Guidelines for time-to-event end point definitions in sarcomas and gastrointestinal stromal tumors (GIST) trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials)†.

BACKGROUND: The use of potential surrogate end points for overall survival, such as disease-free survival (DFS) or time-to-treatment failure (TTF) is increasingly common in randomized controlled trials (RCTs) in cancer. However, the definition of time-to-event (TTE) end points is rarely precise and lacks uniformity across trials. End point definition can impact trial results by affecting estimation of treatment effect and statistical power. The DATECAN initiative (Definition for the Assessment of Time-to-event End points in CANcer trials) aims to provide recommendations for definitions of TTE end points. We report guidelines for RCT in sarcomas and gastrointestinal stromal tumors (GIST). METHODS: We first carried out a literature review to identify TTE end points (primary or secondary) reported in publications of RCT. An international multidisciplinary panel of experts proposed recommendations for the definitions of these end points. Recommendations were developed through a validated consensus method formalizing the degree of agreement among experts. RESULTS: Recommended guidelines for the definition of TTE end points commonly used in RCT for sarcomas and GIST are provided for adjuvant and metastatic settings, including DFS, TTF, time to progression and others. CONCLUSION: Use of standardized definitions should facilitate comparison of trials' results, and improve the quality of trial design and reporting. These guidelines could be of particular interest to research scientists involved in the design, conduct, reporting or assessment of RCT such as investigators, statisticians, reviewers, editors or regulatory authorities.

Thromboembolic Events Associated with Thalidomide and Multimodality Therapy for Soft Tissue Sarcomas: Results of RTOG 0330.

Introduction. RTOG 0330 was developed to address the toxicity of RTOG 9514 and to add thalidomide (THAL) to MAID chemoradiation for intermediate/high grade soft tissue sarcomas (STSs) and to preoperative radiation (XRT) for low-grade STS. Methods. Primary/locally recurrent extremity/trunk STS: ≥8 cm, intermediate/high grade (cohort A): >5 cm, low grade (cohort B). Cohort A: 3 cycles of neoadjuvant MAID, 2 cycles of interdigitated THAL (200 mg/day)/concurrent 22 Gy XRT, resection, 12 months of adjuvant THAL. Cohort B: neoadjuvant THAL/concurrent 50 Gy XRT, resection, 6 months of adjuvant THAL. Planned accrual 44 patients. Results. 22 primary STS patients (cohort A/B 15/7). Cohort A/B: median age of 49/47 years; median tumor size 12.8/10 cm. 100% preoperative THAL/XRT and surgical resection. Three cycles of MAID were delivered in 93% cohort A. Positive margins: 27% cohort A/29% cohort B. Adjuvant THAL: 60% cohort A/57% cohort B. Grade 3/4 venous thromboembolic (VTE) events: 40% cohort A (1 catheter thrombus and 5 DVT or PE) versus 0% cohort B. RTOG 0330 closed early due to cohort A VTE risk and cohort B poor accrual. Conclusion. Neoadjuvant MAID with THAL/XRT was associated with increased VTE events not seen with THAL/XRT alone or in RTOG 9514 with neoadjuvant MAID/XRT.

The sacral chordoma margin.

OBJECTIVE: Aim of the manuscript is to discuss how to improve margins in sacral chordoma. BACKGROUND: Chordoma is a rare neoplasm, arising in half cases from the sacrum, with reported local failure in >50% after surgery. METHODS: A multidisciplinary meeting of the "Chordoma Global Consensus Group" was held in Milan in 2017, focusing on challenges in defining and achieving optimal margins in chordoma with respect to surgery, definitive particle radiation therapy (RT) and medical therapies. This review aims to report on the outcome of the consensus meeting and to provide a summary of the most recent evidence in this field. Possible new ways forward, including on-going international clinical studies, are discussed. RESULTS: En-bloc tumor-sacrum resection is the cornerstone of treatment of primary sacral chordoma, aiming to achieve negative microscopic margins. Radical definitive particle therapy seems to offer a similar outcome compared to surgery, although confirmation in comparative trials is lacking; besides there is still a certain degree of technical variability across institutions, corresponding to different fields of treatment and different tumor coverage. To address some of these questions, a prospective, randomized international study comparing surgery versus definitive high-dose RT is ongoing. Available data do not support the routine use of any medical therapy as (neo)adjuvant/cytoreductive treatment. CONCLUSION: Given the significant influence of margins status on local control in patients with primary localized sacral chordoma, the clear definition of adequate margins and a standard local approach across institutions for both surgery and particle RT is vital for improving the management of these patients.

