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Background Our study is a prospective evaluation of unresectable malignant cancers of the head and neck treated with concomitant chemotherapy and radiotherapy (RT) using delayed accelerated fractionation (concomitant boost). Methods Between January 1988 and March 1995, 82 patients with unresectable cancers of the head and neck were enrolled in this phase II study. Of these, 52 patients were treated and followed for a minimum of 3 years and are the subject of this analysis. All patients had T4 lesions and were stage IV according to the American Joint Committee on Staging Criteria (AJCC). Patients received RT with accelerated fractionation to a total of 70 Gy in 6 weeks using a concomitant-boost technique. Concomitant cis platin (100 mg/M2) was given on days 1 and 22 of RT. Twenty-seven patients received mitomycin-C (7.5 mg/M2) on days 1 and 22, and 1 patient received mitomycin-C on day 1. In addition, 27 patients received adjuvant chemotherapy with cis platin and vinblastine. The mean follow-up was 45 months (range, 36–72 months). The minimum follow-up for surviving patients is 3 years. Results At 3 years, the local control rate was 58%. Three-year local control rates for paranasal sinus, nasopharynx, oropharynx, and larynx/hypopharynx were 78%, 78%, 64%, and 100%, respectively. For all patients, the distant-metastasis-free survival was 56%, and the overall survival rate was 36%. Patients with oral cavity cancers experienced worse overall survival versus other sites, 0% versus 47% (p = .03). Salivary cancers also showed worse survival versus other sites, 0% versus 47%, but was not statistically significant. Severe acute complications occurred in 34% of patients. Treatment-related toxicity also resulted in the death of 2 patients. Severe late complications occurred in 7% of patients. Conclusions Treatment of this poor prognostic group of patients with aggressive chemotherapy and RT produced surprisingly good local control and survival. © 1998 John Wiley & Sons, Inc. Head Neck20: 497–503, 1998.

This article reviews the indications, techniques, and results of brachytherapy in the treatment of non-small cell lung cancer (NSCLC) and selected chest neoplasms. Various isotopes and techniques are used to place radioactive sources directly into a tumor, tumor bed, or the chest. Brachytherapy techniques can be tailored to the clinical situation and can be in the form of permanent interstitial volume or planar implants (radioactive sources permanently imbedded into the tumor or tumor bed) or in the form of temporary interstitial or endoluminal implants (where radioactive sources irradiate a tumor bed over a certain length of time and then are removed). These treatments can be delivered over a short interval (high-dose rate [HDR]) or over a more protracted time (low-dose rate). HDR treatments can be used intraoperatively to deliver a large dose of radiation to a determined target area with selective sparing of surrounding normal structures. Different methods of delivering HDR intraoperative radiation are under investigation. Most reports on brachytherapy for chest malignancies are retrospective and come from a few single institutions. Most of the published data relate to the treatment of NSCLC, but other intrathoracic malignancies, such as malignant pleural mesothelioma and malignant thymoma, have been treated with brachytherapy. To our knowledge, no major randomized trials accurately assess or confirm these retrospective studies yet, complicating the interpretation of these results. Nevertheless, brachytherapy is of value in selected situations and offers the clinician and the patient an innovative method of delivering conformal high-dose radiation to a defined target with preferential sparing of normal surrounding structures. With continued innovations in the development of radioactive isotopes, computerized treatment planning and targeting, and source delivery, brachytherapy should continue to offer an attractive alternative and complement to conventional treatment approaches, and may offer patients improved local control and survival.

Purpose : Local failure is a major obstacle to the cure of locally advanced non small-cell lung cancer. Three-dimensional conformal radiation therapy (3-DCRT) selects optimal treatment parameters to increase dose to tumor and reduce normal tissue dose, potentially representing an enhancement of the therapeutic ratio of radiation therapy for lung cancer. We performed this analysis of 45 non-small cell lung cancer patients treated with 3-DCRT alone, to evaluate the ability of computer derived lung dose volume histograms to predict serious pulmonary toxicity, to assess the feasibility of this approach, and to examine the resulting survival. Methods : There were 28 males (62%) and 17 females (38%). The median age was 65 (range: 38–82). Tumor stage was Stage I/II in 13%, IIIa in 42%, and IIIb in 44%. The histology was squamous in 44%, adenocarcinoma in 36%, and other non-small cell histologies in the others. Only 47% of patients, had combined favorable prognostic factors (i.e. KPS ≤ 80, and ≤5% wt. loss). The median dose of radiation to gross disease was 70.2 Gy (range: 52.2–72 Gy) delivered in fractions of 1.8 Gy, 5 days per week. Results : Seven patients did not complete 3-DCRT due to disease progression outside the port. Follow-up data are mature: the median follow up of the 6 survivors is 43.5 months (35–59). Thoracic progression occurred in 46%. Median survival (all 45 patients.) is 15.7 months and survival is 32% at 2 years and 12% at 59 months. Pulmonary toxicity ≥grade 3 occurred in 9% of patients. Dose volume histograms were available in 31 patients and showed a correlation between risk of pulmonary toxicity and indices of dose to lung parenchyma. Grade 3 or higher pulmonary toxicity occurred in 38% (38) of patients with > 30% of lung volume receiving ≥25 Gy, versus 4% (123) of patients with ≤30% lung receiving ≥25 Gy ( P = 0.04). Grade 3 or higher pulmonary toxicity occurred in 29% (414) of patients with a predicted pulmonary normal tissue complication probability of 12% or higher versus 0% (0/17) in patients with a predicted probability of less than 12% ( P = 0.03). Conclusions : Despite adverse prognostic criteria median survival is encouraging and may be higher than some combined modality approaches. Dose volume histogram parameters may be useful to determine the maximum dose for individual patients and thereby permit avoidance of toxicity.

