Haddock, Michael G.

347 Background: 9,704 was the first phase 3 pancreatic cancer trial to validate the prognostic value of postresection CA19-9 for overall survival (OS), with values > 90/180 associated with worse OS. All pts received adjuvant gemcitabine or 5-FU and chemo-radiotherapy (RT). This analysis evaluates patterns of disease failure. Methods: SMS was negative, positive, or unknown. CA19-9 was analyzed at cut points 90, 180 and continuously. LRF and DF were estimated by cumulative incidence and Gray’s test compared. Cox hazard models were used for multivariate analyses (MVA) and included treatment, tumor site, size and nodal status. To adjust for multiple comparisons a p-value < 0.01 is statistically significant and 0.01 to < 0.05 a trend. Results: 538 pts accrued, with 451 eligible and analyzable for SMS and 385 for CA19-9. For CA19-9, 132 (34%) were Lewis Antigen negative (no CA19-9 expression), 200 (52%) < 90 and 220 (57%) < 180. 188 (42%) had negative margins, 152 (34%) positive and 111 (25%) unknown (i.e., no margin comment in path report; shown to have outcomes similar to negative margin pts). Pts with CA19-9 ≥ 180 were more likely to have tumors ≥ 3 cm and pts with positive SMS more likely to have KPS 60 - 80, T3/T4, or N1 disease. On univariate analysis (UVA) CA19-9 cut at 90 was associated with significant increases in both LRF (trend) and DF; in the gemcitabine arm this was seen in DF, not in LRF; in the 5-FU arm it was seen in both. Results were similar at the 180 cut point and continuously. SMS on UVA was not associated with increase in LRF/DF; see Table. On MVA, CA19-9 > 90 was significantly associated with LRF and DF; positive SMS showed only a trend for DF. Conclusions: Postresection CA19-9 has significant association with both LRF and DF not seen with SMS. These findings support continued use of RT in trials and consideration of dose intensification among pts with elevated postresection CA19-9. Grants: NCI U10, CA21661, CA37422, CA180868, CA180822. Clinical trial information: 0000000. [Table: see text]

119 Background: Radiotherapy (RT) interruptions have a negative impact on outcomes in many epithelial malignancies treated with definitive RT. The purpose of this study was to analyze the impact of RT duration on outcomes in patients (pts) with esophageal cancer treated with definitive chemoradiotherapy (CRT). Methods: Pts treated with definitive CRT on RTOG trials 8501 and 9405 were included. Separate analyses were performed in pts receiving standard dose (SD-CRT; 50 Gy + 5FU + cisplatin) and high dose (HD-CRT; 64.8 Gy + 5FU + cisplatin) CRT. Local (LF) and regional (RF) failure were estimated by the cumulative incidence method. Disease-free (DFS) and overall (OS) survival were estimated by the Kaplan-Meier method. Univariate (UVA) and multivariate (MVA) Cox proportional hazards models were utilized to examine for correlation between RT duration (< vs. ≥ median) with LF, RF, DFS and OS. Results: In the SD-CRT cohort (n=235), 96 pts (41%) had ≥ 1 RT interruption for a median of 3 (IQR 1-6) days. The median RT duration was 39 (IQR 37-43) days. In UVA and MVA, RT duration was not associated with LF, RF, DFS, or OS. Estimated outcome rates are in the table. In the HD-CRT cohort (n=107), 64 pts (60%) had ≥ 1 RT interruption for a median of 3.5 (IQR 2-7.5) days. The median RT duration was 52 (IQR 50-57) days. In UVA, RT duration ≥ 52 days was associated with a 33% reduction in risk of DFS failure (HR=0.66, 95% CI [0.44-0.98], p=0.039) and a 29% reduction in risk of death (HR=0.71, 95% CI [0.48-1.06], p=0.09). When excluding the 25 pts with RT dose < 64.8 Gy, RT duration was not associated with DFS or OS. Conclusions: In pts with esophageal cancer receiving definitive SD-CRT, an association between RT duration and outcomes was not observed. In pts receiving HD-CRT, longer RT duration was associated with improved DFS, which may have been due to a significant number of deaths at RT dose < 64.8 Gy. Supported by NCI U10 grants CA21661, CA180868, CA180822, CA37422. Clinical trial information: NCT00002631. [Table: see text]

