Paclitaxel-based chemoradiotherapy in localized gastric carcinoma: degree of pathologic response and not clinical parameters dictated patient outcome.

PURPOSE: Preoperative chemoradiotherapy may increase the R0 (curative) resection rate, overall survival (OS) duration, and disease-free survival (DFS) duration. We evaluated paclitaxel-based induction chemotherapy and chemoradiotherapy in patients with localized gastric or gastroesophageal adenocarcinoma to determine its feasibility, impact on the R0 resection rate, type of pathologic response, OS, and DFS. PATIENTS AND METHODS: Patients with operable, localized gastric, or gastroesophageal adenocarcinoma were eligible. Staging included endoscopic ultrasonography (EUS) and laparoscopy. Patients received two 28-day cycles of induction chemotherapy of fluorouracil, paclitaxel, and cisplatin followed by 45 Gy of radiation and concurrent fluorouracil plus paclitaxel. The cancer was restaged and surgery was attempted. Postsurgery pathologic findings and R0 resection were correlated with OS and DFS. RESULTS: Forty-one patients were enrolled. Most carcinomas were proximal (83%) and pretreatment stage EUST3 (85%). Forty patients (98%) underwent surgery, and 78% had an R0 resection. We observed a pathologic complete response (pathCR) rate of 20% and a pathologic partial response (pathPR) rate of 15% (< 10% residual cancer cells in the resected specimen). No pretreatment parameter (sex, cancer location, baseline T stage, or baseline N stage) predicted the type of postsurgery pathologic response, OS, or DFS. However, pathCR (P = .02), pathCR + pathPR (P = .006), R0 resection (P < .001), and postsurgery T and N stages (P = .01 and P < .001, respectively) were associated with OS. Same parameters were significantly correlated with DFS. Toxicity was manageable. CONCLUSION: The type of pathologic response but not pretreatment parameters was associated with OS and DFS. Efforts to increase the rate of pathologic response and better systemic cancer control are warranted.

Phase I study of preoperative oral uracil and tegafur plus leucovorin and radiation therapy in rectal cancer.

PURPOSE: Preoperative combined-modality therapy for rectal cancer may allow for sphincter preservation, while decreasing recurrence rates and improving the overall prognosis. Oral chemotherapy with uracil and tegafur (UFT) plus leucovorin (LV) may reduce costs and complications associated with protracted infusions of fluorouracil. Our goal was to evaluate the safety of UFT plus LV combined with preoperative radiation and determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of UFT plus LV in this setting. PATIENTS AND METHODS: Patients with tumor-node-metastasis stage II or III rectal cancer received escalating doses of UFT (starting at 250mg/m(2)/d, with 50-mg/m(2)/d increments between consecutive cohorts) and fixed doses of LV (90 mg/d). The UFT and LV combination was given 5 days per week concurrently with a 5-week course of preoperative radiation totaling 45 Gy (1.8 Gy/fraction). Surgery was performed 4 to 6 weeks after radiation and was followed by four 35-day cycles of fixed doses of UFT and LV (28 days of therapy each cycle). RESULTS: Fifteen patients were treated, and 13 received the full preoperative chemotherapy. All planned radiation was delivered successfully. The MTD of UFT with radiation was 350 mg/m(2)/d with 90 mg/d of LV. Diarrhea was the DLT. Sphincter-preserving surgery was performed in 12 of 14 patients. One patient had progressive disease before surgery. Pathologic evaluation of 14 resected specimens showed a complete response in three cases. CONCLUSION: Preoperative chemoradiation with oral UFT plus LV is feasible and well tolerated and should be further investigated.

American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel.