Background: Thisstudywas conducted to evaluate quality of life in patients treated with primary radiotherapy (RT) for cancer of the base of tongue. Methods: From 1981 to 1990, 36 patients with primary squaradiotherapy. Ages ranged from 35 to 71 years (median, 58 years). T Stage was: T1, n = 11; T2, n = 14; T3, n = 10; T4, n = 1. Thirty-one patients (86%) had palpable cervical lymph node metastases at initial examination (N1, n = 16; N2, n = 11; N3, n = 4). Patients received external beam RT to their primary site and necks, followed by a brachytherapy boost to the tongue. Those with neck nodes also had a neck dissection. The median follow-up is 5 years (minimum, 3 years). Actuarial 5-year local control was 85%; regional control was 96%; distant metastases-free survival was 87.5%; and overall survival, 85%. Twenty-nine of the 30 long-term survivors completed (1) Memorial Symptom Assessment Scale (MSAS), (2) Functional Assessment of Cancer Therapy (FACT), (3) Performance Status Scale for Head and Neck Cancer(PSS), and (4) a sociodemographic and economic questionnaire. At the time of cancer diagnosis, 62% were employed full-time, and 21% were employed part-time; 83% were earning >$20,000/year, and 59% were earning >$60,000/year. Results: At follow-up, annual incomes were similar to those at initial examination. Of those who had been working full-time, 72% were still in full-time work, and of those who had been working part-time, 83% were still in part-time work. Average PSS scores were 90 for eating in public, 96 for understandability of speech, and 68 for normalcy of diet. On the MSAS, the following symptoms had prevalence: >30% xerostomia, difficulty swallowing, decreased energy, pain, worrying, insomnia, cough, drowsy, change In taste, and irritability. Scores on the FACT exceeded published values collected for a mixed cancer population. Conclusions: The overwhelming majority of patients achieved excellent functional status and quality of life and could maintain their prediagnosis earning potential and employment status after primary radiation for advanced base of tongue cancer.

Background Although the standard therapy for locally advanced hypopharyngeal cancer remains surgery and postoperative radiotherapy (RT), alternative treatment approaches include induction chemotherapy and RT. The purpose of this retrospective study was to compare the long-term outcome of these treatments performed in a single institution. Methods Twenty-six patients with advanced, resectable, squamous cell carcinoma of the hypopharynx were treated with induction chemotherapy and definitive RT (group I), reserving laryngectomy for salvage. The induction phase of therapy consisted of 2–3 cycles of cisplatin-based chemotherapy followed by conventional fractionated RT to doses of 66–70 Gy. The outcomes of this group of patients were compared with the outcomes of 30 patients with hypopharyngeal cancer who were treated at our institution with surgery and postoperative RT (group II). The median follow-up times of the surviving patients in groups I and II were 5 and 9 years, respectively. Results The local recurrence-free survival at 5 years from the completion of therapy for group I was 50%, compared with 69% for group II (p = .41). Among patients with T3–T4 primary tumors, the 5-year local control rates were 58% and 59% for groups I and II, respectively (p = .78). The likelihood of larynx preservation, free of local disease at 5 years for group I, was 52%. The 5-year neck recurrence-free survival for groups I and II were 47% and 69%, respectively (p = .66). Among patients with N2–N3 stage disease, the 5-year incidence of neck failure for groups I and II were 73% and 68%, respectively (p = .74). The 5-year distant metastases-free survival for groups I and II were 67% and 57%, respectively (p = .19). The 5-year disease-free survival rates for groups I and II were 30% and 42%, respectively (p = .9). The 5-year overall survival rates for groups I and II were 15% and 22%, respectively (p = .65). Conclusions Nonsurgical therapy for advanced-stage hypopharyngeal cancer provides survivorship comparable with that achieved with standard approaches of surgery and postoperative RT. However, despite the therapy, the outcome is poor. Future studies will need to explore new treatment strategies in an effort to improve upon the outcome for this group of patients. HEAD & NECK 1996;18:405–411 © 1996 John Wiley & Sons, Inc.

Purpose: The purpose of this study was to assess the feasibility of 103 Pd bracytherapy in the management of primary unresectable carcinoma of the pancreas. Methods and Materials: Between August 1988 and January 1992, 11 patients with biopsy-proven primary unresectable adenocarcinoma of the pancreas were treated with 103 Pd brachytherapy during laparotomy. The median age was 66 (range 57–70). The most common presenting symptoms were weight loss (eight patients), pain (six patients), and nausea/vomiting (four patients). Less common symptoms were jaundice (two patients), early satiety (two patients), and ascites (one patient). All patient underwent laparotomy and surgical staging. Eight patients had T3N0M0 disease, two patients had T3N1M0 disease, and one patient had T3N1M1 disease. The surgical procedure performed was biliary bypass in six patients, biopsy only in four patients, and gastric bypass in one patient. The average tumor dimension was 4.0 cm. The median activity, matched peripheral dose (MPD) and implanted volumes were 95.3 mCi, 124.4 Gy, and 33 cm 3 , respectively. The median initial dose rate was 0.21 Gy per hour. Five patients received postoperative external beam radiation therapy (median 45 Gy) and seven patients received chemotherapy postoperatively. The median follow-up was 7 months (range 1–19). Results: The median survival for the entire group of patients was 6.9 months. Ten of 11 patients have died, with 1 patient presently alive and receiving chemotherapy for metastatic disease to the liver, but without local progression radiographically. Five of 11 patients (45%) were locally controlled, defined as either a complete response or freedom from progression at the site of the implant as evaluated by computed tomography scan. In the other six patients, the median time to local progression was 6.9 months. Five patients developed distant metastases (four liver, one subcutaneous nodule). Two patients failed in regional sites (one omentum, one paraaortic lymph node). Four of 11 patients (36%) developed acute postoperative complications that included one gastric outlet obstruction, one duodenal perforation, and two with sepsis. One of 11 patients (9%) developed a late complication of radiation enteritis 5 months after implantation. The median survival for patients experiencing complications was 1.7 months as compared to 8.4 months for the patients who did not develop a complication ( p = 0.10). Pain relief was obtained in five out of six (83%) for the patients presenting with pain for a median duration of 24 weeks. Local control did not appear to be related to the MPD, dose rate, implanted volume, treatment with external beam irradiation, or the use of chemotherapy. Patients were more likely to develop a complication if the MPD was greater than 115 Gy (four out of six patients) as compared to those whose MPD was less than 115 Gy (one out of five patients) p = 0.12). Conclusions: Because there was no improvement in median survival over conventional modalities, and the complication rate was high; we do not recommend 103 Pd brachytherapy as a component of the treatment of unresectable adenocarcinoma of the pancreas.

