Background— Toxicity, pathologic CR, and long term outcomes are reported for the neoadjuvant therapies assessed in a randomized phase II trial for operable esophageal adenocarcinoma, staged II-IVa by endoscopy/ultrasound (EUS). Methods— 86 eligible patients (pts) began treatment. Arm A preoperative chemotherapy was cisplatin (C) 30mg/m 2 and irinotecan (I) 50 mg/m 2 on days (d) 1, 8, 22, 29 of 45 Gy radiotherapy (RT) over 5 weeks. Adjuvant therapy was C 30 mg/m 2 and I 65 mg/m 2 d 1, 8 q21 days × 3. Arm B therapy was C 30 mg/m 2 and paclitaxel (P) 50 mg/m 2 d 1, 8, 15, 22, 29 with RT, followed by adjuvant C 75 mg/m 2 and P 175 mg/m 2 day 1 q21 days × 3. Stratification included EUS stage and performance status (PS). Results— In Arm A, median overall survival (ms) was 35 m and the 5, 6, and 7 year survivals were 46%, 39%, and 35% whereas for arm B it was 21 m and 27%, 27%, and 23%, respectively.. Median PFS Summary— The long term survival results of an Oncology Group randomized phase II study assessing outcome of neoadjuvant preoperative paclitaxel/cisplatin/radiotherapy (RT) or irinotecan/cisplatin/RT in esophageal adenocarcinoma demonstrate that neither regimen achieved results that would justify study as potentially superior to other standard regimens. These are the results, including long term survival outcome, of E1201 a randomized phase II trial of neoadjuvant preoperative paclitaxel/cisplatin/radiotherapy or irinotecan/ cisplatin/RT in locally advanced esophageal adenocarcinoma with, for the two arms: The pathologic complete response were 17% and 15%, respectively, median survival: 21 months and. 35 months, and 7 year survival: 23% vs. 35%. The results did not appear superior to other regimens, and implications for therapy and future trial design are discussed.

To assess the risk of ipsilateral subclinical neck nodal involvement for early T-Stage/node positive/HPV-related oropharyngeal carcinoma. We retrospectively identified all the patients that underwent upfront neck dissection for oropharyngeal squamous cell carcinoma at Johns Hopkins (JH) as part of their initial management since 1998. We further selected the patients that fulfilled all of the following criteria: (1) early clinical T-Stage (cT1 – 2); (2) cN+ at presentation; (3) no previous/synchronous tumors; (4) no previous neck surgery or `neck violation`; (5) multi (3+) level neck dissection at JH; (6) neck specimen processed by surgical levels; and (7) tumor positive for HPV (ISH) and/or p16 (IHC). From the pathology report, we extracted the prevalence rate of involvement of levels I – V. Then, for each nodal level we computed the negative predictive value (NPV) based on literature data of sensitivity/specificity for CT (Curtin et al., Radiology, 1998). Here we report 1-NPV or the risk that a level that does not contain any node larger than 10 mm harbors subclinical disease. Ninety-four patients met the criteria. Most of patients had primary tumors in the tonsil (n = 65, 69.9%) or the base of tongue (n = 25, 26.9%). Clinical T-Stage was as follows: T1, 58 patients (62.4%); and T2, 36 patients (38.7%). Neck surgery consisted of radical neck dissection (RND) in 11 patients (11.8%), modified RND in 61 patients (65.6%), and selective neck dissection in 22 patients (23.7%). As result, level I, II, III, IV, and V had been dissected in 83, 94, 94, 90, and 76 patients, respectively. The prevalence of pathologic involvement and the risk of subclinical disease in each neck are reported in the Table. In this contemporary series of HPV-related oropharyngeal disease, levels II – IV are to be considered at risk of containing disease even when negative at CT; conversely, the risk of involvement of levels I and V is very low (<3%) even when ipsilateral to pathologically proven neck disease, questioning their inclusion in any target volume.TableNeck levelInvolvement at pathologyRisk of involvement when negative on CTIB8.4%2.8%II89.4%72.1%III38.3%16.0%IV20.0%7.1%V2.6%0.8% Open table in a new tab

Purpose/Objective(s)To define the roles of radiotherapy and chemotherapy on the risk of grade 3+ mucositis during IMRT for oropharyngeal cancer.Materials/Methods140 consecutive patients treated with IMRT for oropharyngeal cancer at two Institutions in non-overlapping treatment era were selected for the present analysis. 62 pts were treated at UTMB from May 2002 to April 2007; 78 pts at JHU from August 2007 to December 2009. All patients were treated with a dose painting approach, 3 dose levels (GTV, high and low risk CTV) and comprehensive bilateral neck treatment under the supervision of the same RadOnc (GS). 