Carboplatin/paclitaxel or carboplatin/vinorelbine followed by accelerated hyperfractionated conformal radiation therapy: a preliminary report of a phase I dose escalation trial from the Carolina Conformal Therapy Consortium.

The maximum tolerated dose of conformal radiation therapy delivered at 1.6 Gy bid is being assessed in patients with unresectable stage IIB-IIIB non-small cell lung cancer who have been treated with induction regimens consisting of carboplatin plus paclitaxel or carboplatin plus vinorelbine. Data from the early stages of this parallel phase I study show that the two induction regimens are similar in toxicity and that both induce partial responses in 45% of patients. Both regimens can be followed by conformal radiotherapy using an accelerated hyperfractionated schedule to a dose of at least 80 Gy without experiencing unacceptable toxicity. Key morbidity observed thus far has involved the esophagus. Further cohorts of patients will receive higher doses of conformal radiotherapy (in 6.4 Gy increments) until the maximum tolerated dose is reached.

73.6 Gy and beyond: hyperfractionated, accelerated radiotherapy for non-small-cell lung cancer.

PURPOSE: To assess results with twice-daily high-dose radiotherapy (RT) for non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between 1991 and 1998, 94 patients with unresectable NSCLC were prescribed > or = 73.6 Gy via accelerated fractionation. Fifty were on a phase II protocol (P group); 44 were similarly treated off-protocol (NP group). The clinical target volume received 45 Gy at 1.25 Gy bid (6-hour interval). The gross target volume received 1.6 Gy bid to 73.6 to 80 Gy over 4.5 to 5 weeks using a concurrent boost technique. Overall survival (OS) and local progression-free survival (LPFS) were calculated by the Kaplan-Meier method. Median follow-up durations for surviving P and NP patients were 67 and 16 months, respectively. RESULTS: Total doses received were > or = 72 Gy in 97% of patients. The median OS by stage was 34, 13, and 12 months for stages I/II, IIIa, and IIIb, respectively. LPFS was significantly longer for patients with T1 lesions (median, 43 months) versus T2-4 (median, 7 to 10 months; P =.01). Results were similar in the P and NP groups. Acute grade > or = 3 toxicity included esophagus (14 patients; 15%), lung (three patients; 3% [one grade 5]), and skin (four patients; 4%). Grade > or = 3 late toxicity in 86 assessable patients included esophagus (three patients; 3%), lung (15 patients; 17% [three grade 5]), skin (five patients; 6%), heart (two patients; 2%), and nerve (one patient; 1%). CONCLUSION: This regimen yielded favorable survival results, particularly for T1 lesions. Acute grade > or = 3 toxicity seems greater than for conventional RT, though most patients recovered. Late grade > or = 3 pulmonary toxicity occurred in 17%. Because of continued locoregional recurrences, we are currently using doses > or = 86 Gy.

A new three-dimensional dose distribution reduction scheme for tubular organs.

In tubular structures, spatial aspects of the dose distribution may be important in determining the normal tissue response. Conventional dose-volume-histograms (DVHs) and dose-surface-histograms (DSHs) lack spatial information and may not be adequate to represent the three-dimensional (3D) dose data. A new 3D dose distribution data reduction scheme which preserves its longitudinal and circumferential character is presented. Dose distributions were generated at each axial level for esophagus or rectum in 123 patients with lung cancer or prostate cancer. Dose distribution histograms at each axial level were independently analyzed along the esophageal or rectal circumference to generate dose-circumference-histogram (DCH) sheets. Two types of plots were then generated from the DCH sheet. The first considered the percentage of the circumference at each axial level receiving various doses. The second considered the minimum dose delivered to any percentage of the circumference at each axial level. The DCH as a treatment planning tool can be easily implemented in a 3D planing system and is potentially useful for the study of the relationship between the complication risk and the longitudinal and circumferential dose distributions.

A neural network to predict symptomatic lung injury.

