Cumulative Incidence Of Locoregional Failure Research Articles

Patterns of Failure, Low-Volume Relapse, and Subsequent Ablative Management in Locally Advanced Non-Small Cell Lung Cancer Treated With Definitive Chemoradiation and Consolidation Immune Checkpoint Inhibitors

The objective of this study was to describe the patterns of failure, frequency of low-volume relapse (LVR), and candidacy for ablative therapy at time of disease progression (PD) after chemoradiation and consolidative immunotherapy (CRT + ICI) in patients with stage III non-small cell lung cancer. We identified 229 consecutive patients with stage III non-small cell lung cancer treated with CRT + ICI between October 2017 and December 2021 at a single institution. PD was classified as isolated locoregional failure (LRF), isolated distant failure (DF), or synchronous LRF + DF. Any LRF was subclassified as in-field failure, marginal failure, or out-of-field failure. LVR was defined as 3 or fewer sites of PD in any number of organs. Ablative candidates were defined as having 5 or fewer sites of PD radiographically amenable to high-dose radiation or surgery. Time-to-event data were calculated using cumulative incidence analysis and Kaplan-Meier methods. Multivariable Cox modeling was used to examine the correlations between characteristics of relapse and postprogression survival. Of the 229 patients, 119 (52%) had PD. Of these 119 patients, 20 (21%) had isolated LRF, 28 (24%) had synchronous LRF + DF, and 71 (60%) had isolated DF. Of the 48 patients with any LRF, 28 (58%) had in-field failure, 10 (21%) marginal failure, and 10 (21%) out-of-field failure. The cumulative incidence of LRF and DF was 13% (95% CI, 9.2%-18%) and 32% (95% CI, 26%-38%) at 1 year and 19% (95% CI, 14%-24%) and 39% (95% CI, 33%-46%) at 2 years, respectively. Overall, 64 patients (54%) were considered to have LVR. At time of PD, 60 patients (50%) were eligible for ablative therapy. Patients with LVR had longer median survival versus with high-volume relapse (37.4 vs 15.2 months, P < .001). On multivariable analysis, LVR (hazard ratio, 0.32; 95% CI, 0.18-0.56; P < .001) was associated with improved postprogression survival. After CRT + ICI, approximately half of patients experience LVR at time of PD and are candidates for ablative therapies. Prospective trials are needed to validate the optimal treatment strategy for LVR.

Patterns of Failure for Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer

Peri-operative chemotherapy has emerged as the standard of care in the treatment of locally advanced gastric cancer. Improved treatment strategies are needed for patients with a poor response to neoadjuvant chemotherapy and postoperative chemoradiation has been proposed as a potential method of treatment intensification. We aimed to describe the patterns of failure for patients with no or partial response (NR, PR) to pre-operative chemotherapy. We retrospectively reviewed charts of patients with locally advanced gastric cancer treated at our institution from 2008 to 2022 with pre-operative chemotherapy followed by surgery with a D2 resection. We excluded patients who received pre-operative or post-operative radiation therapy, or patients who had a complete response (CR) following neoadjuvant chemotherapy. Cumulative incidence of locoregional failure (LRF) and distant metastases (DM) were calculated from the time of diagnosis with competing risk analysis with death as a competing risk and censored at the last follow up. Overall survival (OS) was analyzed using Kaplan-Meier. A total of 57 patients were identified and 60% are male. Median follow-up time was 31.3 months (range 6.9-181.5 months), and the median age at diagnosis was 68 years old (range 30-86). The most used pre-operative chemotherapy regimen was FLOT (38.6%), followed by FOLFOX (29.8%), and ECF/ECX/EOX (19.3%), and a majority of patients (57.9%) received adjuvant chemotherapy. The most common histology was adenocarcinoma (85.9%), and 61.4% of patients had poorly differentiated disease. Thirty-three (57.9%), and 9 patients (15.8%) were characterized as PR and NR to neoadjuvant therapy by pathology, respectively. The distribution of pathologic stages following neoadjuvant chemotherapy were as follows: 17 patients (29.8%) with Stage IA-B, 12 patients (21.1%) with Stage IIA-B, 15 patients (26.3%) with Stage IIIA, 9 patients (15.8%) with Stage IIIB, and 3 patients (5.3%) with Stage IIIC disease. Two patients had positive lymph nodes with a T0 primary tumor. Median OS was 51.4 months (95% confidence interval [CI] 39.8-68.4) for the entire cohort, and 92.1 months (95% CI 34.6-73.0) versus 42.8 months (95% CI 23.1-88.0) for patients with a PR, and NR, respectively (p = 0.14). The 2-year cumulative incidence of LRF and DM was 7.4% (95% CI 0.4-14.3) and 36.3% (95% CI 23.6-49.1), respectively. Of the five patients who experienced LRF, three of the patients also eventually or concurrently developed DM. 60% of these patients would have had their first site of recurrence covered by standard post-operative radiation treatment volumes. Patients with locally advanced gastric cancer who do have less than a CR to chemotherapy have poor outcomes due to high rates of DM. Adjuvant locoregional therapy such as radiation is unlikely to affect survival while DM is the predominant pattern of progression. Further studies are needed to identify adjuvant therapies to improve distant control.

