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Purpose : To evaluate the impact of prolonged overall radiation treatment (RT) time and surgery-to-radiation interval on local control (LC) and disease-specific survival (DSS) of surgically staged endometrial cancer patients in relation to known prognostic factors. Methods and Materials : Between 1971 and 1993, 195 endometrial cancer patients received postoperative RT at the Fox Chase Cancer Center. All patients underwent total abdominal hysterectomy (TAH), with 38% also having lymph node sampling. All patients received whole pelvic external beam RT to a median dose of 45 Gy (range 40 to 60 Gy). Sixty-nine percent received a vaginal cuff boost with either low dose rate or high dose rate brachytherapy. Tumor and treatment factors were analyzed for impact on LC and DSS. Median follow-up was 47 months (range : 6 to 187 months). Results : The overall actuarial 5-year LC rate was 85%. In multivariate analysis, tumor grade, pathologic stage, external radiation dose, and surgical lymph node evaluation were independent prognostic variables for improved LC. Surgery-to-radiation interval of greater than 6 weeks was a marginally signficant factor for decreased LC (p = 0.06). Overall RT time and external beam treatment time did not appear to impact LC rates. The overall actuarial 5-year DSS rate was 86%. In multivariate analysis, depth of myometrial invasion, tumor grade, and pathologic stage were independent prognostic variables for DSS. In addition, a surgery-to-radiation interval of greater than 6 weeks was significantly associated with decreased DSS (p < 0.005). Conclusions : Surgery-to-radiation interval of greater than 6 weeks is a significant independent prognostic variable for decreased DSS and a marginally significant variable for decreased LC in patients irradiated postoperatively for endometrial cancer. Other time factors (overall RT time and external beam treatment time) did not appear to impact outcome. Based on this analysis, postoperative radiation therapy for endometrial cancer should be initiated within 6 weeks following surgery.

Purpose : To evaluate the influence of dose fractionation and other factors on the development of late complications in mandibular bone, muscle, and mucosa of the oral cavity after external beam radiation therapy for carcinoma of the tonsil. Methods and Materials : A retrospective analysis was made of the results in 676 patients treated with a spectrum of fractionation regimens in nine centers during the years 1976–1985. Only severe (Grades 3–4) late complications were analyzed. Purpose : With more than 5 years follow-up, it was found that total dose was a factor for all three types of compliations, but that in other respects, the radiobiology of late-(>3 months) developing mucosal ulcerations was different from that for mandibular necrosis and muscle injury. Dose per fraction was a significant factor for bone and muscle (estimated α/β values of 0.85 Gy and 3.1 Gy, respectively). By contrast, mucosa showed no influence on response from change in fraction size over the range of approximately 1.0–3.5 Gy. Complications in bone and muscle were not related to overall treatment duration, whereas there was a significant inverse relationship for mucosa breakdown. The rate of development of complications was fastest in mucosa and slowest in bone. The appearance of complications by 4 years after treatment was about 80% of those developing by 8 years in the mucosa, 66% in muscle, and about 50% in bone. The high α/β ration, inverse relationship with overall treatment duration, and faster development of mucosal complications suggests that they may develop as a consequence of earlier mucosal injury. As anticipated, adequate retrospective analysis of acute complications could not be amde even when objective criteria such as weight loss, unplanned delays in completing treatment, or hospitalizations during treatment were the measures. Field size was a significant factor for mandible complications, but not for muscle or mucosa. Conclusions : The radiobiological characteristics of bone and muscle were those characteristics of other late-responding tissues, whereas late sequelae in mucosa had radiobiological parameters similar to those for acute responses. Field size was a significant factor for bone complications but not for others.

We demonstrate the 5-year survival rate for patients with prostate cancer treated by irradiation, the value of the conformal technique and prostate specific antigen (PSA) doubling times after irradiation.The outcome of 502 consecutive patients with stages T1 to T3 prostate cancer treated by irradiation alone is reported. PSA doubling times before and after failure are reported for 13 patients and posttreatment PSA doubling times are reported for 93 consecutive patients in whom radiation failed.The actuarial survival with biochemical freedom from disease (PSA nadir 1.5 or less not increasing) at 5 years was 44% for all patients, 50% for the conformal treatment group and 39% for the conventional therapy group. PSA doubling times after radiation failure were variable, with 42% greater than 12 months.The 5-year survival rate for patients with prostate cancer treated by irradiation is excellent. The conformal technique is superior to conventional therapy and there is no evidence that irradiation accelerates the growth rate of prostate cancer.

Purpose : The incidence of adenocarcinoma of the esophagus is increasing, but the optimal treatment for this disease is unknown. We evaluated the efficacy of chemoradiation and chemoradiation followed by esophagectomy as treatment for adenocarcinoma of the esophagus in sequential prospective nonrandomized phase II studies. Methods and Materials : Between May 1981 and June 1992, all previously untreated patients (N = 35) with potentially resectable adenocarcinoma of the esophagus (clinical Stage I or II) were treated with curative intent in sequential prospective Phase II studies. From May 1981 to August 1987, 11 patients (median age 66) were treated with concurrent chemotherapy [mitomycin C, and 5-fluorouracil (5-FU)] and radiotherapy to a median dose of 60 Gy (CRT group). From September 1987 to June 1992, 24 patients (median age 65) were treated with the same regimen of chemoradiation followed by planned esophagectomy (CRT + PE group). Of these, 12 patients (median age 62) actually underwent esophagectomy (CRT + E subgroup). Results : The median overall survival was 19 months for the CRT group and 15 months for the CRT + PE group. For the CRT + E subgroup, the median overall survival was 33 months. The 3-year actuarial overall survival for the CRT and the CRT + PE groups were 36 and 28% (p = 0.949). The subset of patients treated with chemoradiation followed by esophagectomy had a 3-year actuarial overall survival of 33% (p = 0.274). The 3-year actuarial freedom from local failure rates were similar : 62% in the CRT group vs. 58% in the CRT + PE group. Of the 12 patients who underwent esophagectomy (CRT + E group), 9 (75%) were free of local failure. Four of 12 (33%) patients had no pathologic evidence of malignancy in their surgical specimen. Six of 11 patients (55%) in the CRT group were free of local failure at the time of analysis. Two of five patients in this group who had local recurrence at 2 and 10 months underwent surgical salvage with subsequent survivals of 20 and 100 months, respectively. Treatment-related mortality was 0 out of 11 in the CRT group and 2 out of 24 in the CRT + PE group. Dysphagia relief was similar in the CRT group vs. the CRT + E subgroup ; however, a greater percentage of patients treated with chemoradiation alone had normal long-term swallowing function when compared to those patients also undergoing esophagectomy (100% vs. 73%). Conclusion : High-dose chemoradiation alone appears to provide similar survival and relief of dysphagia compared with high-dose chemoradiation followed by esophagectomy for patients with potentially resectable esophageal adenocarcinoma. Local failure may be higher in patients undergoing chemoradiation compared to chemoradiation followed by esophagectomy, but surgical salvage is possible, thus providing similar overall local control. However, because of the small number of patients in each group, these treatment modalities need to be further evaluated in a prospective randomized Phase III study.

Although prostate specific antigen (PSA) density appears to be an important discriminator between benign and malignant prostatic disease, conflicting data exist concerning its prognostic value. The present study was undertaken to confirm whether PSA density represents a new prognostic indicator of disease-free survival for prostate cancer treated with conformal radiotherapy. Between April 1989 and December 1992, 186 patients with organ confined prostate cancer were treated with definitive irradiation according to previously published conformal guidelines. The PSA density was defined as the ratio of the pretreatment serum PSA (ng./ml.) to the prostate volume (ml.) as determined from treatment planning computerized tomography. The median PSA density was 0.15 with a range of 0.02 to 2.12. A statistically significant advantage in actuarial freedom from biochemical relapse was noted for patients with pretreatment PSA levels less than 15 ng./ml. when compared to those with higher pretreatment PSA levels...

