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Purpose : Although hyperthermia has been used for more than two decades in the treatment of pelvic tumors, little is known about the potential impact of heat on rectal toxicity when combined with other treatment modalities. Because rectal toxicity is a concern with radiation and may be exacerbated by hyperthermia, definition of the association of thermal dose parameters with rectal toxicity is important. In this report, we correlate rectal toxicity with thermal dose parameters for patients treated with hyperthermia and radiation for prostate cancer. Methods and Materials : Thirty patients with T2b-T3b disease (1992 American Joint Committee On Cancer criteria) enrolled in a Phase II study of external beam radiation ± androgen-suppressive therapy with two transrectal ultrasound hyperthermia treatments were assessed for rectal toxicity. Prostatic and anterior rectal wall temperatures were monitored for all treatments. Rectal wall temperatures were limited to 40°C in 19 patients, 41°C in 3 patients, and 42°C in 8 patients. Logistic regression was used to estimate the log hazard of developing National Cancer Institute Common Toxicity Criteria Grade 2 toxicity based on temperature parameters. The following were calculated: hazard ratios, 95% confidence intervals, p values for statistical significance of each parameter, and proportion of variability explained for each parameter. Results : Gastrointestinal toxicity was limited to Grade 2. The rate of acute Grade 2 proctitis was greater for patients with an allowable rectal wall temperature of >40°C. In this group, 7 of 11 patients experienced acute Grade 2 proctitis, as opposed to 3 of 19 patients in the group with rectal wall temperatures limited to 40°C (p = 0.004). Preliminary assessment of long-term toxicity revealed no differences in toxicity. Hazard ratios for acute Grade 2 proctitis for allowable rectal wall temperature, average rectal wall Tmax, and average prostate Tmax were 9.33 (p = 0.01), 3.66 (p = 0.03), and 2.29 (p = 0.08), respectively. A model combining these three parameters explained 48.6% of the variability among groups. Conclusion : Rectal toxicity correlates with maximum allowable rectal wall temperature, average rectal wall Tmax, and average prostate Tmax for patients undergoing transrectal ultrasound hyperthermia combined with radiation for treatment of advanced clinically localized prostate cancer. Further definition of this association of thermal dose parameters with rectal toxicity in treatment of pelvic malignancies with hyperthermia should advance the goal of delivering thermal therapy in an effective yet safe manner.

Late cardiac morbidity and mortality among left breast cancer survivors treated with radiation therapy is related to cardiac volume included in the radiation portals. To determine if respiratory maneuvers can help decrease cardiac volume included in the radiation portals for left-sided breast cancer, 17 women with breast cancer, who had undergone left breast radiation therapy, underwent cardiac magnetic resonance imaging (MRI). Cardiac volume within the radiation portals was assessed from a transverse stack of eight, 10-mm thick, contiguous slices, covering the entire heart and obtained during breathholding at (1) endtidal volume (ETid) and (2) deep inspiration. Fourteen subjects (93% of those who completed the study) had inclusion of at least a portion of their heart within the radiation portals at ETid (median: 25.9 cm3, range 4.2-119.1 cm3). In all subjects, inspiratory breathholding decreased irradiated cardiac volume [median change: -18.1 cm3 (-49%), por = 0.001 vs. ETid]. In 21% of patients, the entire heart could be displaced outside the radiation field with deep inspiration. Age was not correlated with change or percentage change in cardiac volume with respiratory maneuvers. We conclude that in breast cancer patients, deep inspiratory maneuvers significantly decrease irradiated cardiac volume included in the left breast radiation field. Such an approach during delivery of radiation therapy allows preservation of radiation dosage to the breast, while reducing cardiac involvement and possible associated cardiovascular toxicity.

Purpose: A previous study of healthy female volunteers suggested that deep inspiratory breath holding can reduce the cardiac volume in the treatment portals for left-breast cancer treatment. The reduction of irradiated cardiac volume may be important considering the reported late cardiac morbidity and mortality and the frequent coexistent use of potentially cardiotoxic chemotherapy in breast cancer patients. In the present study, we evaluated the heart volume in the fields and, thus, the true benefit of this respiratory maneuver in breast cancer patients undergoing CT simulation. Materials and Methods: Fifteen patients (median age, 53) were studied. For each patient, CT scans were performed both when the patient breathed normally (quiet respiration) and when the patient held her breath after a deep inspiration. Tangential fields were planned using the same medial, lateral, superior, and inferior borders on skin for the normal breathing and the breath-holding configurations. The cardiac and left-lung volumes within the tangential fields were calculated for both breathing configurations. Multiple scan series were performed for the breath-holding configuration to provide a more accurate delineation of the cardiac tissue and to study the reproducibility of the patient’s position between different cycles of deep inspiration. Results: None of the patients had difficulty holding her breath for 20 s. The cardiac volume in the field was reduced (−86 ± 24%; p < 0.001) when patients held their breath after a deep inspiration compared to when breathing normally. For 7 patients (47%), deep inspiration moved the heart completely out of the radiation fields. The expansion of the lung tissue due to deep inspiration also increased the absolute lung volume in the tangential fields (183 cm3 vs 97 cm3, p < 0.001). However, the fractional volume of the left lung in the field was essentially unchanged. For all but 1 patient, the maximum difference between the external body contours from different breath holding cycles was 5 mm and occurred at the lateral aspect of the breast. At the medial aspect, as indicated by the position of the midline marker, the variations were well within the currently accepted tolerance for patient positioning during tangential treatment. Conclusions: Deep-inspiration breath holding substantially reduces cardiac volume in the tangential fields for left-sided breast cancer treatment. The variation between patient positions at different cycles of breath holding was found to be reasonably small. Therefore, it appears feasible to reduce cardiac radiation by treating patients with intratreatment minifractions lasting 10–15 s while patients hold their breath.