Predictive Value of Dynamic Tumor Volume Changes in Stage III Non-Small Cell Lung Cancer Treated with Chemoradiation and Consolidative Immunotherapy

Concurrent chemoradiation (CRT) followed by Immunotherapy is standard of care in unresectable, locally advanced, non-small cell lung cancer (NSCLC). We hypothesize that on-treatment dynamic changes in tumor volume may predict oncologic outcome in Stage III NSCLC. Stage III NSCLC patients who were treated with definitive CRT of 60 Gy in 30 fractions over 6 weeks with concurrent platinum-based concurrent chemotherapy followed by consolidative immunotherapy were retrospectively reviewed. We manually delineated the gross tumor volumes (GTV) of patients on cone beam computed tomography (CBCT) acquired on day 1, 15, 29 and 43. GTV reduction was quantified as the percent difference in volume on each CBCT as compared to CBCT Day 1. Mid-treatment response (MTR) and End of treatment response (ETR) was defined at day 29 (at 40 Gy) and day 43 (at 60 Gy), respectively. Loco-regional control (LRC) and overall survival (OS) was evaluated by Kaplan-Meier analysis, with log-rank test for groups stratified as per treatment response. Multivariate Cox regression analysis was performed to identify additional prognostic factors. We evaluated 24 consecutively treated patients from 01/2016 to 08/2019, with a median follow-up of 30.5 months. Median age was 69 years (range 51-84). Adenocarcinoma histology was present in 58 % and squamous cell carcinoma in 42% patients. The tumor stage IIIA in 38% and Stage IIIB in 62% patients. All patients received definitive CRT with at least 2 cycles of immunotherapy (median 8 cycles). The median ETR at CBCT43 was 49.5% (range, 1%-84.7%). 1-year cumulative incidence of loco-regional failure (LRF) was 27% versus 10% in patients with ETR <49.5% as compared to patients with greater ETR (p = 0.31). The median MTR at CBCT29 was 32.7% (range, 1%-81%). 1-year cumulative incidence of LRF was 28% versus 9% in patients MTR <32.7% as compared to patients with higher response (p = 0.03). The 3-year actuarial LRC of all patients was 51% which was significantly better in higher MTR (70% vs 30%; p = 0.02, log-rank) as compared to lower MTR. The 3-year actuarial OS for all patients was 45% which was 54% in patients with higher MTR verses 37% in low responders (p = 0.09). On multivariate analysis, age and T-stage were significant factors associated with LRC. Histologic subtype showed no impact on our findings. Stage III NSCLC patients with approximately one-third (33%) reduction of GTV on mid-treatment CBCT during CRT have significantly improved LRC and a trend towards improved OS. This approach may justify early adaptive intensification of RT or application of additional therapies in patients with non-optimal response. Additional large prospective study of CBCT is needed to determine whether treatment can be tailored based on tumor response, to improve outcomes.

Patterns of Recurrence After Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer and the Role for Adjuvant Radiation.

Improved treatment strategies are needed for patients with locally advanced gastric cancer with poor response to neoadjuvant chemotherapy. We aimed to describe patterns of failure for patients with no or partial response (NR, PR) to preoperative chemotherapy. We analyzed patients with locally advanced gastric cancer treated from 2008 to 2022 with preoperative chemotherapy followed by surgery with D2 resection. We excluded patients who received radiation. Cumulative incidence of locoregional failure (LRF) and distant metastases (DM) were calculated. For patients with recurrent abdominal disease, hypothetical radiation clinical treatment volumes (CTV) were contoured on postoperative scans and compared with patterns of recurrence. A total of 60 patients were identified. The most used preoperative chemotherapy was FLOT (38.6%), followed by FOLFOX (30%) and ECF/ECX/EOX (23.3%). Four (6.7%), 40 (66.7%), and 9 patients (15%) had a complete pathologic response (CR), PR, and NR to neoadjuvant therapy, respectively. Among patients without a CR, 3-year overall and progression-free survival rates were 62.3% (95% CI 48-76.6%) and 51.3% (95% CI 36.9-65.7%), respectively. Three-year cumulative incidence of LRF and DM were 8.4% (95% CI 0.4-16.4%) and 41.0% (95% CI 26.3-55.4%), respectively. Absolute rates of patients having the first site of recurrence encompassed by a postoperative radiation CTV was 2.0% for patients without a CR and 0% for patients with NR. Patients with locally advanced gastric cancer with less than a CR to chemotherapy have poor outcomes due to high rates of DM. Adjuvant locoregional therapy such as radiation is unlikely to affect survival.

Phase 1 Dose Escalation of Stereotactic Body Radiation Therapy and Concurrent Cisplatin for Reirradiation of Unresectable, Recurrent Squamous Cell Carcinoma of the Head and Neck

