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Cytotoxic chemotherapy in advanced non–small cell lung cancer with poor performance status: A retrospective analysis from routine clinical practice
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Cytotoxic chemotherapy in advanced non–small cell lung cancer with poor performance status: A retrospective analysis from routine clinical practice Harish Kancharla a, Naresh Gundu a, Neha Pathak a, Ilavarasi Vandidassane a, Sachin Khurana a, Deepam Pushpam a, Deepali Jain b, Sunil Kumar c, Sushmita Pathy d, Anant Mohan e, Prabhat Singh Malik a,∗ a
Department of Medical Oncology, All India Institute of Medical Sciences, Delhi, India Department of Pathology, All India Institute of Medical Sciences, Delhi, India c Department of Surgical Oncology, All India Institute of Medical Sciences, Delhi, India d Department of Radiation Oncology, All India Institute of Medical Sciences, Delhi, India e Department of Pulmonary Medicine and Sleep Disorders, All India Institute of Medical Sciences, Delhi, India b
a b s t r a c t Background: Platinum-based combination chemotherapy is recommended as the standard treatment for patients with advanced non–small-cell lung cancer (NSCLC), but its benefit is limited to patients with performance status (PS) of 0 or 1. However, it is not clear whether these benefits apply to patients with poor performance status (PS 2 and above) and there are no predictors of outcome to suggest whom to treat. The patients with poor performance status (PS 2 and above) accounts for a significant portion (up to 30%) of patients of our practice. In this retrospective analysis, we have analyzed our experience of chemotherapy in patients with poor performance status. Method: A retrospective analysis of patients of advanced NSCLC with poor PS (ECOG PS 2 or more), treated with chemotherapy from October, 2016 to June, 2018 was done. Patients with driver mutations who were treated with first line tyrosine kinase inhibitors were excluded. Hospital case records were reviewed for baseline characteristics, treatment details, and outcome data. Kaplan-Meier curves were drawn to estimate progression free survival. Log-rank test was used to assess factors affecting survival. Data was analyzed using STATA ver 11 (StataCorp. 2009. College Station, TX: StataCorp LP). P value <0.05 was taken as significant. Result: A total of 96 patients were included in
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Declaration of Competing Interest: The authors have nothing to disclose. Correspondence to: Prabhat Singh Malik, Department of Medical Oncology, All India Institute of Medical Science, Ansari Nagar, Delhi 110029, India. E-mail address: [email protected] (P.S. Malik). ∗
https://doi.org/10.1016/j.currproblcancer.2020.100550 0147-0272/© 2020 Elsevier Inc. All rights reserved.
Please cite this article as: H. Kancharla, N. Gundu and N. Pathak et al., Cytotoxic chemotherapy in advanced non–small cell lung cancer with poor performance status: A retrospective analysis from routine clinical practice, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2020.100550
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the analysis. The median age of the patients was 62 years (range 30-84 years). Majority (67.7%) was males and 65% patients were smokers (current or former). Patients with ECOG PS (Eastern Cooperative Oncology Group Performance Status) of 2 constituted 64.5% of this cohort and 34 patients (33.5%) had an ECOG PS of 3 or 4. The most common chemotherapy regimen used was combination of weekly paclitaxel (60 mg/m2 ) and carboplatin (AUC2) in 57.8%. Most patients (64%) could complete 4 or more cycles of chemotherapy, however, 15 patients (15.7%) could receive only 1 cycle. Grade 3/4 toxicities were observed in 22 (23%) % patients, which were hematological in most cases (anemia and thrombocytopenia). At least one point improvement in ECOG PS from baseline during chemotherapy was observed in 43 patients (45%) after 4 cycles of chemotherapy. Objective response and disease control rates were 20% and 48.42%, respectively. After a median follows-up of 11.2 months, median progression free survival was 6.3 months (95% confidence interval 5-10.63). On univariate analysis, we found that male sex and use of weekly paclitaxel-carboplatin were associated with better progression-free survival PFS. Conclusion: Systemic chemotherapy in modified doses and schedules in advanced NSCLC patients with PS 2 and above is feasible and may be associated with better symptom palliation with clinical benefit and improved survival. © 2020 Elsevier Inc. All rights reserved.
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Keywords: Chemotherapy; Non–small cell Lung carcinoma; Poor performance status
Introduction Lung cancer is the most common cancer and cause of cancer related mortality worldwide accounting for the largest number of deaths (1.8 million deaths, 18.4% of the total).1 In India, it is the most common cancer and cause of cancer related deaths in males. Most patients with non–small-cell lung cancer (NSCLC) have distant/advanced disease at the time of diagnosis, and the 5-year survival for these patients is as low as 3%-4%.2 Apart from stage, ECOG performance status (PS) is one of the strong determinants of outcome. Most treatment guidelines recommend best supportive care alone to the patients with ECOG PS 3 and 4 in absence of driver mutations.3-7 There is equipoise about standard treatment modality in patients with ECOG PS 2. Most therapeutic clinical trials exclude these patients. This poor prognosis subgroup accounts for approximately 20%-30% of patient’s population in routine clinical practice. Factors responsible for poor PS are higher age, comorbidities, poor nutritional status, and high disease burden. Patients with advanced NSCLC harboring a targetable driver mutation can still be benefited with appropriate tyrosine kinase inhibitors (TKIs) since these agents are associated with low toxicity and good possibility of antitumor response. However, in absence of driver mutations, cytotoxic chemotherapy might results in higher toxicity, which may outweigh the anticipated benefit. However, poor PS is a heterogeneous population, and it can be postulated that those with poor PS attributable to high tumor burden might benefit from chemotherapy. Data regarding use of cytotoxic chemotherapy in patients with poor PS is scarce. In this retrospective analysis, we have analyzed the data of patients with poor performance status treated with cytotoxic chemotherapy on clinician discretion in our practice.