Background. This paper presents the results of external beam treatment of prostate cancer. Long term results are represented by the U.S. national averages from the Patterns of Care study. The modern innovations of three-dimensional-assisted conformal treatment are also shown to demonstrate the technologic progress in external beam treatment, the effect of pretreatment prostate specific antigen (PSA), the inaccuracy of clinical end points used for 30 years, and the new early outcome standards for the 1990s. Methods. The Patterns of Care study has surveyed the national practice for processes of care and outcome of care in the United States. Ten- and 15-year outcomes are reported for patients treated in 1973 and 1978 by external beam irradiation. The conformal radiation therapy program developed at Fox Chase Cancer Center since 1989 is used to illustrate the advantage of this technology, the importance of pretreatment PSA level on outcome, the inaccuracies in clinical end point evaluation, and the reduction in morbidity associated with conformal treatment. Three hundred seventy-three consecutive patients treated with conformal therapy were compared with 129 consecutive conventionally treated patients for survival end points. The outcome of 460 consecutive patients with pretreatment PSA are presented by pretreatment PSA level. Late morbidity is presented for 208 consecutive conformal treated patients who received 68-71 Gy to the center of the prostate. Cancer control is defined as biochemical control of cancer (bNED) and requires a nonrising PSA with a nadir of less than or equal to 1.5 ng/ml. Results. Conformal treatment was superior to conventional in 12-month PSA response (P = 0.00005), 4-year bNED (P < 0.005), and multivariate analysis (P < 0.04). The difference between clinical absence of disease and bNED at 4 years was 8% for pretreatment PSA less than 10 ng/ml, 51% for PSA 10-20 ng/ml, and 57% for pretreatment PSA greater than 20 ng/ml. Acute morbidity of conformal therapy was reduced (P < 0.00001), and late morbidity was observed at 5 years in only 4.2% of 208 consecutive patients treated to 68-71 Gy. Conclusions. The conformal treatment method is superior to conventional treatment, and this technology should be further developed and disseminated. Dose escalation beyond 68-71 Gy is not indicated by these data, although these results are preliminary, with short term follow-up for the conformal group and longer follow-up for the conventional group. PSA evaluation of cancer control shows that 83% of patients presenting with a pretreatment PSA level less than 10 are bNED at 5 years and only 13% of those with pretreatment PSA level greater than 20. Cancer 1995 ;75 :1972-7.

This report reviews the anatomical, pathophysiological, and clinical aspects of radiation injury to the central nervous system (CNS). Despite the lack of pathognomonic characteristics for CNS radiation lesions, demyelination and malacia are consistently the dominant morphological features of radiation myelopathy. In addition, cerebral atrophy is commonly observed in patients with neurological deficits related to chemotherapy and radiation, and neurocognitive deficits are associated with diffuse white matter changes. Clinical and experimental dose-response information have been evaluated and summarized into specific recommendations for the spinal cord and brain. The common spinal cord dose limit of 45 Gy in 22 to 25 fractions is conservative and can be relaxed if respecting this limit materially reduces the probability of tumor control. It is suggested that the 5% incidence of radiation myelopathy probably lies between 57 and 61 Gy to the spinal cord in the absence of dose modifying chemotherapy. A clinically detectable length effect for the spinal cord has not been observed. The effects of chemotherapy and altered fractionation are also discussed. Brain necrosis in adults is rarely noted below 60 Gy in conventional fractionation, with imaging and clinical changes being observed generally only above 50 Gy. However, neurocognitive effects are observed at lower doses, especially in children. A more pronounced volume effect is believed to exist in the brain than in the spinal cord. Tumor progression may be hard to distinguish from radiation and chemotherapy effects. Diffuse white matter injury can be attributed to radiation and associated with neurological deficits, but leukoencephalopathy is rarely observed in the absence of chemotherapy. Subjective, objective, management, and analytic (SOMA) parameters related to radiation spinal cord and brain injury have been developed and presented on ordinal scales.

PURPOSE To determine the 5-year rate of survival with no evidence of disease (NED) using strict biochemical criteria in men with prostate cancer treated by external-beam radiotherapy alone and to examine possible clinical and treatment factors that predict the likelihood of NED survival. MATERIALS AND METHODS Five hundred men with clinically localized prostate cancer consecutively treated with external-beam radiotherapy alone with no prior, concomitant, or adjuvant endocrine therapy were identified. All patients had serial serum prostate-specific antigen (PSA) values determined after treatment and 451 patients had pretreatment PSA values determined. The median follow-up duration is 20 months (range, 2 to 72; mean, 36). RESULTS The 5-year rate of overall survival in this group of patients was 80%. The 5-year rate of survival without clinical evidence of disease (cNED) was 72%. The 5-year rate of survival without evidence of clinical, radiographic, or biochemical relapse (bNED) was 51%. Multivariate analysis demonstrated that a pretreatment serum PSA level < or = 15 ng/mL was the most important predictor of bNED survival (P < .0001). Patients with early-stage (T1, T2a/b) tumors and a pretreatment serum PSA less than 15 ng/mL had a 3-year rate of bNED survival of 86%. The rate of bNED survival for patients with a pretreatment PSA level greater than 15 ng/mL was 38% at 3 years. CONCLUSION Pretreatment serum PSA level is the most important predictor of treatment outcome in this group of patients treated with definitive radiotherapy alone. External-beam radiation alone can produce acceptable early rates of bNED survival in patients with clinically organ-confined tumors and a pretreatment PSA level < or = 15 ng/mL. To produce acceptable results in those patients with pretreatment PSA levels more than 15 ng/mL, effective adjuvant treatments in addition to aggressive local treatments are necessary.

302 Background: Our purpose was to assess the utilization of dose escalated radiotherapy (RT) in Stage III NSCLC patients in the United States from 2004-2013, a period when no Level 1 evidence on dose escalation was published. Methods: Data on all NSCLC patients treated with RT were extracted from the National Oncology Data Alliance (NODA), a pooled database of cancer registries from >150 US hospitals. The NODA contains the same data submitted to state cancer registries and SEER, but also contains RT dose fields that are manually verified by trained staff. Search algorithms to identify patients with complete RT dose data and who met the RTOG 0617 eligibility criteria were developed and validated by manual chart review at two institutions. The search algorithm positive predictive values for RT dose and RTOG 0617 eligibility were 97% and 91%, respectively. The primary endpoint was utilization of dose escalated RT, defined as >70 Gy. Multivariate logistic regression (MVA) was used to measure the association of treatment year with dose escalated RT use in two predefined periods straddling the early closure of RTOG 0617 on 6/17/2011: Period 1 2004-2010 and Period 2 2010-2013. To address potential limitations in generalizability, we repeated the same analysis in the National Cancer Database (NCDB). Results: The percentage of patients treated with >70 Gy increased monotonically from 22% in 2004 to 37% in 2010 and then declined to 20% in 2012. On MVA, increasing utilization of doses >70 Gy was observed during Period 1 (p70 Gy in Stage III NSCLC patients treated from 2004-2010 followed by a decline after 2010. RT dose may be an important standardization metric in national quality initiatives.

Purpose: To determine pretreatment prostate-specific antigen doubling times (PSADT) in patients referred for definitive radiotherapy. Methods and Materials: One hundred and seven patients with histologically proven nonmetastatic prostate cancer and an elevated prostate-specific antigen (PSA) who were referred for radiation therapy had three serum PSA values obtained prior to the start of definitive therapy. Prostate-specific antigen doubling times were calculated by linear regression. Results: Prostate-specific antigen values increased during the period of observation in 78 patients (73%). Forty-three patients (40%) had calculated PSADT of less than 2 years and of those patients with pretreatment serum PSA values of greater than 10 ng/mL more than 50% has calculated PSADT of less than 2 years. Conclusions: A significant of minority of patients referred for radiotherapy have calculated PSADT of less than 2 years. The significance of this relatively fast growth rate is as yet undertermined, but suggests that patients referred for radiotherapy may have aggressive disease prior to treatment.

Radiation myelopathy is a rare but devastating injury to the spinal cord that usually results from an excessive radiation dose. In this chapter, we discuss the traditional and current understandings of the pathogenesis of this injury. A distinction is made between radiation damage, which occurs at the subcellular level, and radiation injury, which occurs at the tissue and organ level in response to radiation damage. Recent findings regarding the amelioration and treatment of both radiation damage and radiation injury are explored. These studies are promising developments but, as always, there are attendant caveats.