Patients with locoregional recurrence of squamous cell carcinoma of the head and neck (SCCHN) have relatively poor outcomes; therefore, stereotactic body radiation therapy (SBRT) has been investigated for this patient population. We performed a phase 1 clinical trial to establish a maximum tolerated dose of SBRT with concurrent cisplatin in previously irradiated locoregional SCCHN. Patients with recurrent SCCHN who had previously undergone radiation therapy to doses ≥45 Gy to the area of recurrence ≥6 months before enrollment and who were not surgical candidates or refused surgery were eligible. SBRT was delivered every other day for 5 fractions. Starting dose level was 6 Gy×5 fractions, followed by 7 Gy×5 fractions and 8 Gy×5 fractions. Chemotherapy consisted of cisplatin given before every SBRT fraction at a dose of 15 mg/m2. Patients were monitored for dose-limiting toxicities (DLT) that occurred within 3 months from the start of SBRT. Secondary endpoints included locoregional failure, distant metastasis, and overall survival. Twenty patients were enrolled, with 18 patients evaluable for endpoints. One patient at dose level 1 (30 Gy) died of unknown causes 2 weeks following completion of treatment. Therefore, an additional 3 patients were accrued to the 30-Gy dose level, with no further DLTs observed. Three patients were then accrued at dose level 2 (35 Gy) and 9 patients at dose level 3 (40 Gy) without DLTs. At a median follow-up of 9.5 months, cumulative incidence of locoregional failure at 2 years was 61% (95% confidence interval [CI], 12%-66%), cumulative incidence of distant metastasis was 11% (95% CI, 74%-100%) at 2 years, and overall survival was 22% (95% CI, 9%-53%) at 2 years. Concurrent cisplatin and reirradiation with an SBRT dose of ≤40 Gy was safe and feasible in patients with locoregionally recurrent or second primary SCCHN.

Prognostic Importance of Nodal Microenvironment beyond Extracapsular Extension in Breast Cancer Outcomes

<h3>Purpose/Objective(s)</h3> Lymph node (LN) involvement and extracapsular extension (ECE) play important roles in breast cancer risk stratification, management, and outcome. Involvement of other axillary tissues (AXT) excised during surgery is often omitted in pathology reports and its prognostic significance is yet to be elucidated. <h3>Materials/Methods</h3> Medical records of 1,919 breast cancer patients with pathologic lymph nodes treated at our institution from 2000-2019 was retrospectively reviewed. Extensive details of LN involvement are reported by pathologists at our institution and were divided into 4 groups: LN+ only, LN+ECE, LN+AXT without ECE, and LN+ECE+AXT. AXT was defined as the involvement of lymphatic vessels, blood vessels, soft tissue metastasis, matted unspecified masses and combination of any of those forms. The primary endpoint was the impact of AXT on locoregional failure (LRF) defined as recurrence in either breast/chest wall/axilla/supraclavicular fossa, on axillary failure (AF) defined as recurrence in the axilla only and on distant failure (DF) defined as metastasis. Subgroup analysis explored the differences between types of AXT and Cox Hazard models were used. <h3>Results</h3> Among 1,919 patients analyzed, 995 had LN+ only involvement, 534 had LN+ECE, 81 had LN+AXT without ECE, and 309 had LN+ECE+AXT. The overall median follow-up was 6.5 years. The 10 years cumulative incidence of LRF was 5.9%, 6.4%, 11.8% and 10.9% in LN only, LN+ECE, LN+AXT without ECE and LN+ECE+AXT groups, respectively. The 10 years cumulative incidence of AF was 0.92%, 0.83%, 4.1% and 4.4% in LN+ only, LN+ECE, LN+AXT without ECE and LN+ECE+AXT groups, respectively. The 10 years cumulative incidence of DF was 15.7%, 23%, 23.5% and 42.1% in LN+ only, LN+ECE, LN+AXT without ECE and LN+ECE+AXT groups, respectively. On multivariable analysis controlling for number of malignant LN, ECE, tumor biology, grade and size, type of axillary surgery and radiation dose delivered to the draining lymphatics, the presence of other AXT was significantly associated with LRF (HR:2.3, P<0.01), AF (HR:4.7, P<0.01) and DF (HR: 1.4, P=0.02). ECE and number of malignant LN were not associated with LRF and AF, but rather associated with DF (HR:1.4, P=0.009 and HR:1.03, P=0.002, respectively). Delivery of 50 Gy or more to draining lymphatics was associated with better axillary control (HR:0.3, P=0.01) compared to 45 Gy. No significant difference between 45 Gy and 50 Gy to the lymphatics was observed for LRF and DF. Subgroup analysis did not show a difference between the described forms of AXT on LRF and DF. <h3>Conclusion</h3> Pathologic evaluation of the axilla's microenvironment beyond tumor deposits in lymph nodes and ECE is important to ensure adequate local control in the axilla. Given the higher risk of recurrence posed by tumor infiltration into surrounding axillary tissues, delivery of at least 50Gy to lymphatics should be considered. Our findings demonstrate the need for pathology reports to include assessment of the axilla's microenvironment.

Nasal vestibule squamous cell carcinoma: a population-based cohort study from DAHANCA

Background Cancer of the nasal vestibule is a rare type of malignancy dominated by squamous cell carcinoma (SCC), and with poor survival. The treatment is either radiotherapy, surgery or a combination of both. Previous studies have shown a 5-year disease-specific survival of 74% and overall survival (OS) of 50%. Our objective was to describe the consecutive cohort of patients diagnosed with SCC of the nasal vestibule in Denmark from 2008 until 2018 and evaluate prognostic factors and treatment outcome using locoregional failure (LRF), disease-specific mortality (DSM), and OS as endpoints. Methods All patients diagnosed with SCC of the nasal vestibule from 2008 until 2018 were identified in the nationwide clinical database, DAHANCA and were followed for LRF and death (DSM and OS) until March 2021. OS was analysed using Kaplan–Meier estimator, and cumulative incidence of LRF and DSM were analysed using the Aalen–Johansen estimator. Analysis of prognostic factors was performed using Cox proportional hazard models. Results A total of 162 patients were identified. The median age was 71 years and 54% were male. Disease stage at the time of diagnosis were stage I (70%), II (17%), III (2%) and IV (11%). Curatively intended treatment was performed in 146 patients (90%), of which treatment failure occurred in 42 patients (29%). Most failures occurred at the primary tumour site (64%). Cancer Patient Pathways recommended time to treatment was fulfilled in 71% of patients. The 5-year OS and DSM in patients treated with curative intent were 65% and 11%, respectively. Stage was a significant independent prognostic factor. No difference in LRF, DSM or OS were shown between the applied treatments. Conclusions Stage is the main independent prognostic factor, and failure most commonly appear at the primary tumour site.