e16614Background: Stereotactic body radiotherapy (SBRT) is an evolving and promising treatment modality for prostate cancer but without mature data compared with other definitive therapies. There i...

Purpose To review the outcomes of a prospective management approach using ipsilateral neck radiotherapy in the treatment of node-positive squamous cell carcinoma of the tonsil with a well-lateralized primary lesion. Methods and Materials Between August 2003 and June 2007, 20 patients who presented with squamous cell carcinoma of the tonsil, without involvement of the base of the tongue or midline soft palate, and with Stage N1-N2b disease were prospectively treated with radiotherapy to the primary site and ipsilateral neck. In addition, 18 patients received concurrent chemotherapy. The actuarial freedom from contralateral nodal and in-field progression was determined. Acute and late toxicity were prospectively evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3, and Radiation Therapy Oncology Group criteria. Results The nodal disease was Stage N1 in 4 patients, N2a in 3 patients, and N2b in 13 patients. At a median follow-up 19 months (range, 12–40), no in-field or contralateral nodal recurrences had been observed. The 2-year freedom from distant metastasis rate was 87.4%. The actuarial 2-year disease-free and overall survival rates were both 79.5%. Late Radiation Therapy Oncology Group grade 2 xerostomia occurred in 1 patient (5%). No late Grade 3 or greater toxicity was observed. No patient was feeding tube dependent at their last follow-up visit. Conclusion In carefully selected patients with node-positive, lateralized tonsillar cancer, treatment of the ipsilateral neck and primary site does not appear to increase the risk of contralateral nodal failure and reduces late morbidity compared with historical controls. Although the outcomes with ipsilateral radiotherapy in the present series were promising, these findings require longer follow-up and validation in a larger patient cohort.

The goal of this article is to review the various indications for the application of external beam radiotherapy in the management of thyroid cancer. This article includes a discussion of published literature to define risk variables that increase the risk of recurrence after surgery that might be mitigated by the use of radiation therapy. Clinical outcomes, recent technologic advances in treatment planning and radiation delivery, and potential morbidity associated with treatment are also reviewed.

A new class of membrane-active ether lipid (EL) analogs of platelet-activating factor were studied for in vitro anti-HIV-1 activity. Human T-cell (CEM-ss) monolayers or suspension cultures were used to determine effects of structural modifications of Type A phosphorus-containing and Type B nonphosphorus EL analogs on (a) the inhibitory concentration50 (IC50) for HIV-1 syncytial plaque formation and cell growth, and, (b) virus budding at the cell plasma membrane. Results indicate that representative Type A and Type B EL inhibit HIV-1 but not herpes simplex virus type 2 plaque formation when added before or up to 2 days after viral infection. Anti-HIV-1 activity does not involve direct inactivation of virus infectivity. Type A EL (IC50 range = 0.2-1.4 microM) with alkyoxy, alkylthio, or alkyamido substitution at glycerol position 1 and ethoxy or methoxy substitution at position 2, and Type B compounds (IC50 range = 0.33-0.63 microM) with an inverse choline or nitrogen heterocyclic substitution at position 3 have selective activity against HIV-1-infected T-cells. EL treatment of HIV-1-infected cells is associated with subsequent release of reverse transcriptase activity, but infectious virus production is inhibited with time after infection. Electron microscopic examination of HIV-1-infected and EL-treated cells revealed absence of detectable budding virus at the plasma membrane but presence of intracytoplasmic vacuolar virus particles. In summary, these data suggest that EL analogs are a novel class of agents that induce defective intracytoplasmic vacuolar HIV-1 formation in T-cells. Being membrane interactive, EL are ideally suited for combination chemotherapy with DNA-interactive anti-HIV nucleoside analogs.

Purpose To perform an independent validation of an anatomy-based inverse planning simulated annealing (IPSA) algorithm in obtaining superior target coverage and reducing the dose to the organs at risk. Method and Materials In a recent prostate high-dose-rate brachytherapy protocol study by the Radiation Therapy Oncology Group (0321), our institution treated 20 patients between June 1, 2005 and November 30, 2006. These patients had received a high-dose-rate boost dose of 19 Gy to the prostate, in addition to an external beam radiotherapy dose of 45 Gy with intensity-modulated radiotherapy. Three-dimensional dosimetry was obtained for the following optimization schemes in the Plato Brachytherapy Planning System, version 14.3.2, using the same dose constraints for all the patients treated during this period: anatomy-based IPSA optimization, geometric optimization, and dose point optimization. Dose–volume histograms were generated for the planning target volume and organs at risk for each optimization method, from which the volume receiving at least 75% of the dose (V 75% ) for the rectum and bladder, volume receiving at least 125% of the dose (V 125% ) for the urethra, and total volume receiving the reference dose (V 100% ) and volume receiving 150% of the dose (V 150% ) for the planning target volume were determined. The dose homogeneity index and conformal index for the planning target volume for each optimization technique were compared. Results Despite suboptimal needle position in some implants, the IPSA algorithm was able to comply with the tight Radiation Therapy Oncology Group dose constraints for 90% of the patients in this study. In contrast, the compliance was only 30% for dose point optimization and only 5% for geometric optimization. Conclusions Anatomy-based IPSA optimization proved to be the superior technique and also the fastest for reducing the dose to the organs at risk without compromising the target coverage.