Background. The patterns of radiation care of elderly patients with prostate cancer treated with radiation therapy have not been described. As our population ages and screening increases the number of patients diagnosed, this becomes an important issue. Methods. The U.S. national surveys in prostate cancer conducted by the Patterns of Care Study in radiation oncology and the prostate cancer database from the Department of Radiation Oncology of the Fox Chase Cancer Center (Philadelphia, PA) have been used to compare processes and outcomes of conventional radiation treatment with conformal three-dimensional (3D) radiation treatment in elderly patients (older than or equal to 70 years) compared with younger patients

Purpose: An experiment was conducted to test for the existence of a volume effect in radiation myelopathy using Rhesus monkeys treated with clinically relevant field sizes and fractionation schedules. Methods and Materials: Five groups of Rhesus monkeys were irradiated using 2.2 Gy per fraction to their spinal cords. Three groups were irradiated with 8 cm fields to total doses of 70.4, 77, and 83.6 Gy. Two additional groups were irradiated to 70.4 Gy using 4 and 16 cm fields. The incidence of paresis expressed within 2 years following the completion of treatment was determined for each group. Maximum likelihood estimation was used to determine parameters of a logistic dose response function. The volume effect was modeled using the probability model in which the probability of producing a lesion in an irradiated volume is governed by the probability of the occurrence of independent events. This is a two parameter model requiring only the estimates of the parameters of the doseresponse function for the reference volume, but not needing any additional parameters for describing the volume effect. Results: The probability model using a logistic dose-response function fits the data well with the D 50 = 75.8 Gy for the 8-cm field. No evidence was seen for a difference in sensitivities for different anatomical levels of the spinal cord. Most lesions were type 3, combined white matter parenchymal and vascular lesions. Latent periods did not differ significantly from those of type 3 lesions in humans. Conclusion: The spinal cord exhibits a volume effect that is well described by the probability model. Because the dose response function for radiation myelopathy is steep, the volume effect is modest The Rhesus monkey remains the animal model most similar to humans in dose response, histopathology, and latency for radiation myelopathy.

We retrospectively examined the surgical, medical, radiotherapeutic and technical factors associated with late small bowel and nonsmall bowel morbidity.The medical records of 224 patients with cancer of the rectum and rectosigmoid treated mainly with abdominoperineal resection or anterior resection and postoperative radiotherapy at the University of Texas M.D. Anderson Cancer Center from 1973 to 1990 were reviewed. The median dose was 54 Gy (range 34-66 Gy) at 1.8-2 Gy per fraction using various techniques (23 had extended fields to L1 or L2; pelvic fields were treated with anterior-posterior in 85, 83 had a 3-field plan and 33 had a 4-field "box"). A positioning technique that treats patients on an open table-top device was used in 78 patients to move the small intestine out of the pelvis. Bladder distension was used in eight. Forty-seven patients received concomitant 5-fluorouracil. Small bowel series were performed in 122 patients to assess the volume of small bowel inside the pelvis below the conjugate line.In 29 patients, the median time to the development of small bowel obstruction was 7 months (range 0-69 months); 18 patients required reoperations. The small bowel obstruction rate was 30% in patients treated with daily extended field radiotherapy, 21% in those with a single pelvic field and 9% with multiple pelvic fields. Small bowel obstruction was positively correlated with postsurgical adhesions prior to radiotherapy and absence of reperitonealization at the time of initial surgery (p0.05). There was no correlation of small bowel obstruction with a history of hypertension, diabetes, prior surgery, history of abdominal infections, postoperative infections, wound healing, pathologic tumor stage, types of surgical procedures, sites of primary tumor, age, or sex. Patients developing small bowel obstruction had larger amounts of small bowel assessed radiologically below the conjugate line than those without complications. With the open table-top device, the small bowel obstruction rate was 3%. In 47 patients treated with radiation and chemotherapy on the open table-top device, the small bowel obstruction rate was 15%, but these patients had more small bowel inside the pelvis than those without the complication. The median time to the development of nonsmall bowel obstruction in 29 patients was 8 months (range 0-85 months), and the nonsmall bowel obstruction complications were significantly correlated with postoperative infection. Most nonsmall bowel obstruction complications were in the genitourinary tract and occurred in patients who had abdominoperineal resection.The open table-top device, by moving the small bowel out of the treatment field, reduces small bowel obstruction in patients treated with radical surgery and postoperative radiotherapy for cancer of the rectum and rectosigmoid. This technique is facile, reproducible, and does not require patient compliance.

Background and purpose To evaluate residual patient setup errors and daily dose variations of different less-than-daily image guidance (IG) strategies in the delivery of external beam radiotherapy for esophageal cancer. Material and methods Daily image-guided setup data for 25 consecutive esophageal cancer patients treated with helical tomotherapy were evaluated. Seven less-than-daily IG strategies with different imaging frequencies were simulated. For each IG strategy, the daily residual setup errors were calculated. Using TomoTherapy Planned Adaptive software, daily dose variations to the clinical target volume, heart, and lungs were evaluated in five representative patients. Results With 0% (60%) IG frequency, the margins required for adequate coverage of the clinical target volume were 13 mm (10 mm), 14 mm (11 mm), and 5 mm (5 mm) in the left–right, superior–inferior, and anterior–posterior directions, respectively. Even with 60% IG frequency, 10% of the fractions had more than 10% decrease in the dose level covering 95% of the target, and 14% and 13% of the fractions had more than 10% increase in total lung volume receiving at least 0.8 Gy per fraction, and heart volume receiving at least 1.2 Gy per fraction, respectively. Conclusion Substantial residual setup errors would occur for treatment fractions without IG even if the most frequent less-than-daily IG strategy was to be used, which could lead to significant daily dose variations for the target volume and adjacent normal tissues. Daily image guidance is recommended throughout the course of treatment in conformal radiotherapy for esophageal cancer.

Radiation myelopathy is a feared and generally avoidable complication of thoracic irradiation. A better understanding of the radiation response of the spinal cord and advances in radiation therapy delivery techniques mean that this complication should be preventable in nearly all treatment situations. A better understanding of the pathogenesis of the injury has lead to the protection of the spinal cord from radiation in experimental studies and to the possible treatment of radiation myelopathy.

Background. Major goals of concurrent radiation and chemotherapy in the treatment of esophageal cancer are the early restoration and long-term maintenance of swallowing function. The purpose of this study was to determine the impact of concurrent radiation and chemotherapy on swallowing function. Methods. Between September 1980 and September 1990, 120 patients with esophageal cancer were treated at the Fox Chase Cancer Center on the basis of one of three prospective nonrandomized protocols using concurrent chemotherapy and radiation. Swallowing function was retrospectively assessed in these patients by use of a swallowing-function scoring system. In addition, patients who had long-term control of their esophageal cancer underwent a more detailed analysis of swallowing function. Results. Initial improvement in dysphagia occurred in 88% of the 102 assessable patients, with a median time to improvement of 2 weeks. There was no difference in overall percentage of initial improvement for patients with adenocarcinoma versus squamous cell carcinoma. Patients with distal tumors, however, showed both earlier and higher frequency of initial improvement than did patients with tumors in the upper two-thirds of the thoracic esophagus (95% versus 79%). Local relapse-free survival of definitively treated patients at 3 years was 60% and was significantly better for patients with Stage I (76%) versus Stage II cancers (55%) (P < 0.05). All 25 patients treated with curative intent who survived for more than 1 year without evidence of disease were able to eat soft or solid foods and had a benign stricture rate of only 12%. Even in patients with advanced disease who were treated with palliative intent, 91% had an initial improvement in swallowing function and 67% had improvement in swallowing function that lasted until death. Conclusions. High-dose concurrent radiation and chemotherapy provides rapid improvement in dysphagia, and this improvement results in normal or near-normal swallowing function of long duration.

To examine the impact of adjuvant radiotherapy (RT) and surgical technique on survival in retroperitoneal soft-tissue sarcoma.A retrospective analysis was conducted using the National Oncology Database, a proprietary database of aggregated tumor registries owned by IMPAC(R) Medical Systems (Sunnyvale, CA). Patients who received definitive surgery with negative or microscopic-positive margins were included. Multivariate analysis was performed using the Cox proportional hazards model. Survival curves were estimated by the Kaplan-Meier method and were compared for statistical significance (P0.05) using the log-rank test.Two hundred sixty-one patients met inclusion criteria. The median follow-up was 59 months (range 0.2-186 months). The 5-year cause-specific survival (CSS) and local failure-free survival (LFFS) were 73% and 66%, respectively. Grade, margin status, and histology were independent predictors for CSS (P0.05). Adjuvant RT was associated with a significant improvement in LFFS over surgery alone (hazard ratio = 0.42, 95% confidence interval 0.21-0.86, P0.05). Patients receiving simple excision and RT had a 5-year LFFS of 88%, significantly higher than wide resection with or without RT (log-rank, P0.05).Adjuvant RT is associated with a lower risk of local relapse compared to surgery alone. The impact of surgical technique on adjuvant RT efficacy warrants further study.

