Stage IIIA Disease Research Articles

Real-world treatment patterns and clinical outcomes in early stage non-small cell lung cancer (eNSCLC) in Canada.

e20504 Background: The prognosis of eNSCLC remains uniformly poor. An understanding of current therapies and outcomes can provide insights into how novel therapies can be integrated into our management paradigm. Methods: We conducted a large, retrospective, population-based cohort study of de novo eNSCLC patients (stages IB, IIA, IIB, and IIIA) diagnosed in Alberta, Canada between 2010-2019 using electronic medical records and administrative claims data. The primary objectives were to describe treatment patterns and survival outcomes among eNSCLC patients. In addition, we examined the association between systemic therapy (ST) and overall survival (OS) using multivariable Cox proportional hazards models. Results: A total of 5,126 eNSCLC patients were included. The stage distributions were: 31.0% IB, 13.4% IIA, 17.7% IIB, and 37.9% IIIA. The mean (SD) age was 71.3 (10.3) years and 52.5% were female. 45.3% of patients were referred to a medical oncologist, ranging from 23.7% in stage IB and 58.3% of IIIA. Among stage IB and II patients, 59.2% and 58.1% received surgery, respectively, while 25.7% of stage IIIA patients underwent surgery. 23.6% of patients initiated ST, ranging from 3.5% in stage IB to 38.5% in IIIA. ST use increased over the study period by 9.3% and 19.5% in stage IIB and IIIA disease, respectively. Median follow-up for the cohort was 21.86 months; median OS was 28.18 months (95% CI: 26.56-29.69). Median OS for stage IB, IIA, IIB, and IIIA were 49.01 (95% CI: 45.00-54.15), 36.56 (95% CI: 32.94-42.25), 29.23 (95% CI: 25.32-33.11), and 16.50 (95% CI: 15.39-17.59). Findings from the Cox analyses are tabulated (see Table). For stage IIB and IIIA individuals who received surgery, adjuvant ST was also associated with a decreased likelihood of death [hazard ratios (HR) of 0.77 (95% CI: 0.56-1.07) and 0.69 (95% CI: 0.54-0.89), respectively]. Conclusions: In a Canadian real-world setting, stage IIB and IIIA patients who received adjuvant ST tended to have better survival than patients who did not. However, a considerable proportion of patients are not referred to a medical oncologist to be considered for ST. Improving referral pathways appears to be an essential step to ensure that emerging novel therapies are implemented effectively in the real world so that potential survival gains from new drugs can be realized.[Table: see text]

Adjuvant lenvatinib after radical resection in patients with hepatocellular carcinoma (HCC): Preliminary analysis of a prospective, multi-center, single-arm study.

e16158 Background: Chinese guidelines recommend surgical resection for patients with China Liver Cancer (CNLC) Stage Ia−IIIa HCC (equal to BCLC stage A/B and selected patients with BCLC stage C). Despite treatment, however, patients with CNLC stage IIb (tumor number > 3) and IIIa (vascular invasion) disease have a high recurrence risk and poor overall survival (OS). Here we assessed the efficacy and safety of adjuvant lenvatinib in patients with high risk of disease recurrence. Methods: In this multi-center, single-arm, prospective clinical trial (NCT04227808), patients underwent radical (R0) resection for CNLC Stage IIb/IIIa HCC within 4-6 weeks were eligible and received treatment of lenvatinib (8 or 12 mg/day for body weight < 60 and ≥60 kg, respectively. Dose modifications were permitted due to adverse reactions) until disease recurrence, intolerable toxicity or death. The primary endpoint was 1-year recurrence-free survival (RFS), and secondary endpoints included OS and safety. The total planned enrollment for this study is 50 patients and here we report our preliminary analysis results. Results: A total of 59 patients were screened from Mar 2020 to Dec 2021 and 50 were enrolled in the study. By the cut of date (Dec 31, 2021), 42 patients had at least one set of follow-up data and were included in the present analysis. The 42 patients were predominantly male (83.3%, n = 35), and the median age was 55.5 years (range: 26–73). 78.6% (n = 33) were HBV-positive and 21.4% (n = 9) of disease were non-viral. Five patients (11.9%) had CNLC Stage IIb and 37 (88.1%) had CNLC Stage IIIa HCC. The median duration of treatment was 8.4 months (range: 1.7-18.7) with a median follow-up of 11.3 months (95% CI: 6.6−15.9). 24% (n = 10) had experienced dose reduction or delay. The 1-year RFS rate was 50.5%, while the median RFS was 16.5 months (95% CI: 11.3–21.7). Two deaths occurred: one secondary to disease recurrence and one from hepatic encephalopathy without recurrence. In total, 90.5% (n = 38) of patients experienced ≥1 treatment-related adverse events (AE) of any grade, and five patients (11.9%) had grade 3 treatment-related AEs (thrombocytopenia in two cases, proteinuria in two cases, and elevated aspartate aminotransferase in one case). There was no treatment-related death. Conclusions: Adjuvant lenvatinib was well-tolerated in patients with CNLC Stage IIb/IIIa HCC after R0 resection. The median RFS was longer than our historical data (mRFS = 9.03 months), and these findings warrant further investigation in a controlled study. Funding: Eisai Co., Ltd. Clinical trial information: NCT04227808.

