[en] Purpose: The risk of local failure after wedge resection alone for non-small cell lung carcinoma (NSCLC) is high, even in patients with pathologic Stage T1N0 tumors with negative resection margins, as shown in the recent Lung Cancer Study Group Trial. The purpose of this study is to determine the outcome of treatment with postoperative radiotherapy (XRT) after wedge resection for NSCLC and identify prognostic factors for local recurrence and survival. Methods: A retrospective review was performed of 24 consecutive patients treated with wedge resection and postoperative radiotherapy at our institution from 1987 through 1995. Patients did not undergo formal lobectomy because of concurrent medical illness (pulmonary or cardiac) or refusal. Patients were referred for XRT because of concerns about the margins of resection and/or positive lymph nodes. All patients had clinical stage I disease, although the majority of patients (N=15) were pathologically 'upstaged' as follows: T2N1: 2 patients; T3N0: 7 patients; T1-2N2: 6 patients. All patients had wedge resection, with 14 patients having negative margins, 8 having positive margins, and 2 having 'uncertain' margins. While 11 patients had selected lymph node sampling, no patient had a formal lymph node dissection. Patients received XRT to the tumor bed and hilum, with all but two patients also receiving irradiation to part or all of the mediastinum. The median initial XRT field size was 195 cm² (approximately 13x15 cm); customized blocking was used in all fields. The median final dose was 62 Gy. Results: Median followup for all patients is 17 months, while median followup for surviving patients is 36 months (range 19 - 88 months). Local failures occurred in 4 of 24 patients, for a crude local control rate of 83% and a 3-year actuarial local control rate of 77%. For patients with positive or uncertain margins of resection, local control was 74% compared with 81% for patients with negative margins of resection (p=NS). The 3-year actuarial overall survival for all patients is 24%. Survival was strongly influenced by nodal status; there were no 3-year survivors among the 8 patients with positive nodes (p<.01). For the 7 patients with negative margins and negative lymph nodes, corresponding to the population of patients generally considered to be most appropriate for wedge resection (although 3 of the 7 patients in this subgroup had T3N0 tumors), the 3-year actuarial local control was 100%, compared with 63% for the 17 patients with positive nodes and/or positive/uncertain margins (p=.12). Overall survival for these 7 patients was 71%, compared with only 6% for the remaining 'high risk' patients (p<.005). There was one treatment related death: one patient with a large T3N0 tumor and uncertain resection margins was treated to a very large field (10x29 cm) and died without documented evidence of disease, presumably from complications of severe candidal esophagitis and severe malnutrition. There were no cases of severe or life-threatening radiation pneumonitis. Conclusion: While lobectomy remains the standard operation for NSCLC, postoperative XRT offers good local control after wedge resection, including a 74% local control rate among patients with positive or uncertain margins. However, the survival rate was relatively poor due to the high rate of distant metastases, reflecting the advanced pathologic stage of most patients in this series. Patients found to have positive nodes and/or positive margins who are not candidates for completion lobectomy should be considered for innovative clinical trials of chemoradiotherapy or other new agents

[en] Purpose: To determine the rate of tumor response and patterns of relapse following combined hormonal-radiation therapy of adenocarcinoma of the prostate and to measure the survival in a group of men with tumor metastatic to pelvic lymph nodes. Methods and Materials: 66 patients with adenocarcinoma of the prostate with pathologically confirmed pelvic lymph node involvement were treated with combined radiation therapy and hormonal therapy. An additional five patients declined hormonal therapy. The patients treated with combined therapy represented a group with locally advanced disease including 44 patients (67%) with T3 or T4 tumors and 51 patients (80%) had N2 or N3 lymph node metastases. The pelvic lymph nodes were treated to a dose of 45 Gy and the prostate was boosted to a dose of 65 to 71 Gy. Hormonal therapy began up to 2 months before radiation and continued indefinitely. Patients were allowed to select their hormonal therapy and could choose DES (2 patients), orchiectomy (21 patients), LHRH agonist (7 patients) or combined androgen blockade (34 patients). Results: Median follow-up is 49 months (range 12 to 131 months) and 21 patients have been followed for longer than 5 years. There have been 15 recurrences the entire group including three local recurrences in the prostate, seven patients with distant metastases, four patients with biochemical recurrences without clinical evidence of disease, and one patient where the location was unknown. Two of the PSA recurrences occurred in patients who elected to discontinue hormones after less than 3 years of therapy. The overall survival at 5 and 8 years is 94 and 84%, the clinical disease free survival is 85 and 67%, and the biochemical disease-free survival is 78 and 47%. There was no increased toxicity of the combined modality regimen compared to the expected effects of radiation and hormonal therapy. Conclusion: Combined hormonal and radiation therapy represents an effective treatment option for patients with adenocarcinoma of the prostate metastatic to pelvic lymph nodes. Combined modality therapy appears to extend the disease-free survival and allow patients to maintain their independent function