PURPOSE: To determine clinical practice guidelines for the use of bisphosphonates in the prevention and treatment of bone metastases in breast cancer and their role relative to other therapies for this condition. METHODS: An expert multidisciplinary panel reviewed pertinent information from the published literature and meeting abstracts through May 1999. Additional data collected as part of randomized trials and submitted to the United States Food and Drug Administration were also reviewed, and investigators were contacted for more recent information. Values for levels of evidence and grade of recommendation were assigned by expert reviewers and approved by the panel. Expert consensus was used if there were insufficient published data. The panel addressed which patients to treat and when in their course of disease, specific drug delivery issues, duration of therapy, management of bony metastases with other therapies, and the public policy implications. The guideline underwent external review by selected physicians, members of the American Society of Clinical Oncology (ASCO) Health Services Research Committee, and the ASCO Board of Directors. RESULTS: Bisphosphonates have not had an impact on the most reliable cancer end point: overall survival. The benefits have been reductions in skeletal complications, ie, pathologic fractures, surgery for fracture or impending fracture, radiation, spinal cord compression, and hypercalcemia. Intravenous (IV) pamidronate 90 mg delivered over 1 to 2 hours every 3 to 4 weeks is recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy. For women with only an abnormal bone scan but without bony destruction by imaging studies or localized pain, there is insufficient evidence to suggest starting bisphosphonates. Starting bisphosphonates in patients without evidence of bony metastasis, even in the presence of other extraskeletal metastases, is not recommended. Studies of bisphosphonates in the adjuvant setting have yielded inconsistent results. Starting bisphosphonates in patients at any stage of their nonosseous disease, outside of clinical trials, despite a high risk for future bone metastasis, is currently not recommended. Oral bisphosphonates are one of several options which can be used for preservation of bone density in premenopausal patients with treatment-induced menopause. The panel suggests that, once initiated, IV bisphosphonates be continued until evidence of substantial decline in a patient's general performance status. The panel stresses that clinical judgment must guide what is a substantial decline. There is no evidence addressing the consequences of stopping bisphosphonates after one or more adverse skeletal events. Symptoms in the spine, pelvis, or femur require careful evaluation for spinal cord compression and pathologic fracture before bisphosphonate use and if symptoms recur, persist, or worsen during therapy. The panel recommends that current standards of care for cancer pain, analgesics and local radiation therapy, not be displaced by bisphosphonates. IV pamidronate is recommended in women with pain caused by osteolytic metastasis to relieve pain when used concurrently with systemic chemotherapy and/or hormonal therapy, since it was associated with a modest pain control benefit in controlled trials. CONCLUSION: Bisphosphonates provide a meaningful supportive but not life-prolonging benefit to many patients with bone metastases from cancer. Further research is warranted to identify clinical predictors of when to start and stop therapy, to integrate their use with other treatments for bone metastases, to identify their role in the adjuvant setting in preventing bone metastases, and to better determine their cost-benefit consequences.

Preoperative chemoradiation for patients with pancreatic cancer: toxicity of endobiliary stents.

PURPOSE: A recent multicenter study of preoperative chemoradiation and pancreaticoduodenectomy for localized pancreatic adenocarcinoma suggested that biliary stent-related complications are frequent and severe and may prevent the delivery of all components of multimodality therapy in many patients. The present study was designed to evaluate the rates of hepatic toxicity and biliary stent-related complications and to evaluate the impact of this morbidity on the delivery of preoperative chemoradiation for pancreatic cancer at a tertiary care cancer center. PATIENTS AND METHODS: Preoperative chemoradiation was used in 154 patients with resectable pancreatic adenocarcinoma (142 patients, 92%) or other periampullary tumors (12 patients, 8%). Patients were treated with preoperative fluorouracil (115 patients), paclitaxel (37 patients), or gemcitabine (two patients) plus concurrent rapid-fractionation (30 Gy; 123 patients) or standard-fractionation (50.4 Gy; 31 patients) radiation therapy. The incidences of hepatic toxicity and biliary stent-related complications were evaluated during chemoradiation and the immediate 3- to 4-week postchemoradiation preoperative period. RESULTS: Nonoperative biliary decompression was performed in 101 (66%) of 154 patients (endobiliary stent placement in 77 patients and percutaneous transhepatic catheter placement in 24 patients). Stent-related complications (occlusion or migration) occurred in 15 patients. Inpatient hospitalization for antibiotics and stent exchange was necessary in seven of 15 patients (median hospital stay, 3 days). No patient experienced uncontrolled biliary sepsis, hepatic abscess, or stent-related death. CONCLUSION: Preoperative chemoradiation for pancreatic cancer is associated with low rates of hepatic toxicity and biliary stent-related complications. The need for biliary decompression is not a clinically significant concern in the delivery of preoperative therapy to patients with localized pancreatic cancer.

