Serious complications associated with stereotactic ablative radiotherapy and strategies to mitigate the risk.

The clinical applications of stereotactic body radiotherapy or stereotactic ablative radiotherapy (SABR) for the treatment of primary and metastatic tumours of different organ sites have been expanding rapidly in the recent decade. SABR requires advanced technology in radiotherapy planning and image guidance to deliver a highly conformal ablative dose precisely to targets (or tumours) in the body. Although this treatment modality has shown promising results with regard to tumour control, some serious complications have been observed and reported. In order to achieve a favourable therapeutic ratio, strategies to mitigate the risk of complications must be in place. This overview will summarise the reported serious complications caused by SABR and strategies to mitigate the risk will be discussed.

SU-E-J-87: Building Deformation Error Histogram and Quality Assurance of Deformable Image Registration.

PURPOSE: To quantify the systematic error of a Deformable Image Registration (DIR) system and establish Quality Assurance (QA) procedure. METHODS: To address the shortfall of landmark approach which it is only available at the significant visible feature points, we adapted a Deformation Vector Map (DVM) comparison approach. We used two CT image sets (R and T image sets) taken for the same patient at different time and generated a DVM, which includes the DIR systematic error. The DVM was calculated using fine-tuned B-Spline DIR and L-BFGS optimizer. By utilizing this DVM we generated R' image set to eliminate the systematic error in DVM,. Thus, we have truth data set, R' and T image sets, and the truth DVM. To test a DIR system, we use R' and T image sets to a DIR system. We compare the test DVM to the truth DVM. If there is no systematic error, they should be identical. We built Deformation Error Histogram (DEH) for quantitative analysis. The test registration was performed with an in-house B-Spline DIR system using a stochastic gradient descent optimizer. Our example data set was generated with a head and neck patient case. We also tested CT to CBCT deformable registration. RESULTS: We found skin regions which interface with the air has relatively larger errors. Also mobile joints such as shoulders had larger errors. Average error for ROIs were as follows; CTV: 0.4mm, Brain stem: 1.4mm, Shoulders: 1.6mm, and Normal tissues: 0.7mm. CONCLUSIONS: We succeeded to build DEH approach to quantify the DVM uncertainty. Our data sets are available for testing other systems in our web page. Utilizing DEH, users can decide how much systematic error they would accept. DEH and our data can be a tool for an AAPM task group to compose a DIR system QA guideline. This project is partially supported by the Agency for Healthcare Research and Quality (AHRQ) grant 1R18HS017424-01A2.

SU-E-T-460: Isoeffective Dose Display (EQD2) for Composite Plan of Radiosurgery and Conventional 3D Radiotherapy.

PURPOSE: Direct addition of doses between plans with different fractionation fails to provide accurate dose-response information to anticipate clinical outcome. To combine different fractionation patterns, first-order biological model correction for dose-rate must be included. Moreover, 3-D isoeffect patterns of the combined doses must be displayed so that overlap area to elegant volumes can be avoided. The linear quadratic (LQ) model and biologically effective dose (BED) method were used to produce a combined plan in equivalent 2 Gy fractions (EQD2) for radiosurgery and conventional 3D radiotherapy. METHODS: For patients with multiple courses of radiotherapy, dose distributions of the prior and boost treatment plans were converted to BED. The fraction size specified by the prescription was applied globally for each BED calculation, α/ß ratio of 10 and 2.5 was used for early and late effect, respectively. Image registration with CT or MR was performed for initial and boost plans. The registration information was applied to dose distributions to obtain the composite EQD2. RESULTS: As a demonstration of this method, two patients were selected who had combined treatments from substantially different modalities. A patient with liver cancer initially received radiotherapy of 30 Gy/10 Fx and re-irradiation with CyberKnife radiosurgery (15 Gy/1 Fx). The combined plan showed that the PTV received EQD2 of 63.8 Gy. Another patient had brain metastasis treated with GammaKnife of 18 Gy (50% isodose) followed by conventional 3D whole brain radiation of 30 Gy/10 Fx. The minimal combined tumor EQD2 was 74.5 Gy. Early and late calculated responses showed that all critical organ doses were within tolerance. CONCLUSIONS: For patients receiving radiation with different fractionation schemes, combined isoeffective dose distributions were calculated and displayed. In both cases, crucial information regarding 3-D dose distributions assisted the physicians in determining whether tolerance limits of overlap areas of retreated critical structures were preserved.