A nonlinear neural network that simultaneously uses pre-radiotherapy (RT) biological and physical data was developed to predict symptomatic lung injury. The input data were pre-RT pulmonary function, three-dimensional treatment plan doses and demographics. The output was a single value between 0 (asymptomatic) and 1 (symptomatic) to predict the likelihood that a particular patient would become symptomatic. The network was trained on data from 97 patients for 400 iterations with the goal to minimize the mean-squared error. Statistical analysis was performed on the resulting network to determine the model's accuracy. Results from the neural network were compared with those given by traditional linear discriminate analysis and the dose-volume histogram reduction (DVHR) scheme of Kutcher. Receiver-operator characteristic (ROC) analysis was performed on the resulting network which had Az = 0.833 +/- 0.04. (Az is the area under the ROC curve.) Linear discriminate multivariate analysis yielded an Az = 0.813 +/- 0.06. The DVHR method had Az = 0.521 +/- 0.08. The network was also used to rank the significance of the input variables. Future studies will be conducted to improve network accuracy and to include functional imaging data.

Clinical and dosimetric predictors of radiation-induced esophageal toxicity.

PURPOSE: To evaluate the incidence, severity, and clinical/dosimetric predictors of acute and chronic esophageal toxicities in patients with non-small cell lung cancer (NSCLC) treated with high-dose conformal thoracic radiation. METHODS AND MATERIALS: Ninety-one patients with localized NSCLC treated definitively with high-dose conformal radiation therapy (RT) at Duke University Medical Center (DUMC) were reviewed. Patient characteristics were as follows: 53 males and 38 females; median age 64 yr (range 46-82); stage I--16, II--3, IIIa--40, IIIb--30, X--2; dysphagia pre-RT--6 (7%). Treatment parameters included: median corrected dose-78.8 Gy (range 64.2-85.6); BID fractionation-58 (64%); chemotherapy-43 (47%). Acute and late esophageal toxicities were graded by RTOG criteria. Using 3D treatment planning tools, the esophagus was contoured in a uniform fashion, the 3D dose distribution calculated (with lung density correction), and the dose-volume (DVH) and dose-surface histograms (DSH) generated. At each axial level, the percentage of the esophageal circumference at each dose level was calculated. The length of circumferential esophagus and the maximum circumference treated to doses >50 Gy were assessed. Patient and treatment factors were correlated with acute and chronic esophageal dysfunction using univariate and multivariate logistic regression analyses. RESULTS: There were no acute or late grade 4 or 5 esophageal toxicities. Ten of 91 patients (11%) developed grade 3 acute toxicity. On univariate analysis of clinical parameters, both dysphagia pre-RT (p = 0.10) and BID fractionation (p = 0.11) tended toward significantly predicting grade 3 acute esophagitis. None of the dosimetric parameters analyzed significantly predicted for grade 3 acute esophagitis. Twelve of 66 assessable patients (18%) developed late esophageal toxicity. Of the clinical parameters analyzed, only dysphagia pre-RT (p = 0.06) tended toward significantly predicting late esophageal toxicity. On univariate analyses, the effects of percent organ volume treated >50 Gy (p = 0.05), percent surface area treated >50 Gy (p = 0.05), length of 100% circumference treated >50 Gy (p = 0.04), and maximum percent of circumference treated >80 Gy (p = 0.01) significantly predicted for late toxicity of all grades. On multivariate analysis, percent organ volume treated >50 Gy (p = 0.02) and maximum percent of circumference treated >80 Gy (p = 0.02) predicted for late toxicity. CONCLUSIONS: Late esophageal toxicity following aggressive, high-dose conformal radiotherapy is common but rarely severe. Dosimetric variables addressing the longitudinal and circumferential character of the esophagus have biologic rationale and are predictive of late toxicity. Further studies are needed to assess whether these parameters are better predictors than those derived from traditional DVHs.

Multimodality nuclear medicine imaging in three-dimensional radiation treatment planning for lung cancer: challenges and prospects.

