Consolidation Radiotherapy in M1a Non-small Cell Lung Cancer Yields Equivalent Outcomes as Locally Advanced Disease

ABBREVIATIONS USED IN THIS ARTICLE

ADC = Adenocarcinoma; BED = Biologically effective dose; BMI = Body mass index; CI = Confidence interval; COPD = Chronic obstructive pulmonary disease; CRT = Conventional radiotherapy; CTRT = Chemotherapy and radiation therapy; EGFR = Epidermal growth factor receptor; EPP = Extrapleural pneumonectomy; GLOBOCAN = Global Cancer Observatory; GTV = Gross tumor volume; HR = Hazard ratio; IQR = Interquartile range; KPS = Karnofsky performance scale; LALC = Locally advanced lung cancer ; MPE = Malignant pleural effusion; NSCLC = Non-small cell lung cancer; OS = Overall survival; PET–CT = Positron emission tomography–computed tomography; PTV = Planned target volume; RT = Radiotherapy; SPSS = Statistical Package for the Social Sciences; SSC = Squamous cell carcinoma; TKI = Tyrosine kinase inhibitor.

INTRODUCTION

Lung cancer is one of the major causes of death all over the world. According to Global Cancer Observatory (GLOBOCAN) 2020 statistics, the global incidence of lung cancer is 22,06,771 patients (11.4%) and the number of deaths is 17,96,144 people (18%). Lung cancer accounts for 5.5% of all cancers in India. In 2020, a total of 72,510 new lung cancer cases were diagnosed in India and there were 66,279 deaths (7.8%).¹ Non-small cell lung cancer (NSCLC) accounts for more than 80% of all lung cancers. In developing countries, approximately 35% of NSCLC patients develop nonmetastatic local disease, whereas in developing countries, less than 10% of patients develop locally advanced disease [(locally advanced lung cancer (LALC)].² Radiochemotherapy is the treatment of choice for stage IIIB and above, advanced, inoperable, nonmetastatic disease. Malignant pleural effusion (MPE) is defined as the accumulation of a large amount of pleural exudate along with the presence of malignant cells in the pleural cavity, pleural fluid, or parietal pleura.^3,4 Lung cancer is the most common cause of MPE, accounting for approximately 40% of all cases. In the seventh edition of the tumor node metastasis classification, the presence of MPE is considered as M1a (stage IV). However, although MPE is an indicator of advanced metastatic disease, it can also occur in patients without extrathoracic disease.⁵ Treatment of patients with MPE without extrathoracic disease is the same as for patients with distant metastases and usually includes palliative chemotherapy without the need for radical surgery or radiation therapy.^6,7 Recent reports show that optimal extrapleural pneumonectomy (EPP) improves overall survival (OS) and the 5-year survival rate is between 22 and 33.7%.^8,9 However, the problem remains as follows: There is little information about the results of this type of treatment. In this article, we present our experience using definitive radiotherapy (RT) in M1a NSCLC patients with MPE without comorbidities who responded to chemotherapy and compared the results with those in LALC receiving radical RT.

MATERIALS AND METHODS

This is a retrospective review of consecutive patients diagnosed with cancer pathologically (biopsy or cytology) between 1 January 2005 and 31 December 2019. Patients with extrapulmonary primary disease but thoracic metastases were excluded. Medical information was recorded in a standard protocol that included detailed information about symptoms, smoking, and other conditions such as hypertension, diabetes, and pneumonia/asthma. As the data included patients treated with RT over 15 years, metastatic workup included ultrasound abdomen and bone scan earlier and positron emission tomography–computed tomography (PET–CT) scanning in affordable patients later on. The performance of the patients was evaluated according to the Karnofsky performance scale (KPS). Cases were classified histologically according to the World Health Organization classification of NSCLC [squamous cell carcinoma (SCC), adenocarcinoma (ADC)]. All patients were treated with a multidisciplinary approach. Patients presenting with dyspnea with shortness of breath were treated with pleural tapping. Patients received either sequential chemoradiotherapy [four cycles of chemotherapy before local RT either platinum-based chemotherapy or tyrosine kinase inhibitor (TKI) based on genotyping status] or concurrent chemoradiotherapy (which was restricted after 2012 due to its toxicity). Since mutation analysis could not be performed in our institution until 2014, the status was unknown. Patients with epidermal growth factor receptor (EGFR) mutation were treated with gefitinib 250 mg once daily, and patients with resolution of pleural effusion were treated with consolidation radiation. Three-dimensional conformal radiation treatment plans were created using appropriate photons (6/15 MV) by the Eclipse treatment planning system (Varian Medical Systems). Radiotherapy is delivered to patients at a dose of 50–66 Gy, depending on the severity of the disease. Clinical data, including radiation therapy (RT, also called radiotherapy) dose, total tumor size, lung index, and esophageal dose, were recorded. The degree of treatment-related pneumonia and esophagitis was recorded during treatment and follow-up. After completing radiation therapy, patients were evaluated every 3 months for the first 2 years and every 6 months thereafter.