Phase III trial comparing whole-pelvic versus prostate-only radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413.

PURPOSE: This trial tested the hypothesis that combined androgen suppression (CAS) and whole-pelvic (WP) radiotherapy (RT) followed by a boost to the prostate improves progression-free survival (PFS) by 10% compared with CAS and prostate-only (PO) RT. This trial also tested the hypothesis that neoadjuvant and concurrent hormonal therapy (NCHT) improves PFS compared with adjuvant hormonal therapy (AHT) by 10%. MATERIALS AND METHODS: Eligibility included localized prostate cancer with an elevated prostate-specific antigen (PSA) < or = 100 ng/mL and an estimated risk of lymph node (LN) involvement of 15%. Between April 1, 1995, and June 1, 1999, 1,323 patients were accrued. Patients were randomly assigned to WP + NCHT, PO + NCHT, WP + AHT, or PO + AHT. Failure for PFS was defined as the first occurrence of local, regional, or distant disease; PSA failure; or death for any cause. RESULTS: With a median follow-up of 59.5 months, WP RT was associated with a 4-year PFS of 54% compared with 47% in patients treated with PO RT (P =.022). Patients treated with NCHT experienced a 4-year PFS of 52% versus 49% for AHT (P =.56). When comparing all four arms, there was a progression-free difference among WP RT + NCHT, PO RT + NCHT, WP RT + AHT, and PO RT + AHT (60% v 44% v 49% v 50%, respectively; P =.008). No survival advantage has yet been seen. CONCLUSION: WP RT + NCHT improves PFS compared with PO RT and NCHT or PO RT and AHT, and compared with WP RT + AHT in patients with a risk of LN involvement of 15%.

Changes in plasma gelsolin concentration during acute oxidant lung injury in mice.

Oxidant stress may contribute to acute lung injury under some circumstances. The rapid depletion of plasma gelsolin following major trauma in patients who subsequently develop respiratory distress suggests that this actin-scavenging protein might protect against delayed pulmonary complications. The specific aim of these experiments was to explore the temporal and quantitative relationship between gelsolin levels and lung damage. Gelsolin levels were measured in three murine models of oxidant injury: immunotargeting of pulmonary endothelium with an H2O2-generating enzyme; continuous exposure to >95% O2; and single high-dose thoracic radiation. The degree of lung injury was inversely related to gelsolin levels in mice treated with glucose oxidase-conjugated antibodies against platelet endothelial cell adhesion molecule-1 (p <0.0001). By 60-72 hours of hyperoxic exposure, gelsolin levels had dropped precipitously in all mice who sustained major lung damage (p <0.0001), establishing a quantitative association between gelsolin concentration and hyperoxic lung injury (r = -0.72; 95% confidence interval: ?0.81 to ?0.59). Gelsolin levels modestly but progressively fell in irradiated mice over the 3 days following treatment (p = 0.012) despite the development of only microscopic lung damage during this timeframe. These findings are consistent with the hypothesis that gelsolin depletion is involved in the pathogenesis of acute oxidant lung injury.

RTOG 96-10: reirradiation with concurrent hydroxyurea and 5-fluorouracil in patients with squamous cell cancer of the head and neck.