To investigate if extracapsular extension (ECE) of axillary lymph node metastases predicts for a decreased rate of disease-free survival or an increased rate of regional recurrence of breast carcinoma.The study population consisted of 368 patients with T1 or T2 breast cancer and pathologically-positive lymph nodes treated with breast-conserving therapy between 1968 and 1986. The median number of sampled lymph nodes was 10. Median follow-up time for the surviving patients was 139 months (range 70-244). Twenty percent of the patients were treated with supraclavicular RT, and 64% received both axillary and supraclavicular RT, with a median dose to the nodes of 45 Gy. The following factors were evaluated: presence of ECE, number of sampled lymph nodes (LN), number of involved LN, size of primary tumor, histologic grade of tumor, presence of lymphatic vessel invasion (LVI), presence of an extensive intraductal component (EIC), radiation dose, use of adjuvant chemotherapy, and age of patient. Recurrences were reported as the 5-year crude sites of first failure, and were divided into breast recurrences (LR), regional nodal failure (RNF, defined as isolated axillary, supraclavicular, or internal mammary recurrence), and distant metastases (DM).One hundred twenty-two patients (33%) had ECE and 246 patients did not. The median number of LN with ECE was 1 (range 1-10) and 20% of patients had ECE inor =4 LN. Patients with ECE tended to be older (median age 51 vs. 47, p = 0.01), and had a higher number of involved LN (median 3 vs. 2, p = 0.005) than patients without ECE. Forty-three percent of patients with ECE hador =4 involved LN compared to 15% of patients without ECE (p0.0001). Models of ECE and the above factors revealed no significant correlation between ECE and either disease-free or overall survival. There was no statistically significant increase in local, regional nodal, or distant failures in patients with ECE as compared to patients without ECE.In this population of patients with nodal involvement, the presence of ECE correlates with the number of involved LN but does not appear to add predictive power to models of local, regional, or distant recurrence when the number of positive LN is included.

Background: The role of conservative surgery and radiation therapy (CS and RT) in the treatment of patients with infiltrating ductal carcinoma is well established. However, the efficacy of CS and RT for patients with infiltrating lobular carcinoma is less well documented. The goal of this study was to examine treatment outcome after CS and RT for patients with infiltrating lobular carcinoma and to compare the results to those of patients with infiltrating ductal carcinoma and patients with mixed ductal–lobular histology. Methods: Between 1970 and 1986, 1624 patients with Stage I or II invasive breast cancer were treated with CS and RT consisting of a complete gross excision of the tumor and ≥6000 cGy to the primary site. Slides were available for review for 1337 of these patients (82%). Of these, 93 had infiltrating lobular carcinoma, 1089 had infiltrating ductal carcinoma, and 59 had tumors with mixed ductal and lobular feature these patients constitute the study population. The median follow-up time for surviving patients was 133 months. A comprehensive list of clinical and pathologic features was evaluated for all patients. Additional histologic features assessed for patients with infiltrating lobular carcinoma included histologic subtype, multifocal invasion, stromal desmoplasia, and the presence of signet ring cells. Results: Five and 10-year crude results by site of first failure were similar for patients with infiltrating lobular, infiltrating ductal, and mixed histology. In particular, the 10-year crude local recurrence rates were 15%, 13%, and l3% for patients with infiltrating lobular, infiltrating ductal, and mixed histology, respectively. Ten-year distant/regional recurrence rates were 22%, 23%, and 20% for the three groups, respectively. In addition, the 10-year crude contralateral breast cancer rates were 4%, 13% and 6% for patients with infiltrating lobular, infiltrating ductal and mixed histology, respectively. In a multiple regression analysis which included established prognostic factors, histologic type was not significantly associated with either survival or time to recurrence. Conclusions: Patients with infiltrating lobular carcinoma have a similar outcome following CS and RT to patients with infiltrating ductal carcinoma and to patients with tumors that have mixed ductal and lobular features. We conclude that the presence of infiltrating lobular histology should not influence decisions regarding local therapy in patients with Stage I and II breast cancer.

