Citations

Abstract RTOG 9402 demonstrated procarbazine (P), lomustine (CCNU/C), and vincristine (V), collectively PCV, added to radiation therapy significantly improved survival for patients with newly diagnosed anaplastic oligodendroglial tumors. The improvement was most pronounced in 1p19q codeleted cases, and to a lesser extent, IDH-mutant cases, with no survival benefit in cases with neither biomarker. Analogous results were observed in other phase III trials. However, vincristine (V) can cause substantial toxicity and requires intravenous administration, both negatively affecting quality of life, with debatable contribution to PCV efficacy. As a randomized trial comparing PCV to PC is unlikely to be conducted, we explored correlations between survival and V-dosing in patients randomized to PCV in RTOG 9402. We performed post-hoc analyses of all evaluable participants (n = 143) randomized to PCV on RTOG 9402, supplemented by restricting the analyses to the chemosensitive molecular subsets (IDH-mutant and/or 1p/19q codeleted, n = 118). Total V dose by quartile (Q) was calculated. Survival from six months post-randomization was compared among V dose groups, adjusting for age, extent of resection (EOR), and Karnofsky Performances Status (KPS) in a Cox proportional hazards model. Higher V dose received correlated with longer survival in multivariate analyses (n = 134, median-Q3 vs. < Q1, HR 0.40 (0.22, 0.73), p = 0.003; ≥Q3 vs. < Q1, HR 0.39 (0.22, 0.72), p = 0.002). Excluding chemoresistant cases (IDH wild-type/not codeleted), survival was also significantly longer in evaluable participants receiving the highest doses of vincristine (≥Q3 vs. < Q1 HR 0.42 (0.21,0.81), p = 0.01). In this post-hoc analysis, higher overall V-dose received correlated with longer survival in evaluable patients with anaplastic oligodendroglial tumors receiving PCV chemotherapy in RTOG 9402. Of note, as vincristine dosing was not assigned by randomization, confounding due to differences in patient characteristics among V dose groups cannot be ruled out. Caution should be exercised when considering discarding V from the PCV regimen.

Abstract BACKGROUND Radiation Therapy Oncology Group 9802 was a phase III trial for patients with centrally confirmed LGG (WHO grade II). Participants ³ 40 years or those with neurosurgeon defined less than gross total resection (GTR) were randomized to radiotherapy (RT) +/- PCV. In a separate cohort, adults age < 40 years with neurosurgeon defined GTR were observed by MRI every 6 months without adjuvant therapy. At last report, outcome for the observation cohort was immature with median follow-up of only 4.4 years. Here, we present mature outcomes for the observation arm. METHODS Eligible adults (as above) were observed by MRI every 6 months. OS and PFS were estimated by Kaplan-Meier method and estimated hazard ratios to characterize the prognostic variables. RESULTS There were 111 eligible patients (median age 30; median KPS = 100). Median follow-up was 16.1 years with 71 (64%) alive at the last follow-up. 79 patients (71%) had progressed with median PFS of 6.9 years. 5, 10, and 15 year-PFS and OS rates were 54%, 39%, 28% and 94%, 77%, and 65%. 1p19q status was codeleted in 32%, IDH1/2 mutant in 78% and MGMT promoter methylated in 39% of tested cases. Multivariate Cox analyses showed that preoperative tumor size ³ 4 cm (HR = 2.43 for PFS, p = 0.001; HR = 2.58 for death, p = 0.016) and residual disease on imaging ³ 1 cm (HR = 2.97 for PFS, P < 0.001; HR = 2.02 for death, p = 0.05) were associated with worse outcomes. Analyses based on molecular results will be presented. CONCLUSION A subset of low-grade gliomas can be observed after the initial resection based on younger age, smaller tumor size, and no residual disease on neuroimaging. This can likely be further refined by prognostic molecular markers. Patients with the most favorable prognostic factors can avoid or delay the acute and long-term side effects of RT and chemotherapy for several years.

