Concurrent Concurrent Chemoradiation Research Articles

Involved Site Radiotherapy in HPV Positive Oropharyngeal Cancer: Patterns of Failure Analysis Across Prospective De-Escalation Trials

HPV-associated oropharyngeal cancers (HPV+OPC) have a favorable prognosis with ongoing efforts to reduce long term toxicity while maintaining oncologic outcomes. One method under investigation includes lowering the elective radiation dose or in some cases omitting radiation to elective lymphatic nodal stations. Furthermore, pre-clinical evidence demonstrates that elective nodal irradiation blunts the anti-tumor immune response in head and neck cancer. This is a pooled secondary analysis reporting patterns of failure in patients (pts) with HPV+OPC enrolled on consecutive induction chemo- or chemoimmunotherapy (IC) based response-adaptive de-escalation trials and treated with involved-site radiotherapy (ISRT). Pts treated on two prospective phase II trials as well as on a prospective cohort registry were included for analysis. Pts with ≥ 50% response to IC based on RECIST 1.1 who received de-escalated definitive radiotherapy (RT) or concurrent chemoradiation (CRT) with ISRT were evaluable. Pts with locally advanced low risk or high-risk HPV+OPC (LR and HR, respectively) were eligible for enrollment. Pts were considered to have HR if at least one of the following criteria was met: T4 primary, N2c-N3 disease (AJCC 7th ed.), or > 10-20 pack years smoking. In the first trial, pts with ≥ 50% response to IC received RT to gross disease plus a 1.5 cm margin (PTV1) and to the next echelon of uninvolved nodes (PTV2). Pts with LR received 50 Gy in 2 Gy daily fractions without chemotherapy; pts with HR received 30 Gy in 1.5 Gy BID fractions to PTV2 with a 15 Gy sequential boost to PTV1 with CRT. In the subsequent trial, pts with ≥ 50% response received RT to PTV1 alone to 50 Gy in 2 Gy daily fractions; concurrent CRT was included if pts had HR. Survival was estimated using the Kaplan Meier method for progression free survival (PFS), locoregional PFS (LRPFS), and overall survival (OS). Patterns of failure analysis was performed by comparing RT plans to radiographic surveillance scans. Of 172 evaluable pts, 119 (69.2%) achieved a ≥ 50% response to IC and received definitive ISRT. 45 (37.8%) pts evaluated received RT to gross disease only plus margin without the next nodal echelon included. With a median follow up of 46 (IQR 34-65) months, 3-year PFS, LRPFS, and OS with their 95% confidence intervals were 96.2% (90.1-98.5%), 97.1% (91.1-99.0%), and 96.2% (90.3-98.6%), respectively. All locoregional failures were in-field and in the high dose region. No failures were observed in the RT omitted neck. This prospective experience demonstrates feasible volume de-escalation using IC response-based selection with progressively smaller elective volumes over time. Notably, despite a marked reduction in elective treatment volume, there were no regional out-of-field failures. IC may allow for selection of pts with favorable tumor biology and microscopic disease sterilization in the regional nodes. Further efforts at elective nodal de-escalation are needed.

Patient-Reported Distress and Acute Care Utilization for Cervical Cancer Patients Undergoing Concurrent Chemoradiation

Although concurrent chemo-radiation (CRT) and brachytherapy (BT) is curative for locally advanced cervical cancer (LACC), it requires complex coordination of care and is associated with treatment-related toxicity. Our objective was to evaluate patient-reported symptoms and social distress in LACC patients undergoing concurrent CRT and BT to determine whether they are predictive of unplanned acute care utilization. Patients with LACC treated with concurrent CRT and BT between 2013-2020 completed the Edmonton Symptom Assessment Scale-revised (ESAS-r; 9 cancer-related symptoms ranked 0-10) and the Social Difficulties Inventory-21 (SDI-21; 21 social issues ranked 0-3) at every visit as part of routine distress screening. Acute care utilization was defined as any unplanned visit to the radiation nursing clinic, urgent care clinic, emergency department or hospitalization within 1 year from starting treatment. A logistic regression model will be used to evaluate associations between ESAS-r and SDI-21 scores and acute care utilization. Among 151 LACC patients, a total of 354 ESAS-r and SDI questionnaires were completed longitudinally. Mean age at diagnosis was 49.9 years (30-90), 44% were FIGO 2B and overall treatment time was 53.6 days (32-135). At baseline, the most prevalent moderate to severe symptoms (ESAS-r score ≥4) were well-being (50%), anxiety (44%), tiredness (43%) and pain (36%). Post-treatment, these persisted in 42%, 27%, 38%, and 26%, respectively. The most common social distress at baseline was financial (33%). Financial distress post-treatment was significantly predictive of worse well-being (OR = 5.80, p<0.06), anxiety (OR = 3.33, p<0.04) and depression (OR = 4.76, p<0.01). Use of acute care within 1 year after starting treatment occurred in 103 patients (68%) for a total of 617 visits: radiation nursing clinic 71.3%, urgent care clinic 4.4%, emergency department 8.3%, hospitalization 16%. On average there were 6.6 visits/patient (0-31), with the average number of days between treatment start and first acute care visit being 17.9 (0-74). Cervical cancer patients undergoing concurrent CRT report prevalent financial distress and moderate to severe symptoms that persist post-treatment. Acute care utilization commonly occurred during treatment, highlighting a time when additional support is needed. Predictive modelling for distress factors resulting in acute care utilization is now underway.

