|Year : 2022 | Volume
| Issue : 1 | Page : 27-32
Treatment outcomes and prognostic factors in locally advanced non-small cell lung cancer – An experience from normal India
Arun Thimmarayappa1, Sushmita Pathy1, Prabhat Singh Malik2, Supriya Mallick1, Ashish Dutt Upadhyay3
1 Department of Radiation Oncology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
|Date of Submission||22-Dec-2020|
|Date of Decision||14-Jan-2021|
|Date of Acceptance||15-Jan-2021|
|Date of Web Publication||18-Aug-2021|
Room no 221, 2nd Floor, Department of Radiation Oncology, BRA-IRCH, All India Institute of Medical Sciences, New Delhi 110 029
Source of Support: None, Conflict of Interest: None
Context: Chemoradiation is the standard of care in locally advanced non-small cell lung cancer (LA-NSCLC). Clinical presentation, disease course, and available treatment options are challenges to overcome. Little is known about the ideal timing and interaction of the two modalities, its relevance in day-to-day decision-making and the treatment outcome.
Aims: The study evaluates the demographic profile, treatment pattern, outcome, and radiotherapy (RT) practice and patient care of LA-NSCLC at a tertiary cancer center.
Setting and Design: This is a retrospective study from a tertiary cancer centre. Archives of patients of LA-NSCLC treated between June 2016 and June 2018 were included in our study.
Materials and Methods: Clinical, demographic characteristics, treatment patterns, and outcomes were recorded. RT practice and patient care process including the integration of RT with other specialties, waiting time, and compliance to treatment were documented and analyzed.
Statistical Analysis: Overall survival (OS) and progression-free survival (PFS) were the primary endpoints of the study. Log-rank test was used for univariate analysis for the factors on OS, and Cox's proportional hazards model was used for multivariate analysis for cofactors on OS.
Results: Two hundred and thirty-two patients of lung cancer were treated during the study period. Fifty-four patients were squamous cell carcinoma, 108 were adenocarcinoma, and 12 were others. Out of 59 patients of LA-NSCLC, 34 underwent definitive chemoradiation. The median follow-up was 11 months (0.7–29), median overall treatment time was 44 days, median PFS was 8.9 months (range: 1.6–28.6), and median OS was 9.4 months (1.7–44.8). Time to start any oncological intervention was 1 month (0.1–4.3) and time to start RT was 2.1 months (0.1–5.4). Adherence to treatment was 91.2%. Age ≥65 and performance status ≥2 were significant for OS on univariate analysis and none on multivariate analysis.
Conclusions: One-third of the cases of NSCLC present in LA stage and a third are suitable for definitive chemoradiation and only 20% undergo the planned treatment.
Keywords: Chemotherapy, non-small cell lung cancer, radiotherapy
|How to cite this article:|
Thimmarayappa A, Pathy S, Malik PS, Mallick S, Upadhyay AD. Treatment outcomes and prognostic factors in locally advanced non-small cell lung cancer – An experience from normal India. J Can Res Ther 2022;18:27-32
|How to cite this URL:|
Thimmarayappa A, Pathy S, Malik PS, Mallick S, Upadhyay AD. Treatment outcomes and prognostic factors in locally advanced non-small cell lung cancer – An experience from normal India. J Can Res Ther [serial online] 2022 [cited 2022 May 26];18:27-32. Available from: https://www.cancerjournal.net/text.asp?2022/18/1/27/324033
| > Introduction|| |
Lung cancer (LC) is the second most common cancer worldwide and accounts for 2206771 new cases in 2020 with 1796144 deaths globally. Being the 4th leading cause of cancer in India it accounts for 66279 deaths in 2020. Nearly 35% of the lung cancers are locally advanced (LA) at presentation, and multimodality approach is the essence of management. However, patterns of care vary with stage of presentation, patient's tolerance for treatment, availability of facilities, and practice prevalence., Concurrent chemoradiation (CCRT) is the standard of care in LA non-small cell lung cancer (LA-NSCLC) as it improves OS by 4%–4.5% at 5 years, compared to sequential chemotherapy and radiotherapy (CTRT). Several studies reported significantly reduced overall risk of death with the addition of chemotherapy (hazard ratio [HR]: 0.71, 95% confidence interval [CI]: 0.64–0.80), though tolerance to concurrent chemoradiotherapy (CCRT) remains debatable and only small proportion of them would complete it. In the day-to-day scenario, because of poor tolerance, many patients receive definitive radiation therapy (RT) alone, and a fraction receives either sequential or concurrent chemoradiation. However, this suitability of therapy is difficult to establish as there are limited data available. Interestingly, various prognostic factors have been identified in the management of LA-NSCLC which are important in decision-making. The current study intends to evaluate the demographic profile, pattern of care, outcome, and prognostic factors at a tertiary cancer centre.