711 Background: For patients with stage IVA rectal cancer with liver metastases treated with curative-intent chemotherapy and surgery, the role of adjuvant pelvic radiotherapy (RT) is unclear. The purpose of this study was to evaluate the impact of pelvic RT on oncologic outcomes in this patient population. Methods: We retrospectively reviewed medical records of all patients with stage IVA rectal adenocarcinoma with liver metastases treated with curative-intent resection of the primary tumor and all liver metastases at our institution between 1991 and 2010. Patient and treatment characteristics were compared between patients who did or did not receive pelvic RT using chi-square and unpaired ttests. Survival and recurrence estimates were calculated from date of initial diagnosis using the Kaplan-Meier method. Local recurrence (LR) was defined as recurrence in the pelvis occurring at or before distant recurrence (DR). Cox regression was used to compare rates of freedom from LR (FFLR), freedom from DR (FFDR), and overall survival (OS) between patients who did or did not receive pelvic RT. Results: The analysis included 65 patients. Median patient age at diagnosis was 59 years (range, 27-87). Tumor stage was T2 (n = 4), T3 (n = 53), or T4 (n = 8). The median number of liver metastases was 2 (range, 1-14). Surgery was low anterior resection (n = 54) or abdominoperineal resection (n = 11). All patients received perioperative fluoropyrimidine based chemotherapy. Pelvic RT was administered to 35 patients (54%), either preoperatively (n = 22) or postoperatively (n = 13). Median RT dose was 50.4 Gy (range 25-58). Patient characteristics were similar for those who did or did not receive pelvic RT. Median follow-up was 3.7 years. The 3-year estimates of FFLR, FFDR and OS were 81% vs 58% (p =.056), 35% vs 29% (p =.75), and 66% vs 71% (p =.81) for RT vs no RT, respectively. Conclusions: In this analysis of patients with stage IVA rectal cancer with liver metastases undergoing curative intent therapy, pelvic RT (vs. no pelvic RT) was associated with a trend to lower rates of LR and similar rates of DR and OS.

277 Background: For patients (pts) with LRR or advanced primary tumors of the UB or ureter, limited therapeutic options exist. Outcomes of combined SR and IOERT are reported here. Methods: From 1983 to 2009, a total of 17 pts with urothelial (16 pts) or squamous cell carcinoma (1 pt) of the UB (n=13) or ureter (n=4) were treated with SR and IOERT. Pts had LRR after radical cystoprostatectomy or nephroureterectomy (n=15) or advanced primary tumor (n=2). Extent of SR was R0 (microscopic negative margins), R1 (microscopic positive margins), and R2 (gross residual tumor) in 7, 1, and 9 pts, respectively. After maximal SR, IOERT was delivered to the tumor bed. Median IOERT dose and energy delivered were 12.5 Gy (range; 10-20) and 9 MeV (range; 6-18), respectively, with 1 (n=15), 2 (n=1), or 3 (n=1) IOERT fields. Sixteen pts also received perioperative external beam radiotherapy (EBRT) with a median dose of 50.4 Gy (range; 21.6- 60). Five pts received concurrent chemotherapy (CT) with perioperative EBRT. Overall (OS), disease-free survival (DFS) and relapse patterns were estimated from the date of SR and IOERT using the Kaplan-Meier method. Results: The median pt age was 63 years (yrs) (range; 51-76). The median follow-up of surviving pts was 3.6 yrs (range; 1.1-10.0). OS and DFS at 1, 2, and 5 yrs were 53%, 31%, and 16%, and 24%, 18%, and 18%, respectively. Central (within the IOERT field), locoregional (tumor bed or first echelon draining lymphatics), and distant relapse at 2 yrs were 15%, 49%, and 67%, respectively. Seven pts received systemic CT after relapse. Mortality within 30 days of SR and IOERT was 0%. Two pts (12%) experienced grade 4-5 (NCI-CTCAE v. 4) toxicity potentially related to the multimodality therapy. Conclusions: For pts with LRR or advanced primary tumor of the UB or ureter, this multimodality therapy including SR and IOERT resulted in durable OS and DFS in a small but significant number of pts. Both LRR and distant relapse were common, indicating a need for more effective systemic therapy along with more refined locoregional therapy. No significant financial relationships to disclose.

