A phase II trial testing the thermal dose parameter CEM43 degrees T90 as a predictor of response in soft tissue sarcomas treated with pre-operative thermoradiotherapy.

We prospectively evaluated whether delivering a thermal dose of > 10 cumulative equivalent minutes at 43 degrees C to >90% of the tumour sites monitored (CEM43 degrees T90) would produce a pathologic complete response (pCR) in > 75% of high-grade soft tissue sarcomas treated pre-operatively with thermoradiotherapy. The impact of thermal dose on local failure (LF), distant metastasis (DM), and toxicity was also assessed. Thirty-five patients > or = 18 years old with grade 2 or 3 soft tissue sarcomas accessible for invasive thermometry were enrolled on the protocol. All patients received megavoltage external beam radiotherapy (RT) in daily fractions of 1.8-2.0 Gy, five times a week, to a median total dose of 50 Gy and an initial hyperthermia treatment (HT) of I h duration utilizing the BSD 2000 with Sigma 60 or MAPA applicators at frequencies of 60-140 MHz. Further HT was given for patients with CEM43 degrees T90 > 0.5 after initial HT ('heatable' patients), twice a week to a maximum of 10 HT or CEM43 degrees T90 > 100. Of the 35 patients entered, 30 had heatable tumours, one of which was inevaluable for pCR or LF as the patient died of DM prior to surgery, leaving 29 evaluable patients. Of these 29 patients, 15 (52%) had a pCR (95% CI: 37-73%), significantly less than the projected rate of > or = 75% (p = 0.02). Of the 25 heatable tumours that achieved CEM43 degrees T90 > or = 10, 14 (56%) had a pCR (95% CI: 39-78%) significantly less than the projected rate (p = 0.06). Three of the 29 patients (10%) with heatable tumours had a LF, versus 1/5 unheatable tumours (p = 0.48). Fourteen of the 30 patients (47%) with heatable tumours developed DM, versus 2/5 unheatable tumours (p = 1.00). Ten of the 30 patients (33%) with heatable tumours developed treatment-induced toxicity. Thus, no correlation of thermal dose with histologic response was observed. Prospective control of CEM43 degrees T90 failed to achieve the projected pCR rate following pre-operative thermoradiotherapy for high-grade soft tissue sarcomas, despite excellent local control. Possible explanations for this outcome are discussed.

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.

Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas.

The adverse prognostic impact of tumor hypoxia has been demonstrated in human malignancy. We report the effects of radiotherapy and hyperthermia (HT) on soft tissue sarcoma oxygenation and the relationship between treatment-induced changes in oxygenation and clinical treatment outcome. Patients receiving preoperative radiotherapy and HT underwent tumor oxygenation measurement pretreatment after the start of radiation/pre-HT and one day after the first HT treatment. The magnitude of improvement in tumor oxygenation after the first HT fraction relative to pretreatment baseline was positively correlated with the amount of necrosis seen in the resection specimen. Patients with <90% resection specimen necrosis experienced longer disease-free survival than those with > or = 90% necrosis. Increasing levels of tumor hypoxia were also correlated with diminished metabolic status as measured by P-31 magnetic resonance spectroscopy.

Monitoring of neoadjuvant therapy response of soft-tissue and musculoskeletal sarcoma using fluorine-18-FDG PET.

UNLABELLED: The purpose of this study was to investigate the potential role of FDG-PET in the monitoring of neoadjuvant therapy of soft-tissue and musculoskeletal sarcomas. METHODS: Nine patients were studied. Neoadjuvant therapy consisted of either chemotherapy or combined radiotherapy and hyperthermia. The FDG-PET studies were obtained, when possible, prior to therapy, 1-3 wk after commencement of therapy, and prior to surgery after completion of neoadjuvant therapy. In two patients, all three studies were completed. The remainder of patients underwent one or two studies at varying timepoints. RESULTS: In tumors treated with combined radiotherapy and hyperthermia, well-defined regions of absent uptake developed within responsive tumors, correlating pathologically with necrosis. Following treatment, a peripheral rim of FDG accumulation was found to correlate pathologically with the formation of a fibrous pseudocapsule. In tumors treated with chemotherapy, FDG accumulation decreased more homogeneously throughout the tumor, in responsive cases. Despite 100% tumor cell kill in some patients, persistent tumor FDG uptake was observed which correlated pathologically with uptake within benign therapy-related fibrous tissue. Significant FDG accumulation was also observed at the site of an uncontaminated incisional biopsy. CONCLUSION: These initial results demonstrate changes in tumor accumulation of FDG during and after neoadjuvant therapy; these changes are dependent on the type of neoadjuvant therapy administered. Prominent FDG accumulation was observed in benign tissues both within and adjacent to the treated tumor.