LBA5002 Background: High-risk, localized prostate cancer (PCa) patients have a relatively poor prognosis. We hypothesized that the addition of adjuvant docetaxel and prednisone to long-term (24 month) AS and radiation therapy (RT) would improve overall survival (OS). Methods: RTOG 0521 opened December 2005 and closed August 2009 with targeted accrual of 600 cases. It was designed to detect improvement in 4-year OS from 86% to 93% with a 51% hazard reduction (HR = 0.49). Under a 0.05 1-sided type I error and 90% power, at least 78 deaths were required to analyze the OS endpoint. Patients had 1) Gleason (Gl) 7-8, any T-stage, and PSA > 20, or 2) Gl 8, ≥ T2, any PSA, or 3) Gl 9-10, any T-stage, any PSA. All had PSA ≤ 150. RT dose was 75.6 Gy. CT consisted of 6, 21-day cycles of docetaxel + prednisone starting 28 days after RT. Results: Of 612 enrolled, 50 were excluded for eligibility issues, leaving 562 evaluable. Median age = 66, median PSA = 15.1, 53% had Gl 9-10, 27% had cT3-4. Median follow-up = 5.5 yrs. 4-yr OS rates were 89% [95% CI: 84-92%] for the AS+RT arm and 93% [95% CI: 90-96%] for the AS+RT+CT arm (1-sided p = 0.03, HR = 0.68 [95% CI: 0.44, 1.03]). There were 52 centrally-reviewed deaths in the AS+RT arm and 36 in the AS+RT+CT arm, with fewer deaths both due to PCa/treatment (20 vs 16) and due to other causes/unknown (32 vs 20) in the AS+RT+CT arm. 5-yr disease-free survival rates were 66% for AS+RT and 73% for AS+RT+CT (2-sided p = 0.05, HR = 0.76 [95% CI: 0.57, 1.00]). There was 1, Gr 5 unlikely-related adverse event (AE) in the AS+RT arm and 2, Gr 5 possibly/probably-related AEs with AS+RT+CT. Conclusions: For high-risk, localized PCa, adjuvant CT improved the OS from 89% to 93% at 4 years. Toxicity was acceptable. This trial was designed with a short OS assessment period and additional follow-up is warranted to determine the long-term benefit of CT to the current standard of care of long-term AS+RT. This project was supported by grants U10CA21661, U10CA180868, U10CA180822, from the National Cancer Institute and Sanofi with additional support from AstraZeneca for Australian site participation. Clinical trial information: NCT00288080.

6038 Background: Locally advanced, high-risk head and neck cutaneous squamous cell carcinomas (CSCC) are typically aggressive. We sought to compare treatment tolerability, disease control and survi...

Purpose To report results of a phase II trial of high-dose-rate intra-operative radiation therapy (HDR-IORT) for malignant pleural mesothelioma (MPM). Methods and materials Seven patients had extrapleural pneumonectomy with IORT (EPP/IORT) and 6 patients had pleurectomy/decortication with IORT (PD/IORT) between 1994 and 1996. IORT was delivered with 192 Ir using a customized applicator with a remote afterloader. A median of 3 sites were treated to a median area of 143 cm 2 . A dose of 1500 cGy was prescribed at each site, with 1000 cGy delivered to the mediastinum. Postoperative external beam radiation therapy (EBRT) was given 3–5 weeks later. Median follow-up was 8 months (range, 1–84 months). Results Five patients developed local failure. Two-year local control and survival rates were 35% and 23%, respectively. Mortality was 2/13 (15%), 1 from each surgical group. Serious complications requiring further intervention occurred in 3/6 (50%) of the EPP/IORT group and 1/5 (20%) of the PD/IORT group. Conclusions HDR-IORT after EPP for MPM is prohibitively toxic and has been abandoned, while its use with PD remains in question.

Purpose The focus of this work is to develop a practical planning method that results in increased dose conformity and reduced treatment time for segmental multileaf collimation (sMLC) based intensity-modulated radiation therapy (IMRT) delivery. Methods and materials Additional regions for dose constraint are introduced within the normal tissue during the planning process by designing a series of concentric ellipsoids around the target. A dose gradient is then defined by assigning dose constraints to each concentric region. The technique was tested at two centers and data for 26 and 10 patients, respectively, are presented allowing for differences in treatment technique, beam energy, ellipsoid definition, and prescription dose. At both centers, a series of patients previously treated for prostate cancer with IMRT were selected, and comparisons were made between the original and new plans. Results While meeting target dose specifications and normal tissue constraints, the average number of beam directions decreased by 1.6 with a standard error (SE) of 0.1. The average time for delivery at center 1 decreased by 29.0% with an SE of 2.0%, decreasing from 17.5 min to 12.3 min. The average time for delivery at center 2 decreased by 29.9% with an SE of 3.8%, decreasing from 11 min to 7.7 min. The amount of nontarget tissue receiving D 100 decreased by 15.7% with an SE of 2.4%. Nontarget tissue receiving D 95 , D 90 , and D 50 decreased by 16.3, 15.1, and 19.5%, respectively, with SE values of approximately 2% at center 1. Corresponding values for D 100 , D 95 , D 90 , and D 50 decreased by 13.5, 16.7, 17.1, and 5.1%, respectively, with SE values of less than 3% at center 2. Conclusions By designating subsets of tissue as concentric regions around the target(s) and carefully defining each region's dose constraints, we have gained an increased measure of control over the region outside the target boundaries. This increased control manifests as two distinct endpoints that are beneficial to the IMRT process: increased dose conformity and decreased treatment time.