The purpose of this study was to determine the utility of quantitative single photon emission computed tomography (SPECT) lung perfusion scans and F-18 fluorodeoxyglucose positron emission computed tomography (PET) during X-ray computed tomography (CT)-based treatment planning for patients with lung cancer. Pre-radiotherapy SPECT (n = 104) and PET (n = 35) images were available to the clinician to assist in radiation field design for patients with bronchogenic cancer. The SPECT and PET scans were registered with anatomic information derived from CT. The information from SPECT and PET provides the treatment planner with functional data not seen with CT. SPECT yields three-dimensional (3D) lung perfusion maps. PET provides 3D metabolic images that assist in tumor localization. The impact of the nuclear medicine images on the treatment planning process was assessed by determining the frequency, type, and extent of changes to plans. Pre-radiotherapy SPECT scans were used to modify 11 (11%) treatment plans; primarily altering beam angles to avoid highly functioning tissue. Fifty (48%) SPECT datasets were judged to be 'potentially useful' due to the detection of hypoperfused regions of the lungs, but were not used during treatment planning. PET data influenced 34% (12 of 35) of the treatment plans examined, and resulted in enlarging portions of the beam aperture (margins) up to 15 mm. Challenges associated with image quality and registration arise when utilizing nuclear medicine data in the treatment planning process. Initial implementation of advanced SPECT image reconstruction techniques that are not typically used in the clinic suggests that the reconstruction method may influence dose response data derived from the SPECT images and improve image registration with CT. The use of nuclear medicine transmission computed tomography (TCT) for both SPECT and PET is presented as a possible tool to reconstruct more accurate emission images and to aid in the registration of emission data with the planning CT. Nuclear medicine imaging techniques appear to be a potentially valuable tool during radiotherapy treatment planning for patients with lung cancer. The utilization of accurate nuclear medicine image reconstruction techniques and TCT may improve the treatment planning process.

Enhancement of replication of genetically engineered herpes simplex viruses by ionizing radiation: a new paradigm for destruction of therapeutically intractable tumors.

Human U-87 malignant glioma xenografts in mice were exposed to ionizing radiation, inoculated with a herpes simplex virus 1 mutant R3616 lacking both copies of the gamma 34.5 gene, or received both virus and radiation. Dual treatment caused a significantly greater reduction in volume or total regression of tumors than either radiation or infection alone. The significantly enhanced oncolytic effects of the combined treatment correlate with two-to five-fold enhanced replication in irradiated tumor cells than in tumors receiving virus only. In addition, in situ hybridization with viral DNA probes showed that infected tumor cells were the dominant landscape of irradiated tumors and much less apparent in the nonirradiated tumors administered this virus.

Radiotherapy for patients with medically inoperable Stage I nonsmall cell lung carcinoma: smaller volumes and higher doses--a review.

BACKGROUND: Surgical resection remains the treatment of choice for patients with stage I nonsmall cell lung carcinoma. However, there is a group of patients who are medically inoperable and are treated with radiotherapy alone. This review summarizes findings from published series of radiotherapy for patients with medically inoperable Stage I lung carcinoma. METHODS: A literature search was used to identify studies of treatment with radiotherapy alone for patients with medically inoperable Stage I nonsmall cell lung carcinoma. Ten studies that utilized megavoltage irradiation to doses of >55 gray (Gy) in conventional fractionation were selected for analysis. RESULTS: Radiotherapy doses were similar throughout the series, with a median dose of 60-66 Gy. However, treatment volumes varied considerably, from small "postage stamp" fields to comprehensive lymph node coverage. Averaging the results of these studies showed that approximately 15% of patients will be long term survivors, 25% will die of intercurrent disease, 30% will die of distant metastatic disease and 30% will die after local failure only. Eight of ten series report Grade 3-5 complications occurring in <2% of patients. Analysis of treatment factors affecting survival revealed a consistent benefit of higher radiotherapy doses in terms of local control or disease free survival. No benefit from prophylactic lymph node irradiation was demonstrated. CONCLUSIONS: Despite the infirm nature of patients with medically inoperable Stage I lung carcinoma, the majority will ultimately die of uncontrolled lung carcinoma. Because complications are uncommon after doses of 60-66 Gy, trials of dose escalation to limited fields are indicated for patients with medically inoperable nonsmall cell carcinoma in an attempt to improve overall survival.

Radiotherapy alone for medically inoperable stage I non-small-cell lung cancer: the Duke experience.