Multi-institutional trial of preoperative chemoradiotherapy in patients with potentially resectable gastric carcinoma.

PURPOSE: In the West, curative (R0) resection is achieved in approximately 50% of patients with localized gastric carcinoma, and more than 60% die of cancer following an R0 resection. A multi-institutional study of preoperative chemoradiotherapy was done to assess the R0 resection rate, pathologic complete response (pathCR) rate, safety, and survival in patients with resectable gastric carcinoma. PATIENTS AND METHODS: Operable patients with localized gastric adenocarcinoma were eligible. Staging also included a laparoscopy and endoscopic ultrasonography (EUS). Patients received up to two 28-day cycles of induction chemotherapy of fluorouracil, leucovorin, and cisplatin, followed by 45 Gy of radiation plus concurrent fluorouracil. Patients were then staged and surgery was attempted. RESULTS: Thirty-four patients were registered at three institutions. One ineligible patient was excluded. Most patients had a promixal cancer and EUST3N1 designation. Twenty-eight (85%) of 33 patients underwent surgery. The R0 resection rate was 70% and pathCR rate was 30%. A pathologic partial response (< 10% residual carcinoma in the primary) occurred in eight patients (24%). EUS T plus N and postsurgery T plus N correlation showed significant downstaging (P = <.01). The median survival time for 33 patients was 33.7 months. Patients achieving a pathCR or pathPR had a significantly longer median survival time (63.9 months) than those achieving less than pathPR (12.6 months; P =.03). There were two treatment-related deaths. CONCLUSION: Our data suggest that the three-step strategy of preoperative induction chemotherapy followed by chemoradiotherapy resulted in substantial pathologic response that resulted in durable survival time. This strategy is worthy of a direct comparison with postoperative adjuvant chemoradiotherapy.

Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma.

PURPOSE: To evaluate the toxicities, radiographic and pathologic responses, and event-free outcomes with combined modality treatment that involves preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with radiographically resectable localized adenocarcinoma of the pancreatic head were entered onto a preoperative protocol that consisted of a 2-week course of fluorouracil (5-FU) 300 mg/m2 daily 5 days per week and concomitant rapid-fractionation radiation 30 Gy, 3 Gy daily 5 days per week. Radiographic restaging was performed 4 weeks after chemoradiation, and patients with localized disease underwent pancreaticoduodenectomy with EB-IORT 10 to 15 Gy. RESULTS: Thirty-five patients were entered onto the study and completed chemoradiation, 34 (97%) as outpatients. Three patients (9%) experienced grade 3 nausea and vomiting; no other grade 3 or 4 toxicities were observed. Of the 27 patients taken to surgery, 20 patients (74%) underwent pancreaticoduodenectomy with EB-IORT. All patients had a less than grade III pathologic response to preoperative chemoradiation. At a median follow-up of 37 months, the 3-year survival rate in patients who underwent combined modality therapy was 23%. CONCLUSION: Combined modality treatment with preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and EB-IORT is associated with minimal toxicity and excellent locoregional control. This represents one approach to maximize the proportion of patients who receive all components of combined modality therapy and avoids the toxicity of pancreaticoduodenectomy in patients found to have metastatic disease at the time of restaging.

Preoperative and postoperative chemoradiation strategies in patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas.

