Does dose reduction of afatinib affect treatment outcomes of patients with EGFR-mutant metastatic non-small cell lung cancer in real-world clinical practice?

Background: Afatinib can be started at a dose lower than the recommended starting dose of 40 mg/day for the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), however treatment outcomes in real-world clinical practice remains unclear. Methods: This retrospective study of patients with NSCLC from 18 major hospitals (public, private or university teaching hospitals) enrolled in Malaysia's National Cardiovascular and Thoracic Surgical Database (NCTSD) assessed the efficacy of lower doses of afatinib on treatment outcomes in a real-world clinical practice. Data on clinical characteristics, afatinib dosing, and treatment outcomes for patients included in NCTSD from 1st January 2015 to 31st December 2020 were analyzed. Results: Of the 133 patients studied, 94.7% had adenocarcinoma. Majority of the patients (60.9%) had EGFR exon 19 deletion and 23.3% had EGFR exon 21 L858R point mutation. The mean age of patients was 64.1 years and majority (83.5%) had Eastern Cooperative Oncology Group performance status of 2-4 at diagnosis. The most common afatinib starting doses were 40 mg (37.6%), 30 mg (29.3%), and 20 mg (26.3%) once daily (OD), respectively. A quarter of patients had dose reduction (23.3%) due to side effects or cost constraints. Majority of the patients had partial response to afatinib (63.2%) whilst 2.3% had complete response. Interestingly, the objective response rate was significantly higher (72.3%) with afatinib OD doses of less than 40 mg compared to 40 mg (54.0%) (P=0.032). Patients on lower doses of afatinib were two times more likely to achieve an objective response [odds ratio =2.64; 95% confidence interval (CI): 1.20-5.83; P=0.016]. These patients had a numerically but not statistically longer median time to treatment failure (TTF). Median TTF (95% CI) for the overall cohort was 12.4 (10.02-14.78) months. Median overall survival (95% CI) was 21.30 (15.86-26.75) months. Conclusions: Lower afatinib doses (<40 mg OD) could be equally effective as standard dose in patients with EGFR-mutant advanced NSCLC and may be more suited to Asian patients, minimizing side effects that may occur at higher dosages of afatinib leading to dose interruptions and affecting treatment outcomes.

Real-World Treatment and Outcomes of ALK-Positive Metastatic Non-Small Cell Lung Cancer in a Southeast Asian Country.

Purpose: Anaplastic lymphoma kinase (ALK) inhibitors are associated with good overall survival (OS) for ALK-positive metastatic non-small cell lung cancer (NSCLC). However, these treatments can be unavailable or limited by financial constraints in developing countries. Using data from a nationwide lung cancer registry, the present study aimed to identify treatment patterns and clinical outcomes of ALK-positive NSCLC in Malaysia. Methods: This retrospective study examined data of patients with ALK-positive NSCLC from 18 major hospitals (public, private, or university teaching hospitals) throughout Malaysia between January 1, 2015 and December 31, 2020 from the National Cardiovascular and Thoracic Surgical Database (NCTSD). Data on baseline characteristics, treatments, radiological findings, and pathological findings were collected. Overall survival (OS) and time on treatment (TOT) were calculated using the Kaplan-Meier method. Results: There were 1581 NSCLC patients in the NCTSD. Based on ALK gene-rearrangement test results, only 65 patients (4.1%) had ALK-positive advanced NSCLC. Of these 65 patients, 59 received standard-of-care treatment and were included in the analysis. Crizotinib was the most commonly prescribed ALK inhibitor, followed by alectinib and ceritinib. Patients on ALK inhibitors had better median OS (62 months for first-generation inhibitors, not reached at time of analysis for second-generation inhibitors) compared to chemotherapy (27 months), but this was not statistically significant (P=0.835) due to sample-size limitations. Patients who received ALK inhibitors as first-line therapy had significantly longer TOT (median of 11 months for first-generation inhibitors, not reached for second-generation inhibitors at the time of analysis) compared to chemotherapy (median of 2 months; P<0.01). Conclusion: Patients on ALK inhibitors had longer median OS and significantly longer TOT compared to chemotherapy, suggesting long-term benefit.

Outcomes of Patients with EGFR-Mutant Advanced NSCLC in a Developing Country in Southeast Asia.

