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J.Y. Chang
Moderator of
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ORAL 20 - Chemoradiotherapy (ID 124)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 7
- Moderators:G. Blumenschein, J.Y. Chang
- Coordinates: 9/08/2015, 10:45 - 12:15, 201+203
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ORAL20.01 - A Systematic Review of Carboplatin-Paclitaxel versus Cisplatin-Etoposide Concurrent with Thoracic Radiation for Stage III NSCLC Patients (ID 600)
10:45 - 12:15 | Author(s): C. Steuer, M. Behera, K.A. Higgins, N. Saba, D. Shin, S. Pakkala, R. Pillai, T.K. Owonikoko, W.J. Curran, C.P. Belani, F. Khuri, S.S. Ramalingam
- Abstract
- Presentation
Background:
The two most commonly used chemotherapy regimens deployed concurrently with thoracic radiation (RT) for patients with unresectable IIIA and IIIB non-small cell lung cancer (NSCLC) are carboplatin/paclitaxel (CP) and cisplatin/etoposide (CE). Because there are no prospective comparisons of these two regimens in this setting, we conducted a systematic review of published trials to compare outcomes and toxicities between CE and CP.
Methods:
Studies which enrolled stage III patients receiving RT with CP or CE were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library) and meeting abstracts. Trials were excluded if they were phase I, enrolled less than 10 pts, or included surgical resection. A systematic analysis of extracted data was performed using Comprehensive Meta Analysis (Version 2.2) software using random and fixed effect models. Clinical outcomes were compared using point estimates for weighted values of median overall survival (OS), progression free survival (PFS), response rate (RR) and toxicities. Two-tailed T-test with a significance level of 0.05 was used for all comparisons.
Results:
3194 patients were included from 32 studies in the CE arm, and 3789 patients from 51 studies in CP. Baseline characteristics of patients on the CE arm versus CP arm were: median age 61 vs. 63 years, male 67.6% vs. 78%, squamous histology 39% vs. 40%, and median radiation dose 62 Gy vs. 63 Gy. There was no significant difference in response rates between CE and CP (65% vs. 56%, p =0.6), respectively. There was no significant difference in median progression free survival (11.5m vs. 9.3m p =0.2), overall survival (19.8m vs. 18.4m, p=0.48), 1-year survival rate (66% vs. 65%, p=0.8), or 3-year survival rate (31% vs. 25%, p=0.4) for CE vs. CP. CE was associated with higher grade 3/4 hematological toxicities than CP, such as neutropenia (53% vs. 23% p<0.0001), thrombocytopenia (14% vs. 6% p=0.001), anemia (16% vs. 8% p=0.06), as well as grade 3/4 nausea/vomiting (20% vs. 9% p=0.018), while rates of grade 3/4 pneumonitis and esophagitis were similar.
Conclusion:
CE and CP regimens were associated with comparable efficacy when used with concurrent radiotherapy for stage III unresectable NSCLC pts. The toxicity profile favored the CP regimen.
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ORAL20.02 - Safety Results of the Consolidation Phase of a Phase III (PROCLAIM): Pemetrexed, Cisplatin or Etoposide, Cisplatin plus Thoracic Radiation Therapy followed by Consolidation Cytotoxic Chemotherapy in Locally Advanced Nonsquamous Non-Small Cell Lung Cancer (ID 645)
10:45 - 12:15 | Author(s): R. Govindan, S. Senan, A. Brade, J. Vansteenkiste, F. Mornex, H.J. Ross, J.P. Van Meerbeeck, C. Hennequin, N. Dickgreber, Y. Wu, J.P. Agarwal, K. Syrigos, F. Griesinger, B. Parente, M. Provencio, A. Hossain, B. San Antonio, J.A. Treat, A. Koustenis, N. Chouaki, E. Vokes
- Abstract
- Presentation
Background:
Standard treatment for inoperable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy. However, many patients die from recurrent disease, indicating that new treatment strategies are needed.