Nivolumab + chemotherapy versus chemotherapy as neoadjuvant treatment for resectable stage IIIA NSCLC: Primary endpoint results of pathological complete response (pCR) from phase II NADIM II trial.

8501 Background: Non-small cell lung cancer (NSCLC) is incurable in most patients with locally advanced stage IIIA disease. Previous results indicate that the use of neoadjuvant chemoimmunotherapy could increase the percentage of cured patients being a promising therapeutic option that has to be tested in randomized clinical trials. Methods: NADIM II (NCT03838159) is an open-label, randomized, two-arm, phase II, multi-center clinical trial. Patients with resectable clinical stage IIIA (per AJCC 7th ed) NSCLC, ECOG PS 0-1, and no known EGFR/ALK alterations were randomized to receive Nivolumab (NIVO) 360mg + Paclitaxel 200mg/m2 + Carboplatin AUC5 for 3 cycles every 21 days (+/- 3 days) as neoadjuvant treatment followed by surgery, or Paclitaxel 200mg/m2 + Carboplatin AUC5 for 3 cycles every 21 days (+/- 3 days) followed by surgery. Patients with R0 resection confirmed by pathological evaluation initiated adjuvant administration of NIVO within the 3rd to 8th week (+7 days) from surgery and for 6 months. The primary endpoint was pathological complete response (pCR) by blinded independent pathological review (BIPR) in the intent-to-treat population (ITT). pCR was defined as 0% viable tumor cells in resected lung and lymph nodes; patients who did not undergo surgery were classified as non-responders. Major pathological response (MPR; ≤ 10% viable tumor) per BIPR, overall response rate (ORR), toxicity profile, and potential predictive biomarkers are secondary endpoints. Results: Between February 8, 2019, and November 11, 2021, 90 patients were enrolled, of whom 87 patients were valid. Neoadjuvant NIVO + chemo significantly increased the pCR rate compared to chemo in the ITT (36.2% vs 6.8%; Relative Risk (RR) 5.25 [99% CI 1.32-20.87]; P = 0.0071). NIVO + chemo also improved MPR rates vs chemo in the ITT (52 % vs 14 %), as well as ORR (74 % vs 48%). Definitive surgery occurred for 91% of pts treated with NIVO + chemo and 69% with chemo; surgery was cancelled rarely due to AEs (1 pts/experimental arm) and due to disease progression in 1 and 4 pts in the experimental and control arm respectively. Grade 3-4-related AEs were reported in 24 % vs 10% in the NIVO + chemo vs chemo arms, respectively. In the ITT experimental arm, patients with pCR had higher PD-L1 TPS (median 70%, IQR 5-90%) compared to non-responders (median 0%, IQR 0-37.5%, P = 0.0035). AUC to predict pCR was 0.734 (95% CI 0.59-0.88; P = 0.005). The pCR rate rises across increasing categories of PD-L1 TPS ( < 1% 14.3%; 1-49% 41.7%; ≥50% 61.1%; P = 0.008). Conclusions: This study confirms the superiority of the chemo-immuno combination in patients with resectable stage IIIA NSCLC in terms of pCR, as well as the feasibility of surgery, with a moderate increase in grade 3-4 toxicity. Thus, this treatment should become the standard of care in these patients. Clinical trial information: NCT03838159.

Impaction Bone Grafting Augmented With a Wire Coil by the Lightbulb Technique for Osteonecrosis of the Femoral Head

BackgroundOsteonecrosis of the femoral head (ONFH) is a debilitating disease that primarily affects the hips of young adults. The purpose of this study is to report the mid-term results of impaction bone grafting augmented with a wire coil using the lightbulb technique for ONFH. MethodsFrom 1998 to 2016, 50 hips with late precollapsed or early postcollapsed ONFH (28 hips with Association Research Circulation Osseous [ARCO] IIC and 22 with IIIA) were treated by impaction bone grafting augmented with a wire coil using the lightbulb technique. The survival rate was analyzed with conversion to total hip arthroplasty (THA) as the end point. ResultsThirty-one of the 50 hips had a successful clinical result without conversion to THA at a mean follow-up of 109.2 months. The 5-year survival rate was 68%, 82.1%, and 50% for the entire cohort, ARCO stage IIC, and ARCO stage IIIA, respectively. The 19 hips that had failed were converted to THA at an average of 52.8 months. The multivariable Cox proportional hazards model showed that an ARCO stage IIIA disease, a lateral lesion, and a necrotic index ≥0.67 were the independent risk factors for conversion to THA. ConclusionAs a head-preserving procedure, the lightbulb technique using impaction bone grafting augmented with a wire coil is worthwhile for patients in an earlier stage of disease and smaller lesion size to postpone the need for THA.