The Role of Surgery in Stage I Small Cell Lung Cancer: A National VA Database Analysis

BackgroundHistorically, limited stage Small Cell Lung Cancer (SCLC) has been treated with concurrent chemoradiation (CRT). While current NCCN guidelines recommend consideration of lobectomy in node-negative cT1-T2 SCLC, data regarding the role of surgery in very limited SCLC is lacking. MethodsData from the National VA Cancer Cube were compiled. A total of 1,028 patients with pathologically confirmed stage I SCLC were studied. Only 661 patients that either received surgery or CRT were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Two survival curves were compared by a Wald test. Subset analysis was performed based on the location of the tumor in the upper vs. lower lobe as delineated by ICD-10 codes C34.1 and C34.3. ResultsFour-hundred and forty-six patients received concurrent CRT; while 223 underwent treatment that contained surgery (93 surgery only, 87 surgery/chemo, 39 surgery/chemo/radiation and 4 surgery/radiation). The median OS for the surgery-inclusive treatment was 3.87 years (95% CI 3.21-4.48) while median OS for the CRT cohort was 2.45 years (95% CI 2.17-2.74). HR of death for surgery-inclusive treatment when compared to CRT is 0.67 (95% CI 0.55-0.81; P < .001). Subset analysis based on the location of the tumor in both the upper or lower lobes showed improved survival with surgery as compared to CRT regardless of the location. HR for the upper lobe was 0.63 (95% CI 0.50-0.80; P < .001) and lower lobe 0.61 (95% CI 0.42-0.87; P = .006). Multivariable regression analysis accounting for age and ECOG-PS shows a HR 0.60 (95% CI 0.43-0.83; P = .002) favoring surgery. ConclusionsSurgery was used in less than a third of patients with stage I SCLC who received treatment. Surgery-inclusive multimodality treatment was associated with a longer overall survival as compared to chemoradiation, independent of age, performance status or tumor location. Our study suggests a more expansive role for surgery in stage I SCLC.

Real-world comparison of survival outcomes with cisplatin versus carboplatin in patients with limited-stage small-cell lung cancer

IntroductionLimited-stage small-cell lung cancer (LS-SCLC) is potentially curable with concurrent chemoradiation (CRT). Cisplatin is the preferred platinum for the chemotherapy backbone in national guidelines. Unfortunately, many LS-SCLC patients are elderly, with comorbidities and poor performance status (PS), which preclude the use of cisplatin. Carboplatin may be a suitable alternative. This analysis evaluates the overall survival (OS) and time to next treatment (TTNT) in LS-SCLC patients receiving concurrent CRT by platinum use. Materials and methodsThe study included LS-SCLC patients in the Flatiron Health nationwide de-identified electronic health record-derived database who received CRT in 2013–2019 with follow-up through May 2020. TTNT and OS were compared using both unadjusted and inverse propensity-weighted Cox proportional hazards models. ResultsThis study included patients treated with carboplatin (n = 600) or cisplatin (n = 572) in combination with etoposide and radiation. Cisplatin patients were younger, had a shorter time from diagnosis to radiation, and had less kidney disease. In an unadjusted analysis, median overall survival (mOS) was greater in the cisplatin group than the carboplatin group with mOS of 22.3 months vs. 19.2 months and Hazard Ratio (HR) of 0.83 (p = 0.01). In the inverse propensity-weighted analysis, this difference was no longer significant (HR 0.93, p = 0.37). No differences were seen in TTNT. ConclusionWhen balancing on key clinical factors, we observed no statistical difference in OS or TTNT by platinum choice in real-world LS-SCLC patients treated with CRT. Although observational, the results from this large data set are consistent with the hypothesis that either cisplatin or carboplatin is an appropriate therapy regardless of health status.

Disease-Free Survival of Patients with Muscle Invasive Bladder Cancer Treated by Radical Cystectomy vs. Bladder-Sparing Therapy at a Nationwide Level

<h3>Purpose/Objective(s)</h3> Organ-sparing treatment has become the standard of curative cancer treatment for many tumor types. For patients with muscle invasive bladder cancer (MIBC), radical cystectomy (RC) is still the recommended treatment according to both the American Urological Association and the European Association of Urology guidelines. An attempted RCT between RC and bladder sparing therapy (BST) failed due to low accrual and noncompliance. A large prospective comparative study is the best alternative to compare outcomes between modalities. We hypothesized that the two-year disease-free survival (DFS) with BST is equal to the DFS with RC in selected patients with non-metastasized MIBC. <h3>Materials/Methods</h3> All patients diagnosed with MIBC between November 2017 and November 2019 were identified via the population-based Netherlands Cancer Registry. Detailed clinical data was retrieved by consulting medical files. Only patients treated with BST or RC were included. BST was defined as patients treated with concurrent chemoradiation (CRT) or external beam radiation followed by brachytherapy (BT). The primary endpoint was DFS, defined as free from muscle invasive locoregional recurrence, distant metastasis or death. Secondary endpoint was overall survival (OS). Two-year follow-up (FU) data were collected Survival was analyzed with a Cox proportional hazards model, we present the crude results in this abstract. Time was defined from treatment start to first event. Patients were censored at end of FU if alive or at last contact if lost to follow-up. <h3>Results</h3> A total of 1429 patients were included, 1100 underwent RC, 283 concurrent CRT and 44 BT. Median follow-up was 22 months (range: 1-43 months). Patients treated by RC and BST had similar DFS with a crude HR 0.96 (95%CI 0.78-1.16). The 2-year DFS for patients treated by RC, concurrent CRT or BT was 56% (95%CI 53-60%), 56% (95%CI 50-63%) and 67% (95%CI 52-82%) respectively. After a median time of 15.8 months, salvage cystectomy was performed in 21 patients (6,4%) of which 17 in the CRT and 4 in the BT group. The 2-year OS for patients treated with RC, concurrent CRT or BT was 63.8% (95%CI 61-67%), 68.3% (95%CI 62-74%) and 85.9% (95%CI 75-96%) respectively. The crude HR for OS was 0.84, 95%CI 0.66-1.05, (p=0.14) for RC vs CRT and 0.40 95%CI 0.17-0.77(p=0.015) for RC vs BT. Our study is limited by the inherent biases of observational data. <h3>Conclusion</h3> At two years, DFS did not significantly differ between patients treated with BST and RC. We conclude that after appropriate selection BST leads to similar DFS rates compared to RC. Nevertheless, these results should be interpreted with care, as the treatment groups were not yet matched for case-mix variables. The results of this study can be used to aid patients and physicians to choose the modality best tailored to their individual preferences.