Background: Although first- and second-generation EGFR TKIs are considered first-line treatment in EGFRm+ NSCLC, most patients develop resistance and progress, commonly, EGFR T790M mutation. The third-generation EGFR-TKI has demonstrated efficacy in patients with progressive disease harboring the T790M mutation and in the first-line setting, bypassing this mode of resistance. The primary objectives of this study are to describe the proportion of EGFRm+ NSCLC patients treated with first-, second- and third-generation EGFR TKIs, and cytotoxic chemotherapy in the first-line setting, and the time on treatment for each category. Secondary objectives are to determine the dropout rate, the rates for T790M mutation testing at disease progression and the type of subsequent treatment. Methods: This multicenter retrospective study utilized data from the Malaysian Lung Cancer Registry that actively registers all lung cancer patients ≥18 years, with primary lung cancer confirmed histologically or cytologically. All patients diagnosed with advanced stages (ie stages IIIB, IIIC and IV) EGFRm+ NSCLC from 1st of January 2015 to 31st December 2019 were included. Results: Of 406 patients with EGFRm+ NCSLC, 351 were treated. Types of first-line treatment were as follows: EGFR-TKIs (first generation - 54.1%, second generation - 25.6% and third-generation - 12.5%) and chemotherapy (7.7%). The median time of treatment for each generation of EGFR-TKI was 12 months, 12 months and 24 months, and 2 months for chemotherapy. The dropout rate was 28.7% (n = 101). Nearly half (49.4%) of patients who were on first- or second-generation EGFR-TKI had further genetic testing via liquid or tissue biopsies upon disease progression. About 24.9% of those who developed disease progression after first- or second-generation EGFR TKI were started on a third-generation EGFR TKI. Conclusion: In the real-world, the management of EGFRm+ advanced NSCLC patients in an Asian cost-restrictive setting may adversely affect the choice of first-line therapy, time on each line of treatment and subsequently the overall survival of patients.

Programmed death-ligand 1 expression and use of immune checkpoint inhibitors among patients with advanced non-small-cell lung cancer in a resource-limited country.

INTRODUCTION: Immune checkpoint inhibitor (ICI) therapy is an established treatment for advanced non-small-cell lung cancer (NSCLC) and programmed death ligand-1 (PD-L1) expression is a recognized biomarker to determine response to therapy. We retrospectively analyzed NSCLC patients in the Malaysia Lung Cancer Registry (MLCR) and report on the clinical characteristics associated with PD-L1 expression and ICI use in Malaysia, a low- to middle-income country. METHODS: All 901 NSCLC patients in the MLCR who were diagnosed from January 1, 2017 to December 31, 2020 from 14 hospitals across the country were analyzed. RESULTS: Out of 901 patients, 505 had PDL-1 testing done with complete data available only in 489 patients. The most common histology was adenocarcinoma (84.7%) followed by squamous cell carcinoma (10.2%). The majority (95%) presented with stage 3 or 4. The number and percentage of patients with PDL-1 tumor proportion scores of ≥50%, 1-49%, and <1% were 138 (28.2%), 158 (32.3%), and 193 (39.5%), respectively. In multivariate analysis, the presence of genomic mutation is the only independent characteristic associated with negative PD-L1 expression (crude odds ratio 0.579, 95% confidence interval 0.399-0.840, p = 0.004). Of 292 patients eligible for ICI therapy, only 100 patients (34.2%) received ICIs. Seventy-eight patients received ICI therapy as first-line treatment, 15 patients as second-line treatment, and 7 patients as third-line treatment. CONCLUSIONS: This is the first analysis on PD-L1 expression and ICI use in Malaysia. Despite the proven efficacy of ICI therapy, only 56% of our patients had PD-L1 tests performed and only 34.2% of eligible patients received ICIs.

Successful resection of a giant thoracic myxoid liposarcoma.

Primary liposarcoma is an extremely rare disease. We report a case of giant thoracic myxoid liposarcoma that occupied the whole left hemithorax and was successfully resected. We discuss the surgical considerations and difficulties encountered, and how we overcome these challenges. This is the third largest thoracic myxoid liposarcoma resection reported, weighing 4 kg.

Extraskeletal Ewing's sarcoma presenting as a mediastinal mass.