Rectosigmoid Cancer — Rectal Cancer or Sigmoid Cancer?

<h3>Purpose/Objective(s)</h3> Locally advanced rectosigmoid adenocarcinomas are treated with either neoadjuvant (NA) chemoradiation or upfront surgery (sx). We determined outcomes with both treatment approaches and whether outcomes vary by anatomic landmarks. <h3>Materials/Methods</h3> We identified 161 pts with non-metastatic T3-T4 and/or N+ rectosigmoid cancers who underwent sx. with NA (radiation with or without chemotherapy) or adjuvant (adj) therapy from 2006 to 2018 at our institution. We included pts with available imaging and with primary tumor located 9-20 cm from the anal verge (AV) on staging CT, MRI, or colonoscopy. We reviewed the relationship of the primary tumor to the peritoneal reflection (PR) and sacral promontory (SP). Comparisons between the NA and adj. groups were performed using Fisher's exact test. Cumulative incidence of locoregional failure (LRF), distant failure (DF), and overall survival (OS) were compared using Kaplan-Meier. <h3>Results</h3> Of the study cohort, 97 pts had NA therapy and 64 pts had upfront sx. Median follow-up was 45.1 months. Pts who had NA therapy were younger, had tumors that were lower and more likely below the PR and with threatened circumferential resection margins (CRM), fewer cycles of adj chemotherapy, and higher cT stage (Table 1). The 3-year OS was 97.5% in the NA group versus 93.7% for upfront sx 2-year cumulative incidence of LRF was 5.2% (NA) vs 5.6% (upfront sx), <i>P</i> = 0.91. 2-year cumulative incidence of DF was 9.2% (NA) vs 10.4% (upfront sx), <i>P</i> = 0.54. Of the 10 pts total with LRF, 8 and 6 occurred in pts with tumors straddling/above the PR and > 10 cm from AV on imaging, respectively. None of the 3 pts with tumors < 10 cm from AV (MRI) treated with NA had LRF, while 16.7% (1/6) of these pts who received upfront sx had LRF. None of the 15 pts with tumors below the PR treated with NA had LRF, while 25% (1/4) of these pts who received upfront sx had LRF. Outcomes did not vary by relationship to the SP. <h3>Conclusion</h3> Pts with locally advanced rectosigmoid cancer treated with NA therapy had tumors closer to the AV and more advanced primaries. Despite these negative prognostic factors, they had cancer control outcomes similar to pts with higher, lower stage tumors treated with upfront sx. Pts with tumors below the PR or < 10 cm from AV may derive more benefit from NA therapy.

Sinonasal cancer in Denmark 2008–2015: a population-based phase-4 cohort study from DAHANCA

Background Sinonasal cancer is considered a rare disease with poor survival. Its treatment has changed profoundly in recent years, primarily following the introduction of intensity-modulated radiation therapy (IMRT) and minimally invasive endoscopic surgery. Danish national guidelines on treatment of patients diagnosed with sinonasal carcinoma were introduced in 2007. The aim of this phase-4 study was to assess the effect of the implementation of guidelines by describing treatment outcomes in a consecutive nationwide cohort. Methods All patients diagnosed with sinonasal carcinoma in Denmark from 2008 to 2015 were identified in the nationwide clinical database, DAHANCA, and were followed until May 2020. Overall survival (OS) was analysed using Kaplan–Meier estimator. Cumulative incidence of locoregional failure (LRF) and disease-specific mortality (DSM) were analysed using the Aalen–Johansen estimator. Competing risks were death from other causes (DSM) and distant failure and death (LRF). Analysis of prognostic factors was performed using Cox proportional hazard analysis. Start of follow-up was time of diagnosis. The results are presented as estimates with 95% confidence intervals (95% CIs). Results A total of 331 patients were identified. Curatively intended treatment was performed in 264 patients (80%). Non-compliance with treatment guidelines was registered in 24 patients (9%). Non-compliance was associated with LRF (hazard ratio [HR], 2.0 [95% CI: 1.1–3.5]). Among patients qualified for curative treatment, failure occurred in 109 patients (41%), primarily at the primary tumour site (81%). Anatomical tumour site and disease stage were independent prognostic factors. The 5-year OS was 56% in patients treated with curative intent, and a combined treatment strategy showed reduced LRF (HR, 0.53 [95% CI: 0.30–0.92]) in a multivariate analysis. Conclusions Guideline compliance and a combined treatment approach reduced the incidence of LRF and thereby increased OS. Our results confirm those of international studies. Treatment of sinonasal carcinoma remains a challenge that requires multidisciplinary team coordination.