With a Grain of Salt

Neoadjuvant treatments for locally advanced lung cancers continue to evolve, and more compelling prospective data are becoming available. Neoadjuvant cytotoxic chemotherapy or radiation for stage I or II disease has not been well supported, with the exception of attempting to downstage tumors before surgical resection.1 Phase II trials established the current standard of care of neoadjuvant chemoradiotherapy followed by surgical resection for superior sulcus tumors, and current guidelines support the role of neoadjuvant treatment for patients with stage IIIA disease, including patients with nonbulky N2 involvement.

A Proposal to Modify the 8th IASLC System: Is it Suitable for T4N2M0 Lung Adenocarcinoma to Be Placed in Stage IIIB?

Purpose:The International Association for the Study of Lung Cancer (IASLC) of TNM staging system has been well accepted as a precise model. However, the latest American Joint Committee on Cancer (AJCC) staging system to solve the different survival and prognosis of lung adenocarcinoma in the same period is still controversial. Therefore, it is necessary to thoroughly explore the applicability between the new system and survival prediction in terms of lung adenocarcinoma.Methods:We recruited 52,517 patients with lung adenocarcinoma from the Surveillence, Epidemiology, and End Results database. Cox regression analysis was performed to determine survival related factors. The mortality rate per 1000 persons per year of the T4N2M0 lung adenocarcinoma stage and other stages were compared. Survival curves were obtained using the Kaplan-Meier analysis and log-rank test.Results:The results of Cox proportional hazards regression analysis showed that age at diagnosis, race, T stage, distant metastasis, extrathoracic extension, radiotherapy, chemotherapy, and surgery are independent factors related to cancer-specific survival (CSS) and all-cause survival. Furthermore, patients with stage IIIA disease (P<0.001) and IIIB disease (P<0.001) excluding stage at T4N2M0 had a significantly lower risk of CSS and all-cause survival than those staged with T4N2M0 disease. The mortality rates per 1000 person-years with patients staged at T4N2M0 lung adenocarcinoma had higher mortality than patients in the same period. The CSS curves of patients with stage T4N2M0 reflected an obvious decline compared with those of stages IIIA disease and IIIB excluding T4N2M0, and there is no significant difference between this curve and stage IIIC patients (P>0.05).Conclusion:The survival rate of patients with T4N2M0 stage was significantly lower than that of patients with IIIA and IIIB stages excluding T4N2M0, there was no significant difference between T4N2M0 and IIIC. It was suggested that this group of patients with stage T4N2M0 were upgraded in the 8th IASLC system.

Impact of AJCC prognostic staging on prognosis and postmastectomy radiotherapy decision-making in hormone receptor-positive and HER2-positive breast cancer.

BackgroundThe role of postmastectomy radiotherapy (PMRT) in patients with node-positive hormone receptor-positive (HoR) and HER2-positive breast cancer (BC) regarding AJCC pathological prognostic staging (PPS) has not been fully determined. This study aimed to validate PPS in patients with node-positive HoR+/HER2+ BC after mastectomy and to investigate the role of PPS on PMRT decision-making in this patient subset.MethodsPatients diagnosed with BC from the Surveillance, Epidemiology, and End Results database were included. Patients were classified based on the anatomical staging (AS) and PPS. Breast cancer-specific survival (BCSS) was calculated.ResultsIn total, 6862 patients were included: 4306 (62.8 per cent) patients received PMRT and 2556 (37.2 per cent) patients had not. Compared to AS, PPS downstaged 5260 patients (76.7 per cent) and no patients were upstaged. The C-index was similar between PPS and AS (0.690 versus 0.682; P = 0.346). Regarding AS, patients who received PMRT had significantly better BCSS than those who had not in stage IIIA (P = 0.017) and stage IIIC (P < 0.001) disease, but not in stage IB (P = 0.675), IIA (P = 0.677), IIB (P = 0.100), and IIIB (P = 0.747) disease. Regarding PPS, patients who received PMRT had significantly better BCSS than those who had not in stage IIIA (P = 0.038) and stage IIIB (P = 0.017) disease, but not in stage IA (P = 0.336), IB (P = 0.893), IIA (P = 0.815), and IIB (P = 0.120) disease. PPS might allow approximately 1390 stage III patients (45.0 per cent) in the AS criterion to avoid PMRT.ConclusionPPS does not provide better risk discriminatory ability in predicting prognosis than AS in patients with node-positive HoR+/HER2+ BC after mastectomy. However, PPS is valuable in providing prognostic counselling to patients and may also guide PMRT decision-making.