Using a large data set, we investigated the impact of the number of resected and involved lymph nodes on overall survival for patients with esophageal cancer.From the National Oncology Database, esophageal cancer cases with data available on the total number of resected and involved nodes as well as other variables were evaluated as it relates to overall survival by multivariate analysis using Cox proportional hazards method. Patients with 0, exactly 1 or 1-3 positive nodes were separately studied to determine the association between the number of lymph nodes resected and overall survival.From 1969 to 2002, 3,144 (17%) of 18,390 esophageal cancer cases with complete data were identified. Increasing number of involved nodes predicted poorer outcome (P10(-6)). Results from studying patients with 0, exactly 1 or 1-3 positive nodes showed that survival improved with increasing number of nodes analyzed up to 12. Three-tier nodal grouping with increasing risk of death were identified, 0, 1-3, andor=4 positive nodes (P10(-5)).The pathological assessment of minimal 12 lymph nodes provides sufficient prognostic information. Three-tier nodal grouping is suggested for the next version of AJCC staging system for esophageal cancer.

The influence of local control on metastatic dissemination was analyzed in 601 patients with clinically staged A2 to C prostate cancer treated by high-energy external beam radiation therapy who did not undergo hormonal manipulation before disease progression. Median follow-up for surviving patients was 7.7 years. Ninety-three patients had locally recurrent disease. The actuarial incidence of metastases in these patients (70% at 13 years) was significantly higher than in the 508 patients without local failure (40% at 13 years, P less than 0.001). High stage, high grade, prior transurethral resection, elevated acid phosphatase, disease fixation to the pelvic sidewall, and failure to perform a baseline bone scan correlated positively with the occurrence of metastases. However, except for a slight excess of Stage C, none of the metastatic predictors were more common in patients who failed locally than in those who did not. The Stage C preponderance does not account for the difference in incidence of metastases between the two groups, in as much as metastases were significantly more common in Stage C when disease recurred locally than when it did not. Thus, local control of prostate cancer does decrease the likelihood of metastatic disease. Moreover, patients with local control experienced a significantly better disease-specific survival than patients who failed locally.

Xerostomia and xerophthalmia are common and potentially serious local side effects of radiotherapy for head and neck cancer. Clinical observations supported by experimental findings show that radiation, even in low doses, causes acute diminutions of saliva and tears by rapidly killing the serous cells of the salivary and lacrimal glands, respectively. Serous acini of salivary and lacrimal glands have similar developmental, morphologic, and functional characteristics. Serous acinar cells are functionally mature, secretory epithelial cells that normally do not divide and are long lived. Irradiation of the salivary and lacrimal glands of rhesus monkeys resulted in selective death of serous acinar cells within 24 hours. The paradigm for acute radiation seroadenosis is intermitotic or interphase cell death caused by apoptosis.

The kidneys are the dose-limiting organs for radiotherapy to upper abdominal cancers and during total body irradiation. The incidence of radiotherapy-associated kidney injury is likely underreported owing to its long latency and because the toxicity is often attributed to more common causes of kidney injury. The pathophysiology of radiation injury is poorly understood. Its presentation can be acute and irreversible or subtle, with a gradual progressive dysfunction over years. A variety of dose and volume parameters have been associated with renal toxicity and are reviewed to provide treatment guidelines. The available predictive models are suboptimal and require validation. Mitigation of radiation nephropathy with angiotensin-converting enzyme inhibitors and other compounds has been shown in animal models and, more recently, in patients.

21 Background: SEER did not report PSA values for the 2014 submission because of inaccurate coding. This inaccuracy was a result of a confusing data entry guideline where PSA is coded in a 3-digit field with an implied decimal between digits 2 and 3. Our study uses original registry data to assess the magnitude and implications of these coding errors. Methods: The National Oncology Data Alliance is a database of more than 150 Commission-on-Cancer compliant tumor registries that use proprietary cancer registry software sold by Elekta AB (Stockholm, Sweden) and contains the same data sent to state tumor registries and SEER. De-identified data from all newly diagnosed prostate cancer cases from 2005-2013 were extracted (n = 89,379). PSA data were acquired from both the Collaborative Staging (CS) Site Specific Factor 1 (SSF1) for prostate cancer and from de-identified text fields. SSF1 contained the error prone datum that was transferred to SEER. The PSA data contained in the text fields, which are used to record lab results, etc. verbatim, were taken to be definitive. PSA values from both SSF1 and text fields were complete in 63,051 patients. AJCC Stage was determined using the clinical T stage field and the SSF fields that code for Gleason score. We calculated the error rates and their directions for PSA stratification into three levels (0 to < 10, 10 to < 20, and ≥ 20) and for the AJCC stage. Results: The measured error rate in PSA values in SSF1 caused by erroneous decimal placement was 9.0%. The resulting error rate in PSA stratification was 7.5%, with the SSF1 PSA value giving a higher PSA category in 4.8% of cases and lower in 2.7%. The consequent error rate in AJCC staging was 2.8% overall, with the PSA error resulting in a higher stage group in 1.9% and lower in 0.9%. Conclusions: Many factors can contribute to the overall error rate in PSA values in SEER data, but we are addressing only the errors associated with the implied decimal. The consequences of this error are modest despite a 9% error rate. However, SSF1 for prostate cancer is not the only confusing SSF introduced by the CS system. The current cancer registry database design is derived from outdated technology and needs restructuring to be a more effective surveillance and research tool.

A rhesus monkey model was used to assay the radiation tolerance of the spinal cord to 60Co radiation given in 2.2 Gy fractions. The D50 was found to be 76.1 Gy (SEM = 1.9 Gy); the estimated doses for 1% and 0.1% myelopathy were 59.1 +/- 5.5 Gy and 52.1 +/- 7.1 Gy, respectively. The latent period ranged from 5 to 20 months and decreased with increasing dose. All symptomatic animals had white-matter parenchymal lesions involving major motor tracts, and most also had vascular lesions in the white matter. Spinal cords of asymptomatic animals had either no histopathologic changes or small white-matter lesions that did not involve motor tracts.

Purpose To characterize the radiation dose–response of the human spinal cord. Methods and Materials Because no single institution has sufficient data to establish a dose–response function for the human spinal cord, published reports were combined. Requisite data were dose and fractionation, number of patients at risk, number of myelopathy cases, and survival experience of the population. Eight data points for cervical myelopathy were obtained from five reports. Using maximum likelihood estimation correcting for the survival experience of the population, estimates were obtained for the median tolerance dose, slope parameter, and α/β ratio in a logistic dose–response function. An adequate fit to thoracic data was not possible. Hyperbaric oxygen treatments involving the cervical cord were also analyzed. Results The estimate of the median tolerance dose (cervical cord) was 69.4 Gy (95% confidence interval, 66.4–72.6). The α/β = 0.87 Gy. At 45 Gy, the (extrapolated) probability of myelopathy is 0.03%; and at 50 Gy, 0.2%. The dose for a 5% myelopathy rate is 59.3 Gy. Graphical analysis indicates that the sensitivity of the thoracic cord is less than that of the cervical cord. There appears to be a sensitizing effect from hyperbaric oxygen treatment. Conclusions The estimate of α/β is smaller than usually quoted, but values this small were found in some studies. Using α/β = 0.87 Gy, one would expect a considerable advantage by decreasing the dose/fraction to less than 2 Gy. These results were obtained from only single fractions/day and should not be applied uncritically to hyperfractionation.

Purpose Patients with malignant phyllodes tumors of the breast (MPTB) are routinely treated with surgery alone. We performed a retrospective study to determine local control rates based on tumor size and type of surgery performed. Methods and Materials We reviewed records of 478 patients with MPTB treated between March 1964, and August 2005. The data were extracted from the IMPAC National Oncology Database consisting of merged tumor registries from 130 hospitals. Results Median follow-up was 64 months (range, 0–410 months). Actuarial 5-year local control rates were 79.4% for 169 lumpectomy patients and 91.2% for 207 mastectomy patients treated by surgery alone. Five-year local control rates for lumpectomy based on tumor size were 91% for 0–2 cm tumors, 85% for 2–5 cm tumors, and 59% for 5–10 cm tumors. For mastectomy patients, 5-year local control rates were 100% for 0–2 cm tumors, 95% for 2–5 cm tumors, 88% for 5–10 cm tumors, and 85% for 10–20 cm tumors. Multivariate analysis of overall survival found several factors to be significant including advancing age with each decade after 50 years of age, appearance of distant metastases, larger primary tumor size, and local control vs. local recurrence (Hazard Ratio [HR] 2.5, p Conclusions Malignant phyllodes tumors of the breast local recurrence rates are 15% or greater for patients with tumors >2 cm treated by lumpectomy alone and tumors >10 cm treated by mastectomy alone. Adjuvant radiation therapy should be evaluated for these patients. This may be especially important because our study showed that local recurrence impacted on survival rates.