Patterns of Failure After Adjuvant Stereotactic Body Radiation Therapy for Pancreatic Cancer With Close or Positive Margins

PurposeThere is no consensus on treatment volumes for adjuvant stereotactic body radiation therapy (SBRT) for pancreatic cancer. Herein, we report patterns of failure after pancreatic SBRT for close/positive margins, which may inform target volume design. Methods and MaterialsAn institutional review board-approved retrospective review of patients with pancreatic adenocarcinoma treated with adjuvant SBRT for close/positive margins from 2009 to 2018 was conducted. Patterns of failure were defined as local (LF) within the tumor bed, regional (RF) within lymph nodes or anastomoses, or distant (DF). The cumulative incidence of locoregional failure was calculated using the cumulative incidence function accounting for the competing risk of death. LFs were mapped to the planning target volume (PTV) and classified as in-field (completely within the PTV), marginal (partially within the PTV), or out-of-field (completely outside the PTV). The location of LFs was compared with the Radiation Therapy Oncology Group 0848 contouring atlas to determine whether standard postoperative radiation therapy volumes would have included the LF. ResultsSeventy-six patients were treated with adjuvant SBRT for close (51.3%) or positive (48.7%) margins. Most (81.6%) received 36 Gy in 3 fractions, with a median PTV volume of 17.8 cc (interquartile range, 12.1-25.6). With a median follow-up of 17.0 months (interquartile range, 7.3-28.4), crude rates of first isolated LF, isolated RF, and DF +/– LF or RF were 9.2%, 6.6%, and 56.6%, respectively. Two-year cumulative incidences of LF, RF, locoregional failure, and DF were 34.9%, 30.8%, 49.2%, and 60.4%, respectively. Of 28 reviewable LFs, 21.4% were in-field while the remainder were completely outside (60.7%) or partially outside (17.9%) the PTV. Most LFs (92.9%) would have been encompassed by the Radiation Therapy Oncology Group consensus target volumes. ConclusionsAfter adjuvant pancreatic SBRT for close/positive margins, the majority of LFs were outside the PTV but within contemporary target volumes for conventional radiation therapy.

Pulmonary resection is associated with long-term survival and should remain a therapeutic option in oligometastatic lung cancer

ObjectivesComprehensive local consolidative therapy led to improved overall survival in oligometastatic non–small cell lung cancer in a recent phase II trial, yet the role of pulmonary resection in ongoing oligometastatic trials is a matter of controversy. We sought to examine outcomes after pulmonary resection with radiotherapy used as a benchmark comparator. MethodsPatients treated at a single institution (2000-2017) with cT1-3N0-2M1 non–small cell lung cancer, 3 or less synchronous metastases, and performance status 0 to 1, and who received comprehensive local consolidative therapy were analyzed according to local consolidative therapy modality for the primary lesion. Progression was analyzed with death as a competing risk. ResultsOf 88 patients meeting inclusion criteria, 63 (71.6%) received radiotherapy for local consolidative therapy modality for the primary lesion and 25 (28.4%) underwent surgery (lobectomy 20/25 [80.0%], pneumonectomy 3/25 [12.0%], sublobar 2/25 [8.0%]). Time from diagnosis to local consolidative therapy modality for the primary lesion was similar. Surgical patients were younger and had lower intrathoracic disease burden. Ninety-day post-treatment mortality was low (surgery 0/25 [0.0%], radiotherapy 1/63 [1.6%]). Median postoperative survival time was 55.2 months (95% confidence interval, 20.1 to not reached), with 1- and 5-year overall survivals of 95.7% and 48.0%, respectively. After radiotherapy, median postoperative survival time was 23.4 months (confidence interval, 17.2-35.9); 1- and 5-year overall survivals were 74.3% and 24.2%, respectively. No differences were observed between modalities in site of first failure, cumulative incidence of locoregional failure (P = .635), or systemic progression (P = .747). ConclusionsPulmonary resection is feasible and associated with long-term survival in selected patients with synchronous oligometastatic non–small cell lung cancer. Surgery should remain a local consolidative therapeutic option for patients with operable oligometastatic non–small cell lung cancer enrolled in ongoing and future randomized clinical trials.

Moderately Hypofractionated Radiotherapy Alone for Stage I-IIB Non-small Cell Lung Cancer.

Introduction: The optimal management of patients with early non-small cell lung cancer (NSCLC) not amenable to surgical resection or stereotactic body radiotherapy (SBRT) or those with hilar nodal involvement ineligible for surgery or concurrent chemoradiotherapy is unclear. This report describes survival outcomes and toxicity profiles of patients treated with hypofractionated radiotherapy (HRT) alone.Methods: A total of 52 patients with Stage I-IIB NSCLC treated with HRT alone between 2010-2018 were reviewed. Patients were categorized as having ultracentral tumors if the planning target volume contacted or overlapped the proximal bronchial tree, esophagus, pulmonary vein or artery. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and the competing risk cumulative incidence of locoregional failure (LRF) and distant failure (DF) were estimated using death without failure as a competing risk. Pneumonitis and esophagitis rates were evaluated as per Acute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.Results: Of the 52 patients analyzed, 50 patients were treated with radiotherapy alone to a dose of 70.2 Gy in 26 fractions, one patient was treated with 68 Gy in 25 fractions and one patient was treated with 65 Gy in 26 fractions. The median age was 72 (range 48-89), 42% of patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 2-3, 46% were stage I and 54% were stage II. Hilar nodal involvement was present in 21% of patients and 74% of node-negative patients had ultracentral primary tumors. Median OS was 39.6 months and the median PFS was 21.0 months. Overall three-year cumulative incidence of LRF and DF were 32% and 34%, respectively. Grade 3 pneumonitis occurred in two (4%) patients. No grade 3+ acute esophagitis or grade 4-5 toxicities were observed.Conclusion: Hypofractionated thoracic radiotherapy consisting of 70.2 Gy is well-tolerated and results in favorable locoregional control for stage I-IIB patients who are not candidates for SBRT, surgery, or concurrent chemoradiotherapy.