Methods:
PROCLAIM is a phase III trial comparing overall survival in patients with unresectable stage III nonsquamous NSCLC receiving pemetrexed+cisplatin (PemCis) and concurrent radiotherapy for 3 cycles followed by 4 cycles of pemetrexed consolidation (Arm A) versus etoposide+cisplatin (EtoCis) and concurrent radiotherapy for 2 cycles followed by consolidation with a platinum-based doublet of choice for up to 2 cycles (Arm B). Possible consolidation therapies in Arm B were EtoCis, vinorelbine+cisplatin (VinCis), and paclitaxel+carboplatin (PacCarb). Overall efficacy and safety results for the intent-to-treat population will be presented in a separate disclosure. Safety was a secondary objective. Interim safety results for the concurrent phase were previously presented. Here we present safety results for the consolidation phase. Treatment-emergent adverse events (TEAEs) were assessed according to the Common Terminology Criteria for Adverse Events (v3.0, CTCAE). TEAE incidences were compared using Fisher’s exact test (two-sided α=0.05).
Results:
Of 598 randomized patients, 555 were treated in the concurrent phase (Arm A: N=283; Arm B: N=272), most of whom (Arm A: n=229 [80.9%]; Arm B: n=202 [74.3%]) continued on to the consolidation phase (Arm B patients: EtoCis [33.5%], PacCarb [26.8%], VinCis [14.0%]). Baseline characteristics, including age, gender, performance status, smoking status, stage, and origin, were well-balanced across arms. Percentages of patients in Arm A completing ≥2, ≥3, and 4 consolidation cycles were 95.2%, 84.3%, and 73.4%, respectively. Percentages of patients in Arm B completing 2 consolidation cycles (maximum) were EtoCis (89.0%), PacCarb (93.2%), and VinCis (86.8%). Mean dose intensities for pemetrexed, etoposide, vinorelbine, cisplatin, paclitaxel, and carboplatin were 95.4%, 94.0%, 84.2%, 91.2%, 88.7%, and 92.7%, respectively. More patients in Arm B, compared to Arm A, experienced dose reductions, dose omissions, and cycle delays. Patients in Arm B reported more grade 3/4/5 drug-related TEAEs than Arm A (51.0% versus 31.0%, p<0.001; Table). Rates of drug-related serious AEs were similar between groups (Arm A: 14.4%; Arm B: 13.4%).Drug-related Grade 3/4/5 TEAEs Occurring in ≥2% of Patients (or of Clinical Relevance) in the Consolidation Phase
CTCAE Arm A (N=229) n (%) Arm B (N=202) n (%) Neutrophils 27 (11.8) 76 (37.6)* Leukocytes 19 (8.3) 29 (14.4) Hemoglobin 6 (2.6) 9 (4.5) Platelets 5 (2.2) 10 (5.0) Febrile neutropenia 7 (3.1) 7 (3.5) Lymphopenia 8 (3.5) 5 (2.5) Pneumonitis/pulmonary infiltrates 5 (2.2) 2 (1.0) Fatigue 2 (0.9) 4 (2.0) Pneumonia 5 (2.2) 0 Esophagitis 0 3 (1.5) *p<0.001, Fisher’s exact test. Note: Of the TEAEs listed here, only one case (0.4%, Arm A, pneumonia) was grade 5.
Conclusion:
During the PROCLAIM consolidation phase, most patients were able to complete the planned number of cycles in either arm, with the highest dose intensity corresponding to pemetrexed. Pemetrexed consolidation had a significantly lower incidence of drug-related grade 3/4/5 TEAEs than the platinum doublets in Arm B. A more detailed analysis of Arm B (by treatment regimen) is underway.
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ORAL20.03 - Radiation Dose Escalation in Patients with Locally Advanced Non-Small Cell Lung Cancer; 60 Month Follow-Up of a Randomized Phase II Trial (ID 1190)
10:45 - 12:15 | Author(s): I. Walraven, M. Van Den Heuvel, E. Schaake, W. Uyterlinde, J. De Jong, J.G. Aerts, F. Koppe, H. Codrington, P. Kunst, E. Dieleman, P. Van De Vaart, M. Verheij, J. Belderbos
- Abstract
- Presentation
Background:
Concurrent chemoradiotherapy imposes beneficial effects on overall survival (OS) in patients with locally advanced non-small cell lung cancer (NSCLC). Nonetheless, the optimal radiation scheme still needs to be identified. The RTOG 0617 trial showed that patients receiving a high dose radiation scheme (37 x 2 Gy) had a significant shorter median OS (22.9 months) as compared to patients receiving a conventional 30 x 2 Gy radiation scheme (28.7 months). Dose escalation using hypo-fractionation however seems promising and might contribute to a better OS. We investigated long term OS in locally advanced NSCLC patients treated with concurrent chemoradiotherapy, using a hypo-fractionation scheme of 24 x 2.75 Gy +/- Cetuximab.