[en] Purpose: To identify factors that may predict for severe radiation pneumonitis or pneumonopathy (RP), we reviewed a set of simple, commonly available characteristics. Methods and Materials: Medical records of 148 lung cancer patients with good performance status (ECOG 0-1) treated definitively with chemoradiation from 6/92-6/98 at the University of Pennsylvania were reviewed. Actuarial survival and the crude rate of severe radiation pneumonitis were determined as a function of several variables. Potential predictive factors examined included age, gender, histology, stage, pulmonary function, performance status (0 vs. 1), weight loss, tumor location, radiation dose, initial radiation field size, chemotherapy regimen, and timing of chemotherapy. Univariate analysis (log-rank test) was performed for each variable. Multivariate analysis was performed using linear regression. Results: Median survival for the entire cohort was 14.7 months. Four patients were inevaluable for pneumonitis due to early death from progressive disease. Of the remaining 144 evaluable patients, 12 (8.3%) experienced severe RP. The most significant factor predicting for severe RP was performance status (p < 0.003). The risk of severe RP was 16% for PS-1 patients vs. 2% for PS-0 patients. Women were significantly more likely to develop severe RP than men (p = 0.01). Among 67 patients for whom pre-radiation therapy pulmonary function data were available, forced expiratory volume of the lung in 1 second (FEV₁) was also significant (p = 0.03). No patient suffering severe RP had a pretreatment FEV₁ > 2.0 liters. The median radiation dose was 59.2 Gy and median initial radiation field size was 228 cm². Neither radiotherapy factor predicted for RP. Other factors studied, including chemotherapy drugs, and schedule, also were not significant predictors of severe RP. Conclusions: Pretreatment performance status, gender, and FEV₁ are significant predictors of severe radiation pneumonopathy, at least when using conventional radiation fields and doses. Complex radiation dose-volume algorithms that attempt to predict lung complication probabilities should probably incorporate these simply obtained clinical parameters

[en] Purpose/Objective: Recent reports have suggested that pretreatment hemoglobin (Hgb) is significantly associated with local control (LC) and overall survival (OS) in patients with T1 and T2 squamous cell carcinoma of the glottic larynx. This study evaluates the association of pretreatment Hgb level and other factors with outcome in patients limited to T1 squamous cell carcinoma of the glottic larynx treated with external beam radiation. Methods: One hundred fifty-eight patients with T1 squamous cell carcinoma of the glottic larynx were analyzed. Median follow-up was 5 years (range 2-22). Median pretreatment Hgb was 14.4 gm/dl (range 8.2-17.2). The following parameters were analyzed for their impact on LC, OS, and disease specific survival (DSS): age, gender, pretreatment Hgb, tumor grade, anterior commissure involvement, field size, total dose, dose per fraction, and overall treatment time. Results: Five year actuarial LC was 84%. Pretreatment Hgb was not a significant predictor for LC when assessed as a continuous variable (p=0.38). LC was 82% for patients with Hgb >13 vs 92% for Hgb ≤ 13 (p=0.13). No other factor was significant for LC. Five year actuarial OS was 74%. On univariate analysis, pretreatment Hgb ≤ 13 gm/dl was a significant factor for poorer OS (78% vs 68%, p=0.004), as were total dose <66 Gy (p=0.0013), and age >61 years (p=0.017). On multivariate analysis, only age >61 (p=0.014) and Hgb ≤ 13 (p=0.001) retained significance for OS. Five year actuarial DSS was 92%. Pretreatment Hgb was not a prognostic factor for DSS, nor were any other analyzed factors. Conclusion: Pretreatment Hgb is not a significant prognostic factor for LC in patients with T1 squamous cell carcinoma of the glottic larynx, but it does predict for a poorer OS without affecting DSS. This suggests that patients with lower pretreatment Hgb may have confounding medical problems which detract from their overall survival