Risk of contralateral nodal failure following ipsilateral IMRT for node-positive tonsillar cancer

PurposeTo determine the risk of contralateral nodal failure following ipsilateral radiotherapy in a series of patients with node-positive tonsillar squamous cell carcinoma. MethodsRetrospective review was used to identify 34 patients with well-lateralized node-positive tonsillar squamous cell carcinoma treated with definitive or adjuvant radiation to the primary site and ipsilateral neck between 2005 and 2015. Contralateral nodal failure, locoregional recurrence, distant metastasis, and overall survival were calculated using actuarial and/or cumulative incidence statistics. ResultsAt last follow-up, contralateral nodal failure was only observed in 1 patient (3%) with N1 disease. At median follow-up of 34 months for surviving patients, the 3-year overall survival probability was 87%, and the 3 year cumulative incidences of locoregional failure and distant metastasis were 6.5% and 7.2%, respectively. No disease-free patient was permanently gastrostomy-dependent. ConclusionIpsilateral radiation treatment with IMRT is effective in node-positive patients with well-lateralized tonsillar cancer, resulting in a low risk of contralateral regional recurrence, even in patients with N2b disease.

Proton Beam Radiation for Head and Neck Cancers: A Single-Institution Report on Feasibility and Early Outcomes

Definitive radiation of the head and neck has become a mainstay for locally advanced head and neck malignancies. This combined with initial surgery and/or adjuvant chemotherapy yields significant morbidity to the patients both short term and long term. This is a review of our prospective registry database of head and neck patients treated with proton beam radiation at our hybrid community practice/academic proton center to highlight our initial experience with relative long term follow up. All patients in our study were treated with the uniform scanning proton beam technology via the IBA system. Standard fractionation schemes with or without chemotherapy were delivered with curative intent. Acute and late toxicities were assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and the by the Radiation Therapy Oncology Group late radiation morbidity scoring system, respectively. The cumulative incidence of locoregional failure (LRF) was calculated with death as a competing risk. The actuarial freedom from distant metastases (FFDM) and overall survival (OS) rates were calculated with the Kaplan-Meier method. A total of 66 patients were analyzed from our prospective registry. We focused on the 36 de-novo patients as our 30 re-irradiation patients are in process in upcoming literature. The scope of our patient population included patients with malignancies of the paranasal sinuses, nasopharynx, oropharynx, hypopharynx, and major salivary gland. Squamous Cell Carcinoma was the predominant histology, but others were Mucoepidermoid Carcinoma, Adenoid Cystic Carcinoma, Undifferentiated Carcinomas and Esthesioneuroblastomas. The median follow up was 33 months (9 – 53). The 2 and 5 year OS rates were 83% and 75%, respectively. The 2 and 5 year FFDM rates were 92% and 80%, respectively. There was 17% and 25% 2 and 5 year LRF rate. The mean time to failure was 17 months post initial proton beam treatment. Acute grade 3+ toxicity rate was 30.5% (mainly skin, mucositis, odynophagia, dysphagia, and anorexia), while the long term grade 3+ toxicity rate was 6% (anorexia and dysphagia). Ten patients had feeding tubes at some point during the radiation therapy, but none remained on tube feedings beyond 6 months post proton radiation therapy. Proton beam radiation of the head and neck can provide excellent disease control along with great sparing of the OARs. Longer follow up is needed with a less heterogeneous population to validate this modality. In addition, with the advent of intensity modulated proton beam radiation, even better conformality of proton beam will hopefully improve the toxicity profiles of even the acute toxicities.

Proton Beam Reirradiation for Recurrent Head and Neck Cancer: Multi-institutional Report on Feasibility and Early Outcomes

Reirradiation therapy (re-RT) is the only potentially curative treatment option for patients with locally recurrent head and neck cancer (HNC). Given the significant morbidity with head and neck re-RT, interest in proton beam radiation therapy (PBRT) has increased. We report the first multi-institutional clinical experience using curative-intent PBRT for re-RT in recurrent HNC. A retrospective analysis of ongoing prospective data registries from 2 hybrid community practice and academic proton centers was conducted. Patients with recurrent HNC who underwent at least 1 prior course of definitive-intent external beam radiation therapy (RT) were included. Acute and late toxicities were assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 and the Radiation Therapy Oncology Group late radiation morbidity scoring system, respectively. The cumulative incidence of locoregional failure was calculated with death as a competing risk. The actuarial 12-month freedom-from-distant metastasis and overall survival rates were calculated with the Kaplan-Meier method. Ninety-two consecutive patients were treated with curative-intent re-RT with PBRT between 2011 and 2014. Median follow-up among surviving patients was 13.3 months and among all patients was 10.4 months. The median time between last RT and PBRT was 34.4 months. There were 76 patients with 1 prior RT course and 16 with 2 or more courses. The median PBRT dose was 60.6 Gy (relative biological effectiveness, [RBE]). Eighty-five percent of patients underwent prior HNC RT for an oropharynx primary, and 39% underwent salvage surgery before re-RT. The cumulative incidence of locoregional failure at 12 months, with death as a competing risk, was 25.1%. The actuarial 12-month freedom-from-distant metastasis and overall survival rates were 84.0% and 65.2%, respectively. Acute toxicities of grade 3 or greater included mucositis (9.9%), dysphagia (9.1%), esophagitis (9.1%), and dermatitis (3.3%). There was 1 death during PBRT due to disease progression. Grade 3 or greater late skin and dysphagia toxicities were noted in 6 patients (8.7%) and 4 patients (7.1%), respectively. Two patients had grade 5 toxicity due to treatment-related bleeding. Proton beam re-RT of the head and neck can provide effective tumor control with acceptable acute and late toxicity profiles likely because of the decreased dose to the surrounding normal, albeit previously irradiated, tissue, although longer follow-up is needed to confirm these findings.