Patients and methods A retrospective analysis was carried out of the case records of patients with advanced NSCLC treated between October, 2016 and June, 2018 at our clinic. Patients with ECOG PS ≥2 who had received one or more cycles of chemotherapy were included in the analysis. Patients who were EGFR (epidermal growth factor receptor) mutated or ALK (anaplastic lymphoma kinase) rearranged and treated with first-line TKIs or TKIs before 4 cycles of chemotherapy were excluded from the analysis. Please cite this article as: H. Kancharla, N. Gundu and N. Pathak et al., Cytotoxic chemotherapy in advanced non–small cell lung cancer with poor performance status: A retrospective analysis from routine clinical practice, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2020.100550
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The hospital case records were reviewed for baseline characteristics, treatment details, and outcome data. Patient’s clinical details, investigations, and treatment details were obtained and entered into a structured pro forma. Performance status of each patient was determined by treating physician using the Eastern Cooperative Oncology Group grading.8 All patients received chemotherapy with either single agent or combination chemotherapy at modified schedules and abbreviated doses. The treatment was given after assessing comorbidities at the discretion of the treating clinicians. Palliative radiotherapy to painful bony sites and whole brain radiotherapy to patients with brain metastasis was given on case to case basis after discussing in multidisciplinary team. Response was assessed at the baseline and after 4 cycles of chemotherapy (CT) by repeat computed tomography scan and labeled as per the Response Evaluation Criteria In Solid Tumors criteria (RECIST v 1.1) which is a set of published rules that define when cancer patients improve (“complete responders [CR] or partial responders [PR]”), stable disease”, or worsen (“progressive disease”) during treatments.9 CR and PR were together classified as “responders” while stable disease and progressive disease clubbed as “no responders.” The objective response rate was defined as the sum of CR and PR, and disease control rate (DCR) was defined as the sum of CR, PR, and stable disease. Toxicity was assessed with Common Terminology Criteria for Adverse Events (CTCAE) v4.0.10
Calculations Kaplan-Meier curve was drawn to estimate progression free survival. Cox regression analysis was performed to assess factors affecting survival. Progression free survival was calculated from the day of start of treatment to date of disease progression or death. Data was censored on October 30, 2018 or the date when the patient was last known to alive without disease progression. Data was analyzed using STATA ver 11 (StataCorp. 2009. College Station, TX: StataCorp LP). Ethics committee approved the project and consent waiver was granted in view of retrospective nature of the study. Patient confidentiality was maintained by annotating the patient identifiers.
Results A total of 96 patients were found to be eligible for this analysis. Median age was 61 years (range 30-84 years) including 23 (24%) patients who were 70 years of age or above. Majority (67.7%) were males and 65% patients were smokers (current or former). Patients with ECOG PS of 2 constituted 64.5% of this cohort but 34 patients (33.5%) had ECOG PS of 3 or 4. Two or more sites of extrathoracic metastasis were present in 34 (35.4%) patients. Brain metastasis at presentation was there in 10 (10.4%) cases and malignant pleural/pericardial effusion was present in 31.2% cases. Almost half (45.8%) patients had one or more comorbidities. The most common histological type was adenocarcinoma and few patients were positive for EGFR and ALK rearrangement (Table 1). The most common chemotherapy regimen used was weekly paclitaxel (60 mg/m2 ) and carboplatin (AUC2) in 57.8% followed by pemetrexed (500 mg/m2 ) with standard folate and B12 supplementation and carboplatin (AUC5) in 16.8% patients. Single agent chemotherapy using paclitaxel was given in 9 (13.6%) patients (Table 2). Most patients (64%) could complete 4 or more cycles of chemotherapy, however, 15 patients (15.7%) could receive only 1 cycle. Some 21% patients could even receive maintenance chemotherapy. Chemotherapy had to be interrupted due to poor tolerance in 20 (21%) patients. Grade 3/4 toxicities (Table 2) were observed in 22 (23%) % patients, which were hematological in most cases (anemia and thrombocytopenia) and there were no treatment related deaths. Please cite this article as: H. Kancharla, N. Gundu and N. Pathak et al., Cytotoxic chemotherapy in advanced non–small cell lung cancer with poor performance status: A retrospective analysis from routine clinical practice, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2020.100550