Purpose: Large superficial (skin, soft tissue sarcoma) lesions located on curved areas are hard to treat with electrons. The Freiburg Flap (Nucletron, Netherlands) is a flexible mesh style surface which can be easily shaped to fit curved surfaces for reproducible HDR fraction delivery. To understand the fundamental dosimetric differences, a dosimetric comparison was made between HDR plesiotherapy (Freiburg applicator for lesions over 4cm) and external electron beam radiotherapy over cases with varying target curvature (both stylized and clinical cases). Methods: Four stylized cases with variable complexity were created using artificial DICOM axial CT slices and RT structures (a square and three curved structures on a 4.5cm radius cylinder). They were planned using Oncentra v4.3 and exported to Pinnacle v9.6 for electrons planning. The HDR source dwell positions were optimized for the best coverage of the targets using graphical optimization. Electron treatment plans were created in Pinnacle using the same CT and RT structures of three HDR cases with surface lesions previously treated with the Freiburg flap. The En face electron plans used 6-12 MeV electrons and 0.5–1 cm bolus was added to increase surface dose. The electron plans were prescribed to an isodose line to conform to the target. Results:more » For all lesions, the average target dose coverage was similar (D90ave of 100% for HDR vs 101% for electrons). For lesions with high curvature, the HDR coverage was better (D90 102% vs D90 97% for electron). For all cases, adjacent structures high dose region was lower for HDR than electrons (D1cc 100% for HDR vs D1cc 111% for electrons). Conclusion: HDR plesiotherapy offers excellent target conformity for superficial targets similar to electrons. However, for lesions with complex curved surfaces, HDR has the advantage to achieve better dose distributions using graphical optimization to spare adjacent normal tissue while maximizing target coverage.« less

4007 Background: RTOG 0436 is a randomized Ph III trial evaluating cetuximab added to concurrent chemoradiation for patients (pts) undergoing non-operative management of esophageal carcinoma (EC). ...

LBA6 Background: RTOG 0436 is a randomized Ph III trial designed to evaluate the benefit of cetuximab added to the concurrent chemoradiation for patients undergoing non-operative management of esophageal carcinoma. Methods: Pts with biopsy-proven squamous cell or adenocarcinoma of the esophagus (T1N1M0; T2-4 AnyN M0; Any T/N M1a) were randomized to weekly concurrent cisplatin (50 mg/m2), paclitaxel (25 mg/m2), and daily radiation 50.4 Gy/1.8 Gy fractions ± weekly cetuximab (400 mg/m2 day 1 then weekly 250 mg/m2). Patients were stratified by histology, tumor size (< 5 cm vs > 5cm), and the status of celiac lymph nodal involvement. Overall survival (OS) was the primary endpoint, with a planned accrual of 420 pts to detect an increase in 2-year OS from 41% to 53%; 80% power and 1-sided 0.025 alpha. An interim analysis of cCR was planned for the first 150 of each histology. Results: The study accrued 344 pts from 2008-2013 and 328 were eligible. Based on interim analyses, the study stopped accruing adeno pts in 5/2012 and SCC pts in 1/2013. Pts were well matched for pretreatment characteristics: 80% with T3/4 disease, 66% N1, and 19% with celiac nodal involvement. Incidence of grade 3/4/5 treatment (tx) related AEs was 45%, 22%, 4% in Arm 1 (cetuximab) and 49%, 17%, 1% in Arm 2 (no cetuximab). A cCR rate of 56% was observed in Arm 1 vs 59% in Arm 2 (p=0.72). No differences were seen in cCR between tx arms for either histology. The 12 and 24 mo OS rates for cCR pts were 79% and 58% vs 53% and 30% for those with residual disease (p

Purpose To evaluate the efficacy and morbidity of combined 3-dimensional conformal radiation therapy (3D-CRT) and brachytherapy for intermediate/unfavorable risk prostate cancer. Materials and Methods Between May 1996 and November 1997, 65 patients with intermediate/unfavorable risk prostate cancer were treated with 3D-CRT (50.4 Gy) followed by a transperineal permanent Pd-103 implant. Patients with one or two adverse prognostic features (PSA > 10 and Gleason ≥ 7) were classified as intermediate risk and unfavorable risk, respectively. Forty-seven patients (71%) had intermediate risk and 18 (29%) had unfavorable disease risk. The median age of this group was 65 years (range, 42–76 years), and the median pretreatment PSA level was 8.0 ng/ml (range, 1.7–42.0 ng/ml). The clinical stage of these patients was as follows: T1c, 36 (55%); T2a, 27 (42%); T2b/T3, 2 (3%). Fifteen patients (23%) had a Gleason ≤ 6, 41 patients (63%) were classified as Gleason 7, and 9 (14%) as Gleason ≥ 8. Fifty-two (80%) received neoadjuvant androgen deprivation (NAAD) for cytoreduction. The median follow-up was 36 months (range, 24–42 months). Results The PSA relapse-free survival rate at 3 years was 87%, with a median PSA value at last follow-up of 0.25 ng/ml. The relapse-free survival was 90% for those who had an initial PSA ≤ 10 ng/ml and 80% for patients who had an initial PSA > 10 ng/ml (p = 0.5). No difference in outcome was observed between patients with intermediate and unfavorable risk disease. Eight patients (13%) developed late Grade 2 rectal bleeding. Twenty-three patients (42%) required medication for urinary symptoms during the first 6 months after therapy. Three patients (5%) noted rare stress incontinence at last follow-up. Of the 44 patients who were potent prior to therapy, 17 (26%) developed erectile dysfunction (ED). Conclusion Although the follow-up is short, the early biochemical outcome of combined 3D-CRT and brachytherapy for intermediate/unfavorable risk prostate cancer is promising. While rectal toxicity is minimal, urinary side effects are more common. Further follow-up is necessary to fully evaluate the efficacy of this combined therapeutic approach. Int. J. Cancer (Radiat. Oncol. Invest.) 90:275–280, 2000. © 2000 Wiley-Liss, Inc.