PURPOSE: The effects of preoperative versus postoperative fluorouracil (5-FU)-based chemotherapy and irradiation on treatment toxicity, duration of treatment, tumor recurrence, and survival were compared in patients who underwent potentially curative therapy for adenocarcinoma of the pancreatic head during a 5-year period. METHODS: From July 1990 to July 1995, 142 patients with localized adenocarcinoma of the pancreatic head deemed resectable on the basis of radiographic images were treated with curative intent using a multimodality approach involving either preoperative or postoperative chemoradiation. Patients with biopsy confirmation of adenocarcinoma and a low-density mass in the pancreatic head identified by computed tomography (CT) received preoperative chemoradiation. Patients without a mass on CT or in whom the preoperative biopsy was negative underwent pancreaticoduodenectomy with planned postoperative chemoradiation. Protocol-based preoperative chemoradiation consisted of external-beam irradiation at a dose of 50.4 Gy (standard fractionation; 1.8 Gy/d, 5 d/wk) or 30 Gy (rapid fractionation; 3 Gy/d, 5 d/wk) combined with continuous infusion 5-FU (300 mg/m2/d, 5 d/wk). Postoperative chemoradiation combined 50.4 Gy of external-beam irradiation (standard fractionation) with continuous-infusion 5-FU. RESULTS: No patient who received preoperative chemoradiation experienced a delay in surgery because of chemoradiation toxicity, but six of 25 eligible patients (24%) did not receive postoperative chemoradiation because of delayed recovery after pancreaticoduodenectomy. No significant differences in toxicities from chemoradiation were observed between groups. Patients treated with rapid-fractionation preoperative chemoradiation had a significantly (P < .01) shorter duration of treatment (median, 62.5 days) compared with patients who received postoperative chemoradiation (median, 98.5 days) or standard-fractionation preoperative chemoradiation (median, 91.0 days). At a median followup of 19 months, no significant differences in survival were observed between treatment groups. No patient who received preoperative chemoradiation and pancreaticoduodenectomy experienced a local recurrence; peritoneal (regional) recurrence occurred in 10% of these patients. Local or regional recurrence occurred in 21% of patients who received pancreaticoduodenectomy and postoperative chemoradiation. CONCLUSION: Delivery of preoperative and postoperative chemoradiation in patients who underwent potentially curative pancreaticoduodenectomy for adenocarcinoma of the pancreatic head resulted in similar treatment toxicity, patterns of tumor recurrence, and survival. Rapid-fractionation preoperative chemoradiation ensured the delivery of all components of therapy to all eligible patients with a significantly shorter duration of treatment than with standard-fractionation chemoradiation given either before or after pancreaticoduodenectomy. Prolonged recovery after pancreaticoduodenectomy prevents the delivery of postoperative adjuvant chemoradiation in up to one fourth of eligible patients.

Forearm hemodynamics and responses to exercise in middle-aged adult-onset diabetic patients.

Much of the difficulty in assessing the progress of diabetic angiopathy and effects of experimental modes of therapy arises from the lack of quick, simple, inexpensive, and noninvasive tests to perform on the circulatory system of human subjects. We report here on values obtained by the use of mercury-in-rubber strain gauge plethysmography on 15 middle-aged, adult-onset diabetics who had minimal clinical evidence of microangiopathy. Standard tests are described for assessing forearm vascular function at rest, during tonic exercise of the fingers, and after interrupted repetitive exercise of the fingers. When matched against a similar aged nondiabetic group, the diabetics had slightly higher forearm vascular resistance at each level of exercise, a marked reduction (approximately 50 per cent) in capillary filtration coefficient, which is believed to be related to vascular filtering surface area, and a slight reduction in venous capacitance at all levels of exercise. The method of mercury-in-rubber strain gauge venous occlusion plethysmography provides the clinician with a sensitive and inexpensive tool with which to follow the evolution of angiopathy in diabetic patients.

p53 immunohistochemical staining predicts residual disease after chemoradiation in patients with high-risk rectal cancer.