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H. Kancharla, N. Gundu and N. Pathak et al. / Current Problems in Cancer xxx (xxxx) xxx Table 1 Demography and clinical characteristics. Parameter Gender Males Females Median age (years) ≥70 years Median symptom duration (months) Smokers Nonsmokers Comorbidities (1 or more) Pleural effusion Brain metastasis Extrathoracic mets (>2 sites) ECOG PS 2 3 4 Histology Squamous cell carcinoma Adenocarcinoma Others Hemoglobin ≤10 g/dL >10) g/dL Serum Albumin <3.5 g/dL ≥3.5 g/dL EGFR mutations positive ALK rearrangement positive
N = 96 65 (67.71%) 31 (32.29%) 62 (30-84) 23 (24%) 3.0 (1-12) 63 (65.62%) 33 (34.38%) 44 (45.8%) 31 (32%) 10 (10.5%) 34 (35.5%) 62 (64.58%) 27 (28.12%) 7 (7.29%) 38 (39.58%) 51 (53.12%) 7 (7.3%) 17 (17.71%) 79 (82.29) 50 (52%) 46 (48%) 4 (4.1%) 3 (3.1%)
Table 2 Treatment details and adverse effects. Induction chemotherapy regimen 1) Pemetrexed- Carboplatin/cisplatin (q3weekly) 2) Paclitaxel –Carboplatin (q3 weekly) 3) Paclitaxel – Carboplatin (qWeekly) 4)Gemcitabine (D1 & D8)- Cisplatin/carboplatin on D1) 5) Single agent paclitaxel (qWeekly)
16 (16.8%) 8 (8.4%) 55 (57.8%) 3 (3.1%) 9 (13.6%)
Number of chemotherapy cycles received 4 or more # Only 1#
61 (64%) 15 (15.7%)
Chemotherapy interruptions due to poor tolerance
20 (21%)
Grade ¾ toxicity 1) Vomiting 2) Diarrhea 3) Mucositis 4) Anemia 5) Thrombocytopenia 6) Neutropenia
22 (23%) 1 (1.05) 2 (2.11) 1 (1.05) 7 (7.37) 8 (8.42 %) 3 (3.16 %)
Objective response and disease control rates were 20% and 48.42%, respectively. After a median follow-up of 11.2 months, the median progression free survival (Fig. 1) was 6.3 months (95% confidence interval [CI] 5-10.63). On univariate analysis, we found that male sex and use of weekly paclitaxel-carboplatin were associated with better PFS. (Table 3). Please cite this article as: H. Kancharla, N. Gundu and N. Pathak et al., Cytotoxic chemotherapy in advanced non–small cell lung cancer with poor performance status: A retrospective analysis from routine clinical practice, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2020.100550
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Fig. 1. Kaplan-Meier curve showing median PFS.
Table 3 Univariate analysis for relative risk of progression. Variable
HR
95% CI
P value
1.0 1.83
1.07-3.13
0.026
1 1.29
0.74-2.24
0.35
1 0.62 0.56
0.34-1.1 0.27-1.16
0.11 0.12
1 0.81
0.44-1.48
0.49
1 1.01
0.59-1.73
0.9
1 1.01
0.52-1.95
0.97
1 1.72
0.91-3.22
0.08
1 0.98
0.52-1.65
0.96
1 1.29 0.48 1.63 0.68
0.49-3.41 0.25-0.91 0.46-5.77 0.29-16
0.59 0.02 0.4 0.38
Gender Male Female ECOG PS 2 3&4 Comorbidities 0 1 ≥2 Extra thoracic metastasis 0 ≥1 Histology Squamous Nonsquamous Hemoglobin ≤10 g/dL >10) g/dL Neutrophilic-Lymphocytic Ratio(NLR) ≤5 >5 S. Albumin <3.5 g/dL ≥3.5 g/dL Type of chemo regimen 1)Pemetrexed- Carboplatin/cisplatin(q3 weekly) 2)Paclitaxel –Carboplatin(q3 weekly) 3)Paclitaxel – Carboplatin(qWeekly) 4)Gemcitabine(D1 & D8)- Cis/carboplatin on D1) 5)Single agent paclitaxel (qWeekly)
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Discussion PS is one of the strongest independent prognostic factors for survival of patients with advanced NSCLC.11-14 ECOG PS 2 and more are usually associated with a poorer prognosis. In absence of targetable driver mutation, the therapeutic approach is nihilistic for these patients. Considering high-risk benefit ratio, best supportive care or single/abbreviated chemotherapy has been suggested for these patients.15 Most clinical trials exclude this poor risk group in view of higher anticipated toxicities. Reasons for poor PS in advanced NSCLC could be high disease burden, advanced age, comorbidities, and poor nutritional state. The subgroup where poor PS is due to high disease burden might still benefit with cytotoxics since it is one of the reversible factors and PS might actually improve if there is some disease response.16 However, this hypothesis has not been formally evaluated. Interpretation of ECOG PS is also variable among physicians and between patients and physicians.17 , 18 In this study, we have retrospectively evaluated the cohort of 96 patients with ECOG PS 2 or more who were treated with systemic chemotherapy based on clinician discretion. Most of the patients in this cohort possibly received chemotherapy since poor PS might have been due to high disease burden as patient >70 years constituted only 24%, only 46% had one or more comorbidities, 19% had Hb ≤10 gm/dL and 50% had albumin ≥3.5 gm/dL. We observed that 45.26% patients showed improvement of at least one point in ECOG PS from baseline during chemotherapy and 64% could complete 4 or more cycles of chemotherapy. Objective response and disease control rates were 20% and 48.42%, respectively which are almost as good as in relatively fit patients. Median progression free survival of 6.3 months (95% CI 5-10.63 months) is relatively higher than expected from this poor risk subgroup. This is possibly a falsely high estimation due to variable timings of radiological assessment, censoring due to short follow up or a selection bias as relatively fitter patients might have been taken up for chemotherapy. Overall survival was not estimated in this study due to small number, limited follow up with less number of events till last follow up and very few deaths were recorded in the case files. In our study, we observed