271 Background: Epidermal growth factor inhibitors show some benefit in the treatment of advanced pancreatic cancer. A trial to evaluate the incorporation of Pmab into a conventional multimodality regimen and continuation as maintenance therapy was conducted in pts with LA disease. Methods: Pts with ECOG PS 0-1, preserved organ function and tumor encompassed within standard radiation fields were eligible. Pmab 6 mg/kg on days 1, 15, 29 and continuous infusion 5-FU 225 mg/m2/d or capecitabine 825 mg/m2 were given with RT. Pts then received weekly gemcitabine 1000 mg/m2 and Pmab on days 1, 15 for three 4-week cycles. Maintenance Pmab was then continued for additional 6 months. RT consisted of 45 Gy to the tumor and regional nodes with a 5.4 Gy boost using conformal techniques. Primary endpoint of one-year survival (OS) with secondary endpoints progression-free survival (PFS), confirmed tumor response, and adverse events (at least possibly related) are reported. Results: 51 pts (23 M: 28 F) were enrolled with a median age of 65 (range: 43-84). Twenty-two pts (43%) received at least 1 cycle of post-chemo-RT, while 29 patients only received chemo-RT. All 51 pts have ended treatment with pts going off study because of: progression (39%), adverse events (27%), refusal (25%), and other reasons (8%). Frequently occurring maximum grade 3/4 AEs across the entire treatment course (chemo-RT + post-chemo-RT chemo) are shown below. With a median follow-up of 12.3 months, survival at 12 months is 50.2% (95% CI: 37.9-66.5%), median survival 12.1 mos (95% CI: 6.8-15.9) and median PFS 7.4 mos (95% CI: 3.7-8.6). Confirmed response rate was 5.9% (1-CR, 2-PR). Conclusions: The addition of Pmab to a conventional chemo-RT regimen provides benefit in terms of median survival. This is similar to reports of other EGFR inhibitors in LA disease. Adverse events, especially during the chemo-RT portion, were considerable and affected administration of subsequent systemic maintenance therapy. [Table: see text]

368 Background: 5-Fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer is associated with high rates of acute morbidity. We have previously shown that dose-painted IMRT (DP-IMRT) significantly reduces grade 3+ GI and dermatologic acute toxicity, as compared to the RTOG 9811 5FU/MMC arm, which used non-conformal radiation techniques. We now report on the two-year outcomes of this DP-IMRT approach. Methods: T2-4N0-3M0 anal canal cancers received 5FU (1,000 mg/m2/day 96 hour infusion) and MMC (10 mg/m2 bolus) days 1 and 29 of DP-IMRT prescribed as follows - T2N0: 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs), 28 fractions; T3-4N0-3: 45 Gy elective nodal, 50.4 Gy ≤ 3 cm and 54 Gy > 3 cm metastatic nodal and 54 Gy anal tumor PTVs, 30 fractions. The following two-year outcomes were assessed: local-regional (LRF) and colostomy failures (CF) using the cumulative incidence method, and disease-free (DFS), overall (OS) and colostomy-free survivals (CFS) using the Kaplan-Meier method. Results: Of 63 accrued patients, 52 were analyzable. Median age was 58 years; 81% female; 54% stage II; 25% IIIA; 21% IIIB. Median follow-up was 23.2 months (0.2-33). Two-year LRF, CF, DFS and 95% confidence intervals are 20% (9%, 31%), 8% (0.4%, 15%) and 77% (62%, 86%), respectively. The causes of death for the 7 patients that died are: anal cancer in 5, morbidity in one and second primary outside the radiation field in one. Two-year comparison data from the RTOG 9811 5FU/MMC arm are shown in the table below. Conclusions: DP-IMRT with 5FU/MMC for the treatment of anal canal cancer yields similar two-year outcomes as the RTOG 9811 conventional radiation, 5FU/MMC arm. Because of the associated acute toxicity sparing, DP-IMRT will be used as the platform, and may allow for radiation dose escalation, in future RTOG anal canal trials. Supported by RTOG U10 CA21661, CCOP U10 CA3742 and ATC U24 CA 81647 NCI grants. [Table: see text] No significant financial relationships to disclose.