This study was conducted to investigate the value of p53 immunohistochemical staining of pretreatment biopsy specimens in predicting the response of rectal cancer to chemoradiation. The study group comprised 42 patients with high-risk rectal cancer treated between July 1990 and July 1995 with a preoperative chemoradiation regimen of 45 Gy of external-beam irradiation and continuous-infusion 5-fluorouracil followed by surgical resection. p53 immunohistochemical staining was performed on pretreatment biopsy specimens. p53 immunohistochemical staining pattern and standard clinical and pathological parameters were correlated with extent of residual cancer in the surgical specimen. Twenty tumors were positive for p53 on immunohistochemical staining, 19 were negative, and 3 were focally positive. Thirteen patients experienced a complete response to chemoradiation. Aberrant p53 protein accumulation, as measured by immunohistochemical staining, correlated inversely with a complete pathological response to chemoradiation (P = 0.005; correlation coefficient = -0.43) and directly with an increased likelihood of residual cancer in the lymph nodes of surgical specimens (P = 0.02; correlation coefficient = 0.39). p53 immunohistochemical staining of pretreatment biopsy specimens correlates with the extent of residual disease after chemoradiation in patients with high-risk rectal cancer.

Phase I trial of gemcitabine combined with radiation for the treatment of locally advanced pancreatic adenocarcinoma.

Gemcitabine has modest activity in the treatment of advanced pancreatic cancer and is a potent radiosensitizer. We conducted a Phase I trial to determine the maximum tolerated dose of weekly gemcitabine delivered concurrently with radiation therapy for the treatment of locally advanced adenocarcinoma of the pancreatic head and to assess the treatment-related toxic effects associated with such a regimen. Eighteen patients with pathologically proven, locally advanced adenocarcinoma of the pancreatic head were enrolled in this study. Patients received seven weekly doses of gemcitabine with 3000 cGy of external beam radiation therapy delivered during the first 2 weeks of therapy. Six patients received gemcitabine at 350 mg/m(2)/week, nine at 400 mg/m(2)/week, and three at 500 mg/m(2)/week. Grade 3-4 hematological toxicity was observed in over half the patients treated. Nonhematological toxicities were significant and included fatigue, anorexia, nausea, vomiting, and dehydration. Forty-four % of the patients required admission to the hospital for management of nausea/vomiting and dehydration. The risk of hospitalization appeared to be dose-related; all of the three patients treated at 500 mg/m(2)/week required hospital admission during treatment. Seventeen patients were evaluated for response, and eight patients (47%) had evidence of a local anticancer effect. Four of these eight patients (24%) had a partial response to therapy. The median survival for the entire group was 6 months. The 1-year survival rate for patients with an objective response to therapy was 66%. The clinical responses observed in this group of patients suggest gemcitabine is a clinically relevant radiosensitizer in patients with pancreatic adenocarcinoma. However, the toxic effects are significant, suggesting that until dose and scheduling issues are explored further, concomitant administration of gemcitabine and radiation therapy should still be considered investigational.

Neoadjuvant chemoradiation for adenocarcinoma of the pancreas.

Adjuvant 5-fluorouracil and concurrent radiation may improve survival following complete surgical resection in patients with pancreatic adenocarcinoma. However, the morbidity and prolonged recovery associated with pancreaticoduodenectomy frequently prevents the timely delivery of postoperative chemoradiation. Therefore, the University of Texas M.D. Anderson Cancer Center (MDACC) has investigated the use of neoadjuvant chemoradiation in potentially resectable pancreatic cancer. We have incorporated a standardized approach to pretreatment staging, operative technique and pathologic evaluation. Our initial experience suggests that preoperative chemoradiation is well tolerated and may reduce loco-regional recurrence. Patients treated with rapid-fractionation preoperative chemoradiation had a significantly shorter duration of treatment compared with patients who received postoperative chemoradiation or standard-fractionation preoperative chemoradiation. New and more potent radiation-sensitizing agents such as gemcitabine may further enhance local control. Novel therapies directed at specific molecular events involved in pancreatic tumorigenesis may be incorporated into preoperative and postoperative regimens to attempt to reduce systemic relapse.

Bone metastases: approaches to management.