Quality of life after resection of a chordoma of the mobile spine.

AIMS: The aim of the study was to compare measures of the quality of life (QOL) after resection of a chordoma of the mobile spine with the national averages in the United States and to assess which factors influenced the QOL, symptoms of anxiety and depression, and coping with pain post-operatively in these patients. PATIENTS AND METHODS: A total of 48 consecutive patients who underwent resection of a primary or recurrent chordoma of the mobile spine between 2000 and 2015 were included. A total of 34 patients completed a survey at least 12 months post-operatively. The primary outcome was the EuroQol-5 Dimensions (EQ-5D-3L) questionnaire. Secondary outcomes were the Patient-Reported Outcome Measurement Information System (PROMIS) anxiety, depression and pain interference questionnaires. Data which were recorded included the indication for surgery, the region of the tumour, the number of levels resected, the status of the surgical margins, re-operations, complications, neurological deficit, length of stay in hospital and rate of re-admission. RESULTS: The median EQ-5D-3L score was 0.71 (interquartile range (IQR) 0.44 to 0.79) which is worse than the national average in the United States of 0.85 (p < 0.001). Anxiety (median: 55 (IQR 49 to 61), p = 0.031) and pain (median: 61 (IQR 56 to 68), p < 0.001) were also worse than the national average in the United States (50), while depression was not (median: 52 (IQR 38 to 57), p = 0.513). Patients who underwent a primary resection had better QOL and less anxiety, depression and pain compared with those who underwent resection for recurrent or residual disease. The one- and five-year probabilities were 0.96 and 0.74 for survival, 0.07 and 0.25 for tumour recurrence, and 0.02 and 0.16 for developing distant metastasis. A total of 25 local complications occurred in 20 patients (42%), and there were 50 systemic and other complications in 25 patients (52%) within 90 days. CONCLUSION: These patient reported outcomes and oncological and surgical outcomes can be used when counselling patients and to aid decision-making when planning surgery. Cite this article: Bone Joint J 2017;99-B:979-86.

13-cis-retinoic acid with alpha-2a-interferon enhances radiation cytotoxicity in head and neck squamous cell carcinoma in vitro.

The treatment of locally advanced squamous cell carcinomas of the head and neck presents a challenge for oncologists. Radiation therapy alone fails to control many of these tumors. Chemotherapy added to radiation therapy has not clearly demonstrated an improvement in survival in the majority of trials reported to date. In this study, we have evaluated whether IFN-alpha-2a and/or 13-cis-retinoic acid (RA) enhance radiation cytotoxicity in a head and neck squamous cell carcinoma cell line (FaDu). Using a clonogenic cell survival assay, IFN-alpha-2a (1000 units/ml) or RA (1 microM) alone did not significantly enhance radiation cytotoxicity. The combination of the two agents, however, significantly increased the cytotoxicity of radiation against FaDu cells. The calculated survival fraction at 2 Gy was decreased from 0.649 with radiation alone to 0.477 when combined with the other two agents (P = 0.016), and the MID was decreased from 3.318 to 2.499 Gy (P = 0.028). A Phase I clinical trial to combine IFN-alpha-2a and/or RA in patients with unresectable head and neck cancer has been initiated.

Measurement of thymidine replacement in patients with high grade gliomas, head and neck tumors, and high grade sarcomas after continuous intravenous infusions of 5-iododeoxyuridine.