Methods:
A 2-armed phase II, multi-center study (NTR2230) was performed with the initial aim to assess the effect of the addition of Cetuximab to concurrent chemoradiotherapy in locally advanced NSCLC patients. Arm A received high dose radiotherapy (24 x 2.75 Gy) and concurrent daily low-dose cisplatin (6 mg/m[2]). Arm B received an identical treatment regimen with the addition of weekly Cetuximab (400 mg/m[2] loading dose one week prior to radiotherapy followed by weekly 250 mg/m[2]). Mortality follow-up information was completed until January 2015. Overall survival (OS) rates were calculated as time from randomization until death from any cause. Kaplan-Meier survival curves were plotted and 1-, 2- and 5-year OS proportions were calculated.
Results:
Between February 2009 and May 2011, 102 patients were randomly allocated in two arms; 51 patients (50%) in arm A and 51 patients (50%) in arm B. Follow-up information was available for 101 patients (99%). Median OS was 33.0 months (interquartile (IQ) range 20.0 to 46.0) and did not significantly differ between the two arms; 33.0 months (IQ-range 13.8 to 52.2) in Arm A and 30.0 months (IQ-range 15.3 to 44.7) in Arm B (Figure 1). 1-,2- and 5-year OS was 75.5%, 59.8% and 36.6%, respectively. Figure 1
Conclusion:
In this 2-armed phase II trial in NSCLC patients receiving concurrent chemoradiotherapy, the addition of Cetuximab to concurrent chemoradiotherapy did not improve 60-month OS in unselected patients with locally advanced NSCLC, in line with the RTOG 0617. However, the median OS was remarkably high when compared to the RTOG 0617: 30 and 33 months versus 23 and 29 months, respectively. Furthermore, 5-year OS was still 36.6%. Dose escalation using hypo-fractionation of 2.75 Gy per fraction might be one of the factors contributing to extended OS in patients with locally advanced NSCLC.
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ORAL20.04 - Discussant for ORAL20.01, ORAL20.02, ORAL20.03 (ID 3288)
10:45 - 12:15 | Author(s): G.M.M. Videtic
- Abstract
- Presentation
Abstract not provided
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ORAL20.06 - Outcomes of Intensity Modulated and 3D-Conformal Radiotherapy for Stage III Non-Small Cell Lung Cancer in NRG Oncology/RTOG 0617 (ID 938)
10:45 - 12:15 | Author(s): S.G. Chun, C. Hu, H. Choy, R.U. Komaki, R.D. Timmerman, S.E. Schild, J.A. Bogart, M.C. Dobelbower, W. Bosch, J.M. Galvin, V.S. Kavadi, S. Narayan, P. Iyengar, C.G. Robinson, R.B. Wynn, A. Raben, M.E. Augspurger, R.M. Macrae, R. Paulus, J.D. Bradley
- Abstract
Background:
Intensity modulated radiation therapy (IMRT) has the potential to improve target coverage and spare toxicity in locally-advanced non-small cell lung cancer (NSCLC). However, the effect of IMRT on outcomes for NSCLC has not previously been assessed in a large prospective cooperative group clinical trial.
Methods:
A secondary analysis was performed in patients with stage III NSCLC in NRG/RTOG 0617, a randomized phase III comparison of standard-dose (60 Gy) versus high-dose (74 Gy) chemoradiotherapy +/- cetuximab. Radiotherapy (RT) technique was stratified by IMRT and 3D-conformal radiotherapy (3D-CRT). Baseline prognostic and RT dosimetric parameters were compared between IMRT and 3D-CRT after adjusting for RT dose levels and cetuximab use. The prognostic value of RT technique with respect to toxicity and efficacy was assessed through multivariate logistic regression (MVA) and Cox proportional hazards model after controlling for RT dose level, cetuximab use and other factors.