Efficacy and Tolerability of Palliative Split-Course Thoracic Chemoradiotherapy for Symptomatic Non–Small Cell Lung Cancer

To assess the efficacy and tolerability of palliative split-course concurrent thoracic chemoradiotherapy (CRT) in patients with incurable locally advanced and metastatic non-small cell lung cancer. All patients with incurable non-small cell lung cancer and symptomatic thoracic disease treated with palliative split-course CRT between March 2006 and February 2013 at a single institution were included in this retrospective study. The primary endpoint was improvement in presenting thoracic symptoms. Secondary endpoints included toxicity, overall survival, and the cumulative incidence of locoregional failure. Fifty-five patients were identified, of whom 89% had distant metastatic disease at the initiation of treatment. The median radiotherapy dose delivered was 40 Gy over 20 fractions. Over 90% of patients were able to complete at least 2 cycles of chemotherapy, and 89% of patients completed the prescribed course of radiotherapy. Forty percent of patients had improvement in all presenting symptoms and 78% experienced improvement in at least 1 symptom. Nine and 2 patients, respectively, experienced grade 1 and 2 esophagitis and 1 patient experienced grade 2 pneumonitis. There were no cases of grade 3 toxicity. With a median follow-up for surviving patients of 4.5 months, the estimated actuarial 6-, 12-, and 24-month overall survival was 56%, 25%, and 13%, respectively. The actuarial 6-, 12-, and 24-month cumulative incidence of locoregional failure was 6%, 14%, and 22%, respectively. Split-course CRT allows for early introduction of systemic therapy while providing durable locoregional control with tolerable morbidity and significant improvement in chest symptomatology. This paradigm is a viable model for chest palliation in selected patients with intact performance status.

The DAHANCA 6 randomized trial: Effect of 6 vs 5 weekly fractions of radiotherapy in patients with glottic squamous cell carcinoma

PurposeThe DAHANCA 6 trial evaluated tumor response and morbidity after moderate accelerated radiotherapy compared to conventional fractionated radiotherapy in patients treated for glottic squamous cell carcinoma (SCC). Further, the failure pattern and incidence of new primary tumors were explored. Patients and methodsSix hundred and ninety-four patients with non-metastatic glottic SCC were randomized between six or five weekly fractions (fx/w) of radiotherapy to the same total dose. The median treatment time was 38 and 46days, respectively. The primary endpoint was loco-regional failure. ResultsMedian follow-up time was 14.5years. Of the 177 failures, 167 involved T-site. The cumulative incidence of loco-regional failure (LRF) was 21.6% in the 6fx/w group and 29.3% in the 5fx/w group and the corresponding hazard rate (HR) of LRF was 0.72 (CI: 0.53–0.97, p=0.04). The effect of acceleration on LRF was especially evident in well differentiated tumors (HR=0.42 (CI: 0.23–0.75) and in T1–2 tumors (HR=0.60 (CI: 0.41–0.89)). The HR of laryngectomy was 0.72 (CI: 0.50–1.04) in the 6fx/w group compared to the 5fx/w group. The hazards of disease-specific death, event-free survival, and overall survival were comparable between the two groups. Significantly more patients experienced severe acute mucositis in the 6fx/w group but the incidence of late morbidity was comparable between the groups. New primary tumors occurred in 22.5% of the patients. ConclusionModerate accelerated radiotherapy significantly improved loco-regional control in patients with glottic SCC.

9P - Patterns of Failure in Pathologic N1 Breast Cancer Patients Treated with Mastectomy and Radiotherapy

Introduction: Pakistan has the highest rate of breast cancer of any South Asian population and the majority of patients present with locally advanced or metastatic disease. We report on patterns offailure and survival in pathologic N1 breast cancer patients treated with mastectomy, adjuvant chemotherapy/hormonal therapy and post-mastectomy radiotherapy (PMRT). Materials and methods: Between 1995 and 2009, the hospital information system identified 400 women with pathologically confirmed N1 breast cancer. Axillary nodes were clinically palpable in 75% of the patients at presentation. All patients were treated with mastectomy (including level I-II axillary dissection). Distribution of pathologic tumor size was up to 2 cm, 2.1 to 5 cm, and more than 5 cm in 16.5%, 58.5%, and 25% of the patients, respectively. Distribution of dissected lymph nodes was one to five, six to nine, and ten and above in 9%, 6% and 85% of the patients, respectively. Median number of dissected lymph nodes were 14 (range 1–37). 92% of the patients received doxorubicin-based chemotherapy either in neo-adjuvant or adjuvant setting. All patients received PMRT, to chest wall only in 12%, to chest wall and supraclavicular fossa in 81.5%, and to chest wall, supraclavicular fossa and axilla in 6.5% of the patients. All patients with positive ER/PR receptors also received hormonal modulation. Median age was 44 years (range 21–83 years). Patterns of failure and disease-free survival (DFS) were determined. Results: Median follow-up duration was 4.4 years. Patterns of failure were, isolated local (LF) in 4%, isolated regional (RF) in 0.5%, distant failure (DF) in 32%, and loco-regional along with distant failure (LRF + DF) in 2.5% of patients. Cumulative incidence of loco-regional failure for patients with a pathologic tumor size of up to 2 cm, 2.1 to 5 cm, and more than 5 cm were 2.5%, 3%, and 5.5%, respectively. These incidences for one to five, six to nine, and more than ten dissected lymph nodes were 2%, 0%, and 9.5%, respectively. The 10 years DFS for the whole group was 55%. Conclusions: The role of PMRT may have some value in terms of loco-regional control in pathologic N1 breast cancer patients. This merits further evaluation in large-scale randomized trials. Disclosure: All authors have declared no conflicts of interest.