Based upon the radiation sensitization properties of the halogenated pyrimidines, 5-iododeoxyuridine (IdUrd) and 5-bromodeoxyuridine, long term i.v. infusions of halogenated pyrimidines in conjunction with fractionated radiation therapy have been evaluated in the treatment of a variety of human malignancies. While clinical studies have attempted to measure the halogenated pyrimidine incorporation, few have successfully related tumor response to the incorporation of IdUrd by the tumor. The present study reports the continuous IdUrd labeling index (number of cells labeled) and the IdUrd corrected replacement (percentage of thymidine replacement in the labeled cells of the population) from the tumors of 17 patients who received continuous infusions of IdUrd (1000 mg/m2/24 h). The tumors treated included four high grade gliomas, five head and neck tumors, four high grade sarcomas, and five other tumors of varying types. Less than 25% of the cells in three of four gliomas incorporated IdUrd after 5-7-day IdUrd infusion time. Corrected replacement for the gliomas ranged from 0 to 4%. In contrast, 63-85% of the cells in the head and neck biopsies were labeled with IdUrd after 3-7-day IdUrd infusions suggesting that these large tumors (3-12 cm diameter) have a high fraction of dividing cells. Corrected replacements values for the head and neck tumor patients ranged from 2.9 to 26.3%. The high grade sarcomas also demonstrated a high percentage of IdUrd labeled cells (57-79%) with three patients having corrected replacements of 7.5-14.2%. The continuous labeling and thymidine replacement data for four patients from whom serial biopsies were taken during IdUrd infusion demonstrated both an increasing IdUrd replacement and continuous labeling index with an increasing duration of IdUrd infusion. The clinical response of both the high grade glioma and head and neck tumor patients indicate that the IdUrd replacement and labeling data may provide some important predictive information with regard to the successful use of the halogenated pyrimidines in clinical radiation trials.

Second malignancies after Ewing's sarcoma: radiation dose-dependency of secondary sarcomas.

BACKGROUND: An excess risk of second malignancies has been reported in survivors of Ewing's sarcoma. We examined a multiinstitutional data base to reevaluate the risk among survivors of Ewing's sarcoma and to identify possible causal factors. METHODS: Information was derived from a data base that included 266 survivors of Ewing's sarcoma. Cumulative incidence rates of second malignancies were calculated. Contributions of clinical features, type and dose of chemotherapy, and cumulative radiation dose to the risk of second malignancies were evaluated. RESULTS: After a median follow-up duration of 9.5 years (range, 3.0 to 30), 16 patients have developed second malignancies, which included 10 sarcomas (five osteosarcomas, three fibrosarcomas, and two malignant fibrous histiocytomas) and six other malignancies (acute myeloblastic leukemia, acute lymphoblastic leukemia, meningioma, bronchioalveolar carcinoma, basal cell carcinoma, and carcinoma-in-situ of the cervix). The median latency to the diagnosis of the second malignancy was 7.6 years (range, 3.5 to 25.7). The estimated cumulative incidence rates at 20 years for any second malignancy and for secondary sarcoma were 9.2% (SD = 2.7%) and 6.5% (SD = 2.4%), respectively. The cumulative incidence rate of secondary sarcoma was radiation dose-dependent (P = .002). No secondary sarcomas developed among patients who had received less than 48 Gy, while the absolute risk of secondary sarcoma was 130 cases per 10,000 person-years of observation among patients who had received > or = 60 Gy. CONCLUSION: The overall risk of second malignancies after Ewing's sarcomas is similar to that associated with treatment for other childhood cancers. The radiation dose-dependency of secondary sarcomas justifies modification in therapy to reduce radiation doses.

Severe acute enteritis in a multiple myeloma patient receiving bortezomib and spinal radiotherapy: case report.

Proteasome inhibitors have been reported to enhance radiosensitivity in vitro. A case of potential clinical interaction between bortezomib, a proteasome inhibitor, and spine radiation is reported. A woman undergoing palliative radiotherapy to the T12 -S2 spine with concurrent bortezomib developed unexpectedly severe, acute radiation enteritis requiring hospital admission. Clinicians are advised to consider the potential for interactions of bortezomib with radiotherapy when the two agents are used simultaneously in the clinic.

Enhancement of fractionated-dose irradiation by retinoic acid plus interferon.