Results:
Of the 482 eligible patients treated with RT, 53% and 47% were treated with 3D-CRT and IMRT, respectively. The IMRT group had more stage IIIB (38.6 vs. 30.3%, P = 0.056), larger PTVs (mean 486 vs. 427 mL, P = 0.005), and larger PTV:lung ratio (mean 0.15 vs. 0.13, P = 0.013). In spite of larger PTV volumes, IMRT was associated with lower lung V20 (P = 0.08), and lower heart doses (V5, V20, V40) than 3D-CRT. In turn, IMRT was associated with a lower rate (3.5 versus 7.9%) of Grade 3+ pneumonitis (P = 0.0653). On MVA, the lung V20 significantly predicted grade 3+ pneumonitis, while the lung V5 and mean lung doses did not. Larger heart V40 was associated with worse OS (HR=1.013, P < 0.001), and the heart V40 was significantly lower in patients treated with IMRT. Patients treated with IMRT were also more likely (37 versus 29%) to receive full doses of consolidative chemotherapy (P = 0.05).
Conclusion:
Although IMRT was used to treat larger and less favorable tumors in RTOG 0617, it was associated with reduced risk of Grade 3+ pneumonitis and higher likelihood of receiving full doses of consolidative chemotherapy. The heart V40, shown to be highly prognostic for survival, can be substantially reduced with IMRT compared to 3D-CRT.
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ORAL20.07 - Survival Impact of Post-Operative Therapy Modalities after Incomplete and Complete Surgical Resection for Non-Small Cell Lung Cancer in the US (ID 1417)
10:45 - 12:15 | Author(s): M.P. Smeltzer, C.C. Lin, X. Yu, A. Jemal, R.U. Osarogiagbon
- Abstract
- Presentation
Background:
Incomplete resection of potentially curable Non-Small Cell Lung Cancer (NSCLC) is a significantly negative clinical event for which adjuvant radiotherapy, chemotherapy, or combined chemo-radiotherapy is often used to reduce mortality risk. After complete (R0) resection, randomized controlled trials and the PORT meta-analysis show radiotherapy to be harmful to patients with stage I-II disease, and of marginal benefit in patients with N2-positive stage IIIA. After incomplete resection (R1/R2), current National Comprehensive Cancer Network (NCCN) guidelines recommend radiotherapy for stage IA/IB and chemo-radiotherapy for patients with stage IIA-IIIA. Adjuvant therapy recommendations after R1/R2 resection have never been verified.
Methods:
With the objective of validating NCCN post-operative therapy guidelines, we evaluated patients with surgically resected pathologic stage I-IIIA NSCLC in the National Cancer Data Base from 2004-2011. Recipients of pre-operative adjuvant therapy and those with no lymph nodes examined were excluded. Post-operative therapy modalities were classified as chemotherapy, radiotherapy, chemo-radiotherapy, or no treatment. Analyses were adjusted for patient demographic, clinical, and surgical characteristics, as well as institutional characteristics. Analyses were conducted by margin status and stage groups based on NCCN classifications (Table I). Unadjusted stage-specific 5-year overall survival (OS) estimates were calculated based on the Kaplan-Meier method and compared across post-treatment modalities with the log-rank test. Survival was modeled with Extended Cox Regression to adjust for all covariates and allow for non-proportional hazards.