PURPOSE To evaluate the safety and efficacy of breast-conserving therapy for young women with a family history (FH) suggestive of inherited breast cancer susceptibility. MATERIALS AND METHODS A total of 201 patients aged 36 or younger at diagnosis treated with breast-conserving surgery and radiation therapy (> or = 60 Gy) for early-stage breast cancer were categorized by FH. FH was considered positive in 29 patients who, at the time of diagnosis, had a mother or sister previously diagnosed with breast cancer before age 50 or ovarian cancer at any age. Clinical, pathologic, and demographic variables; sites of first failure; disease-free survival; and overall survival (OS) were compared between FH-positive and -negative groups. Median follow-up time was 11 years. RESULTS Patient and tumor features were similar between those with and without an FH. Regression analysis of sites of first failure at 5 years demonstrated a risk ratio (RR) of 5.7 for opposite breast cancer for FH-positive patients. Rates of local, regional, and distant failure and disease-free survival or OS did not differ between FH-positive and -negative patients. Age at diagnosis and Ashkenazi heritage were not significantly predictors of patterns of failure. CONCLUSION Breast-conserving surgery combined with radiation therapy is not associated with a higher rate of local recurrence, distant failure, or second (non-breast) cancers in young women with an FH suggestive of inherited breast cancer susceptibility compared with young women without an FH. However, their increased risk of opposite breast cancer should be taken into account when considering breast conservation as a treatment option.

Background Late cardiac morbidity and mortality have been reported among left-breast cancer survivors treated with radiation therapy. Radiation-induced cardiotoxicity is affected by the volume of myocardium included in the radiation portals. We hypothesize that simple respiratory maneuvers may alter the position of the heart relative to the portals without altering the radiation dose delivered to the breast. Methods and Results Fourteen healthy female adult volunteers underwent cardiac MRI to determine the cardiac volume included in the typical left-breast radiation field during respiratory maneuvers. Cardiac volume within the radiation portals was assessed from a transverse stack of 14 1-cm-thick contiguous slices covering the entire heart, obtained during breath holding at end-tidal volume (baseline), deep inspiration, and forced expiration. Thirteen subjects (92%) had inclusion of a portion of the heart within the radiation portals at end-tidal volume (median, 20.9 cm 3 ; range, 1.3 to 88.4 cm 3 ). In these subjects, inspiration decreased the cardiac volume included within the radiation portals (median change: −10.7 cm 3 [−40.2%], P 3 [21.5%]; P Conclusions Inclusion of a portion of the heart in the left-breast radiation field is common. The use of simple inspiratory maneuvers significantly decreases cardiac volume within the radiation portals. Such an approach during delivery of radiation therapy may allow for preservation of radiation dosage to the breast while reducing cardiac involvement and subsequent mortality.

There is a need for more clinical investigation in advanced local breast cancer. Both chemotherapy and endocrine therapy improve disease-free and overall survival and are now a routine part of standard patient care. Dose-intensive chemotherapy should be reserved for younger patients in large, controlled clinical trials. For operable patients, adequate surgical therapy of the breast and axilla remains a standard of care and provides the most important piece of prognostic information (i.e., the number of involved axillary lymph nodes). Tamoxifen treatment of the estrogen receptor-positive postmenopausal patient remains the standard, although chemotherapy may add a further increment to disease-free survival.

Purpose: To examine the long-term pattern and frequency of recurrences after breast-conserving therapy and whether the outcome was influenced by the era of treatment. Methods and materials: From 1968 to 1986, 1870 patients with unilateral Stage I or II breast cancer were treated at the Joint Center for Radiation Therapy. Of these, 1628 underwent goes tumor excision and received a dose >60 Gy to the tumor bed and constituted the study population. Patients were classified as without evidence of disease, dead from other causes (DOC), or by first site of recurrence. First sites of recurrent disease were categorized as distant/regional (DF/RNF or local (LR). Local recurrence was defined as the detection of any invasive site or in situ carcinoma occurring in the ipsilateral breast and was further categorized as: true recurrence (TR), marginal miss (MM), skin recurrence (S), or elsewhere in the breast cancer, (E). Median follow-up in survivors was 116 months. Eighty patients (4.9%) were lost to follow-up at 3–175 months. The population was divided into two time colors: 1968–1982 (1 = 810), with a median follow-up of 143 months, and 1983–1986 ( n -792), with a median follow-up time of 95 months. Result: The overall crude rates of ipsilateral breast recurrence were 7.4 and 13.3% at 5 and 10 years, respectively. Crude rates at 5 and 10 yeare were 5.7 and 9.3% for TR/MM and were 0.9 and 2.8% for E reccurences, respectively. The annual incidence rates for all LR ranged from 0.5 – 2.4% and was relatively constant after the first year. The annual incidence rates for TR/MM ranged from 0.4 to 1.9%, whereas for E recurrences the range was 0.1 – 0.7%. The crude rates of DF/RNF were 16.6 and 23.1 at 5 and 10 years respectively. The annual incidence rates for DF/RNF ranes from 1–5% over all years. Although the positive and node-negative patients. For the 1968–1982 and 1983–1986 cohorts, the 5-year crude rates of ipsilateral breast recurrence were 8.8 and 5.9%, respectively. Conclusion: Distant and regional nodal failures were the predominant form of recurrence. The annual incidence rate of LR was relatively constant over the first decade. True recurrence/marginal miss was the most frequent type of ipsilateral breast recurrence and was highest during years 2 through 7. The risk of a recurrence elsewhere in the breast increased with longer follow-up and was highest during years 8 through 10. The 5-year crude rate of ipsilateral breast recurrence appeared lower in the 1983–1986 patient cohort compared to the 1968–1982 patient cohort (8.8% vs. 5.9%), but the distributions of site of first failure did not differ significantly ( p = 0.13).. Any decrease in ipsilateral breast recurrence likely reflects improvements in mammographic and pathologic evaluation, patient selection, and the increased use of reexcision.