Cancer commonly metastasizes to bone and up to 80% of breast, prostate, and lung cancer patients will have bone metastases. The site and distribution of bone metastases, and the presence of skeletal complications such as pathologic fracture and spinal cord compression affect the patient's prognosis. In many cases, bone metastases are too advanced to be eliminated through chemotherapy or radiotherapy; in these cases, treatment is given to relieve or prevent further symptoms. Several treatments are used in palliative care, including radiation therapy, systemic radiopharmaceuticals, chemotherapy, hormone therapy, and bisphosphonates. Radiotherapy remains the treatment of choice, and radiation treatment given in a single fraction has proven to be an efficient and cost-effective alternative to traditional multifraction radiotherapy courses. Analgesics are important in palliative therapy because they relieve pain while administering and awaiting the relief of pain from treatment. Furthermore, analgesics will relieve persistent levels of pain if complete pain relief is not achieved with therapy. Currently, bone pain is not adequately treated by many physicians and up to 79% of patients experience severe pain in the period before palliative therapy.

Combining gemcitabine with radiation in pancreatic cancer: understanding important variables influencing the therapeutic index.

We compared and evaluated available laboratory and clinical data on the use of concurrent gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and radiation in pancreatic cancer to provide guidance for subsequent prospective research initiatives. Preclinical data suggest that the timing of administration of gemcitabine with respect to radiotherapy is important, but this issue has not yet been confirmed by clinical data. Phase I clinical data indicate that the amount of acute toxicity from the combination of gemcitabine and radiotherapy is strongly related to the dose and schedule of administration of gemcitabine, as well as to the radiation field size. There also appears to be an inverse linear relationship between the maximum tolerated gemcitabine dose and radiation dose. Also important, but less clear, is the infusion rate of gemcitabine as it relates to the systemic efficacy of the drug. The combination of additional agents with gemcitabine and radiation appears to be feasible. Finally, the addition of radioprotectors may enable chemotherapy dose escalation, but safe escalation of the radiotherapy dose with newer techniques has not been established. Semin Oncol 28 (suppl 10):25-33.

Reflections on radiotherapy in Vietnam: political lessons still to be learned.

Radiotherapy in Vietnam represents a stark contrast to the level of care available in the United States. The issue of efficient administration of cancer care with available resources is common to both nations. The challenge for each country is to develop treatment strategies and political policies for effective and accessible care within budgetary constraints. Results of therapy, defined as the restoration of function, must be the measure of efficacy and efficiency. This demands a balance between control of tumor-related symptoms and treatment-related morbidity. The most inefficient use of resources is an ineffective treatment that results in complications, as we observed in Vietnam. As health care policies continue to develop in the United States, we must not fail to focus upon therapeutic outcome as the single most important parameter for measuring success relative to the personal and public investment in medicine.

Improved pain management with daily nursing intervention during radiation therapy for head and neck carcinoma.

This study evaluated the response to a defined mouth care and analgesic treatment protocol for oropharyngeal mucositis in patients undergoing radiation therapy for head and neck carcinoma. Nineteen patients completed a 15 question pain survey before each radiation treatment. Patients were given instructions on the use of mouthwashes and a three-step analgesic protocol: acetaminophen, acetaminophen with codeine suspension, and oral morphine (20 mg/mL) for mild, moderate, and severe pain, respectively. Patients were seen daily by a radiation therapy nurse who reviewed the survey and prompt changes in the prescribed analgesic regimen were then made by a physician. Marked differences in control of pain related to radiation mucositis were observed when compared to patients from our prior study who used the same daily survey but had only sporadic nursing intervention and no analgesic protocol. Patients having daily nursing intervention reported fewer days of moderate/severe pain, had less pain throughout the day, and noted less disturbance in sleep, eating, and energy level. Weight loss of greater than 5 kg was noted in only three patients. Analgesics were used on 77% of treatment days and relieved all or most of the pain in 94% of these days. Daily review of a symptom survey by a radiation therapy nurse, combined with a well-defined strategy for mouth care, and analgesics results in improved pain management of radiation induced oropharyngeal mucositis because of prompt attention to patient needs. Future trials should incorporate defined strategies for oral care and analgesic use to control for possible bias in assessing efficacy.

Dosimetry of the breast for determining carcinogenic risk in mantle irradiation.