PURPOSE This study sought to determine the prognostic significance of the WHO-defined glioma molecular subgroups along with additional alterations, including MGMT promoter methylation and mutations in ATRX, CIC, FUBP1, TERT, and TP53, in NRG/RTOG 0424 using long-term follow-up data. METHODS Mutations were determined using an Ion Torrent sequencing panel. 1p/19q co-deletion and MGMT promoter methylation were determined by Affymetrix OncoScan and Illumina 450K arrays. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and tested using the log-rank test. Hazard ratios were calculated using the Cox proportional hazard model. Multivariable analyses (MVAs) included patient pretreatment characteristics. RESULTS We obtained complete molecular data to categorize 80/129 eligible patients within the WHO subgroups. Of these, 26 (32.5%) were IDHmutant/co-deleted, 28 (35%) were IDHmutant/non-co-deleted, and 26 (32.5%) were IDHwild-type. Upon single-marker MVA, both IDHmutant subgroups were associated with significantly better OS and PFS ( P values < .001), compared with the IDHwild-type subgroup. MGMT promoter methylation was obtained on 76 patients, where 58 (76%) were methylated and 18 (24%) were unmethylated. Single-marker MVAs demonstrated that MGMT promoter methylation was statistically significant for OS ( P value < .001) and PFS ( P value = .003). In a multimarker MVA, one WHO subgroup comparison ( IDHmutant/co-deleted v IDHwild-type) was significant for OS ( P value = .045), whereas MGMT methylation did not retain significance. CONCLUSION This study reports the long-term prognostic effect of the WHO molecular subgroups, MGMT promoter methylation, and other mutations in NRG/RTOG 0424. These results demonstrate that the WHO molecular classification and MGMT both serve as strong prognostic indicators, but that MGMT does not appear to add statistically significant prognostic value to the WHO subgrouping, above and beyond IDH and 1p/19q status.

2518 Background: This study sought to evaluate the prognostic significance of the three WHO-defined molecular glioma subgroups ( IDHwt, IDHmt/non-codel, and IDHmt/codel) in NRG Oncology/RTOG 0424, a phase II trial of high-risk low-grade gliomas treated with radiation (RT) and concurrent and adjuvant temozolomide (TMZ) after biopsy/surgical resection. Notably, this is the first clinical study to evaluate the prognostic value of the WHO subgroups in RT + TMZ-treated high-risk grade II (G2) gliomas using prospectively-collected long-term survival data. Methods: IDH1/2 mutation status was determined by next-generation sequencing. 1p/19q co-deletion status was determined by Oncoscan and/or 450K methylation data. Overall survival (OS) and progression-free survival (PFS) by marker status were determined by the Cox proportional hazard model and tested using the log-rank test in a post-hoc analysis. Patient pre-treatment characteristics were included as covariates in multivariate analyses. Results: Of all the eligible patients (N=129), 80 (62%) had sufficient quality DNA for both IDH and 1p/19q analyses. Of these 80, 54 (67.5%) were IDHmt, and 26 (32.5%) were IDHwt. Of the 54 IDHmt patients, 26 (32.5% of total, 48% of IDHmt) were IDHmt/codel, and 28 (35% of total, 52% of IDHmt) were IDHmt/non-codel. Both IDHmt subgroups were significantly correlated with longer PFS ( IDHmt/co-del = 8.1yrs (5.2-not reached (NR)); IDHmt/non-codel = 7.5yrs (3.9-11.8); IDHwt = 1.0yr (0.6-1.7), p<0.001) and OS ( IDHmt/co-del = 9.4yrs (8.2-NR); IDHmt/non-codel = 8.8yrs (5.9-NR); IDHwt = 2.3yrs (1.4-3.4), p<0.001) relative to the IDHwt subgroup. Upon univariate and multivariate analyses, both molecular IDHmt subgroup comparisons relative to IDHwt remained significant (p<0.001) even after incorporation of known clinical variables. Conclusions: These analyses suggest that G2 glioma patients harboring IDH1/2 mutations, regardless of co-deletion status, demonstrated longer survival with RT + TMZ relative to IDHwt tumors, although sample size is limited and analyses were post-hoc. These results also support the notion that outcomes for IDHwt high-risk G2 gliomas remain dismal (median = 2.3yrs, similar to G3 anaplastic astrocytoma); these patients should be separated from IDHmt patients in future G2 glioma trials, and warrant novel treatment strategies. Funding: U10CA180868, U10CA180822, U24CA196067, CURE, PA Dept. of Health, and Merck. Also, R01CA108633, R01CA169368, RC2CA148190, U10CA180850, BTFC, OSUCCC (all to AC). Clinical trial information: NCT00114140 .

Purpose: NRG/RTOG 0848 was designed to determine whether adjuvant radiation with fluoropyrimidine sensitization improved survival following gemcitabine-based adjuvant chemotherapy for patients with resected pancreatic head adenocarcinoma. In step 1 of this protocol, patients were randomized to adjuvant gemcitabine versus the combination of gemcitabine and erlotinib. This manuscript reports the final analysis of these step 1 data. Methods: Eligibility—within 10 weeks of curative intent pancreaticoduodenectomy with postoperative CA19-9<180. Gemcitabine arm—6 cycles of gemcitabine. Gemcitabine+erlotinib arm—gemcitabine and erlotinib 100 mg/d. Two hundred deaths provided 90% power (1-sided α=0.15) to detect the hypothesized OS signal (hazard ratio=0.72) in favor of the arm 2. Results: From November 17, 2009 to February 28, 2014, 163 patients were randomized and evaluable for arm 1 and 159 for arm 2. Median age was 63 (39 to 86) years. CA19-9 ≤90 in 93%. Arm 1: 32 patients (20%) grade 4 and 2 (1%) grade 5 adverse events; arm 2, 27 (17%) grade 4 and 3 (2%) grade 5. GI adverse events, arm 1: 22% grade ≥3 and arm 2: 28%, ( P =0.22). The median follow-up (surviving patients) was 42.5 months (min-max: <1 to 75). With 203 deaths, the median and 3-year OS (95% confidence interval) are 29.9 months (21.7, 33.4) and 39% (30, 45) for arm 1 and 28.1 months (20.7, 30.9) and 39% (31, 47) for arm 2 (log-rank P =0.62). Hazard ratio (95% confidence interval) comparing OS of arm 2 to arm 1 is 1.04 (0.79, 1.38). Conclusions: The addition of adjuvant erlotinib to gemcitabine did not provide a signal for increased OS in this trial.