To report the 5-year prostate-specific antigen (PSA) relapse-free survival outcome and incidence of long-term morbidity for patients with localized prostate cancer treated with CT-planned permanent I-125 prostate implantation using a transperineal technique (TPI).Between 1989-1996, 248 patients with clinically localized prostate cancer were treated with TPI. The median age was 65 years (range: 45-80 years). The clinical stage was T1c in 143 patients (58%), Stage T2a in 102 (41%), and T2b in 3 (1%). Thirty patients (12%) had Gleason scores6, 158 patients (64%) had Gleason scores of 6, and 60 (24%) had scoresor =7. The median pretreatment PSA was 7 ng/mL (range: 1-58 ng/mL). The median prescribed implant dose was 150 Gy. Patients were characterized as having favorable risk disease if their pretreatment PSA level wasor =10.0 ng/mL and Gleason scoreor = 6; those with one and two adverse prognostic features (PSA10 ng/mL and Gleason score6) were classified as having intermediate and unfavorable risk disease, respectively. PSA relapse was defined according to the American Society of Therapeutic Radiation Oncology Consensus Statement, and toxicity was scored according to the Radiation Therapy Oncology Group morbidity scoring scale. The median follow-up was 48 months (range: 12-126 months).Thirty-eight patients (15%) developed a PSA relapse, and the overall 5-year PSA relapse-free survival (PRFS) rate was 71%. The 5-year PRFS rates for favorable-risk (n = 146), intermediate-risk (n = 85), and unfavorable-risk (n = 17) patients were 88%, 77%, and 38%, respectively (p0.0001). The 5-year PRFS rates among patients treated with a 2-month course of neoadjuvant androgen deprivation (NAAD) prior to TPI compared to patients treated with TPI only were 100% and 77%, respectively (p = 0.03). Multivariate analysis identified pretreatment PSA10 ng/mL and Gleason score6 as independent predictors for biochemical relapse after TPI. The 5-year actuarial likelihood of late Grade 2 urinary toxicity was 41%. The 5-year likelihood of urethral stricture development was 10%, and the median time to stricture development was 18 months. One patient (0. 4%) in the early phase of this clinical experience developed a Grade 4 urethral complication. The actuarial incidence of late Grade 2 rectal bleeding was 9%. One patient (0.4%) developed a Grade 4 rectal complication.Especially for favorable risk disease, the 5-year biochemical outcome with this approach was excellent and appears to be comparable to other therapeutic interventions. Grade 2 urinary symptoms were common in these patients but gradually resolved in most. Improved treatment planning approaches that further constrain the urethral dose without compromising the target volume dose will likely decrease the incidence of Grade 2 and 3 urinary symptoms after TPI.

To evaluate the role of detailed pathologic features in predicting outcome for early-stage prostate cancer treated with I-125 brachytherapy. The pretreatment biopsy slides of 103 patients with T1/T2 and Gleason scores of 4–7 prostatic carcinoma, which was treated by transperineal I-125 implantation, were reviewed retrospectively by a single pathologist (P.B.G.). Biochemical tumor control rates [prostate-specific antigen (PSA) below 1.0] were correlated with pretreatment PSA, Gleason score, the amount of tumor in the biopsy samples, and the presence of perineural invasion.In Cox proportional-hazard, multivariate analysis, the strongest predictors of failure were pretreatment PSA above 10 ng/ml (P = 0.013) and the length of the biopsy specimen replaced by tumor (P = 0.15). The percent of biopsy tissue replaced by tumor (P = 0. 74), perineural invasion (P = 0.78), and Gleason score (P = 0.66) were less predictive of prognosis. It was concluded that pretreatment PSA is the strongest predictor of biochemical failure. Detailed assessment of pathological features on needle biopsy added little prognostic information beyond that of pretreatment PSA alone. Like all other prognostic parameters for prostate cancer, there is considerable overlap in pathologic features between those patients who will or will not be controlled biochemically. Radiat. Oncol. Invest. 6:170–174, 1998. © 1998 Wiley-Liss, Inc.