that male gender and induction regimen (weekly paclitaxel + carboplatin vs other regimens) were significantly associated (P <0.05) with better median progression-free survival (PFS). The 4 independent poor factors that have been previously studied are male sex, anemia, weight loss, and poor Karnofsky PS.19 , 20 Male gender, as opposed to other studies, found to be associated with better clinical outcome in our study. This could be due to majority were males (67.7%) in this cohort of poor risk population and most of the females patients were excluded as they were found to harbor driver mutations and treated with TKIs accordingly. In our study, among patients who could not complete 4 cycles of chemotherapy, the interruption was mostly due to poor tolerance and grade 3/4 toxicity, especially hematological toxicities which were seen in 18 patients. Although cisplatin-containing regimens are usually associated with more nephrotoxicity, nausea, and vomiting, and carboplatin combinations cause more severe thrombocytopenia and other hematological toxicities21 Carboplatin based regimens are still preferred in poor PS due to better nonhematological toxicity profile and ease of administration. A higher rate of toxic deaths has been observed in the Big Lung Trial, which has reported 2.8% and 7.5% risk of treatment related deaths in patients with PS 0-1 and PS 2, respectively.22 It would be always appropriate to know if less intense regimens or single agent chemotherapy can have lesser toxicities and still have efficacy. It has been reported earlier that lower doses of paclitaxel administered weekly along with carboplatin resulted in similar efficacy and lesser neurotoxicity.21 CALGB analysis of study 9730, compared single-agent (paclitaxel) to combination (carboplatin plus paclitaxel) chemotherapy and found that patients treated in the combination chemotherapy group had a statistically significantly better survival in the overall group and in the PS 2 group, with no difference in toxicity between both groups.22 Similar results were seen in 2 small phase II randomized trials. But, it is cautioned to interpret any trials in poor PS patients without standard control group.23 In contrast, pooled analysis of 6 randomized trials has shown that platinum-based doublets improved overall response rate (odds ratio
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3.243; 95% CI 1.883-5.583) and 1-year survival rate (odds ratio 1.743; 95% CI 1.203-2.525) with increased hematological toxicities compared to single agent in patients with PS 2.4 For elderly or with PS 2 patients, single-agent vinorelbine and gemcitabine improve overall survival without compromising the quality of life.5 , 24 In a Phase III trial comparing docetaxel versus vinorelbine in elderly patients with PS ≥2, docetaxel improved PFS (median = 5.5 vs 3.1 months; P <0.001) and response rates (22.7% vs 9.9%; P = 0.019) versus vinorelbine. Similarly a French Intergroup study (IFCT-0501) compared monthly carboplatin plus weekly paclitaxel versus single-agent vinorelbine or gemcitabine in patients aged 70-89 years with PS 0-2 and reported a survival advantage for combination therapy (median overall survival = 10.3 months for doublet versus 6.2 months for monotherapy, hazard ratio = 0.64; 95% CI 0.52-0.78; P < 0.0 0 01).6 A retrospective analysis was done in 485 NSCLC patients, 20% of which constituted poor PS patients (Karnofsky 60-70).This study demonstrated that there was clinical improvement, defined as attainment of good PS, in 25% patients who had poor PS at baseline. This improvement was greater in responders (38%) versus nonresponders (17%).25 Putting all these results and our analysis together, it seems that abbreviated or single agent chemotherapy protocols are feasible in a selective group of patients with poor PS. It may result in improvement in PS and thereby their quality of life. We also propose an adaptive strategy by escalating treatment intensity in patients achieving improvement in PS after initial abbreviated chemotherapy. However, such approach would require formal evaluation and validation in prospective manner before implementing in routine clinical practice. There are several limitations of our study particularly the retrospective nature, small number and multiple chemotherapy regimens used which make its generalization difficult. No formal quality of life assessment has been done. Improvement in PS assessed by various physicians in routine practice that has a high probability of bias and variation further makes the interpretation difficult. In conclusion, the present retrospective study shows the feasibility of systemic chemotherapy in abbreviated doses/regimens in clinically selected group of patients with poor PS, in terms of improvement in PS and PFS. These observations encourage more studies to evaluate objective criteria’s to identify patients from this poor risk group who could benefit with chemotherapy. More response adaptive strategies are required to be developed to tackle this poor risk group patients that constitute a significant proportion in routine clinical practice.