PURPOSE: To evaluate the relative cytotoxicity of fractionated-dose radiation in the presence and absence of 13-cis-retinoic acid (RA) plus alpha-2a-interferon (IFN), as a function of overall treatment time. METHODS AND MATERIALS: Studies were performed with the human squamous cell carcinoma line FaDu, in vitro. Attached exponential phase cells were treated with RA + IFN for 8-10 h and then exposed to single graded doses of radiation, or 1 to 6 doses of radiation at 2 Gy per dose, or to 5 doses of radiation at 2 Gy/dose with a time interval of 4-24 h between treatments. Following irradiation, the cells were incubated with drugs present throughout colony formation, and the fraction of survivors in the presence and absence of the combined drugs was calculated. RESULTS: For single graded-dose irradiation, the surviving fraction ratio at 2 Gy in the absence vs. presence of drugs was 1.27 +/- 0.19 in 3 repeat experiments. Following administration of 6 doses of radiation at 2 Gy/fraction with a 5-h time interval between treatments and, after correcting for cell proliferation between treatments, the surviving fractions differed by a factor of 3.25, again indicating an average difference in survival of 1.26 after each of the 6 2-Gy/fractions. Treatment with 5 2-Gy doses of irradiation with 24 vs. 4 h elapsing between doses, resulted in a 3-fold greater decrease in survival in the presence of drugs vs. no drug. The relatively greater cell kill due to 24 vs. 4 h between treatments was due to drug inhibition of cell proliferation between the more prolonged treatments. CONCLUSIONS: The results of this study indicate that retinoic acid plus interferon both sensitizes and inhibits cell proliferation during treatment. These results suggest that this combination of radiation and drugs, when used concurrently, may be effective for inhibiting tumor cell proliferation or accelerated repopulation during clinical fractionated radiotherapy.

Preoperative irradiation, lymphadenectomy, and 125iodine implantation for patients with localized carcinoma of the prostate.

Fifty-four patients with clinically and surgically localized prostatic carcinoma were treated with low-dose preoperative irradiation (1,050 cGy), pelvic lymphadenectomy, and interstitial 125Iodine implantation. The follow-up range is 2 to 9 years with a median follow-up of 5 years. Overall local tumor control is 92%. Actuarial 5-year survival is 86% and the actuarial disease-free survival at 5 years is 73%. Patients with poorly differentiated tumors have a significantly worse actuarial survival (62%) at 5 years than patients with well (95%) or moderately well differentiated tumors (93%), p = 0.04. Disease-free survival at 5 years was influenced by grade: well (100%), moderate (60%), and poor (48%), p = 0.03. Multivariate regression analysis indicates that only the degree of differentiation (p = 0.05) significantly impacts on survival. Both degree of differentiation (p = 0.04) and nodal status (p = 0.03) significantly influence disease-free survival. Potency has been maintained in 71% of patients potent at the time of implantation. Late reactions have been acceptable to date: bladder outlet obstruction (13%), mild proctitis (13%), cystourethritis (6%), incontinence (2%), and prostatic calculi (2%).

Primary soft tissue sarcomas of the breast: local-regional control with post-operative radiotherapy.

PURPOSE: A retrospective analysis was undertaken to determine the efficacy of postoperative radiotherapy in patients with primary sarcoma of the breast. METHODS AND MATERIALS: Ten patients with high-grade nonmetastatic primary sarcoma of the breast were treated at the National Cancer Institute, NIH, between 1979 and 1989 with mastectomy and adjuvant radiotherapy. Chemotherapy was given to three patients as part of a randomized trial. RESULTS: With a median potential followup of 99 months postoperatively, seven patients remain alive and without evidence of disease 142, 119, 82, 48, 45, 28, and 19 months postoperatively. Three patients died of metastatic disease 7, 25, and 29 months, postoperatively. There were no local or regional failures. Actuarial 5-year disease free and overall survival were 68% and 66%, respectively. CONCLUSION: Sarcomas of the breast have a prognosis similar to that of extremity sarcomas. When adjuvant radiotherapy is used, excellent local control may be achieved.

Sarcomas of the hand and foot: analysis of local control and functional result with combined modality therapy in extremity preservation.

