifosfamide/epirubicin/HT/RT deserves further investigation in the context of localized breast cancer.
The University of Arizona, University of California at San Francisco, City of Hope Medical Center, and University of Wisconsin participated in a Phase I/II protocol to assess the heating ability and ...the toxicity of interstitial thermoradiotherapy using ferromagnetic implantation.
Forty-four patients with advanced primary or recurrent extra-cranial solid malignancies were enrolled in this study. Fourteen gauge catheters were implanted into tumors and, once in the department of Radiation Oncology, loaded with ferromagnetic seeds to deliver a 60 min hyperthermia treatment. Multi-point thermometry was continuously used throughout the heating sessions for all patients, sampling the periphery as well as the core of the tumor. After 192Iridium brachytherapy, 18 patients then had an additional treatment. The mean radiation dose while on protocol was 50.0 Gy, with total doses (including prior radiotherapy) ranging from 20.3-151.8 Gy (median = 88.7 Gy). Response and toxicity were assessed by inspection, palpation, and/or radiologic studies. Forty-one patients were evaluable for response, and there were 55 analyzable hyperthermia treatment sessions.
The complete response rate was 61% (25/41). The partial response rate was 31.7% and only 7.3% failed to respond. Median duration of local control has not yet been reached. The mean maximum, minimum, and mean time-averaged temperatures for all in-tissue sensors were 43.7 degrees C, 38.7 degrees C, and 41.0 degrees C, respectively. Tumor size was the only factor significantly correlated with temperatures or with complete response rate; larger tumors attained higher temperatures but smaller tumors had a higher response probability. Nineteen patients (43%) experienced toxicities, however there was only a 7% (3/44) rate of serious complications (Grade 3 or 4). Prior treatment with hyperthermia was the only factor significantly correlated with serious toxicity.
These results, a 93% total response with only 7% serious toxicity, are encouraging especially in the context of the patient population treated. Phase II/III studies involving ferromagnetic implantation are warranted.
These Hyperthermia Quality Assurance guidelines are a result of a joint workshop of the Hyperthermia Committee of the American College of Radiology and the Hyperthermia Physics Center, which is the ...national quality assurance program under Contract No. N01-CM-37512 with the National Cancer Institute. Hyperthermia technology presently lacks the kind of standardization in equipment, treatment procedures, patient monitoring, and treatment documentation available in radiotherapy. Therefore, preventing unacceptable variability in treatment data demands a strong commitment to in-house quality control procedures and to centralized quality assurance reviews in cooperative multi-institutional trials. This paper presents a set of test procedures necessary to ensure proper operation of equipment, suggests a frequency for such tests, and also includes guidelines on quality control procedures to be used during treatment to improve the safety, effectiveness, and reproducibility of hyperthermia treatments. A set of forms are presented to indicate the minimum data, albeit incomplete, that must be collected for acceptable documentation of treatment. These guidelines should be valuable not only to the new entrants in the field but also to those participating in multi-institutional cooperative hyperthermia trials. They have been approved by the Hyperthermia Committees of American College of Radiology, American Society for Therapeutic Radiology and Oncology, Radiation Therapy Oncology Group and the American Association of Physicists in Medicine.
Disease‐free intervals of 2 to 3 years after treatment of histiocytic lymphoma are generally thought to represent cures; flat survival curves beyond 3 years in several studies support this notion. ...Four case reports of histiocytic lymphoma recurrences 25, 10, 9 and 6 years, respectively, after the initial diagnosis are presented. Histologic confirmation comparing primary and recurrent disease is presented. The potential biological significance of such patient reports is discussed.
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