PURPOSE: To review our experience treating clinical Stage I non-small-cell lung carcinoma with radiotherapy alone using modern techniques and staging. The effect of dose and volume on outcome is to be analyzed. METHODS: Between January 1980 and December 1995, 156 patients with Stage I medically inoperable non-small-cell lung cancer were irradiated at Duke University Medical Center and the Durham Veterans Administration Medical Center. Fifteen patients were excluded from analysis (7 treated with palliative intent, and 8 lost to follow-up immediately following radiation). Characteristics of the 141 evaluable patients were as follows: Median age 70 years (range 46-95); gender: male 83%, female 17%; institution: DUMC 65%, DVAMC 35%; T1N0 54%, T2N0 46%; median size 3 cm (range 0.5 to 8); pathology: squamous cell carcinoma 52%, adenocarcinoma 18%, large cell carcinoma 19%, not otherwise specified 11%; presenting symptoms: weight loss 26%, cough 23%, none (incidental diagnosis) 57%. All patients underwent simulation prior to radiotherapy using linear accelerators of > or = 4 MV. No patients received surgery or chemotherapy as part of their initial treatment. The median dose of radiotherapy (not reflecting lung inhomogeneity corrections) was 64 Gy (50 to 80 Gy) given in 1.2 bid to 3 Gy qid fractionation. The majority of cases included some prophylactic nodal regions (73%). RESULTS: Of the 141 patients, 108 have died; 33% of intercurrent death, 35% of cancer, and 7% of unknown causes. At last follow-up, 33 patients were alive (median 24 months, range 7-132 months). The 2- and 5-year overall survival was 39% and 13%, respectively (median 18 months). The corresponding cause-specific survival was 60%, and 32% (median 30 months). On multivariate analysis, significant factors influencing overall and/or cause-specific survival were age, squamous cell histology, incidental diagnosis, and pack-years of smoking. There was a nonsignificant trend towards improved cause-specific survival with higher radiotherapy doses and larger treatment volumes. On patterns of failure analysis, 42% of failures were local-only and 38% were distant-only. Regional-only failure occurred in 4 patients (7%), 3 of whom failed solely in an unirradiated nodal site. Analysis of factors correlating with local failure at 2 years was performed using a multinominal logistic regression analysis. Significant factors associated with a lower local failure included incidental diagnosis and absence of cough with a strong trend toward significance for higher radiotherapy dose (p = 0.07) and larger treatment volume (p = 0.08). Patients who were locally controlled had an improved cause-specific survival at 5 years over those who were not controlled (46% vs. 12%, p = 0.03). Grade III-V complications occurred in 2 patients (1.5%). CONCLUSION: Patients with clinical Stage I medically inoperable non-small-cell lung cancer treated with contemporary radiotherapy alone achieved a 5-year cause-specific survival of 32%. Uncontrolled lung cancer was the primary cause of death in these patients, and local failure alone represented the most common mode of failure (42%). Patients who were locally controlled had a significantly improved cause-specific survival over those who failed locally. Because higher doses of radiotherapy appear to provide improved local control, studies of dose escalation are warranted until dose-limiting toxicity is observed.

Physical and biological predictors of changes in whole-lung function following thoracic irradiation.