Ewing's sarcoma family of tumors is part of a rare group of malignant neoplasms with small blue, round-cell morphology on hematoxylin and eosin stain, expressing CD99, C-Kit, and Bcl2, and sharing the presence of the translocation t(11:22). Extraskeletal Ewing's sarcoma is a rare disease that typically involves the soft tissues of the trunk or extremities. We describe a case of extraskeletal Ewing's sarcoma presenting as a mediastinal mass in a 16-year-old boy.

Chylopericardium after cardiac surgery can be treated successfully by oral dietary manipulation: a case report.

We report a case of chylopericardium after ascending aorta and aortic valve replacement, which presented as late tamponade. We discuss the various treatment options in this rare condition which can result in serious morbidity or death.

UK waiting time targets in lung cancer treatment: are they achievable? Results of a prospective tracking study.

BACKGROUND: Recent guidelines have specified a number of waiting time targets to prevent delay in the treatment of lung cancer. This study was carried out to assess the quality of lung cancer services and compare with national recommendations. METHODS: All newly diagnosed cases of lung cancer presenting to our institution via general practitioner referral were entered into a prospective tracking study by a dedicated audit officer. From September 2003 to March 2005 a total of 247 patients were entered into the study. Of these 133 (54%) were referred by general practitioners and the remainder 114 (46%) were internal referrals. The Cancer Plan waiting time targets are mainly applicable to GP referrals, which formed the study group. RESULTS: All the patients were seen in chest out-patients clinic within the recommended two weeks period. However there was a delay in starting all forms of treatment. The median waiting time to any form of treatment was 60 days (recommendation 62 days for all patients). CONCLUSION: This data demonstrates that although patients receive out patient consultation in the recommended time period, the National Cancer Plan 62 days GP referral to treatment target is not being achieved. A concerted effort by all clinicians is required to meet the prescribed target times.

Long-term outcomes following VATS lobectomy for non-small cell bronchogenic carcinoma.

OBJECTIVES: Despite advantages regarding pain and muscle function, video-assisted thoracic surgery (VATS) lobectomy is infrequently performed and is particularly controversial in bronchogenic carcinoma. We have, therefore, reviewed our experience with VATS lobectomy for non-small cell lung cancer (NSCLC) in an attempt to define the long-term results of VATS lobectomy in this setting. METHODS: Patients were selected for surgery on the basis of clinical Stage I or II disease with routine use of thoracic/upper abdominal CT scanning and cervical mediastinoscopy. VATS resection was performed using the endoscopic hilar dissection technique. All related hilar nodes were cleared and supportative sampling of mediastinal stations beyond the reach of mediastinoscopy was undertaken. Perioperative data were collected prospectively and oncologic outcomes were assessed by 6 monthly census. RESULTS: One hundred and fifty eight patients (mean age 66 years) underwent 159 VATS lobectomies for NSCLC between May 1992 and December 2001. One patient underwent staged bilateral resections. Twenty further procedures were uneventfully converted to open thoracotomy (rate=11.2%). The median operation time was 130 min and median operative blood loss was 60 ml. The median postoperative stay was 6 days. One patient (0.6%) died following VATS resection from acute respiratory distress syndrome (ARDS). Two VATS resection patients died following discharge but within 30 days of surgery. Combined, inpatient and 30-day outpatient mortality was, therefore, 1.8%. The stage distribution for resected lesions was: Stage I, 117; II, 33 and III, 8. Mean follow-up was 38 months (range: 1-107). Tumour recurred in 36 patients presenting as local recurrence in the hilum or mediastinum in nine (25%), metastatic disease in 23 (63.9%) and unknown pattern in four (11.1%). Kaplan-Meier calculated probabilities of freedom from cancer related or associated death at 60 months were Stage I, 77.9%; II, 51.4% and III, 28.6%. CONCLUSION: VATS lobectomy is a safe procedure which is associated with a low probability for conversion to open thoracotomy. The patterns of cancer recurrence do not suggest inadequate local clearance while the long-term survival data for Stage I NSLC cases is encouraging. We believe that this technique should become the operation of choice for early stage NSCLC.

Spontaneous rupture of the right hemidiaphragm after video-assisted lung volume reduction operation.

Lung volume reduction operation is an important therapeutic option in patients with advanced emphysema. We report a case of spontaneous rupture of the right diaphragm after a video-assisted thoracoscopic surgical procedure for emphysema. The pathophysiology of this complication is also discussed, along with practical points for perioperative management of emphysematous patients.