Purpose : To determine the risk of local-regional failure following post-mastectomy radiotherapy and the incidence of complications associated with such treatment. Methods and Materials : We retrospectively analyzed the results in 309 patients with Stage I–III invasive breast cancer treated with post-mastectomy radiation therapy between 1975 and 1985. The median radiotherapy dose was 45 Gy in 1.8 to 2.25 Gy fractions. One hundred forty-seven (48%) of the patients received adjuvant systemic chemotherapy with 115 (78%) of these receiving a CMF-based or doxorubicin-containing regimen. The median follow-up time of surviving patients was 130 months (range, 28 to 191 months) after mastectomy. Results : Seventeen patients (6%) developed a local-regional failure at an interval of 4 to 87 months after radiotherapy. Moderate or severe complications related to radiotherapy and requiring treatment were uncommon. Symptomatic radiation pneumonitis occurred in four patients (1.3%), arm edema in 18 (5.8%), and brachial plexopathy in 2 (0.6%). Conclusion : We conclude that post-operative radiotherapy is a safe and effective means of reducing local-regional failure following mastectomy. The efficacy of post-mastectomy radiotherapy in improving survival should be addressed in new large randomized controlled studies.

We retrospectively reviewed the response rate and the acute and long-term toxicity of combined treatment using radiation therapy, hyperthermia, and chemotherapy in 29 patients with locally or regionally recurrent or advanced adenocarcinoma of the breast who completed at least 4 of the 6 prescribed hyperthermia treatments as part of a Phase I-II trial. Thirty-nine separate hyperthermia treatment fields were evaluated. Cisplatin alone or cisplatin with etanidazole or bleomycin was delivered just prior to hyperthermia once weekly. Hyperthermia was delivered to a target minimum tumor temperature of 43 degrees C +/- 0.5 for 60 min. Following hyperthermia, a 400 cGy fraction of radiation was given. The radiation fraction size on other days was 200 cGy. Twenty-two fields had previously been irradiated and 17 fields had not. Prior chemotherapy had been given in 24 of 29 patients (83%) and hormonal therapy given in 21 (72%). The median follow-up time is 10 months; 16/29 patients (55%) have died of disease. The overall complete response rate for all fields was 53%. Response rate was not related to any clinical factor, radiation dose, microwave or ultrasound technique, type of chemotherapy, or tumor temperatures, but the number of patients in the study population was small. A statistically significant association between the likelihood of complications and the total radiation therapy dose (previous radiation and present radiation) was found. Persistent ulceration lasting greater than 1 month after completing treatment was seen in 67% of previously irradiated fields compared to 21% of fields that had not been previously treated (p = 0.015). Surgical wound repair was needed for 38% of fields with a history of prior irradiation versus 6% of those without prior treatment (p = 0.050). A statistically significant radiation therapy dose response was found for the likelihood of these complications. None of the hyperthermia temperature parameters studied correlated with an increased risk of complication. We conclude that the combination of radiation therapy, hyperthermia, and chemotherapy results in a high rate of complete response. However, in patients who have been treated with prior radiation therapy, this combination may be more locally toxic than treatment with hyperthermia and radiation therapy alone. The precise impact of chemotherapy on the therapeutic index of hyperthermia and radiation therapy remains to be determined in randomized clinical trials.

BACKGROUND: The authors present long-term results from a phase 2 study that assessed the efficacy of transrectal ultrasound hyperthermia plus radiation with or without androgen suppression for the treatment of locally advanced prostate cancer. METHODS: Patients with clinical T2b-T3bN0M0 disease (according to 1992 American Joint Committee on Cancer [AJCC] criteria) received radiation plus 2 transrectal ultrasound hyperthermia treatments. After the first 4 patients, 6 months of androgen suppression were allowed. The study was designed to assess absolute improvement in the 2-year disease-free survival rate compared with the short-term androgen suppression arm in Radiation Therapy Oncology Group (RTOG) study 92-02. RESULTS: Thirty-seven patients received a total of 72 hyperthermia treatments. The mean cumulative equivalent minutes (CEM) T9043°C was 8.4 minutes. According to the 1992 AJCC classification, there were 19 patients with T2b tumors, 8 patients with T2c tumors, 5 patients with T3a tumors, and 5 patients with T3b tumors. The median Gleason score was 7 (range, 6-9), and the median prostate-specific antigen (PSA) level was 13.3 ng/mL (range, 2-65 ng/mL). Thirty-three patients received androgen suppression. At a median follow-up of 70 months (range, 18-110 months), the 7-year overall survival rate was 94%, and 61% of patients remained failure free (according to the American Society for Therapeutic Radiology and Oncology definition for failure free survival). The absolute rate of disease-free survival at 2 years, which was the primary study endpoint, improved significantly (84%) compared with a rate of 64% for similar patients on the 4-month androgen suppression arm of RTOG 92-02. When Phoenix criteria (PSA nadir + 2 ng/mL) were used to define biochemical failure, 89% of patients were failure free at 2 years. CONCLUSIONS: Hyperthermia combined with radiation for the treatment of locally advanced prostate cancer appeared to be promising. The current results indicated that further study of hyperthermia for the treatment of prostate cancer with optimal radiation and systemic therapy is warranted. Cancer 2010. © 2010 American Cancer Society.