Patterns of Failure by Driver Mutation Status for Patients with Locally Advanced Non-Small Cell Lung Cancer Treated with Chemoradiation and Consolidative Durvalumab

<h3>Purpose/Objective(s)</h3> The standard of care for patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiation (CRT) followed by consolidative durvalumab. Increasingly, mutational profiling has been used to guide treatment decisions. In this study, we investigated whether driver mutation status influences the patterns of failure and rates of oligometastatic disease. <h3>Materials/Methods</h3> Using a single institution database, we identified patients who were treated with CRT followed by consolidative durvalumab for LA-NSCLC from June 2017 to May 2020 and divided them by whether they had driver mutations as defined by EGFR exon 19 deletion, EGFR exon 20 insertion, HER2 exon 20 insertion, EGFR exon 21 mutation (L858R), ALK-EML4 fusion, MET exon 14 skipping, NTRK2 fusion, or KRAS mutation. There mutations were all targetable with the exception that only KRAS G12C is a targetable KRAS mutation. We then identified patients who had disease progression and recorded their patterns of failure (distant vs locoregional) and oligometastatic status (3 or fewer sites). These rates were compared by driver mutation status using Chi-squared tests. Comparisons of time to second progression (PFS2) by oligometastatic and driver mutation status were made using Kaplan-Meier analyses. <h3>Results</h3> The 63 patients in our cohort (of which 36 had driver mutations) had a median follow up of 21.5 months, age of 64.8 yrs, and ECOG of 1 at completion of CRT. 52% were female, 86% had a history of smoking, and 87% were white. 65% had adenocarcinoma. All were treated with concurrent CRT with radiation doses ranging from 60Gy to 77Gy. All received at least one dose of consolidative durvalumab prior to disease progression. A similar proportion of first progressions were distant failures in patients with driver mutations and those without (64% vs. 59%, p=0.71). They also had similar rates of oligometastatic disease (28% vs 48%, p=0.09). Patients with oligometastatic disease did not have improved PFS2 (5.9 months vs 5.9 months, p=0.76) compared to those with polymetastatic disease. However, oligometastatic patients with targetable driver mutations who received salvage local therapy (surgery and/or radiation) without tyrosine kinase inhibitors (TKIs) had dramatically worse PFS2 (4.1 months vs 21.4 months, p=0.01) compared to all patients with driver mutations. Conversely, the use of local therapy without systemic therapy did not lead to worse PFS2 in oligometastatic patients without targetable driver mutations (3.5 months vs 4.5 months, p=0.46). <h3>Conclusion</h3> We show similar patterns of failure and rates of oligoprogression for unresectable LA-NSCLC patients treated with concurrent CRT and consolidative durvalumab regardless of driver mutation status. Initial oligometastatic disease did not decrease the likelihood of subsequent progression. Oligometastatic patients with targetable driver mutations should not receive salvage local therapy alone without initiation of TKIs.

MA06.05 Consolidation Nivolumab and Ipilimumab or Nivolumab Alone Following Concurrent Chemoradiation for Patients with Unresectable Stage III NSCLC

The PACIFIC trial demonstrated that a year of consolidation PD-(L)1 inhibition following concurrent chemoradiation (CRT) for unresectable stage III NSCLC improves overall survival (OS). The optimal duration of consolidation IO therapy in this setting is undefined. Studies in metastatic NSCLC demonstrate that combination PD-(L)1/CTLA-4 inhibition improves OS over chemotherapy alone. This trial evaluated the use of combination Nivolumab (N) plus Ipilimumab (IPI) or N alone for up to 6 months in unresectable stage III NSCLC after concurrent CRT.

Consolidation nivolumab plus ipilimumab or nivolumab alone following concurrent chemoradiation for patients with unresectable stage III non-small cell lung cancer: BTCRC LUN 16-081.