Purpose : Minimal literature exists with 10-year data on neck control in advanced head and neck cancer. The purpose of this study is to determine long-term regional control for base of tongue carcinoma patients treated with primary radiation therapy plus neck dissection. Methods and Materials : Between 1981–1996, primary radiation therapy was used to treat 68 patients with squamous cell carcinoma of the base of tongue. Neck dissection was added for those who presented with palpable lymph node metastases. The T-stage distribution was T1, 17; T2, 32; T3, 17; and T4, 2. The N-stage distribution was N0, 10; N1, 24; N2a, 6; N2b, 11, N2c, 8; N3, 7; and Nx, 2. Ages ranged from 35 to 77 (median 55 years) among the 59 males and nine females. Therapy generally consisted of initial external beam irradiation to the primary site (54 Gy) and neck (50 Gy). Clinically positive necks were boosted to 60 Gy with external beam irradiation. Three weeks later, the base of tongue was boosted with an Ir-192 interstitial implant (20–30 Gy). A neck dissection was done at the same anesthesia for those who presented with clinically positive necks, even if a complete clinical neck response was achieved with external beam irradiation. Neoadjuvant cisplatin-based chemotherapy was administered to nine patients who would have required a total laryngectomy if their primary tumors had been surgically managed. The median follow-up was 36 months with a ranged from 1 to 151 months. Eleven patients were followed for over 8 years. No patients were lost to follow-up. Results : Actuarial 5- and 10-year neck control was 96% overall, 86% after radiation alone, and 100 after radiation plus neck dissection. Pathologically negative neck specimens were observed in 70% of necks dissected after external beam irradiation. The remaining 30% of dissected necks were pathologically positive. These specimens contained multiple positive nodes in 83% despite a 56% overall complete clinical neck response rate to irradiation. Regional failure occurred in only two patients, neither of whom underwent adjuvant neck dissection. Symptomatic neck fibrosis (RTOG grade 3) was not observed. Actuarial 5- and 10-year local control was 88% and 88%, disease-free survival was 80% and 67%, and overall survival was 86% and 52%. Conclusion : For base of tongue cancer, most patients can obtain long-term regional control with no severe complications after definitive radiation therapy, plus neck dissection for those who present with lymphadenopathy. Complete clinical regression of palpable neck metastases after irradiation poorly correlates with pathologic outcome. Our current policy is to include neck dissection at the time of implantation for patients who present with palpable neck metastases. We realize that this therapeutic approach may overtreat some patients, but we are reluctant to change our policy in light of these excellent outcomes.

9525 Background: Determine if prophylactic tadalafil maintains spontaneous (off-drug) erectile function (EF) compared to placebo in patients (pts) treated with radiotherapy (RT) for prostate cancer. Methods: Double-blind 1:1 randomization to tadalafil 5mg daily for 6 mos vs placebo starting with RT. Primary outcomes measured by International Index of Erectile Function (IIEF). Eligibility included pre-RT IIEF Question [Q] 1 response “sometimes/most times/always” able to get an erection. Ps treated with hormones were excluded. Primary outcome was response to IIEF Q1 at 30 wks (6 wks off drug). Pts were stratified by RT modality (external vs. brachytherapy) and age (≤65 vs. >65 years). 182 pts were needed in an intent-to-treat analysis to show a difference from 20% responders with placebo to 40% with tadalafil based on a 2-sided Fishers exact test with α=0.05 and 80% power. Results: We report on 155/222 analyzable/eligible pts. Median age was 63 years, white (73%), and external RT (63%). Mean total dose for external RT was 77.23 Gy and 136.74 Gy for brachytherapy with penile bulb D50 of 24.46 Gy and 31.24 Gy respectively. Most pts completed treatment per protocol (84% tadalafil, 70% placebo). Spontaneous EF at 30 wks from drug start was not different (p=0.99) between arms based on IIEF Q1 response, total IIEF score (52.5 drug vs 52.8 placebo), or score change from baseline (-8.0 drug vs -8.8 placebo). No difference in these outcomes was noted at 1 year. Non-responders at 30 wks were likely to be older (age≥65; p=0.432), but there were no significant predictors at 1 year. About 80% of pts maintained spontaneous EF in both arms. Conclusions: Low-dose daily tadalafil did not preserve EF within the first year of RT for prostate cancer. If tadalafil positively influences delayed RT-induced vasogenic injury, additional time may be needed to observe a benefit to tadalafil as a preventive agent. Alternatively, tadalafil dose modification or altered dosing schedules may be needed to demonstrate a protective effect of this agent when used with RT. Clinical trial information: NCT00951184.

5530 Background: NCCN recommends HNC patients (pts) be treated by providers with experience in HNC management. Whether treatment by experienced providers (measured by no. of pts treated) is associated with HNC survival outcome is unknown. Methods: Analysis included 471 pts in RTOG 0129 with stage III-IVa HNC with known tumor HPV and smoking status randomized to cisplatin concurrent with standard or accelerated fractionation radiotherapy (RT). Participating centers were stratified into pt accrual tertiles (ATs) to 21 RTOG HNC trials from 1997-2002. As a surrogate for experience, we investigated the independent effect of AT on OS and progression-free survival (PFS) in multivariable cox proportional hazards models. Results: Median follow up was 4.8 yrs (range 1.1 - 6.5). In Kaplan-Meier analysis, OS and PFS for pts at centers in the two lower AT (low accruing centers [LAC]) were similar and compared to the upper AT (high accruing centers [HAC]). Median accrual in LAC vs HAC was 11 vs 82 pts. Pts treated at LAC and HAC had similar age, HPV status, pack-years, N stage, comorbidities and study arm assignment (SAA), but pts at LAC had better performance status (PS)(Zubrod 0; 62% vs 52%; p=0.04), fewer T4 tumors (27% vs. 35%; p=0.05) and were more likely uninsured (12% vs 4%; p=0.009). Compared to HAC, LAC pts had significantly worse OS, (5 yr 51.0% vs 69.1%; p = 0.002), and PFS (5 yr 42.7% vs 61.8%; p = 0.001) and more locoregional failure (5 yr 36.4% vs 20.8%; p