PURPOSE: To develop methods of predicting the pulmonary consequences of thoracic irradiation (RT) by prospectively studying changes in pulmonary function following RT. METHODS AND MATERIALS: 100 patients receiving incidental partial-lung irradiation during treatment of tumors in or adjacent to the thorax had whole-lung function assessed via symptoms and pulmonary function tests (PFTs: FEV1-forced expiratory volume 1 s; DLCO-diffusion capacity) before and repeatedly 6-48 months following RT. All had computed tomography-based three-dimensional (3D) dose calculations with lung density heterogeneity corrections for dose-volume histogram (DVH) and normal tissue complication probability (NTCP) calculations. Functional DVHs (DVfH) based on SPECT (single photon emission computed tomography) lung perfusion scans, and serial transforming growth factor-beta (TGF-beta1) levels were available in 50 and 48 patients, respectively. The incidence and severity of changes in whole-lung function were correlated with clinical, physical, and biological factors. Exploratory statistical analyses were performed using chi-square, Pearson correlations, logistic regression, and multiple linear regression. RESULTS: RT-induced symptoms developed in 21 patients. In the overall group, the single best predictor for the development of symptoms was the NTCP (p < 0.05). Pre-RT PFTs alone were less predictive (p = 0.1 for FEV1, p = 0.08 for DLCO). A multivariate model based on pre-RT DLCO and CT-based NTCP was strongly predictive for the development of symptoms (p < 0.001). NTCPs based on SPECT-derived DVf Hs and TGF-beta1 levels did not appear to provide additional predictive value. The presence or absence of pulmonary symptoms was correlated with the decline in PFT 6 months following RT (p < 0.05). In the overall group, the degree of decline in PFTs was not well correlated with any of the dose-volume variables considered. In patients with "good" pre-RT PFTs, there was a relationship between the percent reduction in PFT and dose-volume parameters such as the percent of lung volume receiving > 30 Gy (p < 0.05). CONCLUSION: The extent of alteration in whole-lung function (symptoms or PFT changes) appears to be related to both dose-volume and pre-RT PFT parameters. The data suggest that no one variable is likely to be an adequate predictor and that multivariate predictive models will be needed. Additional studies are underway to develop better predictive models that consider physical factors such as the DVH and regional perfusion, as well as biological/clinical factors such as pre-RT PFTs and TGF-beta1.

Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck.

PURPOSE: Tumor hypoxia adversely affects short term clinical radiation response of head and neck cancer lymph node metastases and long term disease-free survival (DFS) in cervix carcinoma. This study was performed to evaluate the relationship between tumor hypoxia and DFS in patients with squamous carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Pretreatment tumor pO2 was assessed polarographically in SCCHN patients. All patients were AJCC Stage IV and had pretreatment oxygen measurements taken from locally advanced primaries (T3 or T4) or neck nodes > or = 1.5 cm diameter. Treatment consisted of once daily (2 Gy/day to 66-70 Gy) or twice daily irradiation (1.25 Gy B.I.D. to 70-75 Gy) +/- planned neck dissection (for > or = N2A disease) according to institutional treatment protocols. RESULTS: Twenty-eight patients underwent tumor pO2 measurement. The average pre-treatment median pO2 was 11.2 mm Hg (range 0.4-60 mm Hg). The DFS at 12 months was 42%. The DFS was 78% for patients with median tumor pO2 > 10 mm Hg but only 22% for median pO2 < 10 mm Hg (p = 0.009). The average tumor median pO2 for relapsing patients was 4.1 mm Hg and 17.1 mm Hg in non-relapsing (NED) patients (p = 0.007). CONCLUSION: Tumor hypoxia adversely affected the prognosis of patients in this study. Understanding of the mechanistic relationship between hypoxia and treatment outcome will allow for the development of new and rational treatment programs in the future.

The treatment of stage III nonsmall cell lung cancer using high dose conformal radiotherapy.

PURPOSE: To review our experience using conformal treatment planning and high-dose radiotherapy for Stage IIIa and IIIb nonsmall cell lung cancer (NSCLC), and to identify a subset of patients best suited for this approach by analyzing multiple pretreatment patient and tumor characteristics. METHODS AND MATERIALS: Between December 1987 and June 1992, 37 patients with Stage III NSCLC treated with high-dose radiotherapy using conformal radiotherapy were reviewed. The patient characteristics were as follows: Stage IIIa (18 patients), IIIb [19]; T1-2 [13], T3-4 [24]; N0-1 [8], N2-3 [29]; and median age 63. All patients were treated with 1.8-2.0 Gy fractions to a median dose of 66 Gy (range 60-70 Gy). Outcome was analyzed by multiple pretreatment variables including age, sex, Karnofsky performance score, pretreatment symptoms, stage group, T and N stage, tumor volume (calculated from computed tomography (CT) contours), presence of atelectasis, and tumor histology. Outcome was also analyzed by total radiotherapy dose. RESULTS: The median, 1-year and 2-year survival rates for the entire group were 19.5 months, 75 and 37%, respectively. The median, 1-year, and 2-year local progression-free survival rates are 15.6 months, 62 and 23%. There was no difference in survival by stage group (IIIa vs. IIIb) or by T or N stage. Tumor volumes ranged from 47-511 cc in the patients without atelectasis and were not a significant prognostic factor. Histology was found to be a significant prognostic factor, with squamous cell carcinoma having a better overall survival and local progression-free survival than other histologies. No other patient characteristic was found to be significant by either univariate or multivariate analysis. When outcome was analyzed by radiotherapy dose, no dose response was evident in the narrow dose range studied (60-70 Gy). Toxicity included two cases of pneumonitis, which resolved with conservative therapy. CONCLUSION: High-dose conformal radiotherapy, in our experience, results in overall survival rates that compare favorably with trials of chemoradiotherapy or conventional radiotherapy with a low treatment-associated morbidity. However, local progression remains a significant problem despite median radiotherapy doses of 66 Gy. Future trials using escalating radiotherapy doses with conformal radiotherapy are therefore, indicated.