4007 Background: NRG/RTOG 0848 is a 2-step study designed to determine whether erlotinib (E) added to gemcitabine (G) (randomized Ph II) &/or adjuvant radiation with concurrent 5-FU or capecitabine following 6 months of systemic chemotherapy (Ph III), improve survival in patients (pts) with resected pancreatic head adenocarcinoma. The erlotinib results are reported here. Methods: Eligible pts include those with resected pancreatic head adenocarcinoma, pathologic stage T1-T3, N0-1, M0; PS 0-1, & CA19-9 ≤ 180 IU/L. Pts in Arms 1 & 2 received G 1 gm/m2 weekly for 3 weeks in a 28-day cycle for 6 cycles. Pts in Arm 2 also received E 100 mg/day. The primary hypothesis for the E portion was that G+E would increase overall survival (OS) compared to G alone. With a 1-sided alpha of 0.15, 200 OS events provide 80%/90% power to detect a signal for an increase in median OS from 22 to 28.8/30.6 months (mos). OS was estimated by the Kaplan-Meier method & arms compared using the log rank test. The Cox proportional hazards model was used to analyze treatment effect. Results: 336 pts were randomized from 11/17/2009 to 2/28/2014, with 163 pts evaluable for G and 159 for G+E. Median age was 63 years (39-86). Most pts had pathologic T3 disease (78%) & CA19-9 ≤ 90 (93%). There are 32 pts (20%) with grade 4 adverse events (AEs) & 2 pts (1%) with grade 5 AEs on G and 27 (17%) & 3 (2%) on G+E arm, respectively. There are fewer grade ≥ 3 GI AEs on the G arm (22%) as compared to the G+E arm (28%), and 110 (69.2%) & 93 (59.6%) pts received at least 85% of planned G dose for the G & G+E arms, respectively. 58% of E pts received at least 85% of planned E dose. The median follow-up for alive pts is 42.5 mos (min-max: < 1-75). With 203 deaths, median & 3-yr OS (95% CI) are 29.9 mos (21.7-33.4) & 39% (30, 45) for G and 28.1 mos (20.7-30.9) & 39% (31, 47) for G+E; log-rank p = 0.62. The hazard ratio (95% CI) comparing OS of G+E to G is 1.04 (0.79- 1.38). Conclusions: The addition of adjuvant E to G did not provide a signal for increased OS in pts with resected pancreatic head cancer compared to G alone. Accrual to the trial is continuing to answer the Ph III radiation question. Clinical trial information: NCT01013649.

Purpose Some patients with colon cancer have a high risk of local recurrence postoperatively. This trial was undertaken to determine whether radiation therapy added to an adjuvant chemotherapy regimen improves outcome in high-risk patients. Patients and Methods Patients with resected colon cancer with tumor adherence or invasion of surrounding structures, or with T3N1 or T3N2 tumors of the ascending or descending colon were randomly assigned to receive fluorouracil and levamisole therapy with or without radiation therapy. Patients who received chemotherapy and radiation therapy (chemoRT) received 45 to 50.4 Gy in 25 to 28 fractions beginning 28 days after starting chemotherapy. Patient enrollment was terminated because of slow accrual after 222 patients enrolled (original goal was 700 patients); 187 patients were assessable. Results Overall 5-year survival was 62% for chemotherapy patients and 58% for chemoRT patients (P > .50); 5-year disease-free survival was 51% for both groups (P > .50). Toxicity (≥ grade 3) occurred in 42% of chemotherapy patients and 54% of chemoRT patients (P = .04). Leukopenia (≥ grade 3) occurred in 10% of chemotherapy patients and 22% of chemoRT patients (P = .02). No significant difference in nonhematologic toxicity (≥ grade 3) was observed between chemoRT and chemotherapy patients (35% v 44%; P = .26). Conclusion Patients who received chemotherapy or chemoRT had similar overall survival and disease-free survival. Toxicity was higher among chemoRT patients. These results must be interpreted with caution because of the high number of ineligible patients and the limited power of the study to detect potentially meaningful differences.