PURPOSE: To compare the prostate-specific antigen (PSA) relapse-free survival outcome and incidence of late toxicity for patients with early-stage prostate cancer treated at a single institution with either three-dimensional conformal radiotherapy (3D-CRT) or transperineal permanent implantation (TPI) with iodine-125 seeds. MATERIALS AND METHODS: Patients with favorable-risk prostate cancer, defined as a pretreatment PSA of less than or equal to 10.0 ng/mL, Gleason score of 6 or lower, and stage less than or equal to T2b, were selected for this analysis. Between 1989 and 1996, 137 such patients were treated with 3D-CRT and 145 with TPI. The median ages of the 3D-CRT and TPI groups were 68 years and 64 years, respectively. The median dose of 3D-CRT was 70.2 Gy, and the median implant dose was 150 Gy. Prostate-specific antigen relapse was defined according to the American Society of Therapeutic Radiation Oncology Consensus Statement, and toxicity was graded according to the Radiation Therapy Oncology Group morbidity scoring scale. The median follow-up times for the 3D-CRT and TPI groups were 36 and 24 months, respectively. RESULTS: Eleven patients (8%) in the 3D-CRT group and 12 patients (8%) in the TPI group developed a biochemical relapse. The 5-year PSA relapse-free survival rates for the 3D-CRT and the TPI groups were 88% and 82%, respectively (P = .09). Protracted grade 2 urinary symptoms were more prevalent among patients treated with TPI compared with 3D-CRT. Grade 2 urinary toxicity, which was manifest after the implant and persisted for more than 1 year after this procedure, was observed in 45 patients (31%) in the TPI group. In these 45 patients, the median duration of grade 2 urinary symptoms was 23 months (range, 12 to 70 months). On the other hand, acute grade 2 urinary symptoms resolved within 4 to 6 weeks after completion of 3D-CRT, and the 5-year actuarial likelihood of late grade 2 urinary toxicity for the 3D-CRT group was only 8%. The 5-year actuarial likelihood of developing a urethral stricture (grade 3 urinary toxicity) for the 3D-CRT and TPI groups was 2% and 12%, respectively (P CONCLUSION: Both 3D-CRT and TPI are associated with an excellent PSA outcome for patients with early-stage prostate cancer. Urinary toxicities are more prevalent for the TPI group and subsequently resolve or improve in most patients. In addition to evaluating long-term follow-up, future comparisons will require detailed quality-of-life assessments to further determine the impact of these toxicities on the overall well-being and quality of life of the individual patient.

Purpose: Independent validation of IPSA algorithm in obtaining superior target coverage and reduced dose to organs at risk, by comparing with the results of other optimization techniques in HDR brachytherapy.Method and Materials: In a recent prostate HDR brachytherapy protocol study (RTOG‐0321) we used an anatomy based inverse optimization technique known as Inverse Planning Simulated Annealing (IPSA), incorporated as a beta version in the Plato TPS Version 14.2.3 (Nucletron Corp., Veenendaal, The Netherlands) in an effort to satisfy the dose constraints set by the protocol for Prostate, Bladder, Rectum and Urethra. Between the period of June 2005 and November 2006, 20 patients received HDR boost dose of 19 Gy in two fractions to the prostate in addition to an external beam dose of 45 Gy with IMRT technique. 3D Brachytherapytreatment plans were generated using Plato Version 14.2.3. Dosimetry was obtained for the following optimization schemes in Plato, for the same dose constraints for all the patients treated during this time period: Anatomy based IPSA optimization, Geometric optimization on volume and Dose Point optimization on volume. Dose volume histograms were generated for PTV and organs at risk for each optimization method, from which V75 volumes for Rectum, Bladder, and V125 volume for Urethra were determined. Also dose homogeneity index as well as conformal index for the PTV was calculated for each optimization technique. Results: Despite suboptimal needle placement in some implants, using the same dose constraints on all patients, IPSA algorithm was able to comply with the tight RTOG dose constraints for 90% of the patients in this study, whereas it was only 30 % for DPO and only 5% for GO. Conclusion:Anatomy based IPSA optimization proved to be the overall best and fast technique for reducing the dose to organs at risk without compromising target coverage.

Purpose: To identify patient and dosimetric variables predicting for > grade 2 acute morbidity after HDR brachytherapy and 3D-CRT in the treatment of prostate cancer. Materials and Methods: 102 men were treated on a Phase I-II dose escalation trial for intermediate/unfavorable prostate cancer. Pts recieved 6–12 mos of androgen deprivation(AD). HDR consisted of 16.5 Gy Ir-192 in 3 fractions in 62 pts, with dose escalation to 18 Gy in 3 fractions in 40 pts. 3D-CRT consisted of 50–54 Gy using a 4–6 field conformal technique. Median f/u time was 12 mos. (range: 6–30 mos). Acute toxicity was assessed using the RTOG morbidity scale. Base-line and sequential IPSS scores, and dosimetric parameters were correlated with acute toxicity. Results: Grade 2 GU toxicity at 1, 3, 6, and 12 months for 55 patients with f/u > 12 months was 26%, 15%, 3% and 9%, respectively. One pt (2%) developed a urethral stricture (grade 3 GU). The max urethral dose and baseline IPSS score correlated with acute GU toxicity. The mean urethral dose among patients experiencing Grade 2 GU toxicity was 2.1 Gy vs 1.9 Gy for Grade 1 toxicity and 1.7 Gy for Grade 0. The mean pre-trt IPSS score in patients with grade 2 toxicity was 11 vs 6 for Grade 0/1. The IPSS post-trt score at 12 mos, normalized in 70%. The incidence of grade 2 rectal bleeding at 1, 3, 6, and 12 months for 55 patients were 7%, 7%, 2%, and 2% respectively. No Grade 3 GI toxicities occurred. Only Pre-trt IPSS score (p = 0.008) was predictive of GU toxicity. Age (p = 0.04), Max-Urethral Dose (p = 0.03), and lymph nodes treated(p = 0.02) were predictive of Grade 2 GI toxicity. In multivariate analysis, IPSS score predicted for GU morbidity, (p = 0.008). No difference was seen in GU or GI symptoms in the two dose levels (p = 0.09, and 0.16 respectively) Conclusion: Excellent acute tolerance was observed. The incidence of acute grade 2/3 morbidity correlated with max urethral dose from HDR-BRT and baseline IPSS scores. Dose escalation is feasible.