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Marc De Perrot
Moderator of
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MS 23 - Management of N2 NSCLC: What “Operable” Means? (ID 545)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Locally Advanced NSCLC
- Presentations: 5
- Moderators:G. Lyons, Marc De Perrot
- Coordinates: 10/18/2017, 14:30 - 16:15, F203 + F204 (Annex Hall)
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MS 23.01 - What Type of Lung Cancer Cannot be Resected? (ID 7749)
14:30 - 14:50 | Presenting Author(s): Marc De Perrot
- Abstract
- Presentation
Abstract not provided
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MS 23.02 - When Do Surgeons Quit Resection During Surgery? (ID 7750)
14:50 - 15:10 | Presenting Author(s): Jessica Donington
- Abstract
- Presentation
Abstract:
Reasons surgeons “quit” cancer operations are typically related to finding additional sites of disease, inability to perform necessary dissection, or disappearance of previously identified disease. In the setting of N2 positive non-small cell lung cancer (NSCLC) the disappearance of disease is not a consideration, so occult sites of disease or inability to perform safe hilar or mediastinal dissection are the most common reasons to back out of an operation once started. Incredibly precise pre-resection imaging has made this an uncommon scenario. Imaging techniques include functional and molecular correlates, and 3 and 4 dimensional reconstructions, which improve detection of very small lesions and appreciation of tumor interactions with adjacent structures. That being said, N2 involvement denotes locally advanced and often aggressive disease and use multimodality treatments and therefore the risk for unexpected findings in the operating room which alter resectability are more frequent than in early stage disease. Occult or unexpected disease encountered by thoracic surgeons in the operating room typically involves the parietal pleura, as occult carcinomatous pleuritis. Additional pulmonary nodules and unanticipated milliary spread are far less common. Pleural studding is defined as M1a disease in the 8[th] edition of AJCC staging. Chemotherapy is the recommended treatment for radiographically identified pleural involvement, but management recommendations are slightly less clear for disease found at the time of surgery. Pulmonary resections are generally contraindicated, but several investigators report favorable outcomes for those who can undergo macroscopic complete resection.[1,2] Carcinomatous pleuritis can escape radiographic detection, the incidence of occult disease at thoracotomy ranges from 1.5% to 4.5% for all lung cancer resections,[3] and is associated with large tumors, non-squamous histology, and lymph node involvement.[2] Carcinomatous pleuritis can escape radiographic detection, the incidence of occult disease at thoracotomy ranges from 1.5% to 4.5% for all lung cancer resections,[] and is associated with large tumors, non-squamous histology, and lymph node involvement. Intraoperative pleural lavage cytology (PLC) is a technique used for detecting subclinical dissemination of malignant cells in the pleural cavity. The boundary between malignant pleural effusion and positive PLC is not particularly well defined and most reports demonstrate a negative impact on prognosis in resected patients, but positive PLC does not upgrade tumors in the current TNM staging system. It also does not preclude resection in a patient with otherwise resectable disease. Similar to pleural studding positive cytology is consistently found to be more common in patients with higher stage and nodal involvement.[4] The presence of bulky N2 disease can greatly increase the complexity of hilar and mediastinal dissection. Modern techniques and intraoperative tools have increased surgeons ability to remove structures once considered unresectable including the spine, carina, and superior vena cava, but direct tumor extension or nodal involvement of the trachea, heart or great vessels can make safe resection impossible. Preoperative imaging typically allows for appropriate planning and decision making about these types of complex resections and controversy exists as to appropriateness of such resections in the setting of N2 disease. Induction therapy can make the pre-operative assessment of involved structures more complicated, differentiation between tumor and treatment effect is not always clear and therefore many surgeons make resection decisions on pre-treatment imaging. A more common scenario in thoracic oncology is that of the patient with marginal pulmonary reserve in whom the hilar resection is complicated by extensive nodal involvement or treatment effect; a pneumonectomy is technically feasible