To assess the incidence of acute gastrointestinal (GI) and genitourinary (GU) injury and the dose-volume response in patients with clinically localized prostate cancer treated with image-guided radiotherapy using helical tomotherapy.Between November 2004 and March 2007, 146 consecutive patients with localized prostate cancer were treated with helical tomotherapy at the City of Hope Medical Center. Of the 146 patients, 70 had undergone prostatectomy. Acute GI and GU toxicities were evaluated using the Radiation Therapy Oncology Group/European Organization for Research and Cancer of Medical scoring system. Events were scored for patients developing Grade 2 or greater morbidity within 90 days after the end of radiotherapy (RT). The dosimetric parameters included the minimal dose received by the highest 10%, 20%, 50%, 80%, and 90% of the target volume, the mean rectal dose, minimal rectal dose, maximal rectal dose, and the volume receivingor =45,or =65, andor =70 Gy. These variables, plus the status of radical prostatectomy, hormonal therapy, RT techniques, and medical conditions, were included in a multivariate logistic regression analysis. A goodness-of-fit evaluation was done using the Hosmer-Lemeshow statistic.A dose-response function for acute GI toxicity was elicited. The acute GI Grade 2 or greater toxicity was lower in the definitive RT group than in the postoperative RT group (25% vs. 41%, p0.05). Acute GU Grade 2 or greater toxicity was comparable between the two groups. No grade 3 or greater complications were observed. No dosimetric variable was significant for GU toxicity. For acute GI toxicity, the significant dosimetric parameters were the minimal dose received by 10%, 20%, and 50% of the target volume and the mean rectal dose; the most predictive parameter was the minimal dose received by 10% of the target volume. The dose-modifying factor was 1.2 for radical prostatectomy.The results of our study have shown that acute rectal symptoms are dose-volume related. Postprostatectomy RT resulted in a greater incidence of acute GI toxicity than did definitive RT. For postoperative RT, it would be prudent to use different dose-volume limits.

8581 Background: Ablative dose total body irradiation (TBI) of 800 cGy in combination with high-dose melphalan (MEL) was found to be too toxic. TMI, an image-guided targeted TBI using TomoTherapy i...

143 Background: In 2011, the USPSTF issued a draft recommendation that PSA not be used for prostate cancer screening in men irrespective of age. Here we present early measures of the potential consequences of this recommendation. Methods: Data on men diagnosed with prostate cancer from January, 2005 through June, 2013 were extracted from the National Oncology Data Alliance (Elekta/IMPAC Medical Systems, Inc., Sunnyvale, CA). This proprietary database of merged tumor registries captures newly diagnosed cancer cases at more than 150 hospitals in the United States. Data were available through 2013 compared to 2011 in Surveillance, Epidemiology, and End Results (SEER). The data in the NODA are identical to the data sent to state tumor registries and SEER in regions that participate in SEER. Date of diagnosis, age, race, T stage, Gleason score, and PSA were collected. Patients were classified into their respective National Comprehensive Cancer Network (NCCN) risk group. Data were available and analyzed for 87,562 men. Frequencies were examined by date of diagnosis, grouped in six-month intervals. Trends were assessed using linear regression. Results: From 2005 to 2011, the percentage of men with PSA>10 decreased gradually. From 2011 to 2013, the percentage increased by 3.0% per year (p10 increased by nearly double the rate for men of all ages from 2011 to 2013. No significant trends in Gleason score were observed; the frequency of men with higher T stages generally decreased over the entire period without a notable change after 2011. The percentage of men with intermediate or higher risk cancer was stable at 70-73% prior to 2011, but rose by 2.9 % per year after 2011 (p

Purpose: To develop a treatment technique to spare normal tissue and allow dose escalation in total body irradiation (TBI). We have developed intensity-modulated radiotherapy techniques for the total marrow irradiation (TMI), total lymphatic irradiation, or total bone marrow plus lymphatic irradiation using helical tomotherapy. Methods and Materials: For TBI, we typically use 12 Gy in 10 fractions delivered at an extended source-to-surface distance (SSD). Using helical tomotherapy, it is possible to deliver equally effective doses to the bone marrow and lymphatics while sparing normal organs to a significant degree. In the TMI patients, whole body skeletal bone, including the ribs and sternum, comprise the treatment target. In the total lymphatic irradiation, the target is expanded to include the spleen and major lymph node areas. Sanctuary sites for disease (brain and testes) are included when clinically indicated. Spared organs include the lungs, esophagus, parotid glands, eyes, oral cavity, liver, kidneys, stomach, small and large intestine, bladder, and ovaries. Results: With TBI, all normal organs received the TBI dose; with TMI, total lymphatic irradiation, and total bone marrow plus lymphatic irradiation, the visceral organs are spared. For the first 6 patients treated with TMI, the median dose to organs at risk averaged 51% lower than would be achieved with TBI. By putting greater weight on the avoidance of specific organs, greater sparing was possible. Conclusion: Sparing of normal tissues and dose escalation is possible using helical tomotherapy. Late effects such as radiation pneumonitis, veno-occlusive disease, cataracts, neurocognitive effects, and the development of second tumors should be diminished in severity and frequency according to the dose reduction realized for the organs at risk.

Purpose: To use pretreatment megavoltage-computed tomography (MVCT) scans to evaluate positioning variations in pitch, roll, and yaw for patients treated with helical tomotherapy. Methods and Materials: Twenty prostate and 15 head-and-neck cancer patients were selected. Pretreatment MVCT scans were performed before every treatment fraction and automatically registered to planning kilovoltage CT (KVCT) scans by bony landmarks. Image registration data were used to adjust patient setups before treatment. Corrections for pitch, roll, and yaw were recorded after bone registration, and data from fractions 1–5 and 16–20 were used to analyze mean rotational corrections. Results: For prostate patients, the means and standard deviations (in degrees) for pitch, roll, and yaw corrections were −0.60 ± 1.42, 0.66 ± 1.22, and −0.33 ± 0.83. In head-and-neck patients, the means and standard deviations (in degrees) were −0.24 ± 1.19, −0.12 ± 1.53, and 0.25 ± 1.42 for pitch, roll, and yaw, respectively. No significant difference in rotational variations was observed between Weeks 1 and 4 of treatment. Head-and-neck patients had significantly smaller pitch variation, but significantly larger yaw variation, than prostate patients. No difference was found in roll corrections between the two groups. Overall, 96.6% of the rotational corrections were less than 4°. Conclusions: The initial rotational setup errors for prostate and head-and-neck patients were all small in magnitude, statistically significant, but did not vary considerably during the course of radiotherapy. The data are relevant to couch hardware design for correcting rotational setup variations. There should be no theoretical difference between these data and data collected using cone beam KVCT on conventional linacs.

Purpose: To evaluate dose conformity, dose homogeneity, and dose gradient in helical tomotherapy treatment plans for stereotactic radiosurgery, and compare results with step-and-shoot intensity-modulated radiosurgery (IMRS) treatment plans. Methods and Materials: Sixteen patients were selected with a mean tumor size of 14.65 ± 11.2 cm 3 . Original step-and-shoot IMRS treatment plans used coplanar fields because of the constraint of the beam stopper. Retrospective step-and-shoot IMRS plans were generated using noncoplanar fields. Helical tomotherapy treatment plans were generated using the tomotherapy planning station. Dose conformity index, dose gradient score index, and homogeneity index were used in plan intercomparisons. Results: Noncoplanar IMRS plans increased dose conformity and dose gradient, but not dose homogeneity, compared with coplanar IMRS plans. Tomotherapy plans increased dose conformity and dose gradient, yet increased dose heterogeneity compared with noncoplanar IMRS plans. The average dose conformity index values were 1.53 ± 0.38, 1.35 ± 0.15, and 1.26 ± 0.10 in coplanar IMRS, noncoplanar IMRS, and tomotherapy plans, respectively. The average dose homogeneity index values were 1.15 ± 0.05, 1.13 ± 0.04, and 1.18 ± 0.09 in coplanar IMRS, noncoplanar IMRS, and tomotherapy plans, respectively. The mean dose gradient score index values were 1.37 ± 19.08, 22.32 ± 19.20, and 43.28 ± 13.78 in coplanar IMRS, noncoplanar IMRS, and tomotherapy plans, respectively. The mean treatment time in tomotherapy was 42 ± 16 min. Conclusions: We were able to achieve better dose conformity and dose gradient in tomotherapy plans compared with step-and-shoot IMRS plans for intracranial stereotactic radiosurgery. However, tomotherapy treatment time was significantly larger than that in step-and-shoot IMRS.