8509 Background: The PACIFIC trial demonstrated that a year of consolidation PD-(L)1 inhibition following concurrent chemoradiation (CRT) for unresectable stage III NSCLC improves overall survival (OS). The optimal duration of consolidation IO therapy in this setting is undefined. Studies in metastatic NSCLC demonstrate that combination PD-(L)1/CTLA-4 inhibition improves OS over chemotherapy alone. This trial evaluated the use of combination Nivolumab (N) plus Ipilimumab (IPI) or N alone for up to 6 months in unresectable stage III NSCLC after concurrent CRT. Methods: This is a randomized phase II, multicenter trial of 105 pts with unresectable stage IIIA/IIIB NSCLC. All pts received concurrent CRT and were then enrolled and randomized 1:1 to receive N 480mg IV q4wks (Arm A) for up to 24 weeks or N 3mg/kg IV q2 wks + IPI 1mg/kg IV q6 wks (Arm B) for up to 24 weeks. The primary endpoint is 18-month PFS compared to historical controls of CRT alone for arm A (30%) and CRT followed by Durva for arm B (44%). Secondary endpoints include OS and toxicity. Results: From 9/2017 to 4/2021, 105 pts were enrolled and randomized, 54 to N alone (A) and 51 to N + IPI (B). The baseline characteristics for arm A/B: median age (65/63), male (44.4%/56.9%), stage IIIA (55.6%/56.9%), stage IIIB (44.4%/43.1%), non-squamous (57.4%/54.9%), and squamous (42.6%/45.1%). The percentage of pts completing the full treatment was 70.4% on A and 56.9% on B (p = 0.15). Median f/u was 24.5 and 24.1 months on A and B, respectively. The 18-month PFS was 62.3% on A (p &lt; 0.1) and 67% on B (p &lt; 0.1), and median PFS was 25.8 months and 25.4 months, respectively. Median OS was not reached on either arm, but the 18- and 24-month OS estimates were 82.1% and 76.6% for A and 85.5% and 82.8% for B, respectively. Treatment-related adverse events (trAE) on arm A/B were 72.2%/80.4%, and grade ≥3 trAEs on arm A/B were 38.9%/52.9%. There was 1 grade 5 event on each arm (COVID19-A, Cardiac Arrest-B). The number of pts with grade ≥2 pneumonitis were 12 (22.2%) on A and 15 (29.4%) on B, with 5 (9.3%) and 8 (15.7%) grade ≥3 events, respectively. The most common ( &gt; 10%) non-pneumonitis trAEs on A were fatigue (31.5%), rash (16.7%), dyspnea (14.8%), and hypothyroidism (13%), and on B were fatigue (31.4%), diarrhea (19.6%), dyspnea (19.6%), pruritus (17.7%), hypothyroidism (15.7%), rash (15.7%), arthralgia (11.8%), and nausea (11.8%). Conclusions: Following concurrent CRT for unresectable stage III NSCLC, both N and N + IPI demonstrated improved 18-month PFS compared with historical controls despite a shortened interval (6 months) of treatment. OS data are still maturing but 18- and 24-month OS estimates compare favorably to prior consolidation trials. Toxicity for N alone was similar to prior single-agent trials, and the combination of N + IPI resulted in a higher incidence of trAE’s, although consistent with prior reports. Clinical trial information: NCT03285321.

Are two too many when it comes to the treatment of anal canal cancer with concurrent radiation and mitomycin C?

3 Background: Concurrent chemoradiation (CRT) with 2 doses of 5-fluorouracil (5-FU) and mitomycin C (MMC) is the standard of care for anal canal cancer (ACC) in North America while 1 dose of MMC is an acceptable practice. Given the lack of randomized data of 1 vs 2 doses of MMC on disease outcomes, we have conducted a population-based study to elucidate the impact of 1 vs. 2 doses of MMC on patterns of treatment failure (POF) and outcomes in ACC treatment. Zainab Al Habsi, Aswin Abraham, Mustafa Al Balushi, Gabriella Tankel, Karen Mulder, Heather Warkentin, Dan Schiller, Keith Tankel, Nawaid Usmani, Diane Severin, Kim Paulson, Hatim Karachiwala, Clarence Wong, Tirath Nijjar, Kurian Joseph. Methods: Data was collected from the provincial cancer registry of patients with stage I-III ACC who were treated with concurrent CRT from 2000 to 2018. Recurrence free survival (RFS), overall survival (OS), and ACC specific survival were calculated. Results: 428 patients with a median age of 58 years (29-88 years) were included in this analysis. 234 (54.7%) patients received 1 dose of MMC and 194 (45.3%) received 2 doses of MMC. At a median follow-up of 78.5 months (5-252 months), 89 (20.8%) patients developed disease recurrence: 44 (10.3%) loco-regionally, 39 (9.1%) distally and 6 (1.4%) had both local and distant recurrences. Cox Regression analysis showed that the dosage of MMC did not have an impact on overall recurrence (HR = 0.883, p = 0.561), whereas stage III was associated with increased risk for recurrence (HR = 5.238, p = 0.021). Subgroup analysis showed an association of stage IIIb and IIIc with recurrence (HR = 13.33, p = 0.008 and HR = 6.933, p = 0.011 respectively), but was not impacted by the use of 1 vs. 2 doses of MMC. The dosage of MMC did not show any association with local recurrence (HR = 1.136, p = 0.655) or distant recurrence (HR = 0.743, p = 0.267). However, in Stage IIIc patients, 2 doses of MMC showed a trend towards improved distant RFS (HR = 0.626,p = 0.084). Conclusions: Our analysis showed that the patterns of failure and the risk of loco-regional and distant failures were similar between patients who received 1 vs. 2 doses of MMC for stage groups I to IIIc. These finding support routine use of single dose of MMC along with 5FU and radiotherapy for definite chemoradiation. However, a trend towards better RFS was demonstrated with a second dose of MMC in patients with stage IIIc disease.

P63.11 Real-World Survival Outcomes of Patients with Limited Stage Small Cell Lung Cancer (LS-SCLC) by Choice of Platinum Chemotherapy