PURPOSE: The records of 28 patients with sarcomas of the hand and foot treated at the National Cancer Institute (NCI) between 1977 and 1992 were reviewed to assess local control and functional results. METHODS AND MATERIALS: Histologic types included 15 cases of the Ewing's sarcoma family of tumors, 7 cases of alveolar rhabdomyosarcoma, and 6 cases of nonrhabdomyosarcoma soft tissue sarcomas. Median age of all patients was 18 years (range 4-61), with a median potential follow-up of 114 months following diagnosis. Surgery varied from incisional biopsies for Ewing's Sarcoma and rhabdomyosarcoma lesions to complete excision when possible for nonrhabdomyosarcoma soft tissue sarcoma lesions. Amputation was not primarily performed, except in two patients who underwent ray resections of hand lesions (patients 13 and 24). Radiotherapy generally consisted of 50 Gy/25 fractions (fx)/5 weeks for Ewing's Sarcoma, 54 Gy/30 fx/6 weeks for rhabdomyosarcoma, and 63 Gy/35 fx/7 weeks for nonrhabdomyosarcoma soft tissue sarcomas. Chemotherapy was administered on various NCI protocols. RESULTS: Actuarial local control for Ewing's Sarcoma was 84% at 5 and 10 years. All but one survivor are capable of hand/foot function for routine activities without orthotic requirements. Five of six patients (83%) who died of metastatic disease had functional distal extremities. Actuarial local control for rhabdomyosarcomas was 100%, with equivalent function. No patient developed a second malignancy in the treatment field. CONCLUSIONS: Although equivalent local control may be achieved in these lesions with either amputation or radiotherapy, a prudent management course would be to defer amputation for management of local recurrences. Many patients with these lesions fail in distant sites only and die without local failure. For these patients and for those who remain long-term survivors, we believe a functional hand and foot provides a better quality of life than a prosthesis.

Photodynamic therapy for chest wall recurrence in breast cancer.

Photodynamic therapy is the use of a sensitizer (dihematoporphyrin ethers) which is preferentially retained in tumor cells and activated by subsequent light delivery resulting in a selective tumoricidal effect. Between 1986 and 1989, we treated 20 patients with photodynamic therapy for chest wall recurrence of breast cancer. Responses were seen (20% complete response, 45% partial response, 35% no response), but the duration of response was short (average 2.5 months). Complications, in decreasing frequency, included pain, ecchymoses, blistering, ulceration and necrosis in the area of tumor involvement on the chest wall. One patient required skin flap reconstruction for full thickness necrosis. A limitation to this mode of therapy is that the sensitizer currently used is activated by light at a wavelength of 630 nm. This light can penetrate to a tissue depth of only 0.5 to 1.0 cm; thus, deeper disease cannot be treated. Future research must focus on the development of a clinically useful photosensitizer that can be activated by light at longer wavelengths and thereby achieve deeper tissue penetration. This would greatly expand the patient population for which this therapy is useful.

Time-dose considerations in the treatment of anal cancer.

PURPOSE: To analyze the impact of patient and treatment parameters in concurrent chemoradiation treatment for anal carcinoma. METHODS AND MATERIALS: Retrospective review of 50 MO anal cancer patients treated from 1984-1994. Most patients received concurrent 5-FU, mitomycin, and radiation. Local control and disease-free/overall survival were determined and analyzed according to patient and treatment parameters. RESULTS: With 43 month median follow-up, projected overall survival is 66% at 5 and 8 years. Disease-free survival is 67% at 5 years and 59% at 8 years. Local control is 70% at 5 and 8 years. Doses of > or =54 Gy are associated with improved 5-year survival (84 vs. 47%, p = 0.02), disease-free survival (74 v. 56%, p = 0.09), and local control (77 vs. 61%, p = 0.04). Although local control, disease-free survival, and overall survival were improved in patients whose overall treatment time was <40 days, this was not statistically significant. Outcome in the four patients with pretreatment hemoglobin (Hgb) <10 appeared worse with 3-year overall survival 50 vs. 68% (p = 0.07), disease-free survival 0 vs. 67% (p = 0.11), and local control 0 vs. 74% (p = 0.05). Projected 5-year overall survival, relapse-free survival, and local control in 4 HIV(+) patients is 0, 75, and 75%. Multivariate analysis reveals that dose (p = 0.02) and Hgb (p = 0.05) independently affect local control, dose (p = 0.02) affects disease-free survival, and dose (p = 0.01), Hgb (p = 0.03), T-stage (p = 0.03), and HIV-status (0.07) independently influence overall survival. CONCLUSION: Radiation doses of > or =54 Gy are associated with significantly improved survival and local control in anal cancer patients treated with chemoradiation. Overall treatment times of less than 40 days are associated with a trend towards improved outcome, but this is not significant. Pretreatment hemoglobin <10 is associated with worse treatment outcome. Survival of HIV (+) patient is poor, but the majority of such patients in this series died of intercurrent disease with their anal carcinomas controlled by chemoradiation.