PURPOSE: Patients with recurrent squamous cell cancer of the head and neck (SCH&N) are generally treated with systemic chemotherapy. Improvement in survival has not occurred, despite an increased objective response rate. This study was undertaken to explore the feasibility and toxicity, and estimate the therapeutic impact of, reirradiation (RRT) with concurrent hydroxyurea and 5-fluorouracil. METHODS AND MATERIALS: The eligibility requirements included SCH&N presenting as a second primary or recurrence > or =6 months after definitive RT to > or =45 Gy, with > or =75% of the tumor volume within the previous field. The cumulative spinal cord dose was limited to 50 Gy, and measurable disease was required. Four weekly cycles were given, each separated by 1 week of rest. A cycle consisted of 5 days, Monday through Friday, of 1.5-Gy twice-daily repeated RT, with the fractions separated by > or =6 h, with 1.5 g of hydroxyurea given 2 h and 300 mg/m2 of a 5-fluorouracil IV bolus given 30 min before each second daily fraction. RESULTS: Eighty-six patients were entered; 81 patients were assessable. The median prior radiation dose was 61.2 Gy. The 4 planned cycles were delivered in 79% of patients. Grade 3 mucositis occurred in 14% of patients, and Grade 4 in 5%. Grade 3 acute pharyngeal toxicity was seen in 17%. Grade 3 neutropenia occurred in 9%, Grade 4 in 10%, and Grade 5 in 7%. Six patients died of treatment-related toxicity. Two died of hemorrhage from the tumor site without thrombocytopenia. With a median follow-up of 16.3 months for living patients, the estimated median overall survival was 8.2 months and the estimated 1-year survival rate 41.7%. Patients treated >3 years after the previous RT had a 1-year survival rate of 48% compared with 35% for patients treated within 3 years (p = 0.017). The 1-year survival rate for patients with a second primary was 54% compared with 38% for patients with recurrence (p = 0.083). CONCLUSION: Repeated RT with concurrent chemotherapy as given in this study is a feasible approach for selected, previously irradiated patients with SCH&N and may produce increased median and 1-year survival rates compared with systemic chemotherapy trials reported in the literature. A randomized study should be conducted to compare these two different approaches.

Risk of death from intercurrent disease is not excessively increased by modern postoperative radiotherapy for high-risk resected non-small-cell lung carcinoma.

PURPOSE: Some studies report a high risk of death from intercurrent disease (DID) after postoperative radiotherapy (XRT) for non-small-cell lung cancer (NSCLC). This study determines the risk of DID after modern-technique postoperative XRT. PATIENTS AND METHODS: A total of 202 patients were treated with surgery and postoperative XRT for NSCLC. Most patients (97%) had pathologic stage II or III disease. Many patients (41%) had positive/close/uncertain resection margins. The median XRT dose was 55 Gy with fraction size of 1.8 to 2 Gy. The risk of DID was calculated actuarially and included patients who died of unknown/uncertain causes. Median follow-up was 24 months for all patients and 62 months for survivors. RESULTS: A total of 25 patients (12.5%) died from intercurrent disease, 16 from confirmed noncancer causes and nine from unknown causes. The 4-year actuarial rate of DID was 13.5%. This is minimally increased compared with the expected rate for a matched population (approximately 10% at 4 years). On multivariate analysis, age and radiotherapy dose were borderline significant factors associated with a higher risk of DID (P =.06). The crude risk of DID for patients receiving less than 54 Gy was 2% (4-year actuarial risk 0%) versus 17% for XRT dose > or = 54 Gy. The 4-year actuarial overall survival was 34%; local control was 84%; and freedom from distant metastases was 37%. CONCLUSION: Modern postoperative XRT for NSCLC does not excessively increase the risk of intercurrent deaths. Further study of postoperative XRT, particularly when using more sophisticated treatment planning and reasonable total doses, for carefully selected high-risk resected NSCLC is warranted.

Advanced oropharyngeal carcinoma treated with surgery and radiotherapy: oncologic outcome and functional assessment.