An analysis of 259 women with 261 treated breasts from nine institutions in Europe and the United States was performed to determine the 10-year results of the treatment of intraductal carcinoma of the breast with definitive irradiation. All patients had undergone complete gross excision of the primary intraductal carcinoma, and definitive breast irradiation was delivered in all cases. The median follow-up time was 78 months (range, 11 to 197 months). The 10-year actuarial overall survival rate was 94%, and the 10-year actuarial cause-specific survival rate (including deaths only from carcinoma of the breast) was 97%. The 10-year actuarial rate of freedom from distant metastases was 96%. There were 28 failures in the breast, and the 10-year actuarial rate of local failure was 16%. The pathologic type of local recurrences showed invasive ductal carcinoma in 14 of 28 recurrences (50%) and noninvasive ductal carcinoma in 14 of 28 recurrences (50%). The median time to local failure was 50 months (range, 17 to 129 months). Twenty-four of 28 patients with local failure were salvaged with additional treatment, generally mastectomy, and 4 of 28 patients with local failure subsequently had distant metastases. Median follow-up time after salvage treatment of breast recurrence was 29 months (range, 3 to 90 months). Two patients without local failure subsequently had distant metastases, one of which occurred after a node-positive, contralateral breast carcinoma. These results demonstrate high rates of overall survival, cause-specific survival, and freedom from distant metastases for the treatment of patients with intraductal carcinoma of the breast. The local recurrences within the treated breast were generally salvaged with additional treatment, although with limited follow-up. Because of the long natural history of intraductal carcinoma of the breast, prolonged and careful follow-up of patients after breast-conservation and definitive irradiation is required. Cancer 68:2337–2344, 1991.

To determine the frequency, pattern, and time course of tumor recurrence in the breast, the outcome of 38 women with ductal carcinoma in situ (DCIS) treated with conservative surgery and radiation therapy between 1976 and 1985 was studied. Surgery typically consisted of local excision without evaluation of the microscopic margins of resection. The median radiation dose to the tumor site was 6400 cGy. With a median follow-up time of 81 months, eight patients (21%) have experienced a recurrence in the breast. The time course to recurrence was protracted in some cases, with failures occurring at 17, 27, 43, 63, 71, 83, 92, and 104 months. The 5-year and 8-year actuarial rates of tumor recurrence in the breast were 8% and 27%, respectively. Seven patients had a recurrence at or near the primary tumor site, four with invasive carcinoma, and one had an invasive recurrence at a site elsewhere in the breast. No clinical or pathologic factor was significantly associated with an increased risk of recurrence, but the number of patients in the study population was small. The authors reached the following conclusions for patients with DCIS treated with conservative surgery and radiation therapy without careful mammographic and pathologic evaluation: (1) recurrence in the breast may be seen in at least one fifth of the patients; (2) recurrence typically occurs at or near the primary site; and (3) recurrence can occur long after treatment. Careful mammographic and pathologic assessment may be useful in reducing the local recurrence rate and should be considered essential if patients are considered for conservative surgery and radiation therapy.

A simple method of estimating the amount of lung irradiated in patients with breast cancer would be of use in minimizing lung complications. To determine whether simple measurements taken at the time of simulation can be used to predict the lung volume in the radiation field, we performed CT scans as part of treatment planning in 40 cases undergoing radiotherapy for breast cancer. Parameters measured from simulator films included: (a) the perpendicular distance from the posterior tangential field edge to the posterior part of the anterior chest wall at the center of the field (CLD); (b) the maximum perpendicular distance from the posterior tangential field edge to the posterior part of the anterior chest wall (MLD); and (c) the length of lung (L) as measured at the posterior tangential field edge on the simulator film. CT scans of the chest were performed with the patient in the treatment position with 1 cm slice intervals, covering lung apex to base. The ipsilateral total lung area and the lung area included within the treatment port were calculated for each CT scan slice, multiplied by the slice thickness, and then integrated over all CT scan slices to give the volumes. The best predictor of the percent of ipsilateral lung volume treated by the tangential fields was the CLD. Employing linear regression analysis, a coefficient of determination r 2 = 0.799 was calculated between CLD and percent treated ipsilateral lung volume on CT scan. In comparison, the coefficients for the other parameters were r 2 = 0.784 for the MLD, r 2 = 0.071 for L, and r 2 = 0.690 for CLD × L. A CLD of 1.5 cm predicted that about 6% of the ipsilateral lung would be included in the tangential field, a CLD of 2.5 cm about 16%, and a CLD of 3.5 cm about 26% of the ipsilateral lung, with a mean 90% prediction interval of ±7.1% of ipsilateral lung volume. We conclude that the CLD measured at the time of simulation provides a reasonable estimate of the percent of the ipsilateral lung treated by the tangential fields. This information may be of value in evaluating the likelihood of pulmonary complications from such treatment and in minimizing toxicity.