and would result in complete resection, but the patient would not tolerate that extensive a resection. Sleeve resections are used whenever possible, but widespread hilar and mediastinal scarring can sometimes exclude any safe surgery other than a pneumonectomy. The amount of fibrosis and scarring encountered at resection following induction therapy remains unpredictable. It is known to increase with time, which is why resection is recommended within 12 weeks induction therapy, but within that window, it can be quite variable. Review of recent large prospective trials for resectable IIIA NSCLC can help shed light on how frequently and why surgeons cannot complete the planned resection for N2 positive NSCLC. In the recent SAAK trial which compared induction chemotherapy to induction chemoradiotherapy in high volume operative centers in Europe, all patients who were taken to surgery, had a pulmonary resection, but R2 resections occurred in 3% of the trimodality group and 8% of the bimodality, reasons for incomplete resection were not delineated.[5] In the recent report of pooled data from RTOG 0229 and 0839, evaluating surgical outcomes after high dose induction chemo-radiotherapy, 7 of the 99 patients brought to surgery were not resected, 2 due to occult pleural metastasis, 2 because of persistent N2 involvement in patient with limited pulmonary reserve, and 3 were “unresectable”, 2 because complete resection would require a pneumonectomy and they had poor pulmonary reserve and one due to extensive mediastinal fibrosis.[6] These trials were all limited to experienced thoracic surgeons, indicating that the inability to complete a planned resection for IIIA NSCLC remains a rare but real phenomenon even in skilled surgical hands. References 1. Fukuse, T., et al., The prognostic significance of malignant pleural effusion at the time of thoracotomy in patients with non-small cell lung cancer. Lung Cancer, 2001. 34(1): p. 75-81. 2. Iida, T., et al., Surgical Intervention for Non-Small-Cell Lung Cancer Patients with Pleural Carcinomatosis: Results From the Japanese Lung Cancer Registry in 2004. J Thorac Oncol, 2015. 10(7): p. 1076-82. 3. Fukui, T. and K. Yokoi, The role of surgical intervention in lung cancer with carcinomatous pleuritis. J Thorac Dis, 2016. 8(Suppl 11): p. S901-S907. 4. Toufektzian, L., et al., Pleural lavage cytology: where do we stand? Lung Cancer, 2014. 83(1): p. 14-22. 5. Pless, M., et al., Induction chemoradiation in stage IIIA/N2 non-small-cell lung cancer: a phase 3 randomised trial. Lancet, 2015. 386(9998): p. 1049-56. 6. Donington, J., et al. safety and Feasibility of Lobectomy folowing Concurrent Chemotherapy and High Dose Radiation for Stage IIIA NSCLC: Pooled Surgical Results of NRG Oncology RTOG 0229 and 0839. in American Asociation for Thoracic Surgery. 2017. Boston, MA.
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MS 23.03 - What is Resectable N2 Disease, and What is Unresectable N2 Disease: A Medical Oncologist's Viewpoint (ID 7751)
15:10 - 15:30 | Presenting Author(s): Hidehito Horinouchi
- Abstract
- Presentation
Abstract:
Various treatment strategies, including chemotherapy, radiotherapy and surgery have been developed for patient populations with N2 lymph node metastasis, especially clinical stage IIIA-N2 non-small cell lung cancer (cIIIA-N2 NSCLC). For potentially resectable patients, clinical trials including surgical treatment have been published. Among them, EORTC-08941, INT-0139, ESPATUE examined the efficacy of adding surgical treatment with chemotherapy and radiotherapy in randomized design. In the INT-0139 study, surgery after induction chemoradiotherapy (CRT) demonstrated a 7% gain on 5-year survival, however, it failed to show statistical significance mainly because of treatment-related death in patients received pneumonectomy after induction CRT. Although the contribution of surgery was recognized, the additional effect of surgery over CRT has not been confirmed consistently in other trials. On the other hand, trials investigating newer medical treatment and higher radiotherapy dose have been conducted for patients with unresectable stage III NSCLC. In this patient population, so-called third generation cytotoxic agents whose effects were confirmed in patients with advanced disease, including paclitaxel (WJTOG0105), docetaxel (OLCSG 0007), vinorelbine and pemetrexed (PROCLAIM) with platinum have been actively examined but failed to show improvement compared to older agents (etoposide, vindesine and mitomycin C). Furthermore, high-dose radiotherapy (74Gy) with platinum-doublet chemotherapy showed strikingly shorter survival than conventional radiation dose (60Gy) in RTOG-0617. After these continuous efforts, CRT stayed as standard for those patients