| > Materials and Methods|| |
The study was conducted with the approval of the institutional ethics committee. Medical records of patients registered between June 2016 and June 2018 were retrieved. Patients of LA-NSCLC were included in the study. Records were checked for completeness, and incomplete records were excluded. The demographic details (age, gender, performance status (PS),comorbidity, symptoms at presentation), tumor parameters (histology, epidermal growth factor receptor (EGFR), and anaplastic lymphoma kinase (ALK) mutation status, stage (Tumor Node Metastasis (TNM) 6th edition), hematological and biochemical parameters (baseline hemoglobin, serum albumin) and treatment parameters (date of start of any oncological treatment, neoadjuvant chemotherapy (NACT), RT details – date of start of RT, technique, and dose) were recorded in a pre-designed proforma.
As per institutional protocol, all patients underwent baseline staging workup with contrast-enhanced computed tomography (CECT) of the chest and abdomen and metastatic workup with metabolic imaging or computed tomography (CT) scan. All patients underwent contrast-enhanced magnetic resonance imaging (MRI) brain or CECT brain to rule out brain metastasis. Histopathological confirmation was obtained from a tissue biopsy. As per the institutional protocol, patients of LA-NSCLC with a good PS of the Eastern Cooperative Oncology Group (ECOG) 1–3 were planned for curative treatment. Patients of squamous cell carcinoma received NACT with paclitaxel and carboplatin, whereas patients of EGFR- or ALK-negative adenocarcinoma received NACT with paclitaxel and pemetrexed. EGFR- or ALK-positive patients received targeted therapy (is this part of curative cases). Response assessment was made with CT or metabolic imaging after two cycles or after completing induction chemotherapy. Patients with nonprogressive disease, preserved PS, and pulmonary reserve were taken for definitive CCRT or sequential CTRT.
All patients were planned with conformal planning techniques. CT simulation was done on Philips wide-bore CT scanner, and segmentation was done on Monaco treatment planning system. RT was delivered in two phases. In Phase I, 50 Gy was delivered in 25 fractions to the prechemotherapy volume. This was followed by an additional dose of 10 Gy in 5 fractions in Phase II for the post chemotherapy volume. The total dose of 60 Gy in 30 fractions was delivered over 6 weeks by either three-dimensional conformal radiotherapy (3DCRT) or intensity-modulated radiation therapy (IMRT) or volumetric-modulated arc therapy (VMAT) on Versa HD or Synergy S (Elekta™). Patients were kept on follow-up every month for the first 3 months, subsequently every 3 months for up to 2 years, and every 6 months henceforth.
Overall survival (OS) and progression-free survival (PFS) were the primary endpoints of the study. OS was defined from the date of registration to death date or last date of follow-up if alive. PFS was defined from the date of registration to the date of progression or date of last follow-up if not progressed. Log-rank test was used for univariate analysis for the factors on OS, and Cox's proportional hazards model was used for multivariate analysis for cofactors on OS. All the P values were two-sided, and those with ≤0.05 were considered statistically significant. Stata v13 (StataCorp. 2013. Stata Statistical Software: Release 13. College Station, TX: StataCorp LP.) was used to do the statistical analysis.
| > Results|| |
Out of 232 lung cancer patients registered in the Lung Cancer Clinic and Radiotherapy Outpatient's Department at our centre, 9 files had incomplete workup details and were excluded. Of those 223 patients, 174 (78%) were NSCLC. Of these, 67 (38.5%) patients were LA-NSCLC. Eight patients out of 67 were not planned for curative intent due to poor PS and large-volume disease. Fifty-nine (33.9%) patients received planned induction chemotherapy or targeted therapy and were reassessed. Thirty-three out of 67 patients were ineligible for radical RT due to poor PS, progressive disease, etc., The remaining 34 (50.7%) patients received radical RT [Figure 1].