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Current Problems in Cancer journal homepage: www.elsevier.com/locate/cpcancer
Cytotoxic chemotherapy in advanced non–small cell lung cancer with poor performance status: A retrospective analysis from routine clinical practice Harish Kancharla a, Naresh Gundu a, Neha Pathak a, Ilavarasi Vandidassane a, Sachin Khurana a, Deepam Pushpam a, Deepali Jain b, Sunil Kumar c, Sushmita Pathy d, Anant Mohan e, Prabhat Singh Malik a,∗ a
Department of Medical Oncology, All India Institute of Medical Sciences, Delhi, India Department of Pathology, All India Institute of Medical Sciences, Delhi, India c Department of Surgical Oncology, All India Institute of Medical Sciences, Delhi, India d Department of Radiation Oncology, All India Institute of Medical Sciences, Delhi, India e Department of Pulmonary Medicine and Sleep Disorders, All India Institute of Medical Sciences, Delhi, India b
a b s t r a c t Background: Platinum-based combination chemotherapy is recommended as the standard treatment for patients with advanced non–small-cell lung cancer (NSCLC), but its benefit is limited to patients with performance status (PS) of 0 or 1. However, it is not clear whether these benefits apply to patients with poor performance status (PS 2 and above) and there are no predictors of outcome to suggest whom to treat. The patients with poor performance status (PS 2 and above) accounts for a significant portion (up to 30%) of patients of our practice. In this retrospective analysis, we have analyzed our experience of chemotherapy in patients with poor performance status. Method: A retrospective analysis of patients of advanced NSCLC with poor PS (ECOG PS 2 or more), treated with chemotherapy from October, 2016 to June, 2018 was done. Patients with driver mutations who were treated with first line tyrosine kinase inhibitors were excluded. Hospital case records were reviewed for baseline characteristics, treatment details, and outcome data. Kaplan-Meier curves were drawn to estimate progression free survival. Log-rank test was used to assess factors affecting survival. Data was analyzed using STATA ver 11 (StataCorp. 2009. College Station, TX: StataCorp LP). P value <0.05 was taken as significant. Result: A total of 96 patients were included in
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Declaration of Competing Interest: The authors have nothing to disclose. Correspondence to: Prabhat Singh Malik, Department of Medical Oncology, All India Institute of Medical Science, Ansari Nagar, Delhi 110029, India. E-mail address: [email protected] (P.S. Malik). ∗
https://doi.org/10.1016/j.currproblcancer.2020.100550 0147-0272/© 2020 Elsevier Inc. All rights reserved.
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the analysis. The median age of the patients was 62 years (range 30-84 years). Majority (67.7%) was males and 65% patients were smokers (current or former). Patients with ECOG PS (Eastern Cooperative Oncology Group Performance Status) of 2 constituted 64.5% of this cohort and 34 patients (33.5%) had an ECOG PS of 3 or 4. The most common chemotherapy regimen used was combination of weekly paclitaxel (60 mg/m2 ) and carboplatin (AUC2) in 57.8%. Most patients (64%) could complete 4 or more cycles of chemotherapy, however, 15 patients (15.7%) could receive only 1 cycle. Grade 3/4 toxicities were observed in 22 (23%) % patients, which were hematological in most cases (anemia and thrombocytopenia). At least one point improvement in ECOG PS from baseline during chemotherapy was observed in 43 patients (45%) after 4 cycles of chemotherapy. Objective response and disease control rates were 20% and 48.42%, respectively. After a median follows-up of 11.2 months, median progression free survival was 6.3 months (95% confidence interval 5-10.63). On univariate analysis, we found that male sex and use of weekly paclitaxel-carboplatin were associated with better progression-free survival PFS. Conclusion: Systemic chemotherapy in modified doses and schedules in advanced NSCLC patients with PS 2 and above is feasible and may be associated with better symptom palliation with clinical benefit and improved survival. © 2020 Elsevier Inc. All rights reserved.
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Keywords: Chemotherapy; Non–small cell Lung carcinoma; Poor performance status
Introduction Lung cancer is the most common cancer and cause of cancer related mortality worldwide accounting for the largest number of deaths (1.8 million deaths, 18.4% of the total).1 In India, it is the most common cancer and cause of cancer related deaths in males. Most patients with non–small-cell lung cancer (NSCLC) have distant/advanced disease at the time of diagnosis, and the 5-year survival for these patients is as low as 3%-4%.2 Apart from stage, ECOG performance status (PS) is one of the strong determinants of outcome. Most treatment guidelines recommend best supportive care alone to the patients with ECOG PS 3 and 4 in absence of driver mutations.3-7 There is equipoise about standard treatment modality in patients with ECOG PS 2. Most therapeutic clinical trials exclude these patients. This poor prognosis subgroup accounts for approximately 20%-30% of patient’s population in routine clinical practice. Factors responsible for poor PS are higher age, comorbidities, poor nutritional status, and high disease burden. Patients with advanced NSCLC harboring a targetable driver mutation can still be benefited with appropriate tyrosine kinase inhibitors (TKIs) since these agents are associated with low toxicity and good possibility of antitumor response. However, in absence of driver mutations, cytotoxic chemotherapy might results in higher toxicity, which may outweigh the anticipated benefit. However, poor PS is a heterogeneous population, and it can be postulated that those with poor PS attributable to high tumor burden might benefit from chemotherapy. Data regarding use of cytotoxic chemotherapy in patients with poor PS is scarce. In this retrospective analysis, we have analyzed the data of patients with poor performance status treated with cytotoxic chemotherapy on clinician discretion in our practice.