with unresectable N2 disease. Besides CRT, induction therapy followed by surgery has also come to be recognized as a treatment option for potentially resectable N2 disease in major guideline including ACCP, NCCN and ESMO. However, no clear answer has been provided for the question: what is resectable N2 disease, and what is unresectable N2 disease? To refine the heterogeneity in cIIIA-N2 NSCLC patients and show clues to answer the question of resectable/unresectable, we analyzed the data of consecutive patients with cIIIA-N2 NSCLC diagnosed and treated by CRT in National Cancer Center Hospital, Tokyo, Japan. The appearance of the mediastinal lymph nodes (MLNs) was classified into discrete or infiltrative according to the criteria proposed by the ACCP. In addition, the extent of MLN involvement (MLNI) was classified as limited (close to the primary tumor) or extensive (including upper MLNI in the case of tumors in the lower lobes and vice versa). Those with a discrete appearance of the MLNIs and a limited extent of MLNIs at diagnosis could show favorable survival outcomes by CRT without surgery comparable to the data provided by induction CRT followed by surgery. Meanwhile, immune checkpoint inhibition by PD-1/PD-L1 antibody has been being actively examined as adjuvant for early stage resectable NSCLC patients and consolidation therapy for unresectable stage III NSCLC patients after CRT. The PACIFIC is a phase III randomized clinical trial investigating the efficacy of MEDI-4736 (PD-L1 antibody) as consolidative therapy in patients without progression after definitive CRT. Based on the press release by AstraZeneca, MEDI-4736 showed significant prolongation of progression-free survival, suggesting that there is a possibility of changing standard treatment. Under such circumstances that powerful medical treatment option will be introduced in unresectable N2 disease, there is increasing need for an appropriate guidance to select surgical candidates in potentially resectable population. Now is the time to respond to the question of resectable/unresectable that has not been answered for a long time.
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MS 23.04 - What is Resectable N2 Disease, and What is Unresectable N2 Disease: A Radiation Oncologist's Viewpoint (ID 7752)
15:30 - 15:50 | Presenting Author(s): Walter John Curran, Jr.
- Abstract
- Presentation
Abstract not provided
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MS 23.05 - What is Resectable N2 Disease, and What is Unresectable N2 Disease: A Surgeon's Viewpoint (ID 7753)
15:50 - 16:10 | Presenting Author(s): Jhingook Kim
- Abstract
- Presentation
Abstract:
What is Resectable N2 Disease, and What is Unresectable N2 Disease: A Surgeon's Viewpoint Jhingook Kim, MD (Samsung Medical Center, Sungkyunkwan University) The poor prognosis of N2 disease is related to the risk of occult systemic metastasis although N2 disease, by definition, is a localized disease. Therefore, multimodal treatment, including systemically chemotherapy and locally surgery or radiotherapy, is often required. However, the optimal multimodal approaches for N2 disease remain controversial. Although definitive concurrent chemoradiotherapy (CCRT) is considered the standard of care, its oncologic efficacy can be limited by the high rate of local failure. Adding surgical resection to this bimodal treatment as a neoadjuvant treatment setting or replacing the radiotherapy with surgery has been attempted and has achieved enhancement of local control and improved survival, but the main concern regarding this approach is the increased risk of postoperative mortality and morbidity. Since 1995, neoadjuvant CCRT followed by surgical resection has been the preferred treatment modality at our institution, and prospectively and consecutively performed for more than 800 medically fit patients with resectable NSCLC with N2 disease. Figure 1 Fig. 1. Summary of treatment scheme Based on the previous analysis of 574 patients (From 1997 to 2013, 59 years of mean age, 444 men), complete resection was obtained in 543 patients (95%) by lobectomy (418 patients; 73%), pneumonectomy (73 patients; 13%) and sleeve resection (25 patients; 4.3%). Postoperative complications and in-hospital mortality occurred in 199 patients (35%) and 21 (3.7%), respectively. Pathologic complete response was achieved in 72 patients (13%) and 304 (53%) experienced mediastinal clearance. The 5-year overall and recurrence-free survival rates were 47 and 29%, respectively, and the median overall survival and recurrence-free survival were 56 months and 18 months, respectively. The 5-year OS rates were 61% in ypN0, 49% in ypN1, and 35% in ypN2 (p = 0.001). The 5-year RFS rates were 45% in ypN0, 23% in ypN1, and 17% in ypN2 (p < 0.001). Older age, advanced pTstage, persistent N2, large cell carcinoma, and pneumonectomy were independent prognostic factors associated with worse OS and poorer RFS. Evidence such as acceptable early postoperative outcomes, satisfactory local control and encouraging long-term survival has supported the need to expand the indication or situation. When investigating the timing and patterns of recurrence after treatment, of 290 patients with recurrence, 25 (8.4%) experienced loco-regional recurrence, whereas 238 (80.4%) had distant metastases. The hazard rate function for overall recurrence revealed a peak at approximately 8 months after surgery and a marked decline after 2 years (figure 2). The peak recurrence frequency of distant metastasis differed at each site, with isolated brain metastases exhibiting the earliest peak (6 months) and a narrow recurrence interval (15 months). Interestingly, the dynamics of recurrence after trimodality therapy varies according to pathologic factors and response to induction therapy (not specifically related with pre-induction presentation), which may mean personalized consideration of the treatment including surgery. Figure 2 FIG 2. Comparison of the recurrence hazard rate according to the site of distant metastasis. Each organ has a different peak of recurrence, although the peaks and shapes of the hazard rate curves were similar between bone and supraclavicular lymph nodes. Therefore, in this session, we will discuss “resect or not to resect” in several specific situations such as 1) for the patients with invasive T3 or resectable T4 2) for the patients with multi-station, bulky lymph nodes (not every) 3) for the patients with central lung cancer with possible sleeve lobectomy 4) for the old patients (>75 year-old) with comorbidity By the rapid development of the medical sciences, especially in cancer medicine, there would be fundamental changes in the diagnosis and management of N2 disease. Especially, improvement in systemic treatment would have critical impact on the surgical role in locally-advanced lung cancer. Moreover, if systemic tumor burden or minimal residual disease could be assessed at the earliest, surgery would be applied with higher benefit, and thus, the survival outcome would be significantly improved. Therefore, there should be more studies of combined local control (surgery) and systemic control (chemo and/or immunotherapy); either as adjuvant, neoadjuvant or salvage purpose; either with or without radiotherapy; participated by thoracic surgeons, to maximize the survival of the patients from dreadful disease. References 1. Kim HK, Cho JH, Choi YS, et al. Outcomes of neoadjuvant concurrent chemotherapy followed by surgery for non-small cell lung cancer with N2 disease. Lung Cancer 2016; 96:56-92 2. Lee J, Kim HK, Park BJ, et al. Recurrence Dynamics after Trimodality Therapy (Neoadjuvant Concurrent Chemoradiotherapy and Surgery) in Patients with Stage IIIA (N2) Lung Cancer. Lung Cancer (submitted)
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Author of
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MS 23 - Management of N2 NSCLC: What “Operable” Means? (ID 545)
- Event: WCLC 2017
- Type: Mini Symposium
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:G. Lyons, Marc De Perrot
- Coordinates: 10/18/2017, 14:30 - 16:15, F203 + F204 (Annex Hall)
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MS 23.01 - What Type of Lung Cancer Cannot be Resected? (ID 7749)
14:30 - 14:50 | Presenting Author(s): Marc De Perrot
- Abstract
- Presentation
Abstract not provided
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OA 02 - Mesothelioma: Challenges For New Treatment (ID 653)
- Event: WCLC 2017
- Type: Oral
- Track: Mesothelioma
- Presentations: 1
- Moderators:S. Hasegawa, Anna Nowak
- Coordinates: 10/16/2017, 11:00 - 12:30, F205 + F206 (Annex Hall)
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OA 02.06 - Radioimmunotherapy Combining CTLA-4 Blockade or Low-Dose Cyclophosphamide with Local Radiation in Murine Malignant Mesothelioma (ID 8843)
11:55 - 12:05 | Author(s): Marc De Perrot
- Abstract
- Presentation
Background:
Our group has developed a new approach focusing on Surgery for Mesothelioma After Radiation Therapy (SMART), with encouraging results in a phase I/II clinical trial. The impact on the immune system of high-dose hypofractionated radiation therapy is expected to open the door for new combination therapy of immunotherapy and radiation to optimize their synergism on the immune system. The aim of this study is to investigate the antitumor effect of non-ablative hypofractionated radiation combined with anti-CTLA-4 antibody (a-CTLA-4) or low-dose cyclophosphamide (LD-CTX) in murine malignant mesothelioma model.