Hyperthermia is used to treat several pelvic tumours. An important step in establishing a broader role for hyperthermia in treatment of prostate cancer is verification of an acceptable toxicity profile. In this report, short- and long-term toxicity profiles of a completed phase II trial of transrectal ultrasound hyperthermia combined with radiation in treatment of locally advanced prostate cancer are presented.Thirty-seven patients enrolled on a phase II study of external beam radiation +/- androgen suppression with two transrectal ultrasound hyperthermia treatments were assessed for short- and long-term toxicity. Prostatic and anterior rectal wall temperatures were monitored. Rectal wall temperatures were limited to 40 degrees C (19 patients), 41 degrees C (three patients) and 42 degrees C (15 patients). Univariate logistic regression was used to estimate the log hazard of developing NCI CTC Grade 2 toxicity based on temperature parameters. Hazard ratios, 95% confidence intervals, p-values for statistical significance of each parameter and proportion of variability explained for each of the parameters were calculated.Median follow-up was 42 months. Both short- and long-term GI toxicity were limited to grade 2 or less. Acute grade 2 proctitis was greater for patients with allowable rectal wall temperature of40 degrees C. Eleven of 18 patients in this group had acute grade 2 proctitis vs three of 19 patients with rectal wall temperatures limited to 40 degrees C (p = 0.004). Long-term grade 2 GI and GU toxicity occurred in 5% and 19% of patients. No late grade 3 or greater toxicity occurred. Late GI and GU toxicity were not associated with the allowable rectal wall temperature.Transrectal ultrasound hyperthermia combined with radiation for treatment of advanced clinically localized prostate cancer is safe and well tolerated.

179 Background: The optimal management of uncomplicated spinal vertebral metastases has yet to be determined. Preliminary evidence, suggesting single fraction therapy may be associated with fewer gastrointestinal side effects, did not report radiotherapy (RT) technique. Recent clinical experience with more advanced imaging and treatment delivery systems leads us to question if this approach is optimal given the radiation therapy dose to the surrounding normal tissues. The purpose of this study is to examine the impact of current RT techniques on normal tissue dose, which is known to affect acute tolerance of sensitive organs. The focus is on the bowel, an organ known for its radio-sensitivity which can impact quality of life. Methods: In a de-identified treatment planning CT of a patient with spinal metastases, the target volume of vertebrae from T9-L5 was defined and the normal bowel was outlined. Five RT techniques were planned: 1) the former standard, posterior/anterior (PA) 6MV field prescribed to a depth of 5 cm, 2) a PA 18MV field prescribed to a depth of 5 cm, 3) an opposed AP/PA dual energy plan, weighted posteriorly 2:1, 4) a 3-field 18MV plan (PA & 2 posterior oblique fields), and 5) an intensity modulated radiotherapy (IMRT) plan, using 4 arcs. The last 3 techniques were optimized to minimize anterior dose to the bowel. Results: The 5 techniques delivered varying RT doses (Dmax%) to the bowel ranging from the highest (AP/PA dual energy plan) to the lowest (IMRT), expressed as a percentage of the prescription dose. Conclusions: Single fraction RT techniques, with the exception of IMRT, approach tolerance (Dmax%) for some bowel tissue, which may preclude retreatment. IMRT would also allow for dose escalation to the spinal target volume, possibly improving efficacy and reducing the need for retreatment. Future studies should report RT technique, dose and fractionation to optimize efficacy and tolerance. [Table: see text]

189 Background: Tissue perfusion may be a significant factor affecting outcome of prostate cancer treatment. Hyperthermia has been shown to have beneficial anti-cancer effects when combined with other anti-neoplastic modalities including radiation, chemotherapy, and immunotherapy. For instance, hyperthermia may increase prostate perfusion resulting in radiosensitization through increased oxygenation and chemotherapy through enhanced drug delivery. We previously reported significant benefit to the addition of hyperthermia to radiation on a phase II trial for men with locally advanced prostate cancer. To better understand tissue perfusion in patients with prostate cancer and response to hyperthermia, we measured perfusion levels in patients on this trial before and after hyperthermia. Methods: Prostate perfusion was measured before and immediately after heating in a total of 21 hyperthermia treatments in 14 patients with prostate cancer. A trans-rectal ultrasound device with a water cooled jacket was used to heat the prostate. Prostate tissue temperatures were measured using three multisensory thermocouple probes. Perfusion was measured with the TDP-200 Thermal Diffusion Probe, a thermistor-based device which quantifies perfusion with a modified wash-out technique. Results: In 19 treatments in which perfusion was measured before heating, average and standard deviation was 18.3 ± 10.6 ml/100g-min and in 17 treatments in which perfusion was measured after heating, it was 30.7 ± 20.8 ml/100g-min. This represents a statistically significant increase of 68% (p = 0.018). Perfusion increased 12 of 15 treatments in which measurements were obtained before and after hyperthermia. Notably, prostate tissue that was most ischemic prior to heating experienced the largest heat-induced perfusion increase. Conclusions: Prostate perfusion increased significantly with a majority of hyperthermia treatments. Enhanced prostate oxygenation may have been a contributing factor to the benefit noted with hyperthermia in this phase II trial. The use of hyperthermia to augment prostate perfusion to enhance radiation, chemotherapy, and immunotherapy warrants further investigation.