INTRODUCTION/PURPOSE: Surgery and postoperative radiotherapy (XRT) is a standard therapy for locally advanced resectable oropharyngeal carcinoma. This maximizes local-regional control, but does not address the potential for occult distant metastases. Additionally, some patients may suffer poor functional outcome after this intensive local therapy. This report reviews our institutional experience with modern radical surgery and XRT for this disease. METHODS: A retrospective chart review was performed on 51 consecutive patients treated from 1991 to 1997 at the University of Pennsylvania with radical surgery and postoperative XRT. This study included patients with locally advanced, stage III/IV (exclusive of T1-2N1) squamous carcinoma of the oropharynx. All patients had a good performance status (ECOG 0-1). Patients who received adjuvant chemotherapy were excluded. No patient had gross residual disease after surgery; the median XRT dose was 63.7 Gy. Survival, local-regional control (LRC), and freedom from distant metastases (DM) were calculated actuarially. In patients who remained free of disease, functional status was determined using the List Performance Status Scale (PSS). RESULTS: With a median follow-up in surviving patients of 34 months, the 3-year actuarial overall survival was 51%. The 3-year LRC was 73%, and the freedom from DM was 69%. The most significant factor predicting for failure was the number of pathologically positive nodes (P <.001 for survival and DM; P =.003 for LRC). In 29 patients who were evaluable for the List PSS, the mean normalcy-of-diet score was 48; the mean eating-in-public score was 53; and the mean understandability-of-speech score was 75. There was a trend toward better PSS scores in patients with T1-2 tumors versus T3-4 tumors, although this did not reach statistical significance. CONCLUSIONS: Surgery and postoperative XRT offer relatively good LRC and moderate overall survival rates. Results, however, remain suboptimal, particularly with respect to the risk of DM and the functional outcome. These data provide a baseline for comparison with maturing results from multimodality trials in which radical surgery is not used in all patients with locally advanced oropharyngeal carcinoma.

Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate.

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.

Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma.

PURPOSE: As therapy for locally advanced non-small-cell lung carcinoma (NSCLC) improves, brain metastases (BM) may become a greater problem. We analyzed our chemoradiation experience for patients at highest risk for the brain as the first failure site. METHODS: Records for 150 consecutive patients with stage II/III NSCLC treated definitively with chemoradiation from June 1992 to June 1998 at the University of Pennsylvania were reviewed. Most patients (89%) received cisplatin, paclitaxel, or both. All had negative brain imaging before treatment. Posttreatment brain imaging was performed for suspicious symptoms. Incidence of BM was examined as a function of age, sex, histology, stage, performance status, weight loss, tumor location, surgery, radiation dose, initial radiation field, chemotherapy regimen, and chemotherapy timing. RESULTS: Crude and 2-year actuarial rates of BM were 19% and 30%, respectively. Among pretreatment parameters, stage IIIB was associated with a higher risk of BM (P <.04) versus stage II/IIIA. Histology alone was not significant (P <.12), although patients with IIIB nonsquamous tumors had an exceptionally high 2-year BM rate of 42% (P <.01 v all others). Examining treatment-related parameters, crude and 2-year actuarial risk of BM were 27% and 39%, respectively, in patients receiving chemotherapy before radiotherapy and 15% and 20%, respectively, when radiotherapy was not delayed (P <.05). On multivariate analysis, timing of chemotherapy (P <.01) and stage IIIA versus IIIB (P <.01) remained significant. CONCLUSION: Patients with later stage, nonsquamous NSCLC, particularly those receiving induction chemotherapy, have sufficiently common BM rates to justify future trials including prophylactic cranial irradiation.

Phase I study of paclitaxel given by seven-week continuous infusion concurrent with radiation therapy for locally advanced squamous cell carcinoma of the head and neck.