36/140 pts were treated with altered fractionation alone (either 78Gy/60fxs/6wks or 66Gy/30fxs/6wks); all others to 70Gy/35fxs/7wks. Of the latter, 71 received platinum-based concomitant chemotherapy (conc CHT) and 11 received induction CHT. Patients were seen weekly during treatment and mucositis was scored prospectively with blinding to dosimetric data. Peak acute toxicity ≥ confluent mucositis at any point during the course of IMRT was considered the endpoint of this study. A number of clinical and dosimetric factors, including the DVH of the oral mucosa (OM), were considered. For each patient, based on the actual elapsed treatment time, the OM-DVH was rebinned to calculate the DVH per week (wDVH). OM-wDVH of patients with and without grade 3+ mucositis was compared using a two-sided t-testing in order to assess the best predictive region of the wDVH. Uni- and multivariate logistic regression were run to identify predictors of grade 3+ mucositis during IMRT.ResultsOverall 112 patients (80%) developed the endpoint. The region that best discriminated between patients with/without the mucositis defined endpoint was found at 10.1 Gy/w (V10.1) and 21cc (D21), along the x- and y-axis of the absolute cumulative OM-wDVH, respectively. On multivariate analysis D21 (OR=1.017, 95% CI: 1.009-1.024, p < 0.001) was the only independent predictor of grade 3+ mucositis. However, V10.1 and D21 were highly correlated (rho=0.885, p < 0.001) and basically mutually interchangeable in the multivariate model. Conc CHT showed a trend (OR: 3.095, 95% CI: 0.903-6.698, p = 0.079), that became statistically significant when the two patients who received only 1 cycle of CHT were pooled with the patients who did not receive CHT (OR=2.830, 95% CI: 1.032-7.757, p = 0.043). No interaction was detected between dosimetric factors and conc CHT. From the model it can be estimated that conc CHT increased the dose to 21 cc of OM by ≈61.2 cGy per week.ConclusionsRadiotherapy and chemotherapy act independently in determining acute mucosal toxicity; conc CHT increases the risk of mucosal grade 3+ tox ≈3 times over RT alone and it is equivalent to an extra ≈4.3 Gy to 21 cc of OM over a 7-week course. Purpose/Objective(s)To define the roles of radiotherapy and chemotherapy on the risk of grade 3+ mucositis during IMRT for oropharyngeal cancer. To define the roles of radiotherapy and chemotherapy on the risk of grade 3+ mucositis during IMRT for oropharyngeal cancer. Materials/Methods140 consecutive patients treated with IMRT for oropharyngeal cancer at two Institutions in non-overlapping treatment era were selected for the present analysis. 62 pts were treated at UTMB from May 2002 to April 2007; 78 pts at JHU from August 2007 to December 2009. All patients were treated with a dose painting approach, 3 dose levels (GTV, high and low risk CTV) and comprehensive bilateral neck treatment under the supervision of the same RadOnc (GS). 36/140 pts were treated with altered fractionation alone (either 78Gy/60fxs/6wks or 66Gy/30fxs/6wks); all others to 70Gy/35fxs/7wks. Of the latter, 71 received platinum-based concomitant chemotherapy (conc CHT) and 11 received induction CHT. Patients were seen weekly during treatment and mucositis was scored prospectively with blinding to dosimetric data. Peak acute toxicity ≥ confluent mucositis at any point during the course of IMRT was considered the endpoint of this study. A number of clinical and dosimetric factors, including the DVH of the oral mucosa (OM), were considered. For each patient, based on the actual elapsed treatment time, the OM-DVH was rebinned to calculate the DVH per week (wDVH). OM-wDVH of patients with and without grade 3+ mucositis was compared using a two-sided t-testing in order to assess the best predictive region of the wDVH. Uni- and multivariate logistic regression were run to identify predictors of grade 3+ mucositis during IMRT. 140 consecutive patients treated with IMRT for oropharyngeal cancer at two Institutions in non-overlapping treatment era were selected for the present analysis. 62 pts were treated at UTMB from May 2002 to April 2007; 78 pts at JHU from August 2007 to December 2009. All patients were treated with a dose painting approach, 3 dose levels (GTV, high and low risk CTV) and comprehensive bilateral neck treatment under the supervision of the same RadOnc (GS). 36/140 pts were treated with altered fractionation alone (either 78Gy/60fxs/6wks or 66Gy/30fxs/6wks); all others to 70Gy/35fxs/7wks. Of the latter, 71 received platinum-based concomitant chemotherapy (conc CHT) and 11 received induction CHT. Patients were seen weekly during treatment and mucositis was scored prospectively with blinding to dosimetric data. Peak acute toxicity ≥ confluent mucositis at any point during the course of IMRT was considered the endpoint of this study. A number of clinical and dosimetric factors, including the DVH of the oral mucosa (OM), were considered. For each patient, based on the actual elapsed treatment time, the OM-DVH was rebinned to calculate the DVH per week (wDVH). OM-wDVH of patients with and without grade 3+ mucositis was compared using a two-sided t-testing in order to assess the best predictive region of the wDVH. Uni- and multivariate logistic regression were run to identify predictors of grade 3+ mucositis