SCLC is an aggressive cancer with poor overall survival (OS). LS-SCLC is curable with concurrent chemoradiation (CRT). Cisplatin is the preferred chemotherapy backbone in national guidelines. Unfortunately, many patients with LS-SCLC are elderly, have co-morbidities, and have poor performance status (PS) which preclude cisplatin use. Carboplatin may be a suitable alternative. This analysis evaluates the overall survival (OS) and time to next treatment (TTNT) in LS-SCLC patients receiving concurrent CRT, by 1L platinum use. The study included LS-SCLC patients in the Flatiron Health nationwide de-identified electronic health record-derived database who received CRT in 2013-2019, with follow-up through May 2020. The study excluded patients with no documented visit or medication order within 90 days of diagnosis. Patient characteristics were compared between platinum chemotherapy groups using Wilcoxon rank sum tests and chi-squared tests. TTNT and OS were compared using both unadjusted and inverse propensity weighted Cox proportional hazards models. Propensity scores were built using boosted logistic regression minimizing standardized covariate distances for the covariates smoking history, prophylactic cranial irradiation (PCI), race, gender, age, relevant comorbidities, PS, and creatinine clearance (CrCl). This study included patients treated with carboplatin (n=600) or cisplatin (n=572) in combination with etoposide and RT. Cisplatin patients were younger, had shorter time from diagnosis to radiation, and had less kidney disease. Propensity scores adequately balanced covariates between the two groups. In an unadjusted analysis, OS was greater in the cisplatin compared to the carboplatin group (mOS 22.3 vs. 19.2 m, HR 0.83, p=0.01). In the inverse propensity weighted analysis, this difference was no longer significant (HR 0.93, p=0.41). No differences were seen in TTNT.Tabled 1CarboplatinCisplatinpSMDN600572Age (y)69.1 [62.6, 75.1]65.2 [59.0, 70.2]<0.0010.49ComorbiditiesCardiomyopathy: N (%)12 (2.0%)10 (1.7%)0.9190.02Nephropathy: N (%)27 (4.5%)9 (1.6%)0.0060.17Otopathology: N (%)6 (1.0%)3 (0.5%)0.5500.05Neuropathy: N (%)11 (1.8%)9 (1.6%)0.9060.02ECOG0171 (28.5%)150 (26.2%)0.0830.151160 (26.7%)172 (30.1%)2-355 (9.2%)33 (5.8%)CrCl75.4 [58.3, 99.4]87.9 [70.8, 111.8]<0.0010.41 Open table in a new tab *Categorical variables summarized as N (%) and compared via chi-squared tests, quantitative variables summarized as Median [Interquartile range] and compared via Wilcoxon rank sum tests When balancing on key clinical factors, we observe no statistical difference in OS or TTNT by platinum choice in real-world LS-SCLC patients treated with CRT. Although observational, the results from this large data set are consistent with the hypothesis that either cisplatin or carboplatin is appropriate therapy regardless of health status.

Cisplatin versus carboplatin for the treatment of limited-stage small cell lung cancer (LS-SCLC).

8565 Background: Standard of care therapy for LS- SCLC is concurrent chemo-radiation (CRT) with a platinum-etoposide backbone. Cisplatin is traditionally the preferred platinum agent in the curative intent setting. Data comparing the efficacy of the less toxic carboplatin to cisplatin in LS-SCLC are lacking. Methods: Data from the National VA Cancer Cube were collected. Pathologically confirmed cases of LS-SCLC that received concurrent CRT with platinum-based multiagent chemotherapy were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Survival curves were compared by a Wald test. Results: 801 LS-SCLC patients who received carboplatin-based therapy (Carbo-SCLC) and 1018 who cisplatin-based therapy (Cis-SCLC) were included in the analysis. Median OS with Carbo-SCLC and Cis-SCLC were 2.13 years (95% CI 1.97-2.31) and 2.24 years (95% CI 2.09-2.4), respectively (HR=1.04;95% CI, 0.94-1.16; p=0.46). Subset analysis showed similar median OS for Carbo-SCLC and Cis-SCLC in patients with ECOG-PS of 0, 1 and 2, as well as patients in their 50s, 60s and &gt;70. Multivariable regression analysis accounting for age and ECOG-PS shows a HR of 0.99 (95% CI 0.86-1.14; p=0.91). Conclusions: Concurrent CRT with carboplatin-etoposide was associated with similar OS compared to cisplatin-etoposide in LS-SCLC, irrespective of PS and age. Carboplatin’s advantageous toxicity profile and comparable OS indicate that it is an acceptable choice of platinum for LS- SCLC.[Table: see text]

MA12.05 Is there a Role for Surgery in Stage I Small Cell Lung Cancer? A National VA Database Analysis

Historically, limited stage Small Cell Lung Cancer (SCLC) has been treated with concurrent chemoradiation (CRT). While current NCCN guidelines recommend consideration of lobectomy in node-negative cT1-T2 SCLC, data regarding the role of surgery in very limited SCLC is lacking. To our knowledge, only one retrospective study has evaluated the role of surgery in stage I SCLC. Data from the National VA Cancer Cube were compiled. A total of 1,028 patients with pathologically confirmed Stage I SCLC were studied. Only 661 patients that either received surgery or CRT were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Two survival curves were compared by a Wald test. Subset analysis was performed based on the location of the tumor in the upper vs lower lobe as delineated by ICD-10 codes C34.1 and C34.3. Four-hundred and forty-two patients received concurrent CRT; while 219 underwent treatment that contained surgery (92 surgery only, 84 surgery/chemo, 39 surgery/chemo/radiation and 4 surgery/radiation). The median OS for the surgery-inclusive treatment was 3.87 years (95% CI 3.25-4.60) while median OS for the CRT cohort was 2.43 years (95% CI 2.15-2.72). HR of death for surgery-inclusive treatment when compared to CRT is 0.65 (95% CI 0.54-0.79; p<0.001). Subset analysis based on the location of the tumor in upper lobe and lower lobe showed improved survival with surgery as compared to CRT regardless of the location. HR for upper lobe was 0.61 (95% CI 0.48-0.78; p<0.001) and lower lobe 0.60 (95% CI 0.41-0.87; p=0.007). Multivariable regression analysis accounting for age and ECOG-PS shows a HR 0.60 (95% CI 0.42-0.85; p=0.004) favoring surgery. Surgery was used in less than a third of patients with stage I SCLC who received treatment. Surgery-inclusive multimodality treatment was associated with a longer overall survival as compared to chemoradiation, independent of age, performance status or tumor location. Our study suggests a more expansive role for surgery in stage I SCLC.

Microscopic Extranodal Extension in HPV-Negative Head and Neck Cancer and the Role of Adjuvant Chemoradiation.