PURPOSE: Paclitaxel is one of the most active agents for squamous cell carcinoma of the head and neck (SCCHN) and an in vitro radiosensitizer. The dose-response relationship for paclitaxel may depend more on exposure duration than on peak concentration. This National Cancer Institute-sponsored phase I trial was designed to determine the feasibility of combining continuous-infusion (CI) paclitaxel with concurrent radiation therapy (RT). PATIENTS AND METHODS: Patients with previously untreated stage IVA/B SCCHN were eligible. Primary end points were determination of the maximum-tolerated dose, dose-limiting toxicity, and pharmacokinetics for paclitaxel given by CI (24 hours a day, 7 days a week for 7 weeks) during RT (70 Gy/7 weeks). RESULTS: Twenty-seven patients were enrolled and assessable for toxicity. Nineteen of the patients who completed > or = 70 Gy were assessable for response. Grade 3 skin and mucosal acute reactions occurred at 10.5 mg/m(2)/d, but uninterrupted treatment was possible in five of six patients. At 17 mg/m(2)/d, skin toxicity required a 2-week treatment break for all three patients. The mean paclitaxel serum concentration at dose levels > or = 6.5 mg/m(2)/d exceeded that reported to achieve in vitro radiosensitization. Initial locoregional control was achieved in 14 (58%) of 24 of patients treated to 70 Gy, and control persisted in nine (38%). CONCLUSION: CI paclitaxel with concurrent RT is a feasible and tolerable regimen for patients with advanced SCCHN and good performance status. Preliminary response and survival data are encouraging and suggest that further study is indicated. The recommended phase II dose of paclitaxel by CI is 10.5 mg/m(2)/d with RT for SCCHN.

Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate.

PURPOSE: To determine the potential advantage of androgen ablation following standard external-beam radiation therapy in patients with locally advanced (clinical or pathologic T3; clinical or pathologic node positive) carcinoma of the prostate. METHODS AND MATERIALS: In 1987 the RTOG initiated a Phase III trial of long-term adjuvant goserelin in definitively irradiated patients with carcinoma of the prostate. A total of 977 patients were accrued to the study of which 945 remain analyzable: 477 on the adjuvant hormone arm (Arm I); and 468 on the radiation only arm (Arm II) with hormones initiated at relapse. The initial results were reported in the Journal of Clinical Oncology in 1997. RESULTS: With a median follow up of 5.6 years for all patients and 6.0 years for living patients local failure at 8 years was 23% for Arm I and 37% for Arm II (p < 0.0001). Distant metastasis was likewise favorably impacted with the immediate use of hormonal manipulation with a distant metastasis rate in Arm I of 27% and 37% in Arm II (p < 0.0001). Disease-free survival (NED survival) and NED survival with PSA of 1.5 ng/mL (bNED) or less were both statistically significant in favor of the immediate hormone arm (both p < 0.0001). Cause-specific failure was not statistically different with a cause-specific failure of 16% for Arm I and 21% in Arm II (p = 0.23). Overall survival was likewise not statistically different between two arms, with a 49% overall survival at 8 years in Arm I and 47% in Arm II (p = 0.36). Subset analysis of centrally reviewed Gleason 8-10 patients who did not undergo prostatectomy showed that for patients receiving radiation therapy plus adjuvant hormones there was a statistically significant improvement in both absolute (p = 0.036) and cause-specific survival (p = 0.019). CONCLUSIONS: Use of long-term adjuvant androgen deprivation in addition to definitive radiation therapy results in a highly significant improvement in regards to local control, freedom from distant metastasis, and biochemical free survival in unfavorable prognosis patients with carcinoma of the prostate.

Subset analysis of RTOG 85-31 and 86-10 indicates an advantage for long-term vs. short-term adjuvant hormones for patients with locally advanced nonmetastatic prostate cancer treated with radiation therapy.