Acute and long-term effects on limb function of combined modality limb sparing therapy for extremity soft tissue sarcoma.

A retrospective review is presented on 145 patients who underwent limb-sparing surgery and radiation therapy (with or without adjuvant chemotherapy) for their primary soft tissue sarcomas of the extremities on protocol between 1975 and 1986. The focus on our analysis was the acute and long term toxicity of treatment on limb function. The most common acute complication was skin reaction, occurring in 52 patients (36%). Long term (occurring after more than 1 year following all treatment) treatment complications in the extremity were as follows: bone fracture = 6%; contracture = 20%; pain requiring narcotics = 7%; edema greater than 2+ = 19%; moderate to severe decrease in range of motion = 32%; moderate to severe decrease in manual muscle strength = 20%; orthotic device required = 9%; cane or crutch required = 7%; chronic infection = 9%; and tissue induration = 57%. Three amputations for treatment complications were required. Inclusion of more than 50% of the joint in the radiation portal was associated with a higher frequency of contracture. High nominal standard dose (greater than 1760 rets, greater than 63 Gy at 1.8 Gy per fraction) resulted in more painful limbs as well as limbs with increased edema, decreased manual muscle strength, decreased range of motion, and skin telangiectasias. Edema was more often noted in patients with a longer radiation portal (greater than 35 cm), as was tissue induration. Chronic ulcer or infection was more frequently seen in patients with lower extremity tumors and when more than 75% of the extremity diameter was irradiated. Although chemotherapy given concurrent with radiation therapy was associated with a higher number of acute skin reactions, this did not appear to translate into increased long term morbidity. The percentage of patients ambulating without assistive devices and with mild or no pain was 84%. Careful attention to the techniques of radiation therapy may have a significant impact on minimizing acute and long term complications of limb sparing treatment for extremity soft tissue sarcoma.

Phase I study of debulking surgery and photodynamic therapy for disseminated intraperitoneal tumors.

PURPOSE: Phase I study designed to determine the maximum tolerated dose of intraoperative photodynamic therapy (PDT) at laparotomy/debulking surgery in patients with refractory or recurrent, disseminated intraperitoneal tumors. METHODS AND MATERIALS: Patients received dihematoporphyrin ethers (DHE) 1.5-2.5 mg/kg by i.v. injection prior to surgery. Patients resected to < or = 5 mm of residual disease underwent laser light delivery to all peritoneal surfaces. RESULTS: Fifty-four patients entered the study. Thirty-nine underwent resection and light delivery/PDT. PDT dose was escalated by increasing DHE from 1.5 to 2.5 mg/kg, shortening the interval between DHE injection and surgery from 72 to 48 hr, and increasing the light dose. Initially, 630 nm red light alone was used. In this group, PDT of 2.8-3.0 J/cm2 induced small bowel edema and resulted in 3 small bowel perforations after bowel resection or enterotomy. Further light dose escalation, however, was achieved by switching to less penetrating 514 nm green light to the bowel/mesentery. In later patients, whole peritoneal PDT was supplemented with boost doses of 10-15 J/cm2 red light or 5-7.5 J/cm2 green light to high risk areas. Small bowel complications were not seen after switching to less penetrating green light. Dose limiting toxicities occurred in 2 of 3 patients at the highest light dose of 5.0 J/cm2 green light with boost. These patients had pleural effusions that required thoracentesis and postoperative respiratory support for 7-9 days, while one had a gastric perforation. At potential follow-up times of 3.8-43.1 months (median 22.1 months), 30/39 patients are alive and 9/39 are free of disease. CONCLUSION: The maximum tolerated dose of intraoperative PDT following debulking surgery performed 48 hr after intravenous administration 2.5 mg/kg DHE is 3.75 J/cm2 of 514 nm green light to the entire peritoneal surface with boosts to 5.0-7.5 J/cm2 of 514 nm green light or 10-15 J/cm2 of 630 nm red light to sites of gross disease encountered at surgery.

Persistence of thermotolerance in slowly proliferating plateau-phase cells.