during IMRT. ResultsOverall 112 patients (80%) developed the endpoint. The region that best discriminated between patients with/without the mucositis defined endpoint was found at 10.1 Gy/w (V10.1) and 21cc (D21), along the x- and y-axis of the absolute cumulative OM-wDVH, respectively. On multivariate analysis D21 (OR=1.017, 95% CI: 1.009-1.024, p < 0.001) was the only independent predictor of grade 3+ mucositis. However, V10.1 and D21 were highly correlated (rho=0.885, p < 0.001) and basically mutually interchangeable in the multivariate model. Conc CHT showed a trend (OR: 3.095, 95% CI: 0.903-6.698, p = 0.079), that became statistically significant when the two patients who received only 1 cycle of CHT were pooled with the patients who did not receive CHT (OR=2.830, 95% CI: 1.032-7.757, p = 0.043). No interaction was detected between dosimetric factors and conc CHT. From the model it can be estimated that conc CHT increased the dose to 21 cc of OM by ≈61.2 cGy per week. Overall 112 patients (80%) developed the endpoint. The region that best discriminated between patients with/without the mucositis defined endpoint was found at 10.1 Gy/w (V10.1) and 21cc (D21), along the x- and y-axis of the absolute cumulative OM-wDVH, respectively. On multivariate analysis D21 (OR=1.017, 95% CI: 1.009-1.024, p < 0.001) was the only independent predictor of grade 3+ mucositis. However, V10.1 and D21 were highly correlated (rho=0.885, p < 0.001) and basically mutually interchangeable in the multivariate model. Conc CHT showed a trend (OR: 3.095, 95% CI: 0.903-6.698, p = 0.079), that became statistically significant when the two patients who received only 1 cycle of CHT were pooled with the patients who did not receive CHT (OR=2.830, 95% CI: 1.032-7.757, p = 0.043). No interaction was detected between dosimetric factors and conc CHT. From the model it can be estimated that conc CHT increased the dose to 21 cc of OM by ≈61.2 cGy per week. ConclusionsRadiotherapy and chemotherapy act independently in determining acute mucosal toxicity; conc CHT increases the risk of mucosal grade 3+ tox ≈3 times over RT alone and it is equivalent to an extra ≈4.3 Gy to 21 cc of OM over a 7-week course. Radiotherapy and chemotherapy act independently in determining acute mucosal toxicity; conc CHT increases the risk of mucosal grade 3+ tox ≈3 times over RT alone and it is equivalent to an extra ≈4.3 Gy to 21 cc of OM over a 7-week course.

To prospectively assess the change in volume of positive lymph nodes during IMRT. Out of 36 patients treated for oropharyngeal SCC with IMRT ± chemotherapy at Johns Hopkins University from Sept 07 to Dec 08, those with HPV positive disease and with lymph nodes considered positive at physical exam and/or imaging (>1 cm in greatest axial dimension) and no induction chemotherapy were considered. From the planning (pl) contrast enhanced CT, the baseline volume of each positive lymph node was extracted. Moreover, within each positive node, the volume of the hypodense core (with a cut-off CT number of 1045) was computed. Nodes were classified into solid-S (ratio of hypodense to total volume <5%) and hypodense-H (≥5%). Patients underwent weekly repeat plCTs during IMRT. The nodal volume was extracted for each positive node at each CT. Changes in volume are reported as a relative variation considering a baseline volume of 100%. Comparisons were done with the Mann-Whitney U and the chi-square tests as appropriate. 17 patients met the selection criteria and 45 positive lymph nodes were identified. All patients but 1 received concomitant chemotherapy and the average mean dose to positive nodes was 72.4 Gy (SD:1.7 Gy). The mean volume of positive nodes was 9.9 cc (SD:13.5 cc). 25 (55.6%) and 20 (44.4%) nodes were scored S, and H, respectively. Hypodense nodes were observed in 9 patients, where they represented 80% of total positive nodes. Overall, at 4 weeks into IMRT, mean nodal volume was 53.1% of initial volume (SD: 39.8%) and at the end of treatment 37.2% (SD: 30.5%). At both time points, S nodes were significantly smaller than H ones, 33.1% and 24.7% for S vs. 78.0% and 52.4% for H, respectively (p < 0.001 and p = 0.013). Initial nodal volume, when dichotomized by median value, did not affect regression rate at either time point (p = 0.43 and p = 0.60, respectively). Of 20 H nodes, 10 (50%) were found to be enlarged at some point during Weeks 2–8 of IMRT compared to none of the 25 solid ones (p < 0.001). Median enlargement was to 127% (max: 150%) and it was observed for a median time of 3.5 weeks (max: 6 weeks) of treatment. Hypodense nodes are common in patients with HPV associated oropharyngeal carcinoma. Once present, they tend to represent the majority of nodes, suggesting a constant pattern of nodal change in selected patients. Their regression rate during IMRT is significantly slower than solid ones and about half of them actually increase in size during treatment and for a remarkable amount of time.