The evolution of therapeutic approaches for lung cancer illustrates the trend for treatment intensification, with hopes that dose-intense chemotherapy regimens, higher radiation therapy (RT) doses, or novel fractionation schemes will result in prolongation of survival. Current chemotherapy- and RT-intense regimens may not be intensified further without addressing dose-limiting toxicities such as esophagitis. It is important to understand factors pre-disposing to esophagitis so that strategies to minimize its severity can be investigated. Pulmonary complications such as pneumonitis and fibrosis from RT (with or without chemotherapy) are dose and volume dependent. Methods to better identify the target tissues and improved RT-delivery systems may facilitate increasing target doses or reducing doses to adjacent normal tissues. Biologic predictors may allow clinicians in the future to individualize RT treatment based on a patient's toxicity risk profile. Radiation myelopathy is still the most feared radiation complication of lung cancer treatment. The authors address the known parameters that influence the incidence of thoracic radiation myelopathy and the putative factors that could be considered when a clinician may be required to push the spinal cord dose in favor of tumor control.

736 Background: Neoadjuvant chemoradiation therapy (CRT) results in fewer retrieved lymph nodes at the time of surgery for rectal cancer. The extent of optimal regional nodal dissection is based on guidelines developed before neoadjuvant CRT was commonly used. The purpose of this study is to assess the impact of the number of dissected and positive lymph nodes on overall survival (OS) for rectal cancer patients treated with neoadjuvant CRT. Methods: Treatment data were obtained by structured query on all patients with rectal adenocarcinoma (2000-2013) in the National Oncology Data Alliance, a proprietary database of merged tumor registries. Eligible patients were treated with neoadjuvant CRT followed by surgery and had complete data on the number of positive and dissected lymph nodes and dates of treatment. The relationships between number of lymph nodes examined and OS were separately analyzed in patients with 0, exactly 1, or any number of positive nodes. Results: The median number of lymph nodes examined was 11 (interquartile range 6-16). In 4,581 evaluable patients, there was a significant improvement in OS with the examination of more lymph nodes. Number of positive lymph nodes, number of lymph nodes dissected, age, gender, grade, marital status, and race were significant predictors of OS on multivariate analysis. On subset analysis, patients with 0, exactly 1, and any number of positive nodes were found to have better OS with increasing number of lymph nodes dissected up to eight. Increasing overall mortality was observed in patients with 0, 1, 2-4, 5-7, and ≥8 positive lymph nodes. The Kaplan-Meier curves showed a clear statistically significant difference in OS in patients divided into these five nodal groupings (p

This study was undertaken to investigate the relationship of prostatic specific antigen doubling time with disease progression in irradiated patients whose only sign of failure was an abnormal prostatic specific antigen.Post irradiation patients whose only sign of failure was an elevated prostatic specific antigen were followed without treatment. The prostatic specific antigen doubling time was determined and compared to original characteristics of disease, time to elevation of prostatic specific antigen after treatment and time to a second sign of failure.The prostatic specific antigen doubling times varied from 1.2 months to 36 months. The original grade and stage correlated with the doubling time as did the intervals to elevation of prostatic specific antigen and to a second sign of failure.We recommended delaying intervention until the prostatic antigen doubling time can be calculated for patients with prostatic specific antigen elevation as the only sign of failure. Patients with short doubling times (9 months) can be promptly treated while those with longer doubling times (1 year) may have androgen suppression delayed avoiding the cost and morbidity of that treatment.

Highly conformal fields have become achievable in routine clinical practice. The optimal shape of the resultant dose distributions depends on information that is not currently available. This missing information is the dose-volume response of the normal tissues at risk. These functions are now the subject of aggressive research. The research involves collecting the dose-response data, modeling the dose-response function, and fitting the models to the data. The controversies addressed here influence the selection of the biomathematical model that one might use to describe such a function. The form that the dose-volume response function takes depends on the nature of the volume effect. The nature of the volume effect for a given radiation response is the subject of considerable debate. Related to this debate, this report addresses the existence of the volume effect, the existence of a threshold volume, and the existence of functional subunits. The pitfalls relate to the problems in accurate determination and application of the dose-response functions.

Dosimetry studies in patients with non-Hodgkin's lymphoma were performed to estimate the radiation absorbed dose to normal organs and bone marrow from 90Y-Zevalin (yttrium-90 ibritumomab tiuxetan, IDEC-Y2B8) treatment in this phase I/II, multicenter trial. The trial was designed to determine the dose of Rituximab (chimeric anti-CD20, Rituxan, IDEC-C2B8, MabThera), the unlabeled antibody given prior to the radioconjugate to clear peripheral blood B cells and optimize distribution, and to determine the maximum tolerated dose of 90Y-Zevalin [7.4, 11, or 15 MBq/kg (0.2, 0.3, or 0.4 mCi/kg)]. Patients received (111)In-Zevalin (indium-111 ibritumomab tiuxetan, IDEC-In2B8 ) on day 0 followed by a therapeutic dose of 90Y-Zevalin on day 7. Both doses were preceded by an infusion of the chimeric, unlabeled antibody Rituximab. Following administration of (111)In-Zevalin, serial anterior/posterior whole-body scans were acquired. Major-organ radioactivity versus time estimates were calculated using regions of interest. Residence times were computed and entered into the MIRDOSE3 computer software program to calculate estimated radiation absorbed dose to each organ. Initial analyses of estimated radiation absorbed dose were completed at the clinical site. An additional, centralized dosimetry analysis was performed subsequently to provide a consistent analysis of data collected from the seven clinical sites. In all patients with dosimetry data (n=56), normal organ and red marrow radiation absorbed doses were estimated to be well under the protocol-defined upper limit of 20 Gy and 3 Gy, respectively. Median estimated radiation absorbed dose was 3.4 Gy to liver (range 1.2-7.8 Gy), 2.6 Gy to lungs (range 0.72-4.4 Gy), and 0.38 Gy to kidneys (range 0.07-0.61 Gy). Median estimated tumor radiation absorbed dose was 17 Gy (range 5.8-67 Gy). No correlation was noted between hematologic toxicity and the following variables: red marrow radiation absorbed dose, blood T(1/2), blood AUC, plasma T(1/2), and plasma AUC. It is concluded that 90Y-Zevalin administered at nonmyeloablative maximum tolerated doses results in acceptable radiation absorbed doses to normal organs. The only toxicity of note is hematologic and is not correlated to red marrow radiation absorbed dose estimates or T(1/2), reflecting that hematologic toxicity is dependent on bone marrow reserve in this heavily pretreated population.

To better define the appropriate dose for individual prostate cancer patients treated with three-dimensional conformal radiation therapy (3D CRT).Six hundred eighteen patients treated with 3D CRT between 4/89 and 4/97 with a median follow-up of 53 months are the subject of this study. The bNED outcomes were assessed by the American Society for Therapeutic Radiology and Oncology (ASTRO) definition. The patients were grouped into three groups by prostate-specific antigen (PSA) level (10 ng/ml, 10-19.9 ng/ml, and 20+ ng/ml) and further subgrouped into six subgroups by favorable (T1, 2A and Gleason scoreor =6 and no perineural invasion) and unfavorable characteristics (one or more of T2B, T3, Gleason 7-10, perineural invasion). Dose comparisons for bNED studies were made for each of the six subgroups by dividing patients at 76 Gy for all subgroups except the favorable10 ng/ml subgroup, which was divided at 72.5 Gy. Five-year bNED rates were compared for the median dose of each dose comparison subgroup. Dose response functions were plotted based on 5-year bNED rates for the six patient groupings, with the data from each of the six subgroups divided into three dose groups. The 5-year bNED rate was also estimated using the dose response function and compares 73 Gy with 78 Gy.Dose comparisons show a significant difference in 5-year bNED rates for three of the six subgroups but not for the favorable10 ng/ml, the favorable 10-19.9 ng/ml, or the unfavorableor =20 ng/ml subgroups. The significant differences ranged from 22% to 40% improvement in 5-year bNED with higher dose. Dose response functions show significant differences in 5-year bNED rates comparing 73 Gy and 78 Gy for four of the six subgroups. Again, no difference was observed for the favorable10 ng/ml group or the unfavorableor =20 ng/ml group. The significant differences observed in 5-year bNED ranged from 15% to 43%.Dose response varies by patient subgroup, and appropriate dose can be estimated for up to six subdivisions of prostate cancer patients. The appropriate use of high dose with 3D CRT results in 5-year cure rates that equal or exceed other treatments. The national practice must be upgraded to allow the safe administration of 75-80 Gy with 3D CRT.