Real-world Treatment Patterns and Outcomes in Stage III Non-small Cell Lung Cancer: Middle East and Africa – KINDLE Study

IntroductionThe Middle East and Africa (MEA)-KINDLE, as part of a real-world global study, evaluated treatment patterns and survival outcomes in stage III non-small cell lung cancer (NSCLC) in the MEA. Materials and MethodsRetrospective data were analyzed from 33 centers for patients diagnosed between January 01, 2013, and December 31, 2017. Descriptive analyses included clinical-demographics and treatment patterns; inferential statistics evaluated an association of first-line treatment with progression-free survival (PFS) and overall survival (OS). ResultsOf 1,046 patients enrolled, the median (range) age was 61.0 years (24.0-89.0); 83.2% were men, 80.8% were current or past smokers, 58.9% had stage IIIA disease, 47.8% had adenocarcinoma and 20.0% of tested (35/175) had epidermal growth factor receptor mutations. Of 86.0% of patients receiving an initial therapy, about 16% underwent surgical resection. Concurrent chemoradiotherapy (cCRT) (32.3%) was the most frequent treatment modality followed by chemotherapy (CT) alone (19.6%) and sequential CRT (12.1%). Median PFS and OS (months, 95% CI) were 11.8 (10.6, 12.4) and 22.9 (21.2, 26.3), respectively for the overall MEA subset. OS (months) was highest with surgery-based therapies for stage IIIA (IIIA: 37.3, IIIB: 24.1) followed by cCRT (IIIA: 28.9, IIIB: 24.4). Female gender, adenocarcinoma, and cCRT or Sx+CRT in first-line were associated with higher OS (P < .05). ConclusionsThe data reveal an unmet need in stage III NSCLC with worse PFS and OS in the MEA subset than in the global cohort. Better access to newer therapies and quality care will be crucial in improving patient outcomes in the MEA.

An Observational Study on Treatment Outcomes in Patients With Stage III NSCLC in Taiwan: The KINDLE Study

IntroductionPatients with stage III NSCLC represent a very heterogenous group that requires different treatment strategies, especially in patients with N2 (2 nearby lymph nodes having cancer)-positive NSCLC and unresectable EGFR-mutant NSCLC. This real-world study may provide more insights into treatment decisions. MethodsThe KINDLE study is a large, multinational real-world observational study that assessed different treatment strategies in patients with stage III NSCLC. Progression-free survival (PFS) and overall survival (OS) were estimated and compared using Kaplan-Meier and log-rank testing. Patients were classified on the basis of disease stage, resectability, and treatment modalities. ResultsThe Taiwan subgroup enrolled 200 patients. The median PFS and OS values were similar among patients with stage IIIA and stage IIIB disease, but were significantly better in patients who were deemed as a resectable disease than in those who were deemed as an unresectable disease. In patients with N2-positive NSCLC, patients who underwent surgery had better PFS, but not OS, than patients administered with chemoradiotherapy (CRT) (PFS 13.4 vs. 7.3 mo, hazard ratio [HR] = 0.18, p < 0.001; OS 32.4 vs. 22.0 mo, HR = 0.64, p = 0.215). Among patients with unresectable EGFR-mutant NSCLC, OS was significantly poorer after upfront EGFR–tyrosine kinase inhibitors (TKI) than after upfront CRT with sequential EGFR-TKI (27.4 vs. 49.0 mo, HR = 3.09, p = 0.03). ConclusionsOur study suggests that surgery could be added as part of therapy for patients with stage III N2-positive NSCLC. Moreover, upfront CRT with sequential EGFR-TKI seems to be appropriate for stage III unresectable EGFR-mutant NSCLC. Further randomized studies are needed to validate these results.

Treatment patterns and outcomes in early-stage ALK-rearranged non-small cell lung cancer

IntroductionWe evaluated the baseline demographics, treatment patterns, and outcomes of patients with ALK-rearranged early stage (Stage I-III) non-small cell lung cancer (NSCLC). We also evaluated the efficacy and toxicity of durvalumab consolidation treatment in patients with ALK-rearranged unresectable stage III disease. MethodsRetrospective chart-review analysis of all patients with histologically confirmed stage I-III reflexively tested ALK-rearranged NSCLC managed with curative intent at two Canadian Centers. ResultsOf 48 patients, 19 (40%) were stage I, 5 (10%) were stage II and 24 (50%) were stage-III. Median progression-free survival (PFS) was 27.6 months overall (95%CI: 20.5–51.4) and 144.4 months in stage-I, 27.6 months in stage-II and 14.9 months in stage III patients. Of 20 patients with unresectable stage-III disease treated with chemoradiation (9 also received durvalumab consolidation), 18/90% have relapsed. Median PFS was 10.9 months (95%CI:5.9–22.5). A non-significant trend toward improved PFS was seen in patients receiving additional durvalumab compared to patients treated with chemoradiation alone (median PFS, 12.5 vs 5.9 months, p = 0.16). Toxicity-related treatment modifications on subsequent first ALK-TKI at time of metastatic disease were needed in three (33%) patients who had received chemoradiation alone and two (29%) patients with consolidation durvalumab; no relevant pulmonary or hepato-toxicity was observed overall. ConclusionTreatment strategies and PFS of patients with Stage I-III ALK-rearranged NSCLC are similar to patients without molecular driver alterations. Durvalumab consolidation treatment appears generally safe in patients with unresectable stage III ALK-rearranged disease; however, the degree of benefit of such an approach remains unclear.