6011 Background: G is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor with modest single-agent activity in SCCHN. We hypothesized that the addition of G to D will enhance therapeutic efficacy. Methods: Eligibility criteria included R/M SCCHN; any number of prior regimens (excluding D and EGFR inhibitors); ECOG performance status (PS) 2, if previously untreated, or ECOG PS 0–2, if prior chemotherapy for R/M SCCHN or as part of potentially curative therapy < 6 months (mo) earlier. Patients (pts) were randomly assigned to receive D 35 mg/m2 IV on days 1,8,15, every 28 days plus placebo (arm A) or the same D regimen plus G 250 mg orally, once daily (arm B) until disease progression. Stratification factors were PS, prior chemotherapy and weight loss. At the time of progression, treatment could be unblinded and, for pts in the placebo arm, single-agent G 250 mg/d initiated. We sought to demonstrate an improvement in median overall survival (OS) from 6 to 8.4 mo (28.6% reduction in HR). A total accrual of 314 eligible pts and 286 failures were needed to attain 80% power with 2.5% type I error. Results: 270 pts were enrolled (arm A, n = 136; arm B, n = 134). The study was terminated at interim analysis in November 2008 because it was highly unlikely that the primary endpoint could be met. 60% of pts had ECOG PS of 2; 72% had prior chemotherapy. 24 pts in arm A received G at progression. Data on subsequent treatment with EGFR inhibitors were not collected. Median OS was 6 mo in arm A versus 6.8 mo in arm B (p = 0.74); HR 1.04 (95% CI, 0.79–1.35). Objective response rate in 168 evaluable pts was 6% in arm A vs. 14% in arm B (p = 0.16). Median time to progression was 2 mo and 3.5 mo (p = 0.03) and median progression-free survival 2.2 mo and 3.3 mo (p = 0.18) in arms A and B, respectively. Common grade 3/4 adverse events (AE) in arm A (n = 121) vs. B (n = 115) were neutropenia 1/2 vs. 2/0; fatigue 16/4 vs. 14/0; diarrhea 3/0 vs. 11/1; nausea 4/1 vs. 5/0; vomiting 4/0 vs. 1/1; pneumonia 8/1 vs. 6/1. There were 2 grade 5 AE in arm A and 5 in arm B. Conclusions: The addition of G to D is well tolerated and improves time to progression but not survival in previously treated and poor PS pts with R/M SCCHN. [Table: see text]

To the Editor: In the report by Posner et al. (Oct. 25 issue)1 on the treatment of head and neck cancer, we question the authors’ implication that the 91-11 trial of the Radiation Therapy Oncology Group and Head and Neck Intergroup showed that cisplatin–fluorouracil (PF) induction followed by radiotherapy for laryngeal preservation is equivalent to or better than concomitant cisplatin and radiotherapy. The 91-11 trial was not designed to show equivalence.2 Both combinations resulted in better laryngectomy-free survival than did radiotherapy alone, but the composite end point does not account for a preserved larynx in patients whose death was not due to laryngeal cancer (over half the deaths). Rates of laryngeal preservation and locoregional control provide a much better assessment, and for both end points, the rates were significantly better with concomitant cisplatin and radiotherapy than with radiotherapy alone or PF induction followed by radiotherapy, whereas overall survival did not differ significantly.2,3 The results of the 91-11 trial do not justify the use of docetaxel–cisplatin–fluorouracil (TPF) sequential therapy for T3 and low-volume T4 laryngeal cancer. Arlene Forastiere, M.D.