PURPOSE: The benefit of adjuvant hormones in prostate cancer patients receiving definitive radiation therapy (RT) in RTOG 85-31 and 86-10 has previously been reported. This analysis excludes those patients with positive lymph nodes or postprostatectomy to determine the benefit of adjuvant hormones in men with locally advanced nonmetastatic prostate cancer receiving definitive RT. METHODS AND MATERIALS: Nine hundred ninety-three eligible patients from RTOG 85-31 and 86-10 treated between 1987-1992 were included in this study. Five hundred seventy-five patients with T3N0M0 disease were included from RTOG 85-31 and 418 patients with T2b-T4N0M0 disease from RTOG 86-10. Patients randomized to receive long-term hormones (LTH) on 85-31 received goserelin starting the last week of RT and continued indefinitely. Patients treated with short-term hormones (STH) on 86-10 received goserelin and flutamide 2 months prior to and during RT. The median follow-up for all patients in this analysis was 71 months (range, 0.6-129 months). RESULTS: Combining both studies, statistically significant improvements in outcome were observed between the RT and hormones (I) and RT alone (II) groups for biochemical disease-free survival (bNED control) and distant metastases failure (DMF). Statistically significant improvements in bNED control, DMF and cause-specific failure (CSF) were observed for patients receiving LTH compared with STH. In those patients receiving LTH, the benefit in bNED control (p = 0.0002), DMF (p = 0.05), and CSF (p = 0.02) was limited to centrally reviewed Gleason score of 7 and 8-10 tumors. For all patients treated on 85-31, statistically significant improvements for bNED control, DMF, and CSF were observed between Group I and II. Multivariate analysis demonstrated Gleason score and the use of LTH to be independent predictors for bNED control (p < 0.0001), DMF (p < 0.0001), and CSF (p < 0.002). CONCLUSIONS: Based on this analysis, adjuvant long-term hormones compared to short-term hormones resulted in statistically significant improvements in bNED control, DMF, and CSF rates for patients with locally advanced nonmetastatic prostate cancer.

Evaluation of recurrent squamous cell carcinoma of the head and neck with FDG positron emission tomography.

PURPOSE: This study compared the effectiveness of fluorodeoxyglucose (FDG) positron emission tomography (PET) with computed tomography (CT), magnetic resonance imaging (MRI), or both for the assessment of recurrent squamous cell carcinoma of the head and neck. The value of quantifying the standardized uptake values (SUV) to distinguish recurrent neoplasm from inflammatory lesions and normal structures was also evaluated. METHODS: Forty-three patients with head and neck cancer were examined with F-18 FDG PET at least 4 months after their last course of radiation therapy (mean, 11 months). The SUVs were measured in visually identified regions of abnormally increased activity and were compared with the values in normal mucosa, the base of the tongue, and the hard palate to determine if an optimal cutoff value exists for diagnosing recurrence of malignant lesions. The final diagnosis of recurrence was made based on biopsy or at least 6 months' clinical follow-up. RESULTS: FDG PET correctly detected recurrence in 20 of 22 patients who had 45 discrete lesions located in the field of the upper aerodigestive tract. Two false-negative and three false-positive results were identified. The accuracy of FDG PET was 88% (38 of 43 patients), compared with 66% (25 of 38 patients) for CT, MRI, or both. Although there was a significant difference of SUVs (P = 0.0036) between the recurrent lesions and normal structures, the optimal cutoff values were difficult to define. CONCLUSIONS: Visual analysis of FDG PET is significantly more accurate in the diagnosis of recurrent squamous cell cancer of the head and neck than are CT or MRI. However, single SUV quantification does not significantly enhance efficacy.

Radiotherapy with 6-megavolt photons for early glottic carcinoma: potential impact of extension to the posterior vocal cord.