[en] Purpose: To test the hypothesis that androgen ablation before and during radiotherapy for locally advanced carcinoma of the prostate may, by reducing tumor bulk and enhancing tumor cell kill, improve locoregional control and ultimately survival. Methods and Materials: The study was conducted from 1987 to 1991. Eligible patients were those with bulky tumors (T2-T4) with or without pelvic lymph node involvement and without evidence of distant metastases. They were randomized to receive goserelin, 3.6 mg every 4 weeks; and flutamide, 250 mg t.i.d. for 2 months before radiation therapy and during radiation therapy (Arm I), or radiation therapy alone (Arm II). Of 471 randomized patients, 456 were evaluable: 226 on Arm I and 230 on Arm II. Results: As of November 1999, the median follow-up has reached 6.7 years for all patients and 8.6 years for alive patients. At 8 years, androgen ablation has been associated with an improvement in local control (42% vs. 30%, p 0.016), reduction in the incidence of distant metastases (34% vs. 45%, p 0.04), disease-free survival (33% vs. 21%, p=0.004), biochemical disease-free survival = PSA <1.5 (24% vs. 10%, p<0.0001), and cause-specific mortality (23% vs. 31%, p=0.05). However, subset analysis indicates that the beneficial effect of short-term androgen ablation appears preferentially in patients with Gleason score 2-6. In that population, there is a highly significant improvement in all endpoints, including survival (70% vs. 52%, p=0.015). In patients with Gleason 7-10 tumors, the regimen has not resulted in a significant enhancement in either locoregional control or survival. Conclusion: In patients with Gleason score 2-6 carcinoma of the prostate, a short course of androgen ablation administered before and during radiotherapy has been associated with a highly significant improvement in local control, reduction in disease progression, and overall survival

[en] Purpose: Since oxidative injury is implicated in radiation-induced tissue damage to the lung, we studied systemically administered polyethylene glycol (PEGylated) antioxidant enzymes (AOEs) as pulmonary radioprotectors in mice. Methods and materials: C57/bl6 Mice received 13.5 Gy single-dose irradiation to the thorax. One cohort also received 100 μg of a 1:1 mixture of PEG-AOEs {PEG-catalase and PEG-superoxide dismutase (SOD)} intravenously, pre-irradiation and subgroups were evaluated at variable time-points for inflammation and fibrosis. Potential for AOE tumor protection was studied by thoracic irradiation of mice with Lewis lung carcinoma. Results: At 48 h post-irradiation, control irradiated mice had marked elevations of tissue p21, Bax and TGF-β1 in lungs, not seen in irradiated, PEG-AOE-treated mice. TUNEL staining of lung sections was performed at just one time-point (24 h post-irradiation) and revealed a decrease in apoptotic cells with AOE treatment. At four months post-irradiation, these mice had significantly increased pulmonary fibrosis as measured by hydroxyproline content. Mice treated with PEG-AOE prior to irradiation had 4-month hydroxyproline levels that were similar to that of unirradiated controls (p = 0.28). This corresponded to less pulmonary fibrosis as visualized histologically when compared with mice irradiated without AOEs. PEG-AOEs did not prevent post-irradiation pulmonary inflammation or lung cancer response to irradiation. Conclusions: A mixture of PEG-SOD and PEG-CAT successfully diminished radiation pulmonary fibrosis in mice. There was also a corresponding effect on several early biomarkers of lung injury and decreased apoptosis. There were no significant effects on acute pneumonitis or tumor protection