Concurrent chemoradiotherapy (CCRT) for Stage III/IV head and neck cancer improves survival over RT alone, but is associated with increased toxicity, including late pharyngolaryngeal complications. This analysis was done to determine if doses (by 2-D dosimetric analyses) to regions of the pharynx are associated severe late toxicity. This is a retrospective review of pts treated with CCRT regimens from three RTOG trials: 1. RTOG 91-11 Arm 2 (XRT/high-dose cisplatin); 2. RTOG 97-03 Arms 1 and 3 (XRT + 5-FU/cisplatin or cisplatin/paclitaxel); and 3. RTOG 99-14 (accelerated XRT/high dose cisplatin). These studies did not use 3-D conformal RT or IMRT. Dosimetric data including simulation and portal films, treatment prescriptions/records and 2-D dosimetry records were evaluated for 154 evaluable pts (pts NED for at least 2 years and for whom all technical data were available). Reviewers were blinded to pt toxicity outcomes during these analyses. Cumulative doses to four pharyngeal regions were determined for each pt.: 1. Superior oropharynx (adjacent to soft palate); 2. Inferior oropharynx (adjacent to epiglottic tip); 3. Mid-hypopharynx (adjacent to arytenoid cartilage); and 4. Inferior hypopharynx (pharyngoesophageal inlet). Severe late toxicity was defined as Grade 3+ pharyngolaryngeal dysfunction and/or requirement for a long-term feeding tube. Multivariate analysis was performed to determine factors predictive of severe late toxicity. Severe late toxicity was present in 71 of 154 evaluable pts (46%). The rates of severe late toxicity were similar for the three RTOG studies. Pts with severe late toxicity were more likely to be older (mean age 59.7 vs. 54.6; p = 0.0009) and more likely to have KPS <90% (23% vs. 11%; p = 0.05). All other pre-treatment characteristics, XRT tumor dose, and chemo delivery were similar between patients with and without severe late toxicity. Dosimetric analysis showed no significant differences in radiation doses to the superior or inferior oropharynx (p = 0.87 and p = 0.77 respectively). However, radiation doses to the superior and inferior hypopharynx were significantly higher in the group with severe late toxicity (p = 0.015 and p = 0.025, respectively). On multivariate analysis, the only statistically significant covariates associated with severe late toxicity were age (odds ratio 1.062; p = 0.002) and dose to the inferior hypopharynx (odds ratio 1.023; p = 0.016) (both analyzed as continuous variables). The median inferior hypopharynx dose among pts with severe late toxicity (cases) was 58 Gy, compared with 50.6 Gy among pts without severe late toxicity (controls). Higher dose to the inferior hypopharynx is associated with a greater risk of severe late toxicity among pts treated with CCRT for head and neck cancer. More detailed and rigorous dose-volume analyses based on 3-D/IMRT datasets are required, both to confirm this finding and to elucidate future means of decreasing late radiation complications.

Purpose/Objective(s)Management of the neck in patients with oropharyngeal cancer and clinical N2 or greater lymph node disease remains controversial. This study evaluates the optimal timing and necessity of neck dissection in a group of patients who underwent either pre-radiotherapy or post-radiotherapy neck dissection, or observation after definitive radiotherapy.Materials/MethodsFrom 1994–2006 at The Johns Hopkins Hospital, 66 patients with oropharyngeal carcinoma with neck metastases staged T1-4 N2a-3 M0 were treated with radiotherapy as some component of their clinical course. 21 patients underwent pre-radiotherapy neck dissection, 14 underwent planned neck dissection after radiotherapy, and 31 underwent radiotherapy alone without neck dissection. Overall, 47% of patients had T3 or T4 primary tumors. 73% of patients had N2a or N2b disease and the remainder had N2c or N3 disease. Notably, 20 patients (95%) in the pre-radiotherapy neck dissection group had T1 or T2 primary tumors.ResultsThe 5-year actuarial regional control in the neck was 95.2% for patients who underwent neck dissection prior to radiotherapy, 92.3% for patients who underwent planned neck dissection after radiotherapy, and 65.4% for patients who were observed after definitive radiotherapy (p = 0.020). The respective 5-year actuarial overall survival rates were 92.9%, 72.7%, and 58.1% for the three groups (p = 0.024). For patients who underwent definitive radiotherapy only or planned neck dissection after radiotherapy, advanced T-stage was associated with a significantly higher risk of failure in the neck, independent of N-stage. Patients with small T1-2 primaries had a neck control rate of 93.3%, in contrast to 62.9% for those with advanced T3-4 primaries (p = 0.051). For all groups, pre-treatment nodal stage, maximum nodal size, and number of pathological nodes were not significant prognostic factors for ultimate locoregional neck control. In patients undergoing a planned neck dissection post-radiotherapy, the rate of residual nodal positivity was 36% (n = 5). Pre-treatment nodal stage, maximum lymph node size, and post-radiotherapy radiographic findings did not significantly correlate with the ultimate pathologic findings at the time of neck dissection. Postoperative complications after neck dissection were observed in 4 patients (11%).ConclusionsNeck dissection in conjunction with radiotherapy yields good regional control rates for patients with advanced nodal disease. Neck dissection prior to radiotherapy is a valid method for controlling advanced neck metastases from small primaries. Planned post-radiotherapy neck dissection can be considered for all advanced N-stage patients, as it is difficult to predict for persistent disease and long-term outcome based on clinical assessment. However, in selecting which patients should undergo a post-radiotherapy neck dissection, our findings indicate that advanced T stage may better predict for patients who would gain the greatest locoregional control benefit from closer post-radiotherapy surveillance and aggressive surgical management of the neck. Purpose/Objective(s)Management of the neck in patients with oropharyngeal cancer and clinical N2 or greater lymph node disease remains controversial. This study evaluates the optimal timing and necessity of neck dissection in a group of patients who underwent either pre-radiotherapy or post-radiotherapy neck dissection, or observation after definitive radiotherapy. Management of the neck in patients with oropharyngeal cancer and clinical N2 or greater lymph node disease remains controversial. This study evaluates the optimal timing and necessity of neck dissection in a group of patients who underwent either pre-radiotherapy or post-radiotherapy neck dissection, or observation after definitive radiotherapy. Materials/MethodsFrom 1994–2006 at The Johns Hopkins Hospital, 66 patients with oropharyngeal carcinoma with neck metastases staged T1-4 N2a-3 M0 were treated with radiotherapy as some component of their clinical course. 