Pathologic extranodal extension (ENE) is an important adverse feature for human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC), but the prognostic significance of microscopic ENE (ENEmi) and role of adjuvant concurrent chemoradiation (CRT) for ENEmi remain unclear. This study evaluates (1) the prognostic significance of ENEmi in HPV-negative HNSCC and (2) whether adjuvant CRT is associated with improved overall survival (OS) for these patients. Retrospective cohort study. Commission on Cancer (CoC)-accredited facilities. This retrospective cohort study included patients in the National Cancer Database from 2009 to 2015 with pathologic node-positive (pN+) HPV-negative HNSCC with either pathologic ENEmi or no ENE who had undergone margin-negative surgery. The association of ENEmi with OS was evaluated using Cox proportional hazard analyses. Analyses were repeated in patients with ENEmi receiving adjuvant therapy to evaluate the association of adjuvant CRT with OS. We included 5483 patients with pN+ HPV-negative HNSCC, of whom 24% had ENEmi. On multivariable analysis, ENEmi was associated with decreased OS relative to no ENE (adjusted hazard ratio [aHR], 1.43; 95% CI, 1.28-1.59). Among patients with ENEmi who received ≥60 Gy of adjuvant radiation therapy (RT) (n = 617), adjuvant CRT was not associated with improved OS relative to RT (aHR, 0.91; 95% CI, 0.66-1.27). For patients with HPV-negative HNSCC, pN+ with ENEmi is associated with worse OS than pN+ without ENE. However, for patients with ENEmi, concurrent CRT is not associated with improved OS relative to RT. The optimal adjuvant paradigm for ENEmi requires additional investigation.

Adaptive Radiotherapy in Locally Advanced Lung Cancers – Real World Scenario from a Tertiary Cancer Center

Concurrent chemo-radiation (CTRT) for locally advanced lung cancer (LALC) leads to dynamic changes in tumor volume and location especially in patients with large tumor or atelectasis. Using adaptive radiotherapy (ART) prevents under dosage of the tumor and over dosage of the organs at risk (OAR). One hundred forty patients of LALC from Jan 2017 to Dec 2019 were treated with concurrent CTRT. A four-dimensional computed tomography (4D CT) scan was acquired and contouring of gross target volume (GTV) was guided by PET-scan fusion. All patients were planned to receive 60Gy/30 daily fractions with volumetric modulated arc therapy. Cone-beam CT (CBCT) for set-up verification was performed at least twice weekly. Change in anatomy and tumor response was determined on CBCT during weekly radiotherapy audit. Patients suitable for ART were re-simulated and re-planned. GTV now consisted of residual tumor and 5mm isotropic clinical target volume (CTV) was generated and manually extended to include areas suspicious for residual disease. Dose delivered prior to ART and time needed to execute ART (calculated from the day of re-simulation to the day of starting ART) were documented. The volumetric and dosimetric changes were analyzed using paired t-test between the 2 plans for full prescription dose. We also evaluated local control for this cohort. Out of 140 patients, 35 (25%) required re-planning for ART. Median age was 61 years (range 50 - 65). Twenty-six patients (75%) had upper lobe tumors. Fifteen (43%) patients had squamous carcinoma, 13 (37%) had adenocarcinoma, and 7 (20%) had small cell carcinoma. Requirement for ART was anticipated in 10/35 (28%) patients prior to CTRT. The triggers for ART were resolution of atelectasis in 7 (20%) patients, tumor response in 26 (74%) and progression in 2 (6%) patients. A median of 6 CBCTs prior to ART were acquired. A median of 26Gy (IQR 14-36Gy) was delivered prior to ART. While it required 5 days (IQR:3.5-7.5) for executing ART. There was a reduction in mean planning target volume of 23% (544cc - 418 cc; p = 0.003), mean GTV primary of 47% (153cc - 80.8cc; p = 0.024), and GTV nodes of 33.7% (8 cc - 5.3 cc; p = 0.033). The V20 of total lung minus PTV and the mean lung dose increased by 3.7% (18.8% - 19.5%; p = 0.158) and 4.5% (10.9Gy - 11.4Gy; p = 0.274) respectively whereas there was a reduction in heart V20 and Spinal cord Dmax by 18.3% (9.7 Gy to 8.2 Gy; p = 0.005) and 6.7% (36.6 Gy to 34.3 Gy; p = 0.100) respectively. At a median follow up of 14.7 months, the loco regional control rate was 70% and no patient experienced ³ grade 3 toxicity. In our practice approximately 25% patients of locally advanced lung cancer required ART, with tumor response and resolution of atelectasis being the most common triggers. Anticipation of clinically significant change, frequent use of on-board imaging and implementation of ART could prevent under dosage of the tumor and over dosage of OAR.

Durvalumab with Concurrent Definitive Radiation Therapy (DART) for Locally-Advanced Non-Small Cell Lung Cancer - A Phase II Study

Consolidative durvalumab following definitive concurrent chemoradiation (CRT) has become the new standard of care for unresected stage III non-small cell lung cancer (NSCLC) (PACIFIC regimen). However, many unresected or inoperable patients are not ideal candidates for concurrent CRT and are thus treated with sequential CRT or radiation therapy (RT) alone. We therefore initiated a phase II study (clinicaltrials.gov: NCT03999710) to evaluate the efficacy of concurrent durvalumab and RT without chemotherapy in patients who are not candidates for the PACIFIC regimen. This study is a single-arm, single-institution phase II study to determine the progression-free survival of concurrent durvalumab and thoracic RT followed by consolidation with durvalumab (100mg iv q4 weeks) for up to 12 months. Patients with stage II or III NSCLC who are not candidates for concurrent CRT due to a variety of reasons such as medical comorbidities, functional status, or tumor extent are eligible. Any level of PD-L1 expression is permitted. The primary endpoint is an improvement in 2-year progression-free survival of 36% compared to historical results of 20%. A sequential stopping rule is in place to protect patients from excessive toxicity. Secondary objectives include overall survival, response rates, local control and time to distant metastases. Patient-reported outcomes and exploratory biomarkers of blood, tissue and imaging characteristics are being collected. The study is open to accrual at a couple of institutions. Enrollment started in 09/2019, and 5 patients have been accrued to date. Total accrual is 53 patients. This is the first study focusing on the role of concurrent durvalumab and definitive RT in patients who are not candidates for the PACIFIC regimen. If successful it could indicate a potential role of replacing sequential chemotherapy with durvalumab.