[en] Purpose: The results of Phase I/II data testing β-interferon with radiation therapy in a non-small-cell lung cancer population were promising. Based on these data, the Radiation Therapy Oncology Group (RTOG) initiated a Phase III trial to test the efficacy of β-interferon in poor-risk patients with Stages IIIA and IIIB non-small-cell lung carcinoma. Methods: Between September 1994 and March 1998, 123 patients were accrued to this trial. Enrolled patients were not eligible for other chemoradiation studies within the RTOG. Eligibility criteria included histologically confirmed Stage IIIA or IIIB non-small-cell lung cancer (according to American Joint Committee on Cancer) considered clinically inoperable or unresectable at the time of surgery. Patients were required to have a Karnofsky performance status 50-70 or >70 and at least 5% weight loss over the preceding 3 months. Betaseron (recombinant human interferon beta_ser, rHuIFN-β_ser,) was the chosen preparation of β-interferon. The patients randomized to the investigational arm received 16x10⁶ IU of Betaseron by i.v. bolus given 3 days a week (Monday-Wednesday) on Weeks 1, 3, and 5. The Betaseron was given 30 minutes before radiation therapy for a total of nine doses. Irradiation was delivered at 2 Gy per fraction, 5 days a week, for a total of 60 Gy over 6 weeks and was identical for both arms. The primary end point of the trial was overall survival with local control as a secondary end point. Toxicities occurring within 90 days of therapy completion were defined as acute. Results: The median follow-up was 4 years (range: 2.5-6 years) for surviving patients. Seventy-six percent of all patients completed β-interferon. Toxicity was the primary reason for noncompliance. Radiotherapy (RT) compliance was excellent in the RT-alone arm, with 94% completing therapy, compared to 82% in the β-interferon arm (p=0.0475). Grade 3 and 4 acute toxicities were higher on the β-interferon arm (p=0.0249). Grade 3 and 4 acute toxicities were primarily related to lung (n=8) and esophagus (n=7). No Grade 4 or 5 late toxicities were seen for patients in the radiation-alone arm. However, three patients on the β-interferon arm experienced Grade 4 toxicity, and one patient died. The 1-year survival rate for the RT-alone arm was 44% with a median survival time of 9.5 months. The 1-year survival on the β-interferon arm was 42% with a median survival of 10.3 months. There was no statistical difference in survival times (p=0.66). Conclusions: This multicenter, controlled Phase III trial failed to confirm the efficacy of Betaseron in patients receiving definitive radiotherapy for locally advanced, nonmetastatic non-small-cell lung cancer. The use of β-interferon led to greater rates of both acute and late treatment-related toxicity. The RTOG continues to investigate other biologic modifiers that may provide a nontoxic alternative for this poor-risk population

[en] Purpose: To compare, by a secondary analysis, the therapeutic benefits of androgen suppression in protocol prostate cancer patients with relapse after radiotherapy (RT) for locally advanced disease who, in the Phase III trial beginning in 1987, were assigned to receive or not receive a short course of neoadjuvant maximal androgen suppression before definitive RT. Methods and Materials: Between 1987 and 1991, 456 patients were entered in the Radiation Therapy Oncology Group trail 86-10 and randomized to receive (Arm I) or not to receive (Arm II) neoadjuvant hormonal therapy (HT), which was 4 months of goserelin (3.6 mg every 4 weeks) and flutamide (250 mg t.i.d.) before and during RT for bulky T2-T4 tumors. The overall and disease-specific survival after both randomization and salvage HT for patients with relapse was evaluated, as well as the duration of response in those patients undergoing salvage HT. The outcomes in patients who had received neoadjuvant HT vs. those who had not were compared. The median follow-up after randomization for all alive patients was 9.0 years and was 5.5 years for alive patients after beginning salvage HT. Results: Fewer patients received salvage HT on Arm I than on Arm II (45% vs. 63%, p<0.001). The outcomes by randomized treatment arm (I vs. II) from the time of beginning salvage HT were similar. At 5 years after salvage HT, the overall survival rates were 41% and 41% and the disease-specific survival rates were 50% and 50%. At 8 years after randomization, the overall survival rates were 47% and 44% and the disease-specific survival rates were 55% and 56%. Conclusion: Although a 4-month course of neoadjuvant and concurrent maximum androgen suppression and RT (compared with RT alone) significantly increases the freedom from relapse rate and freedom from receiving salvage HT, it does not compromise the long-term beneficial effect of subsequent salvage HT, if needed for relapse. These findings with long follow-up in patients treated for locally advanced disease diagnosed 9-14 years previously should help allay concerns of the possible development of 'resistance' to androgen suppression when 4-month courses of neoadjuvant HT are used before primary treatment