Demographic profile and clinical characteristics
Sixty-seven patients were analysed in the present study. Fifty-seven patients (85%) were aged ≤65 years, with a male preponderance (83.6%). Thirty-five patients (52.2%) were ECOG PS of 0 to 1. Fifty-eight patients (86.6%) had 0–1 comorbidity. Forty-three patients (64.2%) had cough, 35 (52.2%) had chest pain, 27 had (40.3%) hemoptysis, and 34 (50.7%) had breathlessness at presentation. Loss of weight was observed in 43 (64.2%) at presentation. Twenty-eight patients (41.8%) had a hemoglobin of <11 g/dl and 29 (43.3%) had serum albumin of <3.5 g/dl. Thirty-two patients (47.8%) were of squamous cell carcinoma histology and 28 (41.8%) were of adenocarcinoma histology. Out of 34 adenocarcinoma patients, 2 (6%) were EGFR positive, 4 (11.2%) were ALK positive, 16 (47%) were EGFR and/or ALK negative, and the remaining (35.3%) did not have molecular testing done. Nodal evaluation revealed the majority with N2 disease. Out of 67, only 2 patients (3%) were N0, 3 (4.4%) were N1, 40 (59.7%) were N2, and the remaining 17 (25.4%) were N3. Thirty-three patients (49.3%) belonged to Stage IIIA and 34 (50.7%) to Stage IIIB [Table 1].
All cases of LA-NSCLC were evaluated for the intent of treatment. Fifty-nine patients (88%) were planned for curative intent and eight patients (12%) were planned for palliative intent. Curative treatment included NACT or tyrosine kinase inhibitor (TKI) as per the histology, followed by radical RT to the primary with sequential or concurrent chemotherapy as per the institution protocol. Eleven patients (34.3%) of adenocarcinoma received 3-weekly pemetrexed and carboplatin, eight patients (25%) received 3-weekly paclitaxel and carboplatin, six (9.3%) patients received weekly paclitaxel and carboplatin, and the remaining patients (21.9%) received TKI-targeted therapy. Twenty-eight patients (41.8%) received NACT of more than three cycles. Patients underwent a response assessment imaging after scheduled NACT. Twenty-five (42.4%) out of 59 patients were ineligible for radical RT. A total of 33 out of 67 patients of LA-NSCLC received palliative treatment. The reasons for radical treatment not being given were evaluated. Eighteen out of 33 patients had either progressive disease, 7 patients had a poor PS of ECOG PS-4, 5 patients were at risk of radiation toxicity due to large-volume disease, and 3 patients defaulted for treatment. Out of 59 patients planned for curative intent, 3 (3.4%) patients had radiological complete response, 19 (32.2%) had partial response, and 11 (18.6%) had stable disease.
Thirty-four patients received radical RT. Nineteen patients received sequential CTRT and 15 patients received CCRT. Radical RT was delivered by conformal techniques for a median dose of 60 Gy (40–60 Gy) at 1.8–2 Gy per fraction. Twenty-five patients received radiation by 3DCRT, 6 by IMRT, 2 by 2D technique, and 1 patient by VMAT technique. All the 33 patient patients received palliative RT by the 2D technique. Thirty-four patients received radiation to a dose ≥50 Gy with a median overall time of 44 days (29–60 days).
The median follow-up duration was 11 months (0.7–29 months [95% CI: 8.8–22.4]). The median OS was 9.4 months (1.7–44.8 months [95% CI: 11.8–43]). The median PFS was 8.9 months (1.6–28.6 months [95% CI: 9.6–24.2]). The median OS of Stage IIIA and IIIB was 10 months (0.9–44.7 months [95% CI: 10.1–11.7]) and 8.1 months (0.2–25.4 months [95% CI: 7.4–11.6]), respectively. The median PFS of Stage IIIA and IIIB was 9.8 months (1.6–28.6 months [95% CI: 9–28.3]) and 7.3 months (3–25.4 months [95% CI: 6.6–10.5]), respectively. The median time to start any oncological intervention was 1 month (0.1–4.3 months [95% CI: 0.9–1.6]). The median time to start RT was 2.1 months (0.1–5.4 months [95% CI: 2.1–3.8]) [Table 2]. The adherence to radical thoracic radiation was 91.2% (31 out of 34 patients). On univariate analysis of 67 patients, patients aged ≤65 years and those with ECOG performance of 0–1 had better OS [Table 3]. However, on Cox's regression modelling for multivariate analysis, none of them were significant for OS nor PFS.