The role of surgery in stage I small-cell lung cancer: A national VA database analysis.

e21109 Background: Historically, limited stage Small Cell Lung Cancer (SCLC) has been treated with concurrent chemoradiation (CRT). While current NCCN guidelines recommend consideration of lobectomy in node-negative cT1-T2 SCLC, real world data regarding the role of surgery in very limited SCLC is lacking. To our knowledge, only one retrospective study has evaluated the role of surgery in stage I SCLC. Methods: Data from the National VA Cancer Cube were compiled. A total of 1,028 patients with pathologically confirmed Stage I SCLC were studied. Only 661 patients that either received surgery or CRT were included. Interval-censored Weibull and Cox proportional hazard regression models were used to estimate median overall survival (OS) and hazard ratio (HR), respectively. Two survival curves were compared by a Wald test. Subset analysis was performed based on the location of the tumor in the upper vs lower lobe as delineated by ICD-10 codes C34.1 and C34.3. Results: Four-hundred and forty-two patients received concurrent CRT; while 219 underwent treatment that contained surgery (92 surgery only, 84 surgery/chemo, 39 surgery/chemo/radiation and 4 surgery/radiation). The median OS for the surgery-inclusive treatment was 3.87 years (95% CI 3.25-4.60) while median OS for the CRT cohort was 2.43 years (95% CI 2.15-2.72). HR of death for surgery-inclusive treatment when compared to CRT was 0.65 (95% CI 0.54-0.79; p &lt; 0.001). Subset analysis based on the location of the tumor in upper lobe and lower lobe showed improved survival with surgery as compared to CRT regardless of the location. HR for upper lobe was 0.61 (95% CI 0.48-0.78; p &lt; 0.001) and lower lobe 0.60 (95% CI 0.41-0.87; p = 0.007). Multivariable regression analysis accounting for age and ECOG-PS shows a HR 0.60 (95% CI 0.42-0.85; p = 0.004) favoring surgery. Conclusions: Surgery was used in less than a third of patients with stage I SCLC who received treatment. Surgery-inclusive multimodality treatment was associated with a longer overall survival as compared to chemoradiation, independent of age, performance status or tumor location. Our study supports a more expansive role for surgery in stage I SCLC.

Consolidation treatment of durvalumab after chemoradiation in real-world patients with stage III unresectable non-small cell lung cancer.

BackgroundTreatment for stage III non‐small cell lung cancer (NSCLC) of unresectable disease mainly involves concurrent chemoradiation (CRT). Post‐CRT consolidation treatment with durvalumab is a major therapeutic advance that provides survival benefit in this group of patients. However, the performance of this treatment strategy remains to be studied in a real‐world setting.MethodsA total of 31 patients who had disease control post‐CRT were included in the durvalumab early access program (EAP) as an intent‐to‐treat cohort and retrospectively reviewed for post‐CRT progression‐free survival (PFS) and time to metastatic disease or death (TMDD). The neutrophil‐to‐lymphocyte ratio (NLR) at the initiation of durvalumab was analyzed in 29 patients.ResultsThe median time from the completion of concurrent CRT to the initiation of durvalumb was 2.8 months. The objective response was 25.8% and the 12 month PFS and TMDD‐free rate were 56.4% and 66.9%, respectively. The low NLR patients showed a significantly longer post‐CRT PFS (not reach vs. 12.0 months [95% CI: 5.5–not estimable]; P = 0.040; the hazard ratio for disease progression or death, 0.23 [95% CI: 0.05–1.00]; P = 0.048) and the 12 month post‐CRT PFS rate (82.5 vs. 42.6%). The post‐CRT TMDD (not reach vs. 12.6 months, [95% CI: 10.8–not estimable]; P = 0.010; the hazard ratio for distant metastasis or death, 0.11 [95% CI: 0.01–0.88]; P = 0.037) and 12 month post‐CRT TMDD‐free rate (90.9 vs. 57.1%) were also significantly higher in the low NLR patients.ConclusionsDurvalumab consolidation treatment in real‐world patients showed substantial efficacy and the correlation with the NLR level warrants further investigation.

Abstract 3354: Patterns of care for patients with non-operable T1-4 N+ M0 non-small cell lung cancer in the US and outcomes with radiation or chemotherapy monotherapies

Abstract Background Standard management of unresectable N+ M0 non-small cell lung cancer (NSCLC) is concurrent chemoradiation (CRT). However, some patients may receive only radiation therapy (RTmono) or chemotherapy (CTmono) as monotherapies. The primary aim of this study was to investigate the patterns of care in the US and analyze the outcomes achieved with monotherapies. Methods Patients in the National Cancer Database (NCDB) diagnosed in 2004-2013 with N+ M0 NSCLC who did not undergo surgery and received monotherapy with either high dose radiation alone (RTmono) or chemotherapy alone (CTmono) were studied. Patient characteristics and overall survival (OS) were compared with descriptive statistics (chi-square, Kruskal-Wallis, logistic regression), Kaplan-Meier and stratified Cox models, and restricted mean survival times (RMST); all used alpha of 0.05. Findings 74,867 patients received CRT (10,915, 15%), CTmono alone (34,978, 47%), RTmono (2,396, 3%), or no treatment (26,578, 36%). In a multivariable model, RTmono was associated with non-Medicare insurance, academic or research facility, Western geography, lower T and N stages, and older age. CTmono had better RMST compared to RTmono: at 3 years, average survival was 17.9 vs 16.1 months (difference 1.8, 95% CI 1.3-2.3); at 5 years, average survival was 21.6 vs 18.7 months (difference 2.9, 95% CI 2.2-3.6). In stratified Cox models, improved survival was associated with female gender, White race, private insurance, metropolitan location, lower Charlson comorbidity score, lower T and N stage, smaller tumor, younger age, and later year of diagnosis. Interpretation Despite the established benefits of CRT, only 15% of non-operable N+ M0 NSCLC US patients received definitive CRT. Future clinical studies should focus on patients not receiving concurrent CRT, as outcomes with monotherapies (RTmono or CTmono) are suboptimal. Note: This abstract was not presented at the meeting. Citation Format: Ellen Kim, Megan E. Daly, Kenneth Westover, James Murphy, Timur Mitin. Patterns of care for patients with non-operable T1-4 N+ M0 non-small cell lung cancer in the US and outcomes with radiation or chemotherapy monotherapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3354.