Thermotolerance decay rates were determined under rapidly proliferating exponential growth conditions and under high-cell-density plateau-phase growth conditions. Thermotolerance was induced by a marginally toxic initial heat treatment of 10 min at 44 degrees C in Chinese hamster ovary cells. Second dose-response curves were obtained at 24-hr intervals for up to 96 hr after the initial heat treatment. Resistance to second heat treatment had disappeared by 72 hr after the initial heat treatment in proliferating cells, but was evident in plateau-phase cells at 96 hr. Regardless of the proliferative status, thermotolerance decayed in an exponential manner. The half-times of tolerance decay were approximately 13 hr in proliferating cells and 30 hr in plateau-phase cells.

Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of a prospective, randomized, clinical trial.

Thirty-five patients with surgically resected sarcomas of the retroperitoneum were enrolled in a prospective, randomized, clinical trial comparing 20-Gy intraoperative radiotherapy in combination with postoperative low-dose (35- to 40-Gy) external-beam radiotherapy with postoperative high-dose (50- to 55-Gy) external-beam radiotherapy alone. Chemotherapy with doxorubicin hydrochloride, cyclophosphamide (anhydrous), and methotrexate sodium was used for a portion of the trial. Fifteen patients who received intraoperative radiotherapy and 20 control patients were followed up for a minimum of 5 years (median follow-up, 8 years). Median survival times were similar for the group that received intraoperative radiotherapy (45 months) and the control group (52 months). There were no indications of benefit from adjunctive chemotherapy. The number of locoregional recurrences was significantly lower among those who received intraoperative radiotherapy (six of 15) than control patients (16 of 20). Patients who received intraoperative radiotherapy had fewer complications of disabling radiation-related enteritis (two of 15) than control patients (10 of 20), but radiation-related peripheral neuropathy was more frequent among those who received intraoperative radiotherapy (nine of 15) than among control patients (one of 20).

Long-term outcome in 87 patients with low-grade soft-tissue sarcoma.

OBJECTIVE: To describe the long-term clinical outcome of patients with low-grade soft-tissue sarcoma and identify factors that may predict or determine their prognosis. DESIGN: Retrospective chart review with multivariate analysis. SETTING: Large research hospital and referral center. PATIENTS: All patients treated between 1975 and 1990 at the National Cancer Institute (Bethesda, Md) who had a confirmed diagnosis of low-grade soft-tissue sarcoma. INTERVENTIONS: Surgery and radiation therapy. MAIN OUTCOME MEASURES: Local recurrence and overall survival. RESULTS: For patients with nonretroperitoneal lesions, overall survival was excellent, with a history of recurrence, a positive surgical margin, and an absence of adjuvant radiation therapy significantly associated with increased risks of local recurrence. Patients with retroperitoneal lesions not only had an increased risk of local recurrence, but significantly poorer overall survival. CONCLUSIONS: Low-grade soft-tissue sarcomas are associated with excellent overall survival, especially those confined to nonretroperitoneal sites. The risk of local recurrence after resection with negative margins and/or adjuvant radiation therapy is very low and most recurrences can be controlled with further therapy.

Technique of photodynamic therapy for disseminated intraperitoneal malignant neoplasms. Phase I study.

Patients with disseminated intraperitoneal malignant neoplasms were given intra-abdominal photodynamic therapy. Patients received dihematoporphyrin ethers intravenously 48 to 72 hours before laparotomy at doses of 1.5 to 3.0 mg/kg. At operation, as much tumor as possible was resected. Red light (630 nm) was delivered to all peritoneal surfaces from an argon-pumped dye laser at doses ranging from 0.2 to 3.0 J/cm2 in an escalating fashion. Viscera and peritoneal surfaces were anatomically isolated and exposed to light for intervals calculated to deliver the prescribed energy. Light was delivered to mesentery and bowel by a flat-cut optical fiber, while other areas, including diaphragm, viscera, omental bursa, gutters, and pelvis, were delivered light through a diffusing wand. Twenty-three patients (13 with ovarian cancer, eight with sarcoma, and two with pseudomyxoma peritoneii) underwent photodynamic therapy. Five of eight patients cleared positive peritoneal cytologies after treatment. Six patients remained clinically free of disease for up to 18 months, and five patients had treatment-related complications. Intraperitoneal phototherapy is technically feasible and deserving of clinical evaluation.