Daily CT localization has been demonstrated to be a precise method of correcting radiation field placement by reducing setup and organ motion variations to facilitate dose escalation in prostate carcinoma. The purpose of this study was to evaluate the feasibility and accuracy of daily ultrasound-guided localization utilizing daily CT as a standard. The relatively simple computer-assisted ultrasound-based system is designed to be an efficient means of achieving daily accuracy.After five weeks of conformal external beam radiation therapy, 23 patients underwent a second CT simulation. Prostate-only fields based on this scan were created with no PTV margin. On each of the final conedown treatment days, a repeat CT simulation and isocenter comparison was performed. Ten of the above patients also underwent prostate localization with a newly developed ultrasound-based system (BAT) that is designed to facilitate patient positioning at the treatment machine. The portable system, which electronically imports the CT simulation target contours and isocenter, is situated adjacent to the treatment couch. Transverse and sagittal suprapubic ultrasound images are captured, and the system overlays the corresponding CT contours relative to the machine isocenter. The CT contours are maneuvered in three dimensions by a touch screen menu to match the ultrasound images. The system then displays the 3-D couch shifts required to produce field alignment.The BAT ultrasound system produced good quality images with minimal operator training required. The localization process was completed in less than 5 min. The absolute magnitude difference between CT and ultrasound was small (A/P range 0 to 5.9 mm, mean 3 mm +/- 1.8; Lat. range 0 to 7.9 mm, mean 2.4 mm +/- 1.8; S/I range 0 to 9 mm, mean 4.6 mm +/- 2.8). Analysis confirmed a significant correlation of isocenter shifts (A/P r = 0.66, p0.0001; Lat. r = 0.58, p0.003; S/I r = 0.78, p0.0001) in all dimensions, and linear regression confirmed the equivalence of the two modalities.Daily CT localization is a precise method to improve daily target localization in prostate carcinoma. However, it requires significant human and technical resources that limit its widespread applicability. Conversely, localization with the BAT ultrasound system is simple and expeditious by virtue of its ability to image the prostate at the treatment machine in the treatment position. Our initial evaluation revealed ultrasound targeting to be functionally equivalent to CT. This ultrasound technology is promising and warrants further investigation in more patients and at other anatomical sites.

Multileaf collimators (MLCs) are generally believed to be convenient and cost-effective tools for intensity modulation and conformal therapy. They are becoming a standard feature on new accelerators; however, the older units can be retrofitted with modern MLCs. Before such a unit can be clinically used, the beam characteristics must be verified. In this study the beam characteristics of a Siemens double-focused MLC retrofitted to an MD2 linear accelerator are presented. The head leakage along with inter- and intra-leaf radiation transmission were measured using film. The collimator (Sc), phantom (Sp), total (Scp) scatter factors, central axis depth dose, beam profiles for off-axis ratios, penumbra, and surface dose were evaluated for square, rectangular, and irregularly shaped fields. The maximum head leakage was estimated to be < 0.05% in any plane at a distance of 1 m and maximum transmission through the MLC leaves was estimated to be < 1.4% and < 1.1% for the 10 MV and 6 MV beams, respectively. The maximum differences between pre- and post-MLC installation data for the Sc and Scp were < or = 0.7% and < or = 1.4%, respectively. Similarly, the percent depth dose data for all fields and both beam energies were within 1.5% of the original data. The beam profiles measured at various depths were also in agreement with those of the pre-MLC installation data. The measured beam penumbra (20%-80%) showed a range of 7.8 mm-11.0 mm for the 6 MV and 8.4 mm-11.1 mm for the 10 MV beams from smallest to largest fields. These ranges differ by less than a millimeter from those of the old data. The surface dose measurements were slightly lower than the conventional jaw values suggesting that MLC does not produce significant electron contamination. It is concluded that the retrofitted MLC maintains the integrity of the original beam and may provide a cost-effective conformal therapy.

Rectal bleeding is the most common late sequelae of high-dose 3D conformal treatment (3DCRT) for prostate cancer and may limit attempts to improve local control by dose escalation. The clinical course of this complication is reported including time to onset, response to treatment, duration of morbidity, and multivariate analysis for predictors.From March 1989 to June 1995, 670 patients with prostate cancer were treated with 3DCRT at Fox Chase Cancer Center. Eighty-nine patients developed Grade 2 or Grade 3 complications due to rectal bleeding and are analyzed. Multivariate analysis results for predictors of Grade 2 and 3 rectal bleeding are reported as well as time to development, response to initial and retreatment, and duration of morbidity.The median time to occurrence is not significantly different (p = 0.09) for Grade 2 (13 months, range 4-41 months) compared to Grade 3 rectal bleeding (18 months, range 4-40 months), while the corresponding median duration of symptoms was significantly different (p0.0001) being 1 month (range 1-12) vs. 10 months (1-34) for Grade 2 and Grade 3 bleeding, respectively. For Grade 2 bleeding, medication or coagulation was highly effective as initial or retreatment resolving 66 of 73 patients. For Grade 3 bleeding, three patients responded without medication following blood transfusion only, while with multiple coagulations and medication 12 of 16 patients improved toor = Grade 1. Multivariate analysis demonstrates that dose is the only significant factor associated with Grade 2 (p = 0.01) or Grade 3 (p = 0.01) rectal bleeding. Of seven nonresponders to treatment for Grade 2 bleeding, three have died of intercurrent disease at 10, 19, and 26 months, while four are alive with continuing Grade 2 bleeding at 12, 14, 15, and 30 months after onset. The four nonresponders to treatment for Grade 3 bleeding continue to bleed 1, 9, 32, and 35 months after the third coagulation despite continuing care.Chronic rectal bleeding is a sequelae of high-dose conformal treatment of prostate cancer. Grade 2 morbidity responds to medication or limited coagulation (or = 2) in 90% of patients. Grade 3 morbidity responds to medication and multiple coagulations (or = 3) in 75% of patients. The chronicity of Grade 3 morbidity is illustrated by a 10-month median duration for response to treatment, with a range of response extending to 34 months. Nonresponders to treatment have continued to bleed up to 35 months after the third coagulation. Appropriate shielding of the rectal mucosa limiting dose to72 Gy is required to avoid a high incidence of these complications, as dose is the only significant variable associated with rectal bleeding.

Purpose: To assess the utility of image fusion software and compare MRI prostate localization with CT localization in patients undergoing 3D conformal radiation therapy of prostate cancer. Materials and Methods: After a phantom study was performed to ensure the accuracy of image fusion procedure, 22 prostate cancer patients had CT and MRI studies before the start of radiotherapy. Immobilization casts used during radiation treatment were also used for both imaging studies. After the clinical target volume (CTV) (prostate or prostate + seminal vesicles) was defined on CT, slices from the MRI study were reconstructed to precisely match the CT slices by identifying three common bony landmarks on each study. The CTV was separately defined on the matched MRI slices. Data related to the size and location of the prostate were compared between CT and MRI. The spatial relationship between the tip of urethrogram cone on CT and prostate apex seen on MRI was also estimated. Results: The phantom study showed the registration discrepancies between CT and MRI smaller than 1.0 mm in any pair in comparison. The patient study showed a mean image registration error of 0.9 (± 0.6) mm. The average prostate volume was 63.0 (± 25.8) cm 2 and 50.9 (± 22.9) cm 3 determined by CT and MRI, respectively. The difference in prostate location with the two studies usually differed at the base and at the apex of the prostate. On the transverse MRI, the prostate apex was situated 7.1 (± 4.5) mm dorsal and 15.1 (± 4.0) mm cephalad to the tip of urethrogram cone. Conclusions: CT-MRI image fusion study made it possible to compare the two modalities directly. MRI localization of the prostate is more accurate than CT, and indicates the distance from cone to apex is 15 mm. CT-MRI image fusion technique provides valuable supplements to CT technology for more precise targeting of the prostate cancer.