Clinical outcome after neoadjuvant thermoradiotherapy in high grade soft tissue sarcomas.

In the treatment of soft tissue sarcomas, hyperthermia has been demonstrated to enhance tumor necrosis from radiation therapy. The current study reports the clinical course of patients treated with this neoadjuvant therapy regimen. Forty-four patients with deep, undisturbed, nonmetastatic, high grade soft tissue sarcomas completed a neoadjuvant treatment protocol with combined hyperthermia and radiation therapy followed by wide surgical resection. Negative surgical margins were obtained in 40 patients. There was one local recurrence, thus yielding a local control rate of 97.5%. All other failures were either through regional lymphatic spread or pulmonary metastasis. As a group, the patients at 36 months had a 72% overall and a 58% disease-free survival. The most common pathologic diagnosis was malignant fibrous histiocytoma (MFH), which demonstrated a 36-month survival of 52% vs. 82% for others (P = 0.02). Tumor size was not prognostically significant for disease free or overall survival (P = 0.13). Those patients with surgical margins < 1 cm had a significantly lower disease-free survival and overall survival in a multivariate analysis (P = 0.02 and P = 0.006, respectively). Overall survival did not correlate with either the number of hyperthermia treatments received or the amount of tumor necrosis. Although this neoadjuvant protocol results in excellent local control rates, overall survival rates are comparable to adjuvant therapy employing radiation alone.

Therapy monitoring in human and canine soft tissue sarcomas using magnetic resonance imaging and spectroscopy.

PURPOSE: The goals of this study were to determine whether magnetic resonance parameters (a) can identify early during therapy those patients most likely to respond to hyperthermia and radiotherapy, (b) can provide prior to or early during therapy information about the temperature distributions which can be obtained in patients receiving hyperthermia, and (c) can provide an understanding of the effects of hyperthermia on tumor metabolic status. METHODS AND MATERIALS: Twenty-one human patients and 10 canine patients with soft tissue sarcomas treated with preoperative hyperthermia and radiation had a series of magnetic resonance imaging and phosphorous spectroscopy studies done. To address the goals for both the human and canine populations, changes in mean T2 relaxation times, pH, and various phosphometabolite ratios from the pretreatment (Study 1) to the post first hyperthermia study (Study 2) were correlated with treatment outcome; pretreatment magnetic resonance parameters and changes in magnetic resonance parameters (Study 2-Study 1) were compared with various cumulative thermal descriptors; and thermal descriptors of the first hyperthermia were compared with changes in magnetic resonance phosphometabolite ratios. RESULTS: A decrease in adenosine triphosphate/phosphomonoester from study 1 to study 2 is associated with a greater chance of > or = 95% necrosis in surgical resected tumors from human patients, but no significant relationships were observed between changes in tumor pH or phosphometabolite ratios and time to local failure in dogs. Pretreatment magnetic resonance parameters correlated with various thermal dose descriptors in canines but not in humans. Change in adenosine triphosphate/inorganic phosphate and phosphomonoester signal to noise ratio correlated with cumulative thermal descriptors in dogs and humans, respectively. In dogs only, increases in thermal dose resulted in decreases in high energy phosphometabolites. CONCLUSION: Changes in magnetic resonance parameters early during therapy may be predictive of treatment outcome. Pretreatment and changes in magnetic resonance parameters appear to predict how well a tumor will be heated during hyperthermia. Magnetic resonance spectroscopy also appears to be a useful tool to study the effects of various thermal doses on tumor metabolic status.

Vascularized tissue transfer for closure of irradiated wounds after soft tissue sarcoma resection.

During the years 1985 to 1989, 82 patients were included in the soft tissue sarcoma protocol. Preoperative irradiation (50-54 Gy) was performed in all patients before tumor extirpation. Microwave hyperthermia was performed in conjunction with radiation in patients who had gross tumor remaining after initial biopsy. Primary closure with vascularized tissue (flaps) in lieu of conventional wound closure by skin approximation led to less complications (19% versus 51%), fewer secondary procedures for wound closure (10% versus 35%), shorter average hospitalization (15 versus 48 days) and greater limb salvage rate (97% versus 91%). The authors conclude that vascularized tissue (flaps) for primary wound closure in irradiated tissue leads to improved wound healing, and should be considered the procedure of choice for heavily irradiated soft tissue sarcoma defects.

