B. Stea

Interstitial thermoradiotherapy with ferromagnetic implants for locally advanced and recurrent neoplasms

PURPOSE 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. METHODS AND MATERIALS 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. RESULTS 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. CONCLUSION 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.

TREATMENT PLANNING OF TEMPLATE-GUIDED STEREOTAXIC BRAIN IMPLANTS

We have initiated a Phase I clinical trial of interstitial hyperthermia induced with inductively heated ferromagnetic implants in combination with Ir-192 implants for glioblastomas and anaplastic astrocytomas of the brain. For speed and accuracy of the implant procedure, and to control the radiation and thermal dose, a stereotaxic frame is used to position a template. We have modified the Brown-Roberts-Wells frame to be used with a variety of templates which we designed. On the morning of the implant procedure, a CT scan is done, and a CT-based treatment plan is then completed before the patient goes to the operating room. We also describe the CT-based treatment planning system developed to accommodate the template-guided implant and illustrate its clinical use.

Possible relationship between chromosome alterations and in vitro cellular radiosensitivity of human malignant melanoma

In the present study, in vitro radiation survival analysis was performed on 8 human malignant melanoma cell lines with defined karyotypes. Exponentially growing cells were irradiated to doses of 0 to 8 Gy and examined for soft agar clonogenicity. Two groups emerged from this analysis: 4 cell lines with a small shoulder (extrapolation number, n less than 2) and 4 cell lines with a large shoulder (n greater than 2). Of possible significance, 4/4 cell lines with extrapolation numbers greater than 2 demonstrated clonal structural abnormalities of chromosome 7. In contrast, 3/4 cell lines with extrapolation numbers less than 2 had no structural abnormalities of chromosome 7. These very preliminary results suggest that structural alterations of chromosome 7 may be associated with melanoma tumors with high extrapolation numbers.

Efaproxiral red blood cell concentration predicts efficacy in patients with brain metastases

Efaproxiral (Efaproxyn™, RSR13), a synthetic allosteric modifier of haemoglobin (Hb), decreases Hb-oxygen (O2) binding affinity and enhances oxygenation of hypoxic tumours during radiation therapy. This analysis evaluated the Phase 3, Radiation Enhancing Allosteric Compound for Hypoxic Brain Metastases; RT-009 (REACH) study efficacy results in relation to efaproxiral exposure (efaproxiral red blood cell concentration (E-RBC) and number of doses). Recursive partitioning analysis Class I or II patients with brain metastases from solid tumours received standard whole-brain radiation therapy (3 Gy/fraction × 10 days), plus supplemental O2 (4 l/min), either with efaproxiral (75 or 100 mg/kg daily) or without (control). Efaproxiral red blood cell concentrations were linearly extrapolated to all efaproxiral doses received. Three patient populations were analysed: (1) all eligible, (2) non-small-cell lung cancer (NSCLC) as primary cancer, and (3) breast cancer primary. Efficacy endpoints were survival and response rate. Brain metastases patients achieving sufficient E-RBC (⩾483 μg/ml) and receiving at least seven of 10 efaproxiral doses were most likely to experience survival and response benefits. Patients with breast cancer primary tumours generally achieved the target efaproxiral exposure and therefore gained greater benefit from efaproxiral treatment than NSCLC patients. This analysis defined the efaproxiral concentration-dependence in survival and response rate improvement, and provided a clearer understanding of efaproxiral dosing requirements.

Interstitial Hyperthermia with Ferromagnetic Seed Implants: Preliminary Results of a Phase I Clinical Trial

Although the first use of hyperthermia in the treatment of cancer was reported in the 19th century, the use of hyperthermia as a treatment modality has been developing rapidly only over the last ten to fifteen years. Response rates have varied, depending on the size and location of the tumor, but hyperthermia combined with irradiation consistently appears to improve the complete response rate over that seen with irradiation alone by a factor of two, and to increase the response duration as well (Overgaard, 1987, 1989).

Clinical Experience of Interstitial Thermoradiotherapy Using Ferromagnetic Implant Techniques

Interstitial hyperthermia commands much current interest as a method for delivering localized heat treatment to deep-seated as well as superficial tumors. Several interstitial techniques have been developed and used clinically over the past two decades. Interstitial techniques are popular since they can circumvent some problems encountered with non-invasive hyperthermia techniques, such as limited penetration, inefficient and nonuniform power distribution, and excessive heating of adjacent normal tissues. On the other hand, interstitial hyperthermia is an invasive technique and it usually requires general anesthesia. Some patients with bleeding disorders may not be candidates for such an approach. Furthermore, due to the localized nature of the treatment, the resulting temperature distribution may be highly dependent on the blood flow and geometry of the implant. Three major classes of interstitial hyperthermic techniques have been described and developed: interstitial radiofre quency electrodes (IRF), interstitial microwave antennas (IMW), and hot source techniques.