Purpose: Serious late morbidity (Grade 314) from the conformal treatment of prostate cancer has been reported in to 6% of patients based on existing late gastrointestinal (GI) morbidity scales. None of the existing morbidity scales include our most frequently observed late GI complication, which is chronic rectal bleeding requiring multiple fulgerations. This communication documents the frequency of rectal bleeding requiring multiple fulgerations and illustrates the variation in reported late serious GI complication rates by the selection of morbidity scale. Methods and Materials: Between May 1989 and December 1993,352 patients with Tl-T3 nonmetastatic prostate cancers were treated with our four-field conformal technique without special rectal blocking. This technique includes a l-cm margin from the clinical target volume (CTV) to the planning target volume (PTV) in all directions. The median follow-up for these patients was 36 months (range 2-76), and the median center of prostate dose was 74 Gy (range 63-81). Three morbidity scales are assessed: the Radiation Therapy Oncology Group (RTOG), the Late Effects Normal Tissue Task Force (LENT), and our modification of the LENT (FCLENT). This modification registers chronic rectal bleeding requiring at least one blood transfusion and/or more than two coagulations as a Grade 3 event. Estimates for Grade 3/4 late GI complication rates were determined using Kaplan-Meier methodology. The duration of severe symptoms with chronic rectal bleeding is measured from the first to the last transrectal coagulation. Latency is measured from the end of radiotherapy to surgery, first blood transfusion, or third coagulation procedure. Results: Sixteen patients developed Grade 3/4 complications by one of the three morbidity scales. Two patients required surgery (colostomy or sigmoid resection), three required multiple blood transfusions, two required one or two blood transfusions, and nine required at least three coagulations. The median duration of bleeding for those patients requiring multiple procedures was 7 months (range 3-33) and the median latency was 22 months (range 9-40). The 5year actuarial rate of Grade 3/4 complications by each scale are: RTOG 0.7%, LENT 2%, and FC-LENT 6%. The rate of chronic rectal bleeding increases with increasing dose and is low in patients treated with conventional techniques owing to lower doses. Conclusion: Chronic rectal bleeding requiring any blood transfusion(s) or multiple coagulation procedures is our most frequently observed complication. This complication appears late in follow-up and is present for a long duration. We believe this justifies the inclusion of chronic rectal bleeding requiring multiple coagulation procedures as a Grade 3 event in future morbidity scales. Our data illustrate that published Grade 3/4 morbidity rates are highly dependent on the morbidity scale selected, as our data show 0.7% RTOG, 2% LENT, and 6% FCLENT. Obviously, a uniform scale is required that includes the newly recognized serious late effects associated with the conformal treatment of prostate cancer. 0 1997 Elsevier Science Inc. Chronic rectal bleeding, Conformal treatment, Prostate cancer, LENT, Morbidity scales.

Purpose: To determine if portal setup films are an accurate representations of a patient's position throughout the course of fractionated tangential breast irradiation. Methods and Materials:Thirteen patients undergoing external beam irradiation for T1-T2 infiltrating ductal carcinoma of the breast following excisional biopsy and axillary dissection were using an on-line portal imaging device attached to a 6 MV linear accelerator. Medial and lateral tangential fields were imaged and a total of 139 fractions, 225 portal fields, and 4450 images were obtained. Interfractional and intrafractional variations for anatomical parameters including the central lung distance (CLD), central flash distance (CFD), and inferior central margin (ICM) were calculated from these images. A pooled estimate of the random error associated with a given treatment was determined by adding the interfractional and intrafractional standard deviations in quadrature. A 95% confidence level assigned a value of two standard deviations of the random error estimate. Central lung distance, CFD, and ICM distances were then measured for all portal setup films. Significant differences were defined as occurring when the simulation-setup difference was greater than the 95% confidence value. Results: Differences between setup portal and simulation films were less than their 95% confidence values in 70 instances indicating that in 90% of the time these differences are a result of random differences in daily treatment positioning. Conclusions: In 90% of cases tested, initial portal setup films are an accurate representation of a patients daily treatment setup.

Purpose: Conformal radiation technology results in fewer late complications and allows testing of the value of higher doses in prostate cancer. Methods and Materials: We report the biochemical freedom from disease (bNED) rates (BNED) failure in Prostate Specific Antigen (PSA) ≥ 1.5 ng/ml and rising) at 2 and 3 years for 375 consecutive patients treated with conformal technique from 66 to 79 Gy. Median follow-up was 21 months. Biochemical freedom from disease was analyzed for patients treated above and below 71 Gy as well as above and below 73 Gy. Each dose group was subdivided by pretreatment PSA level (

Purpose: Using conventional treatment methods for the treatment of clinically localized prostate cancer central axis doses must be limited to 65–70 Gray (Gy) to prevent significant damage to nearby normal tissues. A fundamental hypothesis of three-dimensional conformal radiation therapy (3DCRT) is that, by defining the target organ(s) accurately in three dimensions, it is possible to deliver higher doses to the target without a significant increase in normal tissue complications. This study examined whether this hypothesis holds true and whether a simple modification of treatment technique can reduce the incidence of late rectal morbidity in patients with prostate cancer treated with 3DCRT to minimum planning target volume (PTV) doses of 71–75 Gy. Methods and Materials: The 257 patients with clinically localized prostate cancer who completed 3DCRT by December 31, 1993 and received a minimum PTV dose of 71–75 Gy are included in th is report. The median follow-up time was 22 months (range: 4–67 months); 98% of patients had follow-up of longer than 12 months. The calculated dose at the center of prostate was 76 Gy in 32 patients. Late rectal morbidity was graded according to the Late Effects Normal Tissue (LENT) scoring system. Eighty-eight consecutive patients were treated with a rectal block added to the lateral fields. In these patients the posterior margin from the prostate to the block edge was reduced from the standard 15 to 5 mm for the final 10 Gy, which reduced the dose to portions of the anterior rectal wall by approximately 4–5 Gy. Estimates of rates for rectal morbidity were determined by Kaplan-Meier actuarial analyses. Difference in morbidity percentages were evaluated by the Pearson chisquare test. Results: Grade 2–3 morbidity developed in 46 out of 257 patients (18%) and in the majority of cases consisted of rectal bleeding. No patient has developed Grade 4 or 5 rectal morbidity. The actuarial rate of Grade 2–3 morbidity is 23% at 24 months and the median time to the development of Grade 2–3 complications is 15 months. A statistically significant dose effect is evident. The incidence of Grade 2–3 rectal morbidity increased as the dose at the center of the prostate increase ( p = 0.05). In patients receiving minimum PTV doses of ≤ 76 Gy the use of a rectal block significantly reduced the incidence of Grade 2–3 toxicity; 6 out of 88 (7%) with a block vs. 30 out of 137 (22%) without a block, ( p = 0.003). Conclusion: The indcidence of late rectal morbidity with 3DCRT to minimum PTV doses of 71–75 Gy is acceptable and to date no Grade 4–5 rectal morbidities have been observed. In our experience, higher doses to the center of the protate are associated with an increased likelihood of developing Grade 2–3 rectal morbidity but treatment techniques that reduce the total dose to the anterior rectal wall have reduced the incidence of late rectal morbidity. If clinical studies indicate improved tumor control with minimum PTV doses above 71 Gy, the dose escalation above 76Gy to the center of the prostate should be persued cautiously with treatment techniques that limit the total dose to the anterior rectal wall.

Purpose: The distribution of pretreatment and posttreatment prostate specific antigen (PSA) doubling times (PSADT) varies widely. This report examines the pretreatment PSADT as an independent predictor of biochemical freedom from disease (bNED) and describes the clinical utility of PSADT. Methods and Materials: Ninety-nine patients with T1-3 NX, M-0 prostate cancer treated between February 1989 and November 1993 have pretreatment PSADTs calculated from three of more PSA levels. Biochemical disease-free (bNED) survival (failure is PSA ≥ 1.5 ngm/ml and rising) is evaluated by multivariate analysis of common prognostic indicators and PSADT. Results: Prostate-specific antigen, doubling time (PSADT) is a significant predictor of survival along with radiation dose. Patients with a pretreatment PSADT od < 12 months show 50% failure by 18 months, while those with PSADT that is not increasing show only 3% failure at 3 years. Conclusions: Prostate-specific antigen doubling time (PSADT) is a predictor of bNED outcome in prostate cancer. Patients with PSADT < 12 months have aggressive disease and should be considered for multimodal therapy. Slow PSADT (≥ 5 years) is observed in 57% of patients, and this end point may be considered in the decision to observe rather than to treat. After treatment failure, the PSADT may be used to determine which patients do not need immediate androgen deprivation.