Development of secondary malignancies following treatment of Hodgkin's disease with radiation (central axis midline dose of 3600-4500 cGy) is a recognized risk, and the incidence in breast cancer has been reported to increase by a factor of 4.3 (95% confidence level 2.0 to 8.4) for patients treated with mantle irradiation. Increased incidence of breast cancer has also been shown in atomic bomb survivors, women who underwent multiple fluoroscopic examinations, and women treated for postpartum mastitis. The dose response, however, for radiation dose above 1000 cGy is virtually unknown. Quantitative analysis of carcinogenesis after radiation is exacerbated by the large dose gradient across the breast (300-4200 cGy for midline doses of 4000 cGy), large individual variation in breast size and treatment field position. We have developed differential dose volume histograms calculated using a 3-dimensional (Eg TAR) algorithm as a potential tool for retrospective and prospective epidemiological evaluation. The breast volume forms a bimodal distribution with respect to dose and with further analysis other quantities, such as mean dose and integral dose, can be calculated from the histograms. Using the mean dose, the linear model for carcinogenesis predicts an increased incidence of secondary breast cancer by a factor of 11.6 and 9.6 for the left and right breast, respectively. The dose calculations has been corrected for inhomonogenities 3-dimensionally and test of the accuracy has been included.

Evaluation and scoring of radiotherapy treatment plans using an artificial neural network.

PURPOSE: The objective of this work was to demonstrate the feasibility of using an artificial neural network to predict the clinical evaluation of radiotherapy treatment plans. METHODS AND MATERIALS: Approximately 150 treatment plans were developed for 16 patients who received external-beam radiotherapy for soft-tissue sarcomas of the lower extremity. Plans were assigned a figure of merit by a radiation oncologist using a five-point rating scale. Plan scoring was performed by a single physician to ensure consistency in rating. Dose-volume information extracted from a training set of 511 treatment plans on 14 patients was correlated to the physician-generated figure of merit using an artificial neural network. The neural network was tested with a test set of 19 treatment plans on two patients whose plans were not used in the training of the neural net. RESULTS: Physician scoring of treatment plans was consistent to within one point on the rating scale 88% of the time. The neural net reproduced the physician scores in the training set to within one point approximately 90% of the time. It reproduced the physician scores in the test set to within one point approximately 83% of the time. CONCLUSIONS: An artificial neural network can be trained to generate a score for a treatment plan that can be correlated to a clinically-based figure of merit. The accuracy of the neural net in scoring plans compares well with the reproducibility of the clinical scoring. The system of radiotherapy treatment plan evaluation using an artificial neural network demonstrates promise as a method for generating a clinically relevant figure of merit.

The American Brachytherapy Society recommendations for brachytherapy of soft tissue sarcomas.

PURPOSE: This report presents the American Brachytherapy Society (ABS) guidelines for the use of brachytherapy for patients with soft tissue sarcoma. METHODS AND MATERIALS: Members of the ABS with expertise in soft tissue sarcoma formulated brachytherapy guidelines based upon their clinical experience and a review of the literature. The Board of Directors of the ABS approved the final report. RESULTS: Brachytherapy used alone or in combination with external beam irradiation is an established means of safely providing adjuvant local treatment after resection for soft tissue sarcomas in adults and in children. Brachytherapy options include low dose rate techniques with iridium 192 or iodine 125, fractionated high dose rate brachytherapy, or intraoperative high dose rate therapy. Recommendations are made for patient selection, techniques, dose rates, and dosages. Complications and possible interventions to minimize their occurrence and severity are reviewed. CONCLUSION: Brachytherapy represents an effective means of enhancing the therapeutic ratio, offering both biologic and dosimetric advantage in the treatment of patients with soft tissue sarcoma. The treatment approach used depends upon the institution, physician expertise, and the clinical situation. Guidelines are established for the use of brachytherapy in the treatment of soft tissue sarcomas in adults and in children. Practitioners and cooperative groups are encouraged to use these guidelines to formulate their treatment and dose-reporting policies. These guidelines will be modified, as further clinical results become available.

Comparison of continuous and pulsed low dose rate brachytherapy: biological equivalence in vivo.