Validation of the 2021 FIGO staging schema for advanced vulvar cancer

ObjectiveThe International Federation of Gynecology and Obstetrics (FIGO) revised the vulvar cancer staging schema in 2021. Previous stage IIIA–B diseases were reclassified based on nodal size (≤5 mm for stage...

Are older patients with non-small cell lung cancer receiving optimal care? A population-based study

Background Results from studies addressing age-related patterns of cancer care have found evidence of unjustified differences in management between younger and older patients. Methods We examined associations between age and clinical presentation, management and mortality in patients diagnosed with non-small cell lung cancer (NSCLC) between 2002 and 2016. Analyses were adjusted for comorbidity and other factors that may have affected management decisions and outcomes. Results The study population encompassed 40,026 patients with NSCLC. Stage at diagnosis did not differ between age groups ≤ 84. The diagnostic intensity was similar in age groups <80 years. In patients with stage IA–IIB disease and PS 0–2, surgery was more common in the youngest age groups and decreased with increasing age, and was rarely performed in those ≥ 85 years. The use of stereotactic body radiotherapy (SBRT) increased with age (≤69 years 5.4%; ≥85 years 35.8%). In patients with stage IIIA disease and PS 0–2, concurrent chemoradiotherapy was more common in younger patients (≤69 years 55.3%; ≥85 years 2.2%). In stage IA–IIIA disease, no major differences in treatment-related mortality was observed. In stage IIIB–IV and PS 0–2, chemotherapy was more common in patients <80 years. However, 58.1% of patients 80–84 years and 30.3% ≥ 85 years received treatment. In stage IA–IIIA, overall and cause-specific survival decreased with increasing age. No age-differences in survival were observed in patients with stage IIIB-IV NSCLC. Conclusion Treatments were readily given to older patients with metastatic disease, but to a lesser degree to those with early stage disease. Significant differences in cause specific survival were observed in early, but not late stage disease. Our findings underscore the importance of individualized assessment of health status and life expectancy. Our results indicate that older patients with early stage lung cancer to a higher extent should be considered for curative treatment.

Impact of Light Chain Isotype on Clinical Features and Outcomes in Systemic AL Amyloidosis

Purpose: In systemic AL amyloidosis, light chain (LC) isotype has been shown to predict outcome in patients undergoing upfront autologous transplantation. However, less than one-third of newly diagnosed AL patients are transplant-eligible. The objective of our study was to characterize the relationship between LC isotype, organ involvement, response, and survival in patients with newly diagnosed AL amyloidosis irrespective of transplant-eligibility.Methods: We performed a retrospective cohort study on 112 patients with AL amyloidosis who had treatment records at Columbia University Irving Medical Center (CUIMC) between 2015-2019. Two-sided Fisher's exact test was used for categorical variables and two-sided Wilcoxon rank sum test was used for continuous variables. Survival analysis was done using Kaplan Meier method. Overall survival (OS) was the time from randomization to death due to any cause. Event-free survival (EFS) was the time to initiation of a subsequent line of therapy or death due to any cause, whichever was earlier. Two-sided log-rank test was used to test differences between survival curves.Results: Kappa LC isotype was seen in 26% of patients. The proportion of patients with Mayo 2004 stage IIIA or IIIB disease in kappa and lambda isotype was 33% and 35% respectively (p=0.91). Bortezomib-based and daratumumab-based initial therapy was administered in 70% and 8% of patients respectively, with 36% having auto-transplant as part of first-line therapy. Patients with kappa LC isotype had a significantly higher baseline difference in free light chain (dFLC) and involved/uninvolved serum free light chain ratio (sFLCr) compared to lambda (median dFLC, 61.5 vs 21.6 mg/dl respectively, p=0.02; and median sFLCr, 63.5 vs 10.6 respectively; p<0.01). Kappa LC isotype was also associated with a near-significant higher bone marrow plasma cell (BMPC) burden at baseline (median BMPCs, 20% vs 10% respectively; p=0.06). Patients with lambda LC isotype had a significantly higher incidence of kidney involvement compared to kappa (64% vs 38% respectively, p=0.02). There was no significant difference in the incidence of t(11;14) between the two groups. The incidence of hematologic very good partial response or better (≥VGPR), involved free light chain less than 20 mg/dl (iFLC<20), and dFLC less than 10 mg/dl (dFLC<10) at the end of first-line therapy was similar in the two groups (Table in Figure 1). There was no difference in cardiac or renal response rates between the two groups. The proportion of patients requiring a subsequent line of therapy in kappa and lambda isotype was 41.4% and 39.8% respectively (p=0.88). At a median follow-up of 43 months for surviving patients, there was no significant difference in event-free survival (hazard ratio (HR) [kappa/lambda]: 0.76 [0.43-1.38]; p=0.37). However, there was a non-significant trend toward superior OS (HR [kappa/lambda]: 0.47 [0.18-1.23], p=0.12; 4-year OS: 86% vs 67% respectively) in patients with kappa LC isotype. Achievement of hematologic ≥VGPR, iFLC<20 mg/dl, and dFLC<10 mg/dl at end of first-line therapy was associated with a superior OS in our cohort irrespective of light chain isotype.Conclusion: Lambda AL amyloidosis is associated with significantly higher renal involvement compared to kappa. Despite a higher baseline disease burden (dFLC, sFLCr, and percent BMPC) in kappa compared to lambda, there was a trend toward superior OS in the former, which may imply decreased tissue toxicity of kappa FLCs. Further studies should investigate proteomic signatures and immunoglobulin gene usage according to light chain isotype and correlation with clinical phenotype. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Role of immunotherapy in stage IIIA non-small cell lung cancer: a narrative review