Patterns of failure following total body irradiation and bone marrow transplantation with or without a radiotherapy boost for advanced neuroblastoma.

PURPOSE: To evaluate the patterns of failure and outcome of patients undergoing high-dose chemotherapy, total body irradiation (TBI), and bone marrow transplantation (BMT) for advanced/relapsed pediatric neuroblastoma, with emphasis on the impact of a radiotherapy boost to primary and metastatic sites. METHODS AND MATERIALS: Between May 1986 and June 1993, 26 patients with advanced neuroblastoma underwent high-dose chemotherapy and TBI followed by BMT at our institution. The majority of patients were over the age of 2 years (73%) and were Stage IV at diagnosis (81%). Multiple metastatic sites were involved including bone (17), bone marrow (15), distant nodes (11), liver (5), lung (4) and brain (1). Twenty patients (77%) received cyclophosphamide (50 mg/kg x 4 days) and TBI as consolidation therapy. TBI was delivered to a total dose of 12 Gy given in 2 Gy twice daily (b.i.d.) fractions over the 3 days preceding bone marrow infusion. A local radiotherapy boost of 8-24 Gy was given to 13 out of 26 patients (50%) to the primary and/or metastatic sites immediately prior to or following induction chemotherapy according to physician judgement. Sites not amenable to a radiotherapy boost included the bone marrow, diffuse/bilateral lung involvement, and multiple bone metastases (> four sites). RESULTS: The actuarial overall survival of the 26 patients was 40.4% at 3 and 5 years, with a progression-free survival at 5 years of 38.5%. Six patients died of transplant-related toxicity (23%). The use of cyclophosphamide as high-dose consolidation chemotherapy was significantly better than other multidrug regimens used in terms of overall survival (p < 0.0001) and progression-free survival (p = 0.0004). The presence of liver involvement prior to BMT was a significant adverse prognostic factor by multivariate analysis. Of the 20 patients surviving the transplant, 10 (50%) underwent a local radiotherapy boost. The patterns of failure were as follows: 3 out of 10 "boost" patients failed overall, none in previous (old) sites of disease only, 1 in new sites only, and 2 in old and new sites; 6 out of 10 "no boost" patients failed overall, 4 in old sites only, none in new sites only, and 2 in old and new sites. There was a trend toward improved 5-year progression-free survival in patients surviving the transplant that received a boost (68% vs. 33%, p = 0.24). A failure analysis was also performed for each of the 59 initially involved sites, of which the majority (64%) were amenable to a radiotherapy boost. Overall, there is a trend toward less failure in sites amenable to a radiotherapy boost that were irradiated (1 out of 10) vs. those not irradiated (6 out of 28). Failure in the liver occurred in three out of four of the patients with liver involvement that did not receive boost radiotherapy, whereas all seven patients with distant nodal involvement were controlled without a boost. Long-term sequelae include learning difficulties (2), cataract formation (1), and hearing loss (2). Sequelae attributable to a radiotherapy boost occurred in only one patient who received whole brain radiotherapy and developed a cataract and learning difficulties. CONCLUSION: We have found an actuarial 5-year survival rate of 40.4% for patients with advanced neuroblastoma treated with BMT, which compares favorably with results of other published series. Disease recurrence following BMT was most common in previous sites of disease. The majority (64%) of these sites were amenable to a radiotherapy boost. An analysis of failure suggests that a low-dose radiotherapy boost improves control of these sites.