21 patients underwent pre-radiotherapy neck dissection, 14 underwent planned neck dissection after radiotherapy, and 31 underwent radiotherapy alone without neck dissection. Overall, 47% of patients had T3 or T4 primary tumors. 73% of patients had N2a or N2b disease and the remainder had N2c or N3 disease. Notably, 20 patients (95%) in the pre-radiotherapy neck dissection group had T1 or T2 primary tumors. From 1994–2006 at The Johns Hopkins Hospital, 66 patients with oropharyngeal carcinoma with neck metastases staged T1-4 N2a-3 M0 were treated with radiotherapy as some component of their clinical course. 21 patients underwent pre-radiotherapy neck dissection, 14 underwent planned neck dissection after radiotherapy, and 31 underwent radiotherapy alone without neck dissection. Overall, 47% of patients had T3 or T4 primary tumors. 73% of patients had N2a or N2b disease and the remainder had N2c or N3 disease. Notably, 20 patients (95%) in the pre-radiotherapy neck dissection group had T1 or T2 primary tumors. ResultsThe 5-year actuarial regional control in the neck was 95.2% for patients who underwent neck dissection prior to radiotherapy, 92.3% for patients who underwent planned neck dissection after radiotherapy, and 65.4% for patients who were observed after definitive radiotherapy (p = 0.020). The respective 5-year actuarial overall survival rates were 92.9%, 72.7%, and 58.1% for the three groups (p = 0.024). For patients who underwent definitive radiotherapy only or planned neck dissection after radiotherapy, advanced T-stage was associated with a significantly higher risk of failure in the neck, independent of N-stage. Patients with small T1-2 primaries had a neck control rate of 93.3%, in contrast to 62.9% for those with advanced T3-4 primaries (p = 0.051). For all groups, pre-treatment nodal stage, maximum nodal size, and number of pathological nodes were not significant prognostic factors for ultimate locoregional neck control. In patients undergoing a planned neck dissection post-radiotherapy, the rate of residual nodal positivity was 36% (n = 5). Pre-treatment nodal stage, maximum lymph node size, and post-radiotherapy radiographic findings did not significantly correlate with the ultimate pathologic findings at the time of neck dissection. Postoperative complications after neck dissection were observed in 4 patients (11%). The 5-year actuarial regional control in the neck was 95.2% for patients who underwent neck dissection prior to radiotherapy, 92.3% for patients who underwent planned neck dissection after radiotherapy, and 65.4% for patients who were observed after definitive radiotherapy (p = 0.020). The respective 5-year actuarial overall survival rates were 92.9%, 72.7%, and 58.1% for the three groups (p = 0.024). For patients who underwent definitive radiotherapy only or planned neck dissection after radiotherapy, advanced T-stage was associated with a significantly higher risk of failure in the neck, independent of N-stage. Patients with small T1-2 primaries had a neck control rate of 93.3%, in contrast to 62.9% for those with advanced T3-4 primaries (p = 0.051). For all groups, pre-treatment nodal stage, maximum nodal size, and number of pathological nodes were not significant prognostic factors for ultimate locoregional neck control. In patients undergoing a planned neck dissection post-radiotherapy, the rate of residual nodal positivity was 36% (n = 5). Pre-treatment nodal stage, maximum lymph node size, and post-radiotherapy radiographic findings did not significantly correlate with the ultimate pathologic findings at the time of neck dissection. Postoperative complications after neck dissection were observed in 4 patients (11%). ConclusionsNeck dissection in conjunction with radiotherapy yields good regional control rates for patients with advanced nodal disease. Neck dissection prior to radiotherapy is a valid method for controlling advanced neck metastases from small primaries. Planned post-radiotherapy neck dissection can be considered for all advanced N-stage patients, as it is difficult to predict for persistent disease and long-term outcome based on clinical assessment. However, in selecting which patients should undergo a post-radiotherapy neck dissection, our findings indicate that advanced T stage may better predict for patients who would gain the greatest locoregional control benefit from closer post-radiotherapy surveillance and aggressive surgical management of the neck. Neck dissection in conjunction with radiotherapy yields good regional control rates for patients with advanced nodal disease. Neck dissection prior to radiotherapy is a valid method for controlling advanced neck metastases from small primaries. Planned post-radiotherapy neck dissection can be considered for all advanced N-stage patients, as it is difficult to predict for persistent disease and long-term outcome based on clinical assessment. However, in selecting which patients should undergo a post-radiotherapy neck dissection, our findings indicate that advanced T stage may better predict for patients who would gain the greatest locoregional control benefit from closer post-radiotherapy surveillance and aggressive surgical management of the neck.