Results:
Among 98,176 NSCLC patients who underwent curative-intent surgery during 2004-2011, 48% were male, 79% white, 34% privately insured, and 58% Medicare insured, with a median age of 68 years. The 5-year OS estimates by treatment modality are shown in Table I (NCCN recommendations highlighted). Margin negative patients with stage IA or IB/IIA who received post-operative radiotherapy had significantly lower OS compared to those with no treatment (both p-values<0.0001). We also observed lower OS with post-operative radiotherapy in margin positive patients with stage IA (p-value=0.0006) and IB/IIA (p-value=0.0302). Survival was significantly higher in persons with stages IB-IIIA who received post-operative chemotherapy compared to no treatment (all p-values<0.0001). Fully adjusted modeling analyses (not shown) yielded similar results.5 Year Survival (P-Value) NCCN Categorized Group Margin Positive Margin Negative Stage IA (T1ab,N0) No Treatment 60%(Ref) 71%(Ref) Chemo-Only 64%(0.86) 74%(0.33) Radiotherapy-Only 24%(0.0006) 47%(<0.0001) Chemo+Rad 44%(0.17) 43%(<0.0001) (N=458) (N=41279) Stage IB (T2a,N0) & Stage IIA (T2b,N0) No Treatment 48%(Ref) 57%(Ref) Chemo-Only 66%(0.0002) 69%(<0.0001) Radiotherapy-Only 30%(0.0302) 41%(<0.0001) Chemo+Rad 39%(0.28) 48%(<0.0001) (N=1016) (N=29111) Stage IIA (T1ab-T2a,N1) & Stage IIB (T3,N0;T2b,N1) No Treatment 27%(Ref) 39%(Ref) Chemo-Only 35%(<0.0001) 55%(<0.0001) Radiotherapy-Only 26%(0.84) 29%(<0.0001) Chemo+Rad 36%(<0.0001) 43%(0.0194) (N=1549) (N=15543) Stage IIIA (T1-3,N2;T3,N1) No Treatment 15%(Ref) 26%(Ref) Chemo-Only 25%(0.0013) 41%(<0.0001) Radiotherapy-Only 11%(0.76) 19%(0.0551) Chemo+Rad 26%(<0.0001) 39%(<0.0001) (N=1109) (N=8111)
Conclusion:
In patients with negative margins, results from the NCDB are consistent with randomized clinical trials and stage-specific NCCN post-operative adjuvant therapy recommendations. However, the NCCN recommendation of post-operative adjuvant radiotherapy for patients with early stage NSCLC with a positive resection margin is not supported by our results and should be further investigated in a randomized clinical trial.
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ORAL20.08 - Discussant for ORAL20.06, ORAL20.07 (ID 3353)
10:45 - 12:15 | Author(s): A. Bezjak
- Abstract
- Presentation
Abstract not provided
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Author of
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P2.02 - Poster Session/ Treatment of Localized Disease – NSCLC (ID 210)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.02-032 - Phase II Clinical Trial of Stereotactic Ablative Radiotherapy (SABR) in Surgically Operable Stage I Non-Small Cell Lung Cancer (STARS) (ID 1254)
09:30 - 17:00 | Author(s): J.Y. Chang
- Abstract
Background:
Standard therapy for operable clinical stage I non-small cell lung cancer (NSCLC) is lobectomy with sampling or dissection of mediastinal lymph nodes. Stereotactic ablative radiotherapy (SABR) has produced local control rates in excess of 95% and has become standard care for medically inoperable stage I NSCLC. However, the role of SABR in operable stage I NSCLC remains controversial due to concerns about the risk of local or nodal recurrence after SABR, either of which could lead to worse OS than that after standard surgery. We report here the preliminary outcome using SABR in clinically operable stage I NSCLC.
Methods:
Patients with clinical T1A(<3 cm)N0M0 biopsy proven operable NSCLC who meet criteria for lobectomy are being enrolled. All patients are staged with chest CT, PET/CT imaging, and EBUS. 54 Gy in 3 fractions was used for peripheral lesions and 50 Gy in 4 fractions for central lesions, respecting critical normal tissue dose volume constraints. SABR plans are typically optimized by using 6 to 12 coplanar or non-coplanar 6-MV photon beams (3-D CRT or IMRT) or Cyberknife or one to three arcs (VMAT). Daily CT-on-rail or a cone-beam CT scans or tumor tracking was used during each radiotherapy fraction.
Results:
Enrollment was started in September 2009, temporally closed in 2013 with 20 patients and re-opened in 2014. The study is ongoing and 58 patients have been enrolled up to date. The median follow-up time for the first 20 patients was 40 months; for all patients, median follow up was 7 months (range 0.8-49.6 months, interquartile 4.7, 22.8 months). No deaths have occurred to date. There was one local failure in the treated lobe that was salvaged with lobectomy. There were 5 cases of regional mediastinal lymph node progression treated with concurrent chemo/radiotherapy. Three of these cases had suspicious lymph nodes by CT and PET before SABR but were enrolled because EBUS was negative. One patient developed distant metastasis and was treated with chemotherapy. No one had grade 3-5 toxicity. Six patients had grade 2 chest wall pain (10.3%) and three patients developed grade 2 pulmonary toxicity (5%).
Conclusion:
SABR is well tolerated with minimal toxicity and promising local control and survival. More stringent mediastinal staging is recommended in the future.