Relationships among tumor temperature, treatment time, and histopathological outcome using preoperative hyperthermia with radiation in soft tissue sarcomas.

The lack of an unambiguous thermal dosimetry continues to impede progress in clinical hyperthermia. In an attempt to define better this dosimetry, a model based on the cumulative minutes during which arbitrary percentages of measured tumor temperature points exceeded an index temperature was tested in patients with soft tissue sarcomas treated with preoperative hyperthermia and conventional radiation therapy. Patients received 5000-5040 cGy at 180-200 cGy per fraction. Hyperthermia was delivered 30-60 minutes after radiation therapy and given for 60 minutes. Patients were randomized between one and two hyperthermia treatments per week for a total of five or 10 treatments, respectively. Lesions were excised 4-6 weeks after completion of hyperthermia/radiation therapy. Successful treatment outcome was considered to be the finding of greater than 80% necrosis of the sarcoma upon histopathologic examination of the resected specimen. Forty-five patients were eligible with thermometry data available in 44 patients. An average of 19 interstitial sites were monitored each treatment per tumor. Sixty percent of tumors had a successful histopathologic outcome. Univariate analysis demonstrated that several descriptors of the temperature distribution were strongly related to treatment outcome; more strongly than nonthermometric factors, such as the number of treatments per week, tumor volume and patient age and more strongly than the commonly used temperature descriptors Tmin and Tmax. Descriptors that incorporated both temperature and time were also superior to the more commonly used descriptors Tmin and Tmax. Multivariate stepwise logistic regression analysis revealed that a descriptor of both the hyperthermia treatment time and the frequency distribution of intratumoral temperatures was the strongest predictor of histopathologic outcome and that the best predictive model combined this time/temperature descriptor and one versus two treatment per week grouping. The more conventional temperature descriptor, minimum measured tumor temperature, did not significantly enhance the predictive power of treatment group. Based on these results, we recommend that descriptors based on both the frequency distribution of intratumoral temperatures and hyperthermia treatment time be tested for relationships with treatment outcome in other clinical data bases. Furthermore, we recommend that temperature descriptors that are less sensitive to catheter placement and tumor boundary identification than Tmin and Tmax (such as T90, T50, and T10) be tested prospectively along with other important thermal variables in Phase II trials in further efforts to define a thermal dosimetry for spatially nonuniform temperature distributions.

Soft-tissue sarcomas: MR imaging and MR spectroscopy for prognosis and therapy monitoring. Work in progress.

The authors studied the usefulness of hydrogen-1 T2 measurements and phosphorus-31 magnetic resonance (MR) spectroscopy as indicators of prognosis and monitors of response to therapy in a group of patients with soft-tissue sarcomas. All eight patients were treated with combined local hyperthermia and fractionated radiation therapy, followed by surgical resection of the tumor. Each patient underwent T2 measurements and five patients underwent MR spectroscopy (phase encoded in one dimension) before treatment, after the first hyperthermia treatment, at the end of the therapy course, and just before surgery. Catheter thermometry was performed at each hyperthermia treatment. The T2 and MR spectroscopic variables were compared with thermometric data and the histologic findings from the complete surgical specimen. Changes in T2 correlated with histologic grade of tumor and thermometric data. The pretherapy tumor pH correlated positively, and changes during therapy in pH, ratio of phosphocreatine to inorganic phosphate (Pi), ratio of nucleoside triphosphate to Pi, and the phosphomonoester signal-to-noise ratio correlated negatively, with the percentage of tumor necrosis on the surgical specimen. These preliminary data suggest MR imaging and MR spectroscopy may be useful in the evaluation of such patients before and during therapy.

Tumor temperature distributions predict hyperthermia effect.