Patterns-of-failure after helical tomotherapy-based chemoradiotherapy for head and neck cancer: Implications for CTV margin, elective nodal dose and bilateral parotid sparing

There is debate about the optimal clinical target volume (CTV) expansion and prophylactic nodal dose (PND) in head and neck IMRT. We evaluated our patterns-of-failure (POF) after helical tomotherapy-based concurrent chemoradiotherapy (CCRT) to assess the oncologic safety of reducing the CTV, PND, and bilateral parotid sparing (BPS). All patients with locally advanced squamous cell carcinoma of the head and neck treated with curative intent CCRT between January 2007 and April 2013 at a single institution were included in this retrospective study. Locoregional recurrences (LRR) were overlaid on the treatment plan, and POF was determined relative to planned dose. One hundred and fourteen patients treated with CCRT were evaluated, 74% of whom underwent BPS. The median follow-up for surviving patients was 29.3 months. The 3-year cumulative incidence of locoregional failure, distant metastasis, progression-free and overall survival were 20%, 20%, 56% and 73% respectively. The local failures (n = 12) were either entirely contained within or centered on the original gross tumor volume (GTV), and all but 2 regional recurrences were in GTV. There were no nodal failures in the low-dose or peri-parotid neck (including ipsilateral neck). Nearly all LRR were located within the GTV suggesting that minimal-to-zero margin is required for CTV 70. The nodal recurrence pattern suggests the safety of routine bilateral parotid sparing and relatively low biologically equivalent dose (54 Gy in 33fx) to the low-risk neck.

Multi-institution Analysis of Concurrent Chemoradiation Therapy With Cisplatin (CDDP) Versus Cetuximab (C225) in Locally Advanced Squamous Cell Carcinoma of the Head and Neck (LA-HNSCC): Can HPV Help Decide Which Agent?: Definitive Management of Head-and-Neck Squamous Cell Carcinoma

Multiple institutions have reported that patients with LA-HNSCC treated with concurrent C225-based radiation therapy (RT) have worse outcomes than those treated with concurrent CDDP. HPV's influence on the treatment efficacy of these two agents is unclear. In the metastatic setting, HPV- patients treated with Panitumumab had improved overall survival (OS), while no difference was found in HPV+ patients. We sought to investigate whether the previously reported differences in outcomes in LA-HNSCC between C225 and CDDP were influenced by HPV Status. We reviewed 147 consecutive patients with LA-HNSCC treated with definitive chemo-RT at one of our 3 institutions with known HPV status. Patients with NPC, oral cavity cancer, or distant metastasis at presentation were excluded. Further, patients who received induction or additional concurrent chemotherapy were excluded. At MSKCC, HPV Status was determined by p16 or HPV ISH; at Beaumont by PCR or p16; and at Washington Univ. by p16 or non-keratinizing histology. Smoking status was divided by those with a 10+ pack-yr history vs those without. Actuarial curves were created and multi-variate Analysis (MVA) was performed with a Cox-regression model. Median follow up in surviving patients was 43 months. 92 (63%) patients were treated with CDDP and 55 (37%) with C225. T-stage, N-stage, smoking, and alcohol consumption were well balanced between the two groups. There were more patients greater than 70 yrs of age in the C225 group (22% vs 6%, p <0.001) and more HPV- patients (44% vs 25%, p=0.03). The 2-year cumulative incidence of loco-regional failure (LRF) was significantly higher with C225 compared to CDDP (41.9% vs 12.6%, p <0.001). Subgroup analysis of patients by HPV status revealed increased 2-yr LRF with C225 in HPV+ patients (33.6% vs 10.4%, p = 0.02) and in HPV- patients (52.6% vs 20.3%, p=0.02). MVA of LRF adjusting for HPV, T Stage, and N Stage continued to show improved outcomes with CDDP (HR=0.26, p =0.002). The 2-year DFS was also significantly worse with C225 compared to CDDP (38.6% vs 82.6%, p < 0.001). Subgroup analysis by HPV revealed worse 2-yr DFS with C225 in HPV+ (46.4% vs 84.8%, p < 0.001) and HPV- patients (29.2 vs 74.9%, p < 0.001). MVA of DFS adjusting for HPV, Age, T stage, N Stage, and smoking demonstrated improved DFS with CDDP (HR = 0.31, p < 0.001). Results for OS were similar. Loco-regional control and DFS are significantly improved with concurrent cisplatin as compared to cetuximab in definitive RT for HNSCC. Both HPV+ and HPV- patients benefit from CDDP-based concurrent therapy in LA-HNSCC.