PURPOSE: Radiation therapy has a high success rate in the treatment of early glottic carcinoma. Excellent outcomes have been reported from centers using cobalt-60 or relatively low-energy (< or = 4 MV) radiation therapy to achieve these results. Whether similar outcomes can be achieved with a 6 MV linear accelerator has been less rigorously evaluated. This study assesses the efficacy of 6 MV radiation therapy for early stage glottic cancer and identifies prognostic factors for local control and overall survival in this common disease. MATERIALS AND METHODS: One hundred twenty-eight consecutive cases of Tis, T1, and T2 squamous cell carcinomas of the glottis from 1982 to 1996 were retrospectively analyzed with regard to local control and survival. All patients were treated with definitive radiation therapy with a 6-MV linear accelerator. Potential prognostic factors for local control and survival were evaluated with univariate and multivariate models. Median follow-up of locally controlled patients was 65 months. RESULTS: The overall 3-year actuarial local control rates for T1 and T2 carcinomas were 86% and 68%, respectively. Patients with lesions involving the posterior third of the vocal cord had significantly worse 3-year local control (76% vs. 86%, P =.038). Radiation therapy technique and overall treatment time did not significantly affect local control. For patients with Tis and T1 lesions, factors associated with significantly worse local control included cordectomy-ineligible disease (P =.024), dose less than 6,600 cGy (P =.024), and lesions limited to the posterior third of the vocal cord (P =.004). Three-year local control was 76%, with doses less than 6,600 cGy and 90% with higher doses. High rates of second primary malignancies were observed and represented the major cause of death. Five-year overall survival was 84%. CONCLUSIONS: The use of 6-MV photons for treatment of early glottic cancer seems to achieve local control similar to that reported with lower-energy photons. However, patients with posterior third involvement had a poorer local control rate with standard radiation therapy, thereby suggesting that alternative approaches be considered.

Morbidity after midline mandibulotomy and radiation therapy.

PURPOSE: To assess the morbidity of mandibulotomy in patients treated for neoplasms of the oropharynx and oral cavity, and to determine if postoperative radiation therapy to the mandibulotomy site carries an increased risk of complications. PATIENTS AND METHODS: The medical charts of 30 patients treated between 1992 and 1996 undergoing midline mandibulotomy for tumors of the oral cavity (7 patients) and oropharynx (23 patients) were retrospectively reviewed. Three patients presented with recurrent disease, 1 of whom was previously irradiated. Twenty-five patients received postoperative radiation after mandibulotomy to a median dose of 60 Gy to the primary tumor bed, whereas 5 patients were treated with surgery alone. The patients were separated into those whose mandibulotomy site was within the radiation treatment field (n = 9), and those whose site was shielded (n = 10). Median follow-up was 27.8 months (range 5-81 months). End points included significant pain involving the mandibulotomy site, trismus, malocclusion, wound infection, osteoradionecrosis, and time to oral intake. RESULTS: There were no postoperative deaths. Minor wound infection or breakdown occurred in 4/30 patients (13%). All of these resolved with local care and parenteral antibiotics. More serious complications involving the mandibulotomy occurred in 2 patients (7%). One patient had chronic wound drainage at the mandibular osteotomy site, which healed after plate removal. Another patient developed osteoradionecrosis. No patient developed trismus or malocclusion. With a median follow-up of 27.8 months, 4 patients have recurred locally. The complication rate was 11% for patients whose mandibulotomy site was irradiated, and 30% for those whose site was shielded. CONCLUSION: Mandibulotomy can be safely performed in patients who are likely to require postoperative external radiation.

Pilot study of organ preservation multimodality therapy for locally advanced resectable oropharyngeal carcinoma.