Patients and methods A retrospective analysis was carried out of the case records of patients with advanced NSCLC treated between October, 2016 and June, 2018 at our clinic. Patients with ECOG PS ≥2 who had received one or more cycles of chemotherapy were included in the analysis. Patients who were EGFR (epidermal growth factor receptor) mutated or ALK (anaplastic lymphoma kinase) rearranged and treated with first-line TKIs or TKIs before 4 cycles of chemotherapy were excluded from the analysis. Please cite this article as: H. Kancharla, N. Gundu and N. Pathak et al., Cytotoxic chemotherapy in advanced non–small cell lung cancer with poor performance status: A retrospective analysis from routine clinical practice, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2020.100550
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The hospital case records were reviewed for baseline characteristics, treatment details, and outcome data. Patient’s clinical details, investigations, and treatment details were obtained and entered into a structured pro forma. Performance status of each patient was determined by treating physician using the Eastern Cooperative Oncology Group grading.8 All patients received chemotherapy with either single agent or combination chemotherapy at modified schedules and abbreviated doses. The treatment was given after assessing comorbidities at the discretion of the treating clinicians. Palliative radiotherapy to painful bony sites and whole brain radiotherapy to patients with brain metastasis was given on case to case basis after discussing in multidisciplinary team. Response was assessed at the baseline and after 4 cycles of chemotherapy (CT) by repeat computed tomography scan and labeled as per the Response Evaluation Criteria In Solid Tumors criteria (RECIST v 1.1) which is a set of published rules that define when cancer patients improve (“complete responders [CR] or partial responders [PR]”), stable disease”, or worsen (“progressive disease”) during treatments.9 CR and PR were together classified as “responders” while stable disease and progressive disease clubbed as “no responders.” The objective response rate was defined as the sum of CR and PR, and disease control rate (DCR) was defined as the sum of CR, PR, and stable disease. Toxicity was assessed with Common Terminology Criteria for Adverse Events (CTCAE) v4.0.10
Calculations Kaplan-Meier curve was drawn to estimate progression free survival. Cox regression analysis was performed to assess factors affecting survival. Progression free survival was calculated from the day of start of treatment to date of disease progression or death. Data was censored on October 30, 2018 or the date when the patient was last known to alive without disease progression. Data was analyzed using STATA ver 11 (StataCorp. 2009. College Station, TX: StataCorp LP). Ethics committee approved the project and consent waiver was granted in view of retrospective nature of the study. Patient confidentiality was maintained by annotating the patient identifiers.
Results A total of 96 patients were found to be eligible for this analysis. Median age was 61 years (range 30-84 years) including 23 (24%) patients who were 70 years of age or above. Majority (67.7%) were males and 65% patients were smokers (current or former). Patients with ECOG PS of 2 constituted 64.5% of this cohort but 34 patients (33.5%) had ECOG PS of 3 or 4. Two or more sites of extrathoracic metastasis were present in 34 (35.4%) patients. Brain metastasis at presentation was there in 10 (10.4%) cases and malignant pleural/pericardial effusion was present in 31.2% cases. Almost half (45.8%) patients had one or more comorbidities. The most common histological type was adenocarcinoma and few patients were positive for EGFR and ALK rearrangement (Table 1). The most common chemotherapy regimen used was weekly paclitaxel (60 mg/m2 ) and carboplatin (AUC2) in 57.8% followed by pemetrexed (500 mg/m2 ) with standard folate and B12 supplementation and carboplatin (AUC5) in 16.8% patients. Single agent chemotherapy using paclitaxel was given in 9 (13.6%) patients (Table 2). Most patients (64%) could complete 4 or more cycles of chemotherapy, however, 15 patients (15.7%) could receive only 1 cycle. Some 21% patients could even receive maintenance chemotherapy. Chemotherapy had to be interrupted due to poor tolerance in 20 (21%) patients. Grade 3/4 toxicities (Table 2) were observed in 22 (23%) % patients, which were hematological in most cases (anemia and thrombocytopenia) and there were no treatment related deaths. Please cite this article as: H. Kancharla, N. Gundu and N. Pathak et al., Cytotoxic chemotherapy in advanced non–small cell lung cancer with poor performance status: A retrospective analysis from routine clinical practice, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2020.100550