PURPOSE: Recent studies of human cell lines cultured in vitro and mathematical modeling of the response of acute and late responding tissues have predicted conditions for the equivalence in terms of cell killing of continuous and pulsed dose rate brachytherapy. The aim of this study was to test these predictions in vivo using an acutely responding normal tissue. METHODS AND MATERIALS: The microcolony assay was used to quantify the survival of jejunal stem cells in vivo. Mice were exposed to graded doses of 60Co delivered continuously or as 1- or 10-min pulses given once-per-hour at an average dose rate of 0.7 Gy/hr. In both cases the total dose-per-hour was 0.7 Gy. Overall exposure times ranged between about 30 and 60 h. Mice were sacrificed 3.5 days after exposure, the bowel removed for routine histological preparation, and number of surviving crypts quantified microscopically. RESULTS: An average dose-per-hour of 0.7 Gy, a pulse width of 10 min, and a pulse frequency of 1 h resulted in biological equivalence of pulsed to continuous treatment. Delivering the pulse in a period of 1 min at a dose rate 10-fold higher resulted in a modest 3-4% shift in the survival curve to lower isoeffective doses. The slopes of the survival curves as described by D(o) values were similar for all treatment regimens tested. CONCLUSION: This in vivo study validates the prediction of biological equivalence between pulsed and continuous brachytherapy at a clinically relevant average dose rate and may generate further interest in this new treatment modality because of its advantages in radiation protection, dose optimization, and cost relative to standard low dose rate brachytherapy techniques.

Improved dose localization with dual energy photon irradiation in treatment of lateralized intracranial malignancies.

Dual energy photon irradiation (6 MV and 20 MV) was compared to conventional treatment planning with 6 MV photons in a lateralized intracranial malignancy. Dose volume analysis was performed of both the tumor plus a 2 cm margin (target volume, TV) and normal tissues (NT). Parallel opposed treatment using weightings of 1:1, 1.5:1, and 2:1 were compared for 6 MV photons alone or in combination with 20 MV photons. Uniform treatment of the TV was accomplished within the 60 Gy isodose. Significant differences were observed, however, in NT volumes receiving greater than or equal to 60 Gy and 45-59 Gy. Dual photon energy reduced treatment of NT volumes to greater than or equal to 60 Gy by 13% (177 cm3 vs 204 cm3 in 2:1 weighting) to 70% (147 cm3 vs 498 cm3 in 1:1 weighting) for comparable plans. Dose optimization was also performed for both 6 MV alone or in combination with 20 MV photons. Usual approaches to achieve dose lateralization with conventional isocentric techniques were applied including parallel opposed 6 MV photons ipsilaterally weighted 3.4:1 (POP), and a 110 degrees arc rotational field used to limit treatment to the eye (ARC). Dual energy photon optimized plans included a three beam parallel opposed plan (TOP) and a mixed photon ipsilateral (IPSI) approach. The technique using parallel opposed 20 MV photons and ipsilateral 6 MV photons (TOP) used beam weightings of 1.1 (contralateral 20 MVX): 1.6 (ipsilateral 6 MVX): 1 (ipsilateral 20 MVX) to achieve dose optimization. The ipsilateral approach with 6 MVX and 20 MVX (IPSI) used beam weightings of 1:1.4, respectively. All optimized plans demonstrated a 41% (120 cm3; POP) to 53% (95 cm3; TOP) improvement over parallel opposed 6 MV photons weighted 2:1 (204 cm3) in NT volume receiving greater than or equal to 60 Gy. Comparison of optimized treatment showed the IPSI plan to be superior, treating 12% of NT volume to greater than or equal to 60 Gy and 38% to 45-59 Gy; the 6 MV POP plan resulted in NT volumes of 15% and 51%, respectively, for those dose levels. Dual photon energy irradiation of lateralized intracranial malignancies allows reduction of dose to normal tissue volumes while achieving excellent coverage of the target volume. Treatment planning should be performed in all lateralized intracranial lesions to achieve dose optimization exploiting depth dose characteristics.