The purpose of this study was to determine the early efficacy and toxicity of a new multimodality organ-preservation regimen for locally advanced, resectable oropharyngeal squamous cell carcinoma (SCC). Patients with T3-4N0-3M0 or T2N2-3M0 oropharyngeal SCC were eligible for this Phase II study. Patients needed the physiologic reserve for surgery and technically resectable tumors. Induction carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) x 2 cycles (q21 days) were given. Objective responders received definitive radiotherapy (XRT), 70 Gy/7 weeks with concurrent weekly paclitaxel. Initially, the dose of paclitaxel was 50 mg/m2/week; because of mucosal toxicity it was reduced to 30 mg/m2/week. Patients with N2-3 disease received post-XRT neck dissection and 2 more cycles of "adjuvant" chemotherapy. In the first 22 patients, the neutropenic fever rate was 27%. Although there has been no grade IV-V toxicity from induction therapy, grade II-III toxicity resulted in an unacceptable delay in starting XRT in 14% of patients. The response rate to induction chemotherapy was 91%. Grade III mucositis occurred in all patients during concurrent chemoradiotherapy. One patient died of pneumonia during concurrent chemoradiotherapy after receiving 26 Gy and 3 doses of paclitaxel 50 mg/m2. No dose-limiting toxicity occurred in 15 patients treated with concurrent paclitaxel 30 mg/m2/week. Actuarial overall survival at 18 months is 82%; local-regional control is 86%. To date, distant metastases have not developed in any patients. This regimen has intense but acceptable acute toxicity. The maximum tolerated dosage of weekly paclitaxel during standard continuous-course XRT is confirmed to be 30 mg/m2/week. The treatment efficacy of this regimen (response rate and short-term local-regional and distant control) is encouraging. Accrual continues to obtain long-term toxicity, efficacy, and quality-of-life data.

Factors predicting severe radiation pneumonitis in patients receiving definitive chemoradiation for lung cancer.

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 (FEV(1)) was also significant (p = 0. 03). No patient suffering severe RP had a pretreatment FEV(1) > 2.0 liters. The median radiation dose was 59.2 Gy and median initial radiation field size was 228 cm(2). 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 FEV(1) 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.

Dual time point fluorine-18 fluorodeoxyglucose positron emission tomography: a potential method to differentiate malignancy from inflammation and normal tissue in the head and neck.

Fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) studies imaging FDG PET imaging is used to detect and stage head and neck cancers. However, the variable physiologic uptake of FDG in different normal structures as well as at inflammatory sites may either obscure a tumor focus or be falsely interpreted to represent tumor activity. Twenty-one patients (9 men, 12 women, median age 59) were scanned serially at two time points, one at 70 min (range 47-112) and the second at 98 min (77-142) after the intravenous injection of 4.3 MBq/kg of FDG. The mean interval between emission scans was 28 min (13-49). Transmission scans were performed and regions of interest (ROIs) were overlayed on the fully corrected images. Standardiued uptake values (SUVs) were generated for the cerebellum, tongue, larynx, every lesion, and a matched contralateral site. Follow-up and pathologic studies revealed 18 squamous cell carcinomas and nine inflammatory or infectious lesions. Tumor SUVs were 4.0+/-1.6 (mean +/- SD) for the first scan and 4. 5+/-2.2 for the second scan. Contralateral SUVs were 1.2+/-0.5 and 1. 1+/-0.5 for the two scans. Tumor SUVs increased by 12%+/-12% as compared with a 5%+/-17% decrease for contralateral sites (P<0.05). SUVs for inflammatory sites (2.0+/-0.7 and 2.0+/-0.9), cerebellum (4. 2+/-1.3 and 4.3+/-1.4), tongue (1.8+/-0.4 and 1.9+/-0.5) and larynx (1.5+/-0.6 and 1.5+/-0.6) remained constant over time (+0.6%, +2.8%, +1.4%, and -2.4%; P<0.05 when compared with tumor SUV changes). The ratio tumor/contralateral SUV increased by 23%+/-29% over time while this ratio for inflamed sites increased by only 5%+/-15% (P=0.07). The time interval between scans correlated with increase in SUV for tumors (r=0.55, P<0.05) but not for any of the other ROIs. Separation was superior when studies were performed more than 30 min apart (P<0.05). These preliminary data suggest that dual time point imaging compatible with a clinical study protocol is helpful in differentiating malignant lesions from inflammation and normal tissues, especially when separated by a sufficient time interval.