: Non-small cell lung cancer (NSCLC) is one of the main leading causes of death by cancer worldwide. Approximately one third of cases are diagnosed at stage III, whose therapeutic strategy based on multimodal treatment has reached a plateau of effectiveness. Treatment with anti-PD-1/PD-L1 [anti-PD-(L)1] antibodies have been stablished in advanced stages due to their improved clinical benefit and acceptable profile of related adverse events. Lately, numerous clinical trials have been designed with diverse approaches to introduce immunotherapy into stages IIIA. The objective of this review is to discuss the different strategies that are being taken in the ongoing clinical trials, taking into account the peculiarities of stage IIIA and the tumor microenvironment. PubMed, major international conferences and clinicaltrials.gov databases were searched from January 1, 1990, to May 11, 2020 using the terms NSCLC, stage III, resectable, unresectable, immunotherapy, checkpoint inhibition, neoadjuvant and adjuvant. In this review we describe, in the context of stage IIIA disease, the impact of anti-PD-(L)1 and conventional therapies on the tumor microenvironment. Moreover, we describe the role of immunotherapy, through the heterogeneous landscape of stage IIIA NSCLC, summarizing ongoing clinical trials in incidental, potentially resectable, and unresectable tumors. We finally discuss the potential of PD-L1, tumor mutation burden (TMB), and T-cell receptor (TCR) repertoire analysis as predictive biomarkers in stage IIIA NSCLC. Initial results seem to favor neoadjuvant over adjuvant treatment, with chemoimmunotherapy combination standing out. Ongoing trials will answer whether immunotherapy can transform stage IIIA from lethal to a curable disease. Additionally, higher pathological response rates observed, open the possibility to establishing it as survival surrogate, speeding up the potential immunotherapy implementation in stage IIIA NSCLC.

The result of adjuvant Vinorelbine plus Cisplatin in completely resected stage IB-IIIA non-small cell lung cancer at Hanoi Medical Unoversity Hospital

Background: Assess clinical, subclinical characteristics of stage IB-IIIA non - small cell lung cancer patients (NSCLC). Evaluating the result of adjuvant vinorelbine plus cisplatin in completely resected stage IB - IIIA NSCLC. Methods: Descriptive study of 70 patients completely resected stage IB - IIIA non - small cell lung cancer were received adjuvant vinorelbine plus cisplatin chemotherapy at Hanoi Medical University Hospital from 01/2016 to 6/2020. Results: The mean age of 56.94 years old, male: female ratio was 2.9:1. 23 (32.8%) patients had postoperative stage IB disease, 24 (34.3%) had stage IIA disease, 13 (18.6%) had stage IIB disease and 10 (14.3%) had stage IIIA disease. The major histological type was adenocarcinoma (78.6%). Median disease free survival was 29.10 ± 1.63 months, and 3 - year survival was 41%. Chemotherapy caused hematologic side effects in 66.67% of patients including neutropenia in 61.4% and grade 3/4 neutropenia in 28.1%. Non - hematologic toxic effects of chemotherapy were reported at low rates and almost mild (grade 1/2). Conclusions: The vinorelbine - cisplatin regimen is an effective regimen in the adjuvant treatment of non - small cell lung cancer, the study showed that the results in disease - free survival and overall survival were comparable to those of other studies in the world. The most common side effect was neutropenia, the other side effects were reported at low rate and usually mild.