|Table 3: Univariate analysis of various parameters for Overall survival and Progression free survival|
Click here to view
| > Discussion|| |
LA-NSCLC constitutes a potentially curable subset of lung cancer patients. However, several factors such as delay in diagnosis due to confounding clinical conditions such as tuberculosis and chronic bronchitis, delayed presentation, and delay in treatment due to logistics in a busy cancer center led to miss of a narrow window of opportunity for curative treatment in lung cancer. The present analysis aims to explore prognostic factors that may help to triage patients best suitable for a certain type of therapy, thereby optimizing the outcome and limiting the toxicity. Besides, we also aim to analyse the demography, treatment patterns, and clinical outcomes of such patients to understand the pattern of care in a real-world scenario. The tolerance to therapy and compliance both need to be balanced carefully as LC patients are mostly elderly as most patients are diagnosed in the sixth or seventh decade with a median age of 70 years.,, In this part of the world, the incidence is more common one decade (median age: 57 years) earlier which is reflected in our analysis as more than 80% of the patients in the current study presented at less than 65 years of age predominantly affecting males (83%) in line with other studies. In this analysis, cough and breathlessness were commonly observed presenting complaints that resemble observation made by Latimer. The present analysis also wants to highlight that weight loss affects nearly 50% of the patients which may be another important reason for poor tolerance and compliance to CTRT. Numerous studies have also highlighted that 28%–59% of NSCLC are diagnosed in Stage III which corroborates closely to the current analysis as 38.5% of the patients were diagnosed in Stage III.,
The standard of care worldwide for LA-NSCLC is CCRT. This treatment regimen is associated with increased rates of esophagitis in comparison to sequential chemotherapy and radiation therapy. This sometimes leads to poor tolerance and therefore is considered optimal in patients presenting with less than 5% weight loss. We at our institute followed a protocol of NACT followed by concurrent chemoradiation as a substantial percentage of patients presented with large-volume disease and poor PS and significant weight loss (65%). In CALGB 39801 trial, patients received induction chemotherapy followed by definitive RT. They reported partial response in 31% and stable disease in 39% of their patients. In our patients, 32% had a partial response and 11% had stable disease. These findings were comparable to other studies.,,,
Yamamoto et al. compared second- and third-generation regimens with concurrent thoracic RT in patients with unresectable Stage III NSCLC and reported a median OS of 22 months. In another trial, Segawa et al. reported that median OS and PFS were 23.5 months and 10.5 months, respectively, when docetaxel and cisplatin were compared with mitomycin, vindesine, and cisplatin regimen. In a similar trial, Belani et al. compared induction chemotherapy followed by either standard thoracic RT or hyperfractionated accelerated RT for patients with unresectable Stage IIIA and B non-small cell lung cancer. The median OS in the standard arm was 14.9 months. In the present analysis, median OS (9.4 months) and PFS (8.9 months) were found to be lower in comparison to the published data which reflects poorer outcome in LA-NSCLC patients. Delay in the start of treatment, use of induction chemotherapy followed by CCRT, use of lower doses of RT in some patients to limit the organ at risk toxicity, weight loss are some of the factors that could have attributed to this lower survival. In the present study, patients younger than 65 years and with PS 0–1 had significantly better survival pointing toward the fact that these patients have better tolerance and compliance to therapy. This information may highlight that older patients and patients with PS ≥2 even with LA-NSCLC should be considered for radiation alone which may improve compliance to therapy.
Oncological management at a tertiary centre is a challenge. With high patient load, initiation of timely treatment is difficult causing delay. The effect of time to start treatment on survival parameters was studied by Gomez et al. The median diagnosis to treatment interval was 27 days and duration less than 35 days was associated with improved survival. Diaconescu et al. studied treatment delays in NSCLC and their prognostic implications. Although in metastatic patients, the HR for survival was 0.93 for every week of treatment delay, for LA-NSCLC, the association was inconclusive. The median time to start RT was longer than an ideal duration of 1 month in our study. A prospective study from our centre by Roy et al. demonstrated that hypofractionated accelerated radiotherapy helps in reducing the waiting time for radiotherapy and OTT and machine load at a high-volume centre. These hurdles highlight the challenges faced during radiotherapy practice in a developing country.
Our study has a few limitations. Being a retrospective analysis, it is associated with various forms of bias. The small patient number for analysis also does not provide the true picture in this subset of lung cancer. Heterogeneity in treatment is another weakness of the study. However, the results of the study truly represent the pattern of care in developing countries and reflect the poorer outcome after all the latest molecular developments. Hence, it is important to improve infrastructure to provide timely treatment to all such patients.
| > Conclusions|| |
LA-NSCLC is a concoction of potentially curable patients who have a narrow window of opportunity. Tailoring the treatment to each patient through multidisciplinary clinics with early intervention, the large patient burden in developing countries with limited access to a comprehensive cancer care facility can be mitigated well.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]