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H. Kancharla, N. Gundu and N. Pathak et al. / Current Problems in Cancer xxx (xxxx) xxx Table 1 Demography and clinical characteristics. Parameter Gender Males Females Median age (years) ≥70 years Median symptom duration (months) Smokers Nonsmokers Comorbidities (1 or more) Pleural effusion Brain metastasis Extrathoracic mets (>2 sites) ECOG PS 2 3 4 Histology Squamous cell carcinoma Adenocarcinoma Others Hemoglobin ≤10 g/dL >10) g/dL Serum Albumin <3.5 g/dL ≥3.5 g/dL EGFR mutations positive ALK rearrangement positive
N = 96 65 (67.71%) 31 (32.29%) 62 (30-84) 23 (24%) 3.0 (1-12) 63 (65.62%) 33 (34.38%) 44 (45.8%) 31 (32%) 10 (10.5%) 34 (35.5%) 62 (64.58%) 27 (28.12%) 7 (7.29%) 38 (39.58%) 51 (53.12%) 7 (7.3%) 17 (17.71%) 79 (82.29) 50 (52%) 46 (48%) 4 (4.1%) 3 (3.1%)
Table 2 Treatment details and adverse effects. Induction chemotherapy regimen 1) Pemetrexed- Carboplatin/cisplatin (q3weekly) 2) Paclitaxel –Carboplatin (q3 weekly) 3) Paclitaxel – Carboplatin (qWeekly) 4)Gemcitabine (D1 & D8)- Cisplatin/carboplatin on D1) 5) Single agent paclitaxel (qWeekly)
16 (16.8%) 8 (8.4%) 55 (57.8%) 3 (3.1%) 9 (13.6%)
Number of chemotherapy cycles received 4 or more # Only 1#
61 (64%) 15 (15.7%)
Chemotherapy interruptions due to poor tolerance
20 (21%)
Grade ¾ toxicity 1) Vomiting 2) Diarrhea 3) Mucositis 4) Anemia 5) Thrombocytopenia 6) Neutropenia
22 (23%) 1 (1.05) 2 (2.11) 1 (1.05) 7 (7.37) 8 (8.42 %) 3 (3.16 %)
Objective response and disease control rates were 20% and 48.42%, respectively. After a median follow-up of 11.2 months, the median progression free survival (Fig. 1) was 6.3 months (95% confidence interval [CI] 5-10.63). On univariate analysis, we found that male sex and use of weekly paclitaxel-carboplatin were associated with better PFS. (Table 3). Please cite this article as: H. Kancharla, N. Gundu and N. Pathak et al., Cytotoxic chemotherapy in advanced non–small cell lung cancer with poor performance status: A retrospective analysis from routine clinical practice, Current Problems in Cancer, https://doi.org/10.1016/j.currproblcancer.2020.100550
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Fig. 1. Kaplan-Meier curve showing median PFS.
Table 3 Univariate analysis for relative risk of progression. Variable
HR
95% CI
P value
1.0 1.83
1.07-3.13
0.026
1 1.29
0.74-2.24
0.35
1 0.62 0.56
0.34-1.1 0.27-1.16
0.11 0.12
1 0.81
0.44-1.48
0.49
1 1.01
0.59-1.73
0.9
1 1.01
0.52-1.95
0.97
1 1.72
0.91-3.22
0.08
1 0.98
0.52-1.65
0.96
1 1.29 0.48 1.63 0.68
0.49-3.41 0.25-0.91 0.46-5.77 0.29-16
0.59 0.02 0.4 0.38
Gender Male Female ECOG PS 2 3&4 Comorbidities 0 1 ≥2 Extra thoracic metastasis 0 ≥1 Histology Squamous Nonsquamous Hemoglobin ≤10 g/dL >10) g/dL Neutrophilic-Lymphocytic Ratio(NLR) ≤5 >5 S. Albumin <3.5 g/dL ≥3.5 g/dL Type of chemo regimen 1)Pemetrexed- Carboplatin/cisplatin(q3 weekly) 2)Paclitaxel –Carboplatin(q3 weekly) 3)Paclitaxel – Carboplatin(qWeekly) 4)Gemcitabine(D1 & D8)- Cis/carboplatin on D1) 5)Single agent paclitaxel (qWeekly)
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Discussion PS is one of the strongest independent prognostic factors for survival of patients with advanced NSCLC.11-14 ECOG PS 2 and more are usually associated with a poorer prognosis. In absence of targetable driver mutation, the therapeutic approach is nihilistic for these patients. Considering high-risk benefit ratio, best supportive care or single/abbreviated chemotherapy has been suggested for these patients.15 Most clinical trials exclude this poor risk group in view of higher anticipated toxicities. Reasons for poor PS in advanced NSCLC could be high disease burden, advanced age, comorbidities, and poor nutritional state. The subgroup where poor PS is due to high disease burden might still benefit with cytotoxics since it is one of the reversible factors and PS might actually improve if there is some disease response.16 However, this hypothesis has not been formally evaluated. Interpretation of ECOG PS is also variable among physicians and between patients and physicians.17 , 18 In this study, we have retrospectively evaluated the cohort of 96 patients with ECOG PS 2 or more who were treated with systemic chemotherapy based on clinician discretion. Most of the patients in this cohort possibly received chemotherapy since poor PS might have been due to high disease burden as patient >70 years constituted only 24%, only 46% had one or more comorbidities, 19% had Hb ≤10 gm/dL and 50% had albumin ≥3.5 gm/dL. We observed that 45.26% patients showed improvement of at least one point in ECOG PS from baseline during chemotherapy and 64% could complete 4 or more cycles of chemotherapy. Objective response and disease control rates were 20% and 48.42%, respectively which are almost as good as in relatively fit patients. Median progression free survival of 6.3 months (95% CI 5-10.63 months) is relatively higher than expected from this poor risk subgroup. This is possibly a falsely high estimation due to variable timings of radiological assessment, censoring due to short follow up or a selection bias as relatively fitter patients might have been taken up for chemotherapy. Overall survival was not estimated in this study due to small number, limited follow up with less number of events till last follow up and very few deaths were recorded in the case files. In our study, we observed that male gender and induction