Dose-dense Paclitaxel and Carboplatin as Neoadjuvant Chemotherapy for Stage IIB/IIIA Non-small Cell Lung Cancer – A Phase II trial

AimsThe approach to potentially resectable non-small cell lung cancer (NSCLC) remains controversial. There is a benefit of neoadjuvant chemotherapy (NACT), but the ideal regimen is unknown. We evaluated the efficacy and safety of dose-dense NACT in potentially resectable NSCLC in this phase II trial. Materials and methodsPaclitaxel at 80 mg/m2 on days 1, 8 and 15 with AUC-6 carboplatin on day 1, 3 weekly for four cycles was evaluated as NACT. Patients with Eastern Cooperative Oncology Group performance status 0–2, stage IIB and IIIA (with only non-bulky N2 nodes) were included. The primary end point was the objective response rate. Secondary end points included toxicity, progression-free survival, recurrence-free survival, complete resection rate and overall survival. The relative dose intensity (RDI) was calculated to define tolerability (CTRI/2016/05/006916). ResultsIn total, 37 patients were enrolled (median age 55 years). Most (78.8%) were smokers. Most patients had adenocarcinoma (57.6%) and stage IIIA disease (81.0%) according to the seventh American Joint Committee on Cancer staging system. Seventy-eight per cent of patients completed four cycles. The objective response rate was 75.6% with a complete response in 10.8%. The mean RDI of paclitaxel was 88.61%, with 68.0% of patients able to maintain an RDI ≥85.0%. In total, 187 toxicity events were recorded (120 grade 1, 64 grade 2 and three grade 3 events). Common toxicities were peripheral neuropathy (20.3%), myalgia (19.8%), nausea (15.7%) and neutropenia (10.2%). There were no treatment-related deaths. Seventeen patients underwent surgery (lobectomy 82.4%). After a median follow-up of 47 months (95% confidence interval 27–50.7 months), the median progression-free survival was 9.6 months (7.4–17.4) and overall survival was 29.2 months (16.0–37.2). ConclusionDose-dense paclitaxel–carboplatin is feasible, safe and efficacious and should be evaluated further in potentially resectable NSCLC.

Survival in Patients With Sentinel Node-Positive Melanoma With Extranodal Extension.

Prognostic parameters in sentinel node (SN)-positive melanoma are important indicators to identify patients at high risk of recurrence who should be candidates for adjuvant therapy. We aimed to evaluate the presence of melanoma cells beyond the SN capsule-extranodal extension (ENE)-as a prognostic factor in patients with positive SNs. Data from 1,047 patients with melanoma and positive SNs treated from 2001 to 2020 at the Istituto Nazionale dei Tumori in Milano, Italy, were retrospectively investigated. Kaplan-Meier survival and crude cumulative incidence of recurrence curves were estimated. A multivariable logistic model was used to investigate the association between ENE and selected predictive factors. Cox models estimated the effect of the selected predictors on survival endpoints. Median follow-up was 69 months. The 5-year overall survival rate was 62.5% and 71.7% for patients with positive SNs with and without ENE, respectively. The 5-year disease-free survival rate was 54.0% and 64.0% for patients with positive SNs with and without ENE, respectively. The multivariable logistic model showed that age, size of the main metastatic focus in the SN, and numbers of metastatic non-SNs were associated with ENE (all P<.0001). The multivariable Cox regression models showed the estimated prognostic effects of ENE associated with age, ulceration, size of the main metastatic focus in the SN, and number of metastatic non-SNs (all P<.0001) on disease-free survival and overall survival. ENE was a significant prognostic factor in patients with positive-SN melanoma. This parameter may be useful in clinical practice as a selection criterion for adjuvant treatment in patients with stage IIIA disease with a tumor burden <1 mm in the SN. We recommend its inclusion as an independent prognostic determinant in future updates of melanoma guidelines.

Endoscopic Modified Medial Maxillectomy for Inverted Papilloma of the Maxillary Sinus.

Sinonasal inverted papilloma (SNIP) is a benign tumor that can be surgically managed by an endoscopic approach. However, SNIP has a high recurrence rate, mainly due to incomplete resection. This study aimed to analyze the outcomes of endoscopic modified medial maxillectomy in treating SINP originating from the maxillary sinus. The authors retrospectively analyzed 24 patients treated for SNIP via endoscopic modified medial maxillectomy at our institution between August 2014 and June 2019. During surgery, the mucosa involved in the tumor was stripped, and the bone underlying the tumor base was completely excised. Demographic data, surgical technique, location of SNIP attachment, complications, follow-up duration, and recurrence were recorded. Twenty four patients with SNIP were identified (16 males). All patients had Krouse stage-III disease. Eleven patients presented with single attachment and 13 with multiple attachments. None of the patients had any complications during surgery. Four patients had postsurgical facial numbness around the cheek and upper lip. After a mean follow-up of 35.12 ± 14.98 months, no recurrence of SNIP was observed. Endoscopic modified medial maxillectomy is a safe and effective technique for treating SNIP. Recurrence can be reduced by complete excision of the attachment sites.