PURPOSE To determine whether left-breast irradiation using modern techniques after breast-conserving surgery leads to an increased risk of cardiac-related mortality. METHODS Between 1968 and 1986, 1,624 patients were treated for unilateral stage I or II breast cancer at the Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA, with conservative surgery and breast irradiation. Seven hundred forty-five patients with a potential follow-up of at least 12 years were analyzed. Clinical, pathologic, and treatment characteristics were compared between the 365 patients (49%) who received left-sided irradiation and the 380 patients (51%) who received right-sided irradiation. The relationship between left-sided breast irradiation and the risk of nonbreast cancer- and cardiac-related mortality was examined. RESULTS There was no significant difference in the distribution of clinical, pathologic, or treatment characteristics between the two groups, with the exception of a small difference in pathologic tumor size (medians, left, 2.0 cm, right, 1.5 cm; P = .007). At 12 years, a majority of patients still were alive. Slightly more patients with left-sided tumors had died of breast cancer (31% v 27%; P = NS). Equivalent proportions from each group died of nonbreast cancer causes (11%), including nine patients (2%) from each group who died from cardiac causes. The risk of cardiac mortality did not increase as time after treatment increased for patients who received left-sided irradiation compared with right-sided irradiation. A model that controlled for clinical, pathologic, and treatment differences showed no significant increase in any category of cause of death (breast, cardiac, or other) for patients who received left-sided irradiation. CONCLUSION These results suggest that modern breast radiotherapy is not associated with an increased risk of cardiac-related mortality within at least the first 12 years after treatment.

Purpose: To determine the impact of intraoperative radiation therapy (IORT) combined with preoperative external beam irradiation and surgical resection in patients with locally advanced, unresectable rectal carcinoma. Methods and Materials: Between 1982 and 1993,40 patients with locally advanced colorectal cancer unresectable at initial presentation were treated with preoperative external beam radiation therapy (median dose 50.4 Gy ). Thirty patients received concurrent 5-fluorouracil. Twenty-seven patients had primary tumors and 13 had recurrent disease; 1 patient had a solitary hepatic metastasis at the time of surgery. Four to 6 weeks after radiation, surgical resection was undertaken, and if microscopic or gross residual disease was encountered, IORT was delivered to the tumor bed. Patients with an unevaluable or high-risk margin were also considered for IORT. IORT was delivered through a dedicated 300-kVp orthovoltage unit. The median dose of IORT was 12.5 Gy (range S-20). The dose was typically prescribed to a depth of 1-2 cm. The median follow-up was 33 months (range 5-100). Results: Thirty-three patients were able to undergo a curative resection (83% ). Five patients had gross residual disease despite aggressive surgery. Seven patients did not receive IORT: six because of clear margins, and one with gross disease that could not be treated for technical reasons. The remainder of the patients (26) received IORT to the site of pelvic adherence. The crude local control rates for patients following complete resection with negative margins were 92% for patients treated with IORT and 33% for patients without IORT. IORT was ineffective for gross residual disease. Pelvic control was none of four in this setting. The crude local control rate of patients with primary cancer was 73% (16 of 22), as opposed to 27% (3 of 11) for these with recurrent cancer. The 5-year actuarial overall survival and local control rates for patients undergoing gross complete resection and IORT were 64% and 75%, respectively. Seventeen of the 26 patients (65%) who received IORT experienced pelvic compIicatious, as opposed to two patients (28% ) who did not receive IORT. The incidence of complications was similar in the patients with primary versus recurrent disease. Al1 cases were successfully treated with the placement of a posterior thigh myocutaneous flap. Of note, no pelvic osteoradionecrosis was seen in this series. Conclusion: Patients with locally advanced carcinoma of the rectum were aggressively treated with combined modality therapy consisting of preoperative external beam radiotherapy, surgery, and IORT. The pelvic control rate was 82% for patients with minimal residual disease. IORT failed to control gross residual disease. The incidence of pelvic wound healing problems was 65% in this series; however, a reconstructive procedure which replaced irradiated tissue with a vascularized myocutaneous flap was successful in treating this complication. We believe that IORT has therapeutic merit in the treatment of locally advanced rectal cancer, particularly in the setting of minimal residual disease. 0 1997 Elsevier Science Inc.

This paper describes the design of a novel ultrasonic therapy system dedicated to the breast cancer treatment and the theoretical investigation of the heating characteristics of the system. The applicator is a cylinder comprised of a stack of rings. Each ring has up to 48 transducers mounted on the inside of the ring and directed towards the centre. The transducers operate in one of two frequency bands (1.8-2.8 MHz and 4.3-40.8 MHz), arranged alternately in each ring. During treatment the patient is positioned in prone position, with the breast immersed in water and surrounded by this array. This design was modelled and optimized by 3-D simulations for a variety of treatment conditions. The simulated results demonstrate that the system has an excellent capability to achieve and maintain a temperature distribution (41.5-44 degrees C) in a quadrant to a whole breast. Initial experiments using a single ring of transducers has been performed to verify the power deposition calculation.