Lymphopenia as a predictor of survival in chemoradiation-treated stage III non-small-cell lung cancer (NSCLC): a multi-center retrospective analysis

Concurrent chemoradiation (CRT) with a platinum-containing regimen is considered standard of care for eligible unresectable stage III non-small-cell lung cancer (NSCLC) patients. Attempts to improve locoregional control, and thereby enhance overall survival (OS), by increasing the dose of radiation failed to do so in a contemporary phase III trial. Better understanding of the effects of radiation on the immune system, particularly absolute lymphocyte counts (ALC), may explain the poorer survival seen with high-dose (HD) radiation compared to low dose (LD). We hypothesized that treatment-induced lymphopenia affects outcomes in stage III NSCLC patients treated with concurrent CRT. The study is a retrospective multi-institution study. Stage III NSCLC patients who received CRT between 1994 and 2014 were categorized into LD RT (≤ 66 Gy) and HD RT (> 66 Gy) groups. Overall survival was assessed using Kaplan-Meier method with log-rank test and Cox proportional hazard regression model to estimate the effect of radiation dose (LD vs. HD groups) on OS. Hematologic values including ALC were evaluated at diagnosis and at intervals during treatment. Patients with pre-existing immunodeficiency states and autoimmune disease were excluded from the analysis. Of the patients, 182 were included in the analysis. Median age was 62 years (range 37–82). Seventy-seven percent were males, 67% Caucasians. Most common types of histology were adenocarcinoma (52%) and squamous cell carcinoma (41%). One-hundred-fifty-four patients received LD RT and 28 received HD RT. Medians (ranges) of pre-treatment ALC were 1730/mm3 (384, 4300) vs. 2065/mm3 (600, 4580) (p = 0.58) between LD and HD groups. Medians (ranges) of nadir ALC were 324/mm3 (20, 2410) vs. 279.5/mm3 (20–930) (p = 0.11) between LD and HD groups. Kaplan-Meier survival curves showed that LD has better OS than the HD group (median survival 31.2 months vs. 13.9 months, p < 0.001). No significant association was detected between RT dose and lymphocytes nadirs or with lymphocyte count prior to RT. HD RT in stage III NSCLC patients is associated with worse survival. Lower nadir lymphocyte counts, independent of dose of radiation, were not associated with decrease in survival. These findings need further validation in larger studies and in patients treated with immune therapy.

Sandwich/Sequential but not Concurrent Chemoradiation Therapy is Associated with Overall Survival for Advanced Endometrial Carcinomas

The GOG 0258 randomized controlled trial demonstrated no benefit in relapse free survival with concurrent chemoradiation (CRT) versus chemotherapy (C) alone for stage III-IVA endometrial carcinomas. We sought to determine whether the delayed initiation of RT with sandwich or sequential CRT regimens is associated with improved overall survival (OS). We utilized the National Cancer Center Database to identify all patients eligible for the GOG 0258 trial (predominantly stage III-IVA carcinomas). All patients underwent surgical staging and received adjuvant multi-agent C with or without RT within 90 days of surgery. Patients who received adjuvant RT were divided into three sequencing regimens: concurrent (RT within 14 days of C), sandwich (RT between 14 and 126 days after C), and sequential (RT between 126 and 180 days after C). A Cox proportional hazards multivariate model was used to determine the associations between each of the sequencing regimens against C alone as a baseline, after adjusting for clinical (histology, age ≥ 65, Charlson co-morbidity index, stage, nodal evaluation, lymphovascular invasion, peritoneal cytology, margin status) and demographic (facility type, race) factors. Subgroup analyses were conducted for the endometrioid and stage IIIC subgroups. We identified 11,644 patients who were diagnosed between 2006 and 2014. The median follow-up was 39.4 months (IQR 23.9, 63.3). The numbers of patients who received C alone, concurrent CRT, sandwich CRT, and sequential CRT were 6911 (59%), 486 (4%), 2634 (23%), and 1613 (14%). 5156 (44%) had grade endometrioid histology, and 7006 (60%) had stage 3C disease. With C alone as a baseline, sandwich (HR = 0.73; p < 0.01) and sequential (0.69; p < 0.01) CRT, but not concurrent CRT (0.87; p = 0.14), were associated with improved OS. Similar results were obtained for the endometrioid subgroup: concurrent (0.91; p = 0.48), sandwich (0.70; p < 0.01), and sequential (0.73; p < 0.01). For the stage IIIC subgroup, the association for concurrent CRT did not reach significance (0.81; p = 0.06), while sandwich (0.70; p < 0.01), and sequential (0.66; p < 0.01) regimens remained significant. These results support the use of sandwich or sequential RT with multi-agent chemotherapy in the adjuvant treatment of women with advanced stage endometrial cancer. Further prospective clinical validation of these results is warranted.