Method:
Balb/c mice were subcutaneously injected with murine mesothelioma AB12 cells into the left flank on day 0 (primary tumor) and into the right flank on day 7 (secondary tumor). Local radiotherapy (LRT) 5 Gy was delivered to primary tumor once daily for 3 consecutive days (total dose: 15 Gy). Mice were randomized into six groups: (1) No treatment, (2) LRT, (3) a-CTLA-4, (4) LRT+a-CTLA-4, (5) LD-CTX, (6) LRT+LD-CTX. We assessed local and abscopal effects by measuring primary and secondary tumor growth. Furthermore, CD4+ and CD8+ T cell proportion in tumor, spleen and peripheral blood were determined by flow cytometry.
Result:
Mice treated with LRT+a-CTLA-4 and LRT+LD-CTX showed the most significant deceleration in primary tumor growth compared to the other 4 groups. Both combination groups showed similar antitumor effects on the primary tumor. The secondary tumor growth tested the abscopal effect tended to be decreased in mice treated with LRT and LRT+a-CTLA-4 or LRT+LD-CTX compared to untreated mice, but the difference was not significant. Quantification of tumor-infiltrating T cells by flow cytometry showed that the percentages of total T cells, and CD4+ and CD8+ T cells in the primary tumor were increased in the combination groups.
Conclusion:
Combination of LRT and immunotherapy showed synergistic antitumor effects in controlling irradiated-tumor growth. CTLA-4 blockade and LD-CTX might be good candidates in combination with radiotherapy.
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P1.13 - Radiology/Staging/Screening (ID 699)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Radiology/Staging/Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.13-004 - The Role of Lymph Node Staging by EBUS-TBNA in Stereotactic Body Radiation Therapy for patients with Non-Small Cell Lung Cancer. (ID 8070)
09:30 - 09:30 | Author(s): Marc De Perrot
- Abstract
Background:
Stereotactic body radiation therapy (SBRT) is an option for treatment of patients with non-small cell lung cancer (NSCLC). Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive, diagnostic modality for mediastinal and hilar staging of NSCLC. We evaluated the diagnostic value of EBUS-TBNA in SBRT candidates and compared it to that of computed tomography (CT) and positron emission tomography (PET) scans.
Method:
Inclusion criteria for this single institutional retrospective study included 1) biopsy-proven or clinically suspicious NSCLC with diameter <6 cm; 2) no evidence of distant metastasis; 3) EBUS-TBNA staging between April 2008 and November 2014; 4) medically SBRT-eligible other than nodal staging. CT and PET positive nodes were defined as short axis ≧1cm and standardized uptake value ≧2.5, respectively. Node positive by clinical-pathologic confirmation (NPCP) was defined as confirmed malignancy by EBUS-TBNA or clinically diagnosed recurrence in hilar or mediastinal lymph nodes within one year after SBRT. The survival after SBRT was compared between CT or PET node-positive but EBUS-TBNA result-negative patients, and a matched cohort (tumor size; radiation dose; operability) who underwent SBRT in our institution within the same time period but without EBUS-TBNA staging.