[en] Purpose: To report on a prospective clinical trial of the use of daily kilovoltage cone-beam computed tomography (CBCT) to evaluate the interfraction and residual error motion of patients undergoing intensity-modulated radiotherapy for head-and-neck cancer. Methods and Materials: Patients were treated with intensity-modulated radiotherapy with an Elekta linear accelerator using a mounted CBCT scanner. CBCT was performed before every treatment, and translational (but not rotational) corrections were performed. At least once per week, a CBCT scan was obtained after intensity-modulated radiotherapy. Variations were measured in the medial-lateral, superoinferior, and anteroposterior dimensions, as well as in the rotation around these axes. Results: A total of 28 consecutive patients (1,013 CBCT scans) were studied. The average interfraction shift was 1.4 ± 1.4, 1.7 ± 1.9, and 1.8 ± 2.1 mm in the medial-lateral, superoinferior, and anteroposterior dimensions, respectively. The corresponding average residual error shifts were 0.7 ± 0.8, 0.9 ± 0.9, and 0.9 ± 0.9 mm. These data indicate that in the absence of daily CBCT image-guided radiotherapy, a clinical target volume to planning target volume margin of 3.9, 4.1, and 4.9 mm is needed in the medial-lateral, superoinferior, and anteroposterior dimensions, respectively. With daily CBCT, corresponding margins of 1.6, 2.5, and 1.9 mm should be acceptable. Subgroup analyses showed that larynx cancers and/or intratreatment weight loss indicate a need for slightly larger clinical target volume to planning target volume margins. Conclusion: The results of our study have shown that image-guided radiotherapy using CBCT for head-and-neck cancer is effective. These data suggest it allows a reduction in the clinical target volume to planning target volume margins by about 50%, which could facilitate future studies of dose escalation and/or improved toxicity reduction. Caution is particularly warranted for cases in which the targets are mobile (e.g., the tongue).

[en] Purpose: Based on preclinical data indicating the radiosensitizing potential of epothilone B, the present study was designed to evaluate the toxicity and response rate of patupilone, an epothilone B, with concurrent radiotherapy (RT) for the treatment of central nervous system malignancies. Methods and Materials: The present Phase I study evaluated the toxicities associated with patupilone combined with RT to establish the maximal tolerated dose. Eligible patients had recurrent gliomas (n = 10) primary (n = 5) or metastatic (n = 17) brain tumors. Dose escalation occurred if no dose-limiting toxicities, defined as any Grade 4-5 toxicity or Grade 3 toxicity requiring hospitalization, occurred during treatment. Results: Of 14 patients, 5 were treated with weekly patupilone at 1.5 mg/m², 4 at 2.0 mg/m², 4 at 2.5 mg/m², and 1 at 4 mg/m². Of 18 patients, 7 were treated in the 6-mg/m² group, 6 in the 8-mg/m² group, and 5 in the 10-mg/m² group. Primary central nervous system malignancies received RT to a median dose of 60 Gy. Central nervous system metastases received whole brain RT to a median dose of 37.4 Gy, and patients with recurrent gliomas underwent stereotactic RT to a median dose of 37.5 Gy. One dose-limiting toxicity (pneumonia) was observed in group receiving 8-mg/m² every 3 weeks. At the subsequent dose level (10 mg/m²), two Grade 4 dose-limiting toxicities occurred (renal failure and pulmonary hemorrhage); thus, 8 mg/m² every 3 weeks was the maximal tolerated dose and the recommended Phase II dose. Conclusion: Combined with a variety of radiation doses and fractionation schedules, concurrent patupilone was well tolerated and safe, with a maximal tolerated dose of 8 mg/m² every 3 weeks.