A site-specific ultrasound hyperthermia system has been designed for the treatment of intact breast. The system incorporates both therapeutic and imaging capabilities utilizing a cylindrical array applicator which surrounds the breast with the patient in a prone position. It is dedicated to optimizing the synergistic effect between thermal therapy and radiation in the treatment of early stage breast disease in patients with an extensive intraductal component of tumor

Hyperthermia causes widespread changes in cellular behaviour in both in vitro and in vivo. We have shown in the present study that heat shock leads to activation of membrane enzyme phospholipase A2, leading to increases in concentrations of arachidonic acid and products metabolized through the cyclooxygenase and 5-lipoxygenase pathways. The eicosanoids are extremely pleiotropic agents and may mediate many of the effects of hyperethermia on cells and tissues. We have shown in this study that the cyclopentanone prostaglandin A2 induces the synthesis of heat shock proteins 70 and 90. The synthesis of hsps was correlated with activation of the cell cycle dependant E2F transcription factor.

Heat shock has a profound influence on the metabolism and behavior of eukaryotic cells. We have examined the effects of heat shock on the release from cells of arachidonic acid and its bioactive eicosanoid metabolites, the prostaglandins and leukotrienes. Heat shock (42-45 degrees) increased the rate of arachidonic acid release from human, rat, murine, and hamster cells. Arachidonate accumulation appeared to be due, at least partially, to stimulation of a phospholipase A2 activity by heat shock and was accompanied by the accumulation of lysophosphatidyl-inositol and lysophosphatidylcholine in membranes. Induction of arachidonate release by heat did not appear to be mediated by an increase in cell Ca++. Stimulation of arachidonate release by heat shock in hamster fibroblasts was quantitatively similar to the receptor-mediated effects of alpha thrombin and bradykinin. The effects of heat shock and alpha thrombin on arachidonate release were inhibited by glucocorticoids. Increased arachidonate release in heat-shocked cells was accompanied by the accelerated accumulation of cyclooxygenase products prostaglandin E2 and prostaglandin F2 alpha and by 5-lipoxygenase metabolite leukotriene B4. Elevated concentrations of arachidonic acid and metabolites may be involved in the cytotoxic effects of hyperthermia, in homeostatic responses to heat shock, and in vascular and inflammatory reactions to stress.

A Phase I–II trial testing the addition of systemic cisplatin (CDDP) to local hyperthermia and radiation was conducted to determine the dose of cisplatin that is tolerable once weekly for 6 weeks and to estimate the therapeutic potential of this trimodality combination in patients with locally advanced malignancies. Cisplatin at 20 mg/m 2 (4 patients), 30 mg/m 2 (8 patients), and 40 mg/m 2 (12 patients) was given rapidly (over 5–10 min) i.v. after prehydration with 1 liter of normal saline. After approximately two-thirds of the cisplatin dose had been delivered, microwave hyperthermia was begun and continued for 60 min; the target minimum tumor temperature was 43°C. Following hyperthermia, a 400 cGy fraction of radiation was delivered to the tumor. On other days during the treatment weeks, additional 200 cGy fractions were given to total doses of 6,000–6600 cGy in patients with full radiation tolerance or 2400–3600 cGy in patients with limited radiation tolerance. The 24 patients in this trial had a median age of 57 years and the predominant sites/tumor types were head and neck/squamous cell carcinoma (9) and chest wall/breast adenocarcinoma (9). Seventeen of the 24 treated tumors (70%) had previously been irradiated. Eighteen patients (75%) had received prior chemotherapy and nine patients (38%) had previously been treated with cisplatin. Bone marrow suppression was dose limiting in patients heavily pretreated with chemotherapy and chest wall radiation. No significant toxicities were observed at the 20 and 30 mg/m 2 dose levels, but 5 of the 12 patients (42%) treated at 40 mg/m 2 required modification of the cisplatin dose because of blood count suppression in four patients and mild renal dysfunction in one patient. Each of the patients with bone marrow suppression, however, had been heavily pretreated except for one patient with thrombocytopenia due to hypersplenism. Nausea and vomiting were mild with use of a standard, multiagent antiemetic regimen. Twelve patients (50%) attained a complete regression (CR) and 12 patients (50%) a partial regression (PR). Complete regression appeared to correlate with smaller tumor volumes (115 cc for CR versus 199 cc for PR patients) and higher tumor temperatures (4.6 average minimum equivalent minutes at 43°C in CR versus 2.0 min in PR patients). Local toxicities included second degree burns in 12 patients (50%) and third degree burns in 6 (25%), but all burns healed in 4–12 weeks without surgical intervention. There was no significant increase in acute radiation reactions. This protocol proved feasible and effective, although time consuming. A cisplatin dose of 30 mg/m 2 i.v. weekly for 6 weeks appears tolerable even in heavily pretreated patients. The dose of cisplatin that is tolerable in untreated patients is at least 40 mg/m 2 weekly for 6 weeks and may well be higher but has yet to be determined.