Conservative surgery and adjuvant radiation therapy in the management of adult soft tissue sarcoma of the extremities: clinical and radiobiological results.

PURPOSE: The outcome of adult patients with soft tissue sarcoma of the extremities treated with conservative surgery and adjuvant irradiation was evaluated to (a) determine the appropriate treatment volume and radiation dosage in the postoperative setting, and (b) correlate in vitro radiobiological parameters obtained prior to therapy with clinical outcome. METHODS AND MATERIALS: Sixty-four consecutive adult patients with soft tissue sarcoma of the extremities (40 lower, 24 upper) who underwent conservative surgery and adjuvant irradiation 7 preoperative, 50 postoperative, 7 perioperative) between 1978 and 1991 were reviewed. The initial radiation field margin surrounding the tumor bed/scar was retrospectively analyzed in all postoperative patients. Initial field margins were < 5 cm in 12 patients, 5-9.9 cm in 32 and > or = 10 cm in 6. Patients with negative pathological margins were initially treated with traditional postoperative doses (64-66 Gy); however, in later years the postoperative dose was reduced to 60 Gy. Thirteen cell lines were established prior to definite therapy, and radiobiological parameters (multitarget and linear-quadratic) were obtained and correlated with outcome. RESULTS: Postoperative patients treated with an initial field margin of < 5 cm had a 5-year local control of 30.4% vs. 93.2% in patients treated with an initial margin of > or = 5 cm (p = 0.0003). Five-year local control rates were similar in patients treated with initial field margins of 5-9.9 cm (91.6%) compared with those treated with > or = 10 cm margins (100%) (p = 0.49). While postoperative patients receiving < 60 Gy had a worse local control than those receiving > or = 60 Gy (p = 0.08), no difference was seen in local control between patients receiving less than traditional postoperative doses (60-63.9 Gy) (74.4% vs. those receiving 64-66 Gy (87.0%) (p = 0.5). The local control of patients treated in the later years of the study, with strict attention to surgical and radiotherapeutic technique, was 87.6%. Severe late sequelae were more frequent in patients treated with doses > or = 63 Gy compared to patients treated with lower doses (23.1% vs. 0%) (p < 0.05). Mean values for Do, alpha, beta, D, n and SF2 obtained from the 13 cell lines were 115.7, 0.66, 0.029, 2.15, 0.262, respectively. Four of the 13 cell lines established prior to therapy ultimately failed locally. The radiobiological parameters of these cell lines were similar to the other nine cell lines in terms of radiosensitivity. CONCLUSIONS: Our data confirm the importance of maintaining an initial field margin of at least 5 cm around the tumor bed/scar in the postoperative setting. No benefit was seen with the use of margins > or = 10 cm. In addition, patients undergoing wide local excision with negative margins can be treated with lower than traditional postoperative doses (60 Gy) without compromising local control and with fewer chronic sequelae. Finally, it does not appear that inherent tumor cell sensitivity is a major determinant of local failure following radiation therapy and conservative surgery in soft tissue sarcoma.

Patterns of failure of complete responders following high-dose chemotherapy and autologous bone marrow transplantation for metastatic breast cancer: implications for the use of adjuvant radiation therapy.