For non-surgical cancer treatment, the influence of patient volume on outcomes is not well defined. In contrast, for complex oncologic surgery results are influenced by volume. Higher frequencies are associated with lower perioperative morbidity and mortality rates. This analysis was undertaken to ascertain if frequency of patient accrual or NCI-CCC designation influenced disease outcome for patients entered into a phase III laryngeal perservation trial. RTOG 9111 compared radiation therapy (RT) given with concurrent chemotherapy (CT), RT alone and induction CT followed by RT. There were 2 comparisons made based on accrual and institution type. Those in the top 1/3 for total accrual were high accruers (HA) compared to those in the bottom 1/3 who or low accruers (LA). NCI-CCC institutions were compared with non-NCI-CCC institutions. Endpoints were eligibility rate, time to laryngectomy (TTL), time to local failure (TTLF), and overall survival (OS). Hazard ratios (HR) and 95% confidence intervals (CI) comparing patient subgroups were estimated using Cox proportional hazards models with assigned treatment as fixed covariate, and were defined such that HR<1 indicated decreased risk for HA or NCI-CCC. 547 patients were entered and 515 were analyzed. The 7 HA institutions entered 176 cases (range 17 to 53; mean 25.1; median 18). The 117 LA institutions entered 196 cases (range 1 to 4; mean 1.7; median 1). The remaining 175 patients were treated at 21 institutions (range 5 and 14 patients; mean 8.3; median 8) but are not included in the models. 24 NCI-CCC accrued 213 patients (range 1 to 53 patients; mean 8.9; median 3.5). The other 121 institutions accrued 334 (range 1 to 18 patients; mean 2.8; median 1). HA and NCI-CCC subgroups had a higher percentage of eligible patients, but neither reached statistical significance at the 0.05 level [(HA vs. LA: 96.6% vs. 92.9%; p = 0.17) (NCI-CCC vs. non-NCI-CCC: 96.7% vs. 92.5%; p = 0.06)]. There were no statistically significant differences detected, or even any large differences estimated that approached statistical significance, for any endpoint for either comparison. Table 1 shows the estimated HR and 95% CI for all comparisons. No difference was found in eligibility, TTL, TTLF and overall survival for any comparison (p > .05). This supports a comparable outcome for non-surgical laryngeal preservation therapy regardless of accrual or NCI-CCC status. We conclude this treatment is translatable among centers if protocol guidelines are followed and appropriate quality oversight through the cooperative group is maintained.Tabled 1EndpointComparisonHR95% CIp-valueTTLHA vs. LA1.090.74, 1.610.66TTLNCI-CCC vs. non-NCI-CCC1.010.73, 1.400.96TTLFHA vs. LA0.870.63, 1.220.42TTLFNCI-CCC vs. non-NCI-CCC0.850.65, 1.130.26OSHA vs. LA0.840.63, 1.110.21OSNCI-CCC vs. non-NCI-CCC0.910.72, 1.160.45 Open table in a new tab

5504 Background: The role of p53 as a prognostic marker in head and neck squamous cell carcinoma (HNSCC) is controversial. The intent of this study was to evaluate rigorously the prognostic value of p53 genetic status. Methods: Tumor samples from 480 HNSCC patients treated surgically with curative intent were collected in a prospective multicenter study over 5 years. 57 cases were not analyzed due to technical or administrative factors. Mutation status was determined in the 423 remaining cases, using p53 chip (GP53 GeneChip from Affymetrix, Inc., Santa Clara, CA) which identifies mutations in exons 2 through 11. Indeterminate calls were investigated using Surveyor and/or DHPLC analysis and all mutations were confirmed with an automated fluorescent system or manual sequencing. Clinical follow-up was accomplished following Eastern Cooperative Oncology Group protocol. Results: Median follow-up of the 423 evaluable subjects was 5.4 years with all patients followed at least 3 years. Mutation of p53 gene was present in 224 (53%) cases. There we significantly fewer mutations in tumors arising in the oropharynx (chi-square p = 0.02). The presence of p53 mutation was significantly associated with decreased overall survival. Median survival for patients with tumors with p53 mutation was 3.1 years compared to 5.4 years fro WT tumors (HR = 1.4, 95% CI =1.1 to 1.8, p = 0.01 log-rank test). This proved to be independent of tumor site in multivariate analysis. When mutations were segregated according to their effect on biological function through alteration of key DNA binding domains a Cox regression analysis revealed a statistically significant linear effect of the more disruptive mutations on overall survival with a HR of 1.3 for comparison of each group to the one of lower risk (more vs. less disruptive mutation v. WT (p = 0.001 Wald test). Conclusions: This large prospective series shows a strong relationship between TP53 mutation and prognosis in HNSCC patients. Furthermore, the biological impact of specific mutations has a predictable graded relation to clinical outcome. The results set the stage for use of p53 genetic status in the design of future clinical trials and support the development of targeted therapy to restore wild-type p53 function. No significant financial relationships to disclose.