Review of clinical hyperthermia (HT) trial results shows that there previously has not been a robust model relating efficacy of HT treatments to characteristics of the temperature distribution. Lack of a model has been an impediment in Phase II trials; these trials must include defining the prescription for HT treatment, optimizing the schedule of HT treatments, and defining quality assurance procedures. We propose a model that is based upon noting that the majority of a tumor volume is contained in the outermost "shell" of a solid tumor, across which shell the radial temperature distribution is assumed to be linear. Any linear distribution can be defined by coordinates of a point and a slope, and we choose the temperature at the radiographically defined edge of a tumor and the slope (dT/dr) across the outer shell as these determinants of the linear radial temperature distribution. A discriminant analysis of success or failure of treatment can then be based upon these two descriptors (Tedge, dT/dr). We have tested this model using data from patients with soft tissue sarcoma (Stage IIB or greater) that have entered an ongoing prospective trial of conventional preoperative radiotherapy (5000 cGy/25 Fx/5 wk) together with HT, the latter randomized to be given once or twice weekly during the 5 week course. Wide local excision of the primary tumor is done 1 month after completion of radiotherapy, and the extent of histologic change in the resected specimen is scored. Our model has an 86% predictive value for lack of complete or nearly complete necrosis in the resected specimen according to whether the time-averaged Tedge and slope during each HT treatment satisfy the equation Tedge + 1.2 (slope in degree C/cm) less than or equal to 40.6 degrees C in all but one treatment at most. Conversely, in 85% of cases with complete or nearly complete tumor necrosis, temperature distributions satisfied Tedge + 1.2 (slope in degree C/cm) greater than 40.6 degrees C during at least one HT treatment. Requiring greater than or equal to one third of treatments of a patient to satisfy the preceeding discriminant equation resulted in 80% of patients being correctly classified as a responder or nonresponder, with only one false positive prediction (patient incorrectly classified as a responder). The model can reveal systematic changes in the edge temperature distribution during the treatment course that are consistent with tumor perfusion changes inferred and measured by independent means.(ABSTRACT TRUNCATED AT 400 WORDS)

Evaluation in cats of a new material for cranioplasty: a composite of plaster of Paris and hydroxylapatite.

The materials ordinarily used to reconstruct bone defects in the calvaria and facial bones either are difficult to shape, are partially resorbed by the body, or are likely to become infected if used near a contaminated area such as the frontal sinus. Calcium sulfate hemihydrate (plaster of Paris) has been known for years to have excellent reparative qualities in bone defects, but ordinarily it is quickly resorbed. Consequently, a new material, a composite of a dense form of plaster of Paris and hydroxylapatite, was devised to provide nonabsorbable hydroxylapatite particles for bone to form around and within during the phase of plaster absorption. Two types of this material were evaluated in cranial defects in cats. Each of the plaster of Paris/hydroxylapatite mixtures was placed into a surgically unroofed frontal sinus and into a contralateral parietal trephine hole in a group of 32 cats. Two cats in each group succumbed to anesthesia, leaving two sets of 30 cats. During the entire follow-up period there was only one other death, with no evidence of wound infection, wound dehiscence, implant rejection, or cerebral dysfunction among the survivors. The cats in each group were sacrificed at 1, 2, 3, 5, 7, 8, 9, 10, or 12 months after operation. Following sacrifice, both the frontal and parietal defects were exposed and examined visually, histologically, and with histomorphometric analysis for new bone formation. New bone formation was present as early as 1 month after operation and continued to increase during the 12 months of the study. Based upon these osteogenic qualities, the ease of shaping the composite, and the lack of infection in the frontal sinus region, it is concluded that this substance could be a valuable new material for human cranioplasty.

Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol.