PURPOSE: To determine the pattern of failure and outcome of patients achieving a complete response following high-dose chemotherapy and autologous bone marrow transplantation for metastatic breast cancer, and to evaluate the use of involved field radiation therapy in this setting. METHODS AND MATERIALS: Thirty-one patients with metastatic breast cancer treated on three successive high-dose chemotherapy and autologous bone marrow transplantation trials between January 1987 and March 1992 who achieved a complete response were evaluated. Twenty-three patients (74.2%) had initially Stage I-II disease. Initial therapy consisted of mastectomy in 19 (74.2%), adjuvant chemotherapy in 19 (61.3%), and adjuvant radiation therapy in 11 (35.5%). All patients underwent induction chemotherapy prior to high-dose intensification. High-dose chemotherapy consisted of cytoxan, thiotepa +/- carmustine. Fourteen patients received radiation therapy prior to (7) or following the high-dose chemotherapy (7) with either the intent to palliate a symptomatic disease site (4) or to attain/maintain a complete response (10). The four palliatively treated sites received 30 Gy in 3.0 Gy fractions, the sites treated definitively received a mean dose of 43.9 Gy (range, 18-64.8 Gy) in 1.5-2.0 Gy fractions. Seventy-two disease sites were present in the 31 patients. The most common sites involved were nodal (23), bone (14), and chest wall/breast (11). Nineteen sites were bulky (> 2 cm in size). Twenty-three sites were irradiated (19 definitively, 4 palliatively). Median follow-up was 18 months (range, 2-49 months). RESULTS: Twenty (64.5%) of the 31 patients relapsed. Eleven of the 17 patients not receiving radiation failed. Seven (63.6%) failed first solely in sites of previous disease involvement and four (36.4%) failed in new sites. This failure pattern was reversed in the patients receiving radiation therapy. Nine of the 14 (64.3%) patients relapsed. Two (22.2%) failed solely in old sites and six (66.7%) solely in new sites. One patient (11.1%) failed simultaneously in both old and new sites. Patients receiving radiation therapy had a similar 2-year actuarial disease-free survival compared to those not treated with radiation (28.3% vs. 32.1%) (p = 0.14). However, patients with less than three sites of disease had a better disease-free survival at 2 years with the addition of radiation therapy (30.0% vs. 17.6%) (p = 0.03). Patients with locoregional disease only had a lower rate of local failure (one out of four vs. three out of five) and a longer mean time to any failure (4.0 months vs. 17.5 months) with the addition of radiation therapy. Of the 72 sites identified, 59 (81.9%) were amenable to radiation therapy either prior to or following the transplant. The use of radiation therapy resulted in a borderline significant improvement in 2-year actuarial control of all sites (82.4% vs. 64.3%) (p = 0.09) as well as of bulky sites (80.0% vs. 51.4%) (p = 0.08). Excluding the four sites treated with palliative intent only, the 2-year actuarial local control of the irradiated sites was 92.8%. None of the 14 treated patients experienced untoward sequelae. CONCLUSION: The predominant site of initial failure in patients with metastatic breast cancer achieving a complete response following high-dose chemotherapy and autologous bone marrow transplantation is in sites of previous disease involvement. Radiation therapy given in conjunction with the high-dose chemotherapy is capable of improving the control of these sites, the majority of which are amenable to treatment with radiation therapy. Our data suggests that patients with less than three sites of disease, bulky disease, and locoregional disease only should be considered for radiation therapy in addition to high-dose chemotherapy.

Comparison of CT-based treatment planning and retrograde urethrography in determining the prostatic apex at simulation.

In 20 consecutive patients who underwent treatment planning, localization of the prostatic apex with CT-based techniques at simulation was compared to location of the apex as defined by retrograde urethrography. In addition, the location of the urethrogram-defined prostatic apex was compared with the bottom of the ischial tuberosities, which is often recommended as the inferior margin of the field. In 15% of the patients there was agreement between the CT-defined apex and the urethrogram-defined apex; in 85% there was discordance. In a majority of patients with discordance, the urethrogram apex was located caudad to the CT-defined apex (71%) with a median difference of .65 cm. In 29% of the patients the urethrogram apex was located superior to the CT-defined apex. Overall, 75% of the patients had discordance between the urethrogram apex and the CT apex of 0.5 cm or greater; 30% had an absolute difference of 1.0 cm or greater. Comparing the location of the prostatic apex with the bottom of the ischial tuberosities revealed that in 15% of the patients the apex was 1.0 cm or less from the bottom of the tuberosities and in 45% it was less than 1.5 cm. This would place the apex of the prostate in the penumbra region of the field and risk undertreatment of the prostate if the bottom of the ischial tuberosities was the inferior margin of the field. Measuring the location of the prostatic apex from the top of the symphysis pubis revealed that a distance of 4.9 cm encompassed the apex in all 20 patients.(ABSTRACT TRUNCATED AT 250 WORDS)