Cause of death among patients with non-small cell lung cancer treated with postoperative radiation therapy (PORT).

e20555 Background: The indications for post-operative radiation therapy (PORT) in locally advanced non-small cell lung cancer (NSCLC) remain undefined and a major concern is the perceived risk of increased mortality from cardiopulmonary causes. The purpose of this study was to quantify the rate of cardiopulmonary death in patients with resected NSCLC receiving PORT using a large national database. Methods: Using the Surveillance, Epidemiology, and End Results (SEER) database for lung cancer, patients with Stage IIIA or Stage IIIB NSCLC according to the 6th AJCC edition treated with surgery followed by PORT, who also received chemotherapy were identified. Cause of death was categorized as due to lung cancer, other cancer, cardiac, pulmonary, or other and reported as a percentage of total deaths at one and 2 years. Kaplan-Meier survival analysis was done to compare overall survival between Stage IIIA and IIIB patients. Results: From 2004 to 2015, 4387 patients with stage IIIA and IIIB meeting the eligibility criteria were identified. The median age at diagnosis was 65 years old, most patients were male (53%), Caucasian (83%), had adenocarcinoma (54.8%), stage IIIA disease (69%), and N2 disease (78%). The median overall survival for Stage IIIA and IIIB patients was 39 months and 27 months respectively (p &lt; 0.001). Among the 2586 patients that died during the study period, the most common COD was lung cancer (81.3%). Cardiac and pulmonary COD occurred in 86 patients (3.3% of deaths) and 84 patients (3.2% of deaths) respectively, whereas 158 patients (6.1%) died from other cancers and 154 (5.9%) from other causes. There were 77 deaths from cardiopulmonary cause at 2 years (1.7% of patients and 2.9% of deaths). Cardiopulmonary COD was more common in patients with stage IIIB compared to IIIA disease (4.9% vs 3.3% of deaths, p &lt; 0.001). Lung cancer was the most common COD both at 1 and 2 years (85%) whereas cardiopulmonary was the COD in 5.2% of patients at 1 year and 5.1% at 2 years. Conclusions: This analysis showed a low cardiopulmonary mortality from PORT in the first 2 years. The role for adjuvant radiotherapy remains undefined and treatment decisions for patients with resected stage III NSCLC should be guided by co-morbidities and the competing risk for death from lung cancer.

Doubling of median overall survival in a nationwide cohort of veterans with stage III non-small cell lung cancer in the durvalumab era.

8546 Background: The standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC) is concurrent chemoradiotherapy followed by durvalumab maintenance based on outcomes from the PACIFIC trial. However, PACIFIC did not include Veterans, a unique population with significant co-morbidities; thus, the impact of durvalumab on survival of Veterans with stage III NSCLC is unknown. Methods: Using the U.S. Department of Veterans Affairs Corporate Data Warehouse, patients with stage III non-small cell lung cancer who received chemoradiotherapy and at least one dose of durvalumab were selected. Kaplan-Meier survival analysis and univariate Cox proportional hazards modeling were used to determine progression-free survival (PFS), overall survival (OS) and independent predictors of PFS and OS. PFS was manually extracted by review of serial surveillance scans. All statistical computations were performed using SAS 9.4 software. Results: 1106 Veterans met our inclusion criteria. The median age was 69. 95.1% (n = 1052) were male. The median Charlson Comorbidity Index was 1. 86.4% (n = 956) reported current or former tobacco use. 48.1% (n = 532) had adenocarcinoma histology, 48.4% (n = 535) squamous cell, 0.5% (n = 5) large cell, 0.3% (n = 3) neuroendocrine, and 0.1% (n = 1) sarcomatoid. 60% (n = 619) had AJCC 8th edition stage IIIA disease, 34.5% (n = 382) stage IIIB, and 3.3% (n = 36) stage IIIC. Median PFS was 19.9 months (95% CI: 16.9 – 23.6) and median OS was 34.9 months (95% CI: 29.7 – not reached). In univariate survival analyses, adenocarcinoma histology (HR 1.14, p = 0.03) predicted progression. Older age (HR 1.03, p &lt; 0.0001) and stage IIIB/IIIC disease (HR 1.05, p = 0.008) predicted inferior OS. 18.4% (n = 204) of patients completed all planned cycles of adjuvant durvalumab. The median number of durvalumab infusions received was 6 (range: 1 – 38). Among evaluable patients, 175 (19.4%) discontinued durvalumab for progression, 211 (23.4%) discontinued for suspected immune-related toxicity and 17 (1.9%) died during treatment. Conclusions: While several factors have led to the improvement of OS in patients with stage III NSCLC over time, we report a doubling of median OS in Veterans with stage III NSCLC who received chemoradiotherapy plus durvalumab as compared to historical cohorts who received chemoradiotherapy alone (1). Veterans in our study received a lower median number of durvalumab infusions as compared to patients in the PACIFIC trial (6 vs. 14), and a significant proportion discontinued durvalumab due to suspected immune-mediated toxicity (23.4%). If further analyses confirm our findings, investigation of alternative dosing regimens and/or dosing intervals of durvalumab in order to balance safety and efficacy of durvalumab therapy in Veterans is warranted. (1) Santana-Davila R et al. J Clin Oncol. 2015 Feb 20;33(6):567-74.