Result:
There were 35 eligible patients (mean age 77±8.2, 24 male). Thirty-two (91.4%) patients had pathological confirmation of NSCLC (mean diameter 2.5±1.0 cm) (T1a N=12, T1b N=15, T2a N=7, T2b N=1). Thirty (85.7%) patients were medically inoperable. After EBUS-TBNA, 20 out of 24 patients who had positive nodes in CT (N=13) or PET (N=17) were ultimately pathologically N0. All eleven image-negative patients were N0 following EBUS-TBNA. Thirty-one patients (20 image positive plus 11 image negative) underwent SBRT. Sensitivity/specificity of CT, PET and EBUS-TBNA for NPCP were 42.9/64.3%, 100/64.3% and 57.1/100%, respectively. Positive predictive value of CT and PET for NPCP was 23.1% and 41.2%, respectively. Negative predictive value of CT, PET and EBUS for NPCP was 81.8%, 100% and 90.3%, respectively. A 1:4 (Case; N=20, Control; N=76) match was obtained. Regional failure-free survival (p=0.71, HR=0.88 CI 0.45-1.74) and disease-free survival (p=0.77, HR=1.10 CI 0.58-2.11) of the Case were not significantly different from the ones of Control. There were no major complications related to EBUS procedures.
Conclusion:
EBUS-TBNA can be considered for invasive staging in SBRT-eligible NSCLC patients with radiographically positive lymph nodes because of its safety and possibility of false positive imaging. If EBUS-TBNA result is negative, these patients may remain candidates for SBRT with comparable outcomes to those who are conventionally selected for SBRT.
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P3.09 - Mesothelioma (ID 725)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Mesothelioma
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.09-007 - Thoracic Asymmetry and Its Impact on Survival after Radiation and Surgery for Malignant Pleural Mesothelioma (ID 9086)
09:30 - 09:30 | Author(s): Marc De Perrot
- Abstract
Background:
Staging for malignant pleural mesothelioma (MPM) remains a challenge due to poor prognostic utility. Other clinical factors may improve and refine the staging system. We investigate the impact thoracic asymmetry at time of initial presentation prior to therapy on survival in MPM patients treated with multimodal therapy.
Method:
We reviewed 93 consecutive treatment naïve MPM patients treated with Surgery for Mesothelioma after Radiation Therapy (SMART protocol) from Sep 2008 to Jul 2015. The right and left axial thoracic areas (defined as the product of the ant-post and med-lat extent of hemithoraces at the level of carina) were used to calculate the asymmetric thoracic ratio (ATR, where 1 is more symmetric, Figure 1). Significant factors were determined using univariate (log rank), multivariate (Cox proportional hazards) as well as recursive partition analysis (RPA). Continuous variables were discretized into binary categories split by its median value.
Result:
After a median follow-up of 15.6 months, 63 (68%) patients recurred, 56 (60%) died. The median ATR was 0.85, ranging from 0.52 to 1.00. On univariate analysis, histology (p=0.003 and 0.0002), gross tumour volume (GTV, p=0.004 and 0.001), and ATR (p=0.00001 and 0.0000002) all significantly impacted both overall and disease free survival, respectively, while mediastinal nodal involvement (p=0.03) was significantly associated with DFS only. On multivariate analysis, histology (p=0.01 and 0.005) and GTV (p=0.02 and 0.016) significantly impacted both overall and disease free survival, respectively. ATR significantly impacted disease free survival (p=0.02, HR=0.06 95% CI 0.02-0.20) and was suggestive of a trend for overall survival (p=0.07). On RPA, ATR<0.848 was significantly (p<0.001) associated with poorer DFS.
Conclusion:
A low asymmetric ratio (ATR<0.848) is significantly associated with poorer outcomes, specifically disease free survival, and is independent of histology and tumor volume. Further study is needed to validate this parameter.