regimen (weekly paclitaxel + carboplatin vs other regimens) were significantly associated (P <0.05) with better median progression-free survival (PFS). The 4 independent poor factors that have been previously studied are male sex, anemia, weight loss, and poor Karnofsky PS.19 , 20 Male gender, as opposed to other studies, found to be associated with better clinical outcome in our study. This could be due to majority were males (67.7%) in this cohort of poor risk population and most of the females patients were excluded as they were found to harbor driver mutations and treated with TKIs accordingly. In our study, among patients who could not complete 4 cycles of chemotherapy, the interruption was mostly due to poor tolerance and grade 3/4 toxicity, especially hematological toxicities which were seen in 18 patients. Although cisplatin-containing regimens are usually associated with more nephrotoxicity, nausea, and vomiting, and carboplatin combinations cause more severe thrombocytopenia and other hematological toxicities21 Carboplatin based regimens are still preferred in poor PS due to better nonhematological toxicity profile and ease of administration. A higher rate of toxic deaths has been observed in the Big Lung Trial, which has reported 2.8% and 7.5% risk of treatment related deaths in patients with PS 0-1 and PS 2, respectively.22 It would be always appropriate to know if less intense regimens or single agent chemotherapy can have lesser toxicities and still have efficacy. It has been reported earlier that lower doses of paclitaxel administered weekly along with carboplatin resulted in similar efficacy and lesser neurotoxicity.21 CALGB analysis of study 9730, compared single-agent (paclitaxel) to combination (carboplatin plus paclitaxel) chemotherapy and found that patients treated in the combination chemotherapy group had a statistically significantly better survival in the overall group and in the PS 2 group, with no difference in toxicity between both groups.22 Similar results were seen in 2 small phase II randomized trials. But, it is cautioned to interpret any trials in poor PS patients without standard control group.23 In contrast, pooled analysis of 6 randomized trials has shown that platinum-based doublets improved overall response rate (odds ratio
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3.243; 95% CI 1.883-5.583) and 1-year survival rate (odds ratio 1.743; 95% CI 1.203-2.525) with increased hematological toxicities compared to single agent in patients with PS 2.4 For elderly or with PS 2 patients, single-agent vinorelbine and gemcitabine improve overall survival without compromising the quality of life.5 , 24 In a Phase III trial comparing docetaxel versus vinorelbine in elderly patients with PS ≥2, docetaxel improved PFS (median = 5.5 vs 3.1 months; P <0.001) and response rates (22.7% vs 9.9%; P = 0.019) versus vinorelbine. Similarly a French Intergroup study (IFCT-0501) compared monthly carboplatin plus weekly paclitaxel versus single-agent vinorelbine or gemcitabine in patients aged 70-89 years with PS 0-2 and reported a survival advantage for combination therapy (median overall survival = 10.3 months for doublet versus 6.2 months for monotherapy, hazard ratio = 0.64; 95% CI 0.52-0.78; P < 0.0 0 01).6 A retrospective analysis was done in 485 NSCLC patients, 20% of which constituted poor PS patients (Karnofsky 60-70).This study demonstrated that there was clinical improvement, defined as attainment of good PS, in 25% patients who had poor PS at baseline. This improvement was greater in responders (38%) versus nonresponders (17%).25 Putting all these results and our analysis together, it seems that abbreviated or single agent chemotherapy protocols are feasible in a selective group of patients with poor PS. It may result in improvement in PS and thereby their quality of life. We also propose an adaptive strategy by escalating treatment intensity in patients achieving improvement in PS after initial abbreviated chemotherapy. However, such approach would require formal evaluation and validation in prospective manner before implementing in routine clinical practice. There are several limitations of our study particularly the retrospective nature, small number and multiple chemotherapy regimens used which make its generalization difficult. No formal quality of life assessment has been done. Improvement in PS assessed by various physicians in routine practice that has a high probability of bias and variation further makes the interpretation difficult. In conclusion, the present retrospective study shows the feasibility of systemic chemotherapy in abbreviated doses/regimens in clinically selected group of patients with poor PS, in terms of improvement in PS and PFS. These observations encourage more studies to evaluate objective criteria’s to identify patients from this poor risk group who could benefit with chemotherapy. More response adaptive strategies are required to be developed to tackle this poor risk group patients that constitute a significant proportion in routine clinical practice.
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