Although conventional therapy (pharmacologic doses of vitamin D and phosphorus supplementation) is usually successful in healing the rachitic bone lesion in patients with X-linked hypophosphatemic rickets, it does not heal the coexistent osteomalacia. Because serum 1,25-dihydroxyvitamin D levels are inappropriately low in these patients and high calcitriol concentrations may be required to heal the osteomalacia, we chose to treat five affected subjects with high doses of calcitriol (68.2 +/- 10.0 ng/kg total body weight/d) and supplemental phosphorus (1-2 g/d) performing metabolic studies and bone biopsies before and after 5-8 mo of this therapy in each individual. Of these five patients, three (aged 13, 13, and 19 yr) were receiving conventional treatment at the inception of the study and therefore showed base-line serum phosphorus concentrations within the normal range. The remaining two untreated patients (aged 2 and 37 yr) displayed characteristic hypophosphatemia before calcitriol therapy. All five patients demonstrated serum calcitriol levels in the low normal range (22.5 +/- 3.2 pg/ml), impaired renal phosphorus conservation (tubular maximum for the reabsorption of phosphate per deciliter of glomerular filtrate, 2.13 +/- 0.20 mg/dl), and osteomalacia on bone biopsy (relative osteoid volume, 14.4 +/- 1.7%; mean osteoid seam width, 27.7 +/- 3.7 micron; mineral apposition rate, 0.46 +/- 0.12 micron/d). On high doses of calcitriol, serum 1,25-dihydroxyvitamin D levels rose into the supraphysiologic range (74.1 +/- 3.8 pg/ml) with an associated increment in the serum phosphorus concentration (2.82 +/- 0.19 to 3.78 +/- 0.32 mg/dl) and improvement of the renal tubular maximum for phosphate reabsorption (3.17 +/- 0.22 mg/dl). The serum calcium rose in each patient while the immunoactive parathyroid hormone concentration measured by three different assays remained within the normal range. Most importantly, repeat bone biopsies showed that high doses of calcitriol and phosphorus supplements had reversed the mineralization defect in all patients (mineral apposition rate, 0.88 +/- 0.04 micron/d) and consequently reduced parameters of bone osteoid content to normal (relative osteoid volume, 4.1 +/- 0.7%; mean osteoid seam width, 11.0 +/- 1.0 micron). Complications (hypercalcemia and hypercalciuria) ensued in four of these five patients within 1-17 mo of documented bone healing, necessitating reduction of calcitriol doses to a mean of 1.6 +/- 0.2 micrograms/d (28 +/- 4 ng/kg ideal body weight per day). At follow-up bone biopsy, these four subjects continued to manifest normal bone mineralization dynamics (mineral apposition rate, 0.88 +/-0.10 micrometer/d) on reduced doses of 1.25-dihydroxyvitamin D with phosphorus supplements (2 g/d) for a mean of 21.3 +/- 1.3 mo after bone healing was first documented. Static histomorphometric parameters also remained normal (relative osteoid volume, 1.5 +/- 0.4%; mean osteoid seam width, 13.5 +/- 0.8 micrometer). These data indicate that administration of supraphysiologic amounts of calcitriol, in conjunction with oral phosphorus, results in complete healing of vitamin D resistant osteomalacia in patients with X-linked hypophosphatemic rickets. Although complications predictably require calcitriol dose reductions once healing is achieved, continued bone healing can be maintained for up to 1 yr with lower doses of 1,25-dihydroxyvitamin D and continued phosphorus supplementation.

Postparathyroidectomy hypocalcemia as an accurate indicator of preparathyroidectomy bone histology in the uremic patient.

19 chronic renal failure patients underwent iliac crest bone biopsy prior to total parathyroidectomy with autotransplantation. The preoperative serum calcium concentration did not correlate with the number of osteoclasts/mm2 present on the preparathyroidectomy iliac biopsy. However, the postparathyroidectomy decrement in serum calcium (mg/dl and percent change) and the osteoclasts/mm2 were strongly correlated (p less than 0.001). In addition, the postoperative fall in serum calcium also correlated with the postoperative change in serum alkaline phosphatase (p less than 0.001). The nadir in postparathyroidectomy serum calcium was attained in a mean of 4.4 +/- 2.7 days. Our results indicate that the preoperative serum calcium concentration does not necessarily reflect active bone resorption, but the postoperative decrement in serum calcium provides an accurate index of preoperative histologic activity. The available data do not provide information with respect to the mechanism of postparathyroidectomy hypocalcemia since either the cessation of bone resorption, continued bone deposition, or a combination of both may be operative.

Newer knowledge of vitamin D and its metabolites in health and disease.

Renewed interest in vitamin D, over the past several years, has resulted in increased knowledge of (1) the metabolic pathways which result in production of an active metabolite, (2) the role of its various metabolities at target tissues, and (3) its interaction with other control systems in the maintenance of calcium/phosphorus homeostasis. Presently, a role for 1, 25-(OH)2 D3 can be identified in the regulation of (1) calcium and phosphorus absorption from the intestine, (2) PTH production, and (3) calcium mobilization from bone (in conjunction with PTH). Several other actions at the kidney, muscle and other organs have been suggested but not proven. In contrast, the actual process of bone mineralization may be dependent, in part, on 25-(OH) D3. Despite these major advances in our knowledge, many gaps remain and controversial data continues unresolved. However, application of this new information to analysis of a wide variety of disease states has resulted in remarkable progress in appreciation of the pathogenesis and appropriate treatment for these diseases. Nonetheless, continued research promises further advances and more precise definition of disease states as well as delineation of the therapeutic role of Vitamin D metabolites in their treatment.