367 Background: On initial publication of GI Intergroup RTOG 98-11, concurrent chemoradiation with 5FU+mitomycin (MMC) decreased colostomy failure (CF) vs induction plus concurrent 5FU+cisplatin (CDDP), but did not significantly impact disease free or overall survival (DFS, OS). The intent of the current analysis is to determine the long-term impact of treatment on survival (DFS, OS, colostomy-free [CFS]), CF and relapse (local-regional [LRF], distant [DM]) in this patient group. Methods: Stratification factors included gender, clinical node status, and primary size. DFS/OS were estimated univariately by Kaplan-Meier method and treatment arms compared by log-rank test. Time to relapse/CF were estimated by cumulative incidence method and treatment arms compared by Gray's test. Multivariate analyses were done with Cox proportional hazard models to test for treatment differences, adjusting for stratification factors. Results: Of 682 patients accrued, 649 were analyzable for outcomes. As seen in the table, 5-yr DFS and OS were statistically better for RT+5FU/MMC vs RT+5FU/CDDP (67.7 v 57.6%, p=.0.0045; 78.2 v 70.5%, p=0.021) with trends toward statistical significance for CFS, LRF, and CF (71.8 v 64.9%, p=0.053; 20 v 26.5%, 11.9 v 17.3%, p=0.092 and 0.075). Similar results were seen in multivariate analysis. Conclusions: Concurrent chemoradiation with 5FU-MMC has a statistically significant impact on DFS and OS vs induction + concurrent 5FU-CDDP and borderline significance for CFS, CF and LRF. Therefore, RT+5FU/MMC remains the preferred standard of care. Potential strategies to improve outcomes include treatment intensification and individualized molecular-based treatment. Supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI). [Table: see text] No significant financial relationships to disclose.

Background. Radiotherapy has been utilized for metastatic and recurrent osteosarcoma and Ewing sarcoma (ES), in order to provide palliation and possibly prolong overall or progression-free survival. Stereotactic body radiotherapy (SBRT) is convenient for patients and offers the possibility of increased efficacy. We report our early institutional experience using SBRT for recurrent and metastatic osteosarcoma and Ewing sarcoma.Methods. We reviewed all cases of osteosarcoma or ES treated with SBRT between 2008 and 2012.Results. We identified 14 patients with a total of 27 lesions from osteosarcoma(n=19)or ES(n=8). The median total curative/definitive SBRT dose delivered was 40 Gy in 5 fractions (range, 30–60 Gy in 3–10 fractions). The median total palliative SBRT dose delivered was 40 Gy in 5 fractions (range, 16–50 Gy in 1–10 fractions). Two grade 2 and 1 grade 3 late toxicities occurred, consisting of myonecrosis, avascular necrosis with pathologic fracture, and sacral plexopathy. Toxicity was seen in the settings of concurrent chemotherapy and reirradiation.Conclusions. This descriptive report suggests that SBRT may be a feasible local treatment option for patients with osteosarcoma and ES. However, significant toxicity can result, and thus systematic study is warranted to clarify efficacy and characterize long-term toxicity.