5573 Background: Adenoid cystic carcinoma (ACC) is usually resistant to chemotherapy. Bortezomib (B) is a highly selective inhibitor of the 26S proteasome which is central for the ubiquitin-proteasome degradation pathway. Inhibition of NF-κB activity achieved by B may be important for inhibition of the growth of ACC. Preclinical studies have shown synergy between B and doxorubicin (D). Methods: Eligibility criteria included incurable ACC, any number of prior therapies but without an anthracycline, unidimensionally measurable disease, ECOG performance status 0–2, ejection fraction within normal limits (WNL), absolute neutrophil count >1500/μL, platelets >100,000/μL, and total bilirubin WNL. Patients (pts) with stable disease (SD) for 9 months or more were excluded. Pts received B 1.3 mg/m2 IV push on days 1,4,8, and 11, every 21 days, until progression. Doxorubicin 20 mg/m2 IV on days 1 and 8 was added at the time of progression. Response assessment was performed after every 2 cycles using RECIST. Immunohistochemistry for biomarkers affected by the ubiquitin-proteasome pathway on baseline tumor and measurement of serum inflammatory and angiogenic cytokines before and in response to therapy were performed. Results: 25 pts were enrolled; 18 were females; median age was 56 years (26–73); distant metastatic sites: lung (21), liver (4), bone (2). Best response to single-agent B: 16 pts (64%) had SD, 7 progressed, and 2 were unevaluable (1 with symptomatic deterioration). The median progression-free survival was 8.5 months. In 4 evaluable pts who received B plus D, 1 partial response and 2 SD were observed. 1 pt died 7 months after starting treatment without documented progression. Worst grade (G) 3/4 toxicities with B alone in 22 evaluable pts were: G3 neutropenia 5%, G4 neutropenia 5%, G3 thrombocytopenia 5%, G3 sensory neuropathy 14%; G3 generalized weakness 5%, G3 fatigue 9%, G3 anorexia 5%, G3 diarrhea 5%, G3 hyponatremia 5%, G3 dyspnea 5%. Conclusions: B was well tolerated and resulted in disease stabilization in a high percentage of pts but no objective responses. Updated response data with the addition of D will be available. No significant financial relationships to disclose.

Chemotherapeutic agents that disrupt the assembly or disassembly of microtubules, including paclitaxel and docetaxel, are among the most commonly prescribed anticancer therapies. However, the utility of taxane-based therapy is limited principally by problems with formulation, slow administration, cumulative neurotoxicity, and resistance in part through induction of P-glycoprotein. The broad-spectrum anticancer activity of taxane therapy has encouraged investigators to identify a class of structurally novel microtubulin-stabilizing agents that could produce comparable outcomes with fewer problems. Preclinical studies indicate that epothilones have a broad spectrum activity in paclitaxel-resistant breast cancer models. Several epothilone analogues have displayed promising antitumor activity in initial clinical trials. Ixabepilone, an epothilone derivative in the later stages of clinical development, has exhibited antitumor activity in breast cancers, with or without previous taxane therapy. The most common adverse events associated with ixabepilone are reversible sensory neuropathy and neutropenia. This review briefly outlines the basic science behind microtubule-targeting agents and examines the preclinical studies of several of these agents in breast cancer models. Also discussed are results from clinical trials of epothilones alone and in combination in patients with breast cancer.

Based on positive results from the Radiation Therapy Oncology Group (RTOG) 85-01 trial, the conventional nonsurgical treatment of esophageal carcinoma is combined-modality therapy. Dose intensification of the RTOG 85-01 regimen, examined in the Intergroup (INT)-0123/RTOG 94-05 trial, did not improve local control or survival. Areas of clinical investigation include the development of combined-modality therapy regimens with newer systemic agents, the use of 18F-fluorodeoxyglucose positron-emission tomography to assist in the development of innovative radiation treatment planning techniques, and the identification of prognostic molecular markers. The addition of surgery following primary combined-modality therapy apparently does not improve survival, but this finding is controversial.