RESULTS

A total of 154 patients were identified in this study; 111 patients (72%) were under 65 years of age. The study population was 82% male, 70% smokers, 21% hypertensive, and 16% diabetic. Stage T4 accounted for 55% of patients and N2 nodal disease accounted for 60% of patients. Fifty percent of the patients had SCC and the other half had adenocarcinoma (Table 1). A total of 36 patients with M1a MPE received definitive RT. In all patients with MPE, dyspnea resolved with pleural tapping and CT/targeted therapy (Fig. 1). Gross tumor volume (GTV) and planned target volume (PTV) were larger in M1a than in the M0 subset (Table 2). The mean effective radiation therapy dose [biologically effective dose (BED)] received by all patients was 72 Gy (IQR, 70–72). Overt pneumonitis (above grade II) occurred in 16% of patients who had received a V20 lung dose above 25% (p = 0.05). Significant esophagitis (above grade II) occurred in 10% of patients, and the mean esophageal dose was higher in these patients (>40 Gy, p = 0.001). At a median FU of 14 months [interquartile range (IQR, 10–22 months)], the median OS was 14 months [95% confidence interval (CI): 12.3–15.6]. Overall, the median OS was higher for women (18 months) than men (13 months, p = −0.03). Patients without diabetes (OS, 14 months) performed better than patients with diabetes (OS, 12 months, p = 0.027). Patients who received higher doses of radiation (BED > 72 Gy) had better survival rate (15 months) compared to those who received BED < 72 Gy (14 months, p = 0.073). The situation worsened in patients who developed grade II or higher esophagitis (9 months vs 15 months, p = 0.00). When we separated the results for M0 and M1, the median target volume was higher in M1a patients compared to M0 patients; 614 cc (IQR, 333−855 cc) and 564 cc (IQR, 391−763 cc). The main factor influencing OS in univariate and multivariate analyses was gender (male vs female) [14 months vs 17 months in M0, 13 months vs 22 months in M1, p = 0.012, hazard ratio (HR), 2], Karnofsky performance (>70 vs <70) (14 months vs 11 months in M0, 18 months vs 13 months in M1, p = 0.04; HR, 0.2), diabetes (present vs not present) (12 months vs 14 months in M0 months, 10 months vs 16 months in M1, p = 0.03; HR, 1.6). Biologically effective dose (<72 vs >72) (12 months vs 15 months in M0, 15 months vs 15 months in M1, p = 0.04; HR, 1.6), radiation esophagitis [(grade II vs grade I) (11 months vs 14 months in M0, 2 months vs 18 months in M1, p = 0.001; HR, 0.36), smokers, etc.; nonsmokers (14 months vs 15 months in M0, 13 months vs 18 months in M1, p = 0.02; HR, 0.48) (Tables 3 and 4, Fig. 2). Only 11 patients were positive for the EGFR mutation. The median OS of patients with EGFR mutation was 22 months (IQR, 8−38 months), while the median OS of patients in the nonmutation group was 14 months (IQR, 10−21 months).

DISCUSSION

To our knowledge, this is one of the few articles discussing the effects of radiation therapy in M1a NSCLC downstaged by chemotherapy. In our country, the number of patients presenting with advanced stage is quite high, ranging from 70% in the west to 90% in the north.^2,10 Radiochemotherapy is the treatment of choice for stage IIIB and above, advanced, unresectable, nonmetastatic disease, and chemotherapy alone or targeted therapy is the standard treatment for stage M1. In addition to its role in LALC, the role of consolidation RT in oligometastatic disease is clear but not so in M1 wet disease. Furthermore, MPE is often an exclusion factor in chemoradiotherapy studies while the role of radical surgery in such cases has been demonstrated.¹¹ The median survival of patients diagnosed with MPE undergoing surgical repair has been reported to be 34 months. Radical surgery is a difficult option in such cases in developing countries where patients have low body mass index (BMI), lower socioeconomic status, and 70% are smokers.^12,13 Therefore, chemotherapy responders have no other option other than maintenance chemotherapy/targeted therapy with an OS of 20 months.¹⁰ We explored the utility of consolidation RT after initial CT to further improve outcomes for patients with good KPS. In our cohort of 154 patients who received successful radiation therapy, 24% of patients presented with MPE which resolved after upfront chemotherapy/targeted therapy (standard of care). Therefore, patients with good KPS and response were offered radical RT. We found their results to be comparable to LALC. However, because this is a retrospective analysis, MPE patients who received radical radiation therapy were carefully selected and did not represent all MPE patients. As our aim was to evaluate the feasibility, tolerability, and benefits of radiation therapy in M1a compared to LALC, we have refrained from mentioning the outcomes of treatment-refractory M1a. Factors affecting the results of M1a are similar to those of M0. Men, smokers, poor KPS, and diabetics had worse survival rates in both the M0 and M1a groups. This observation is similar to those reported in the literature. Contrary to reports in other series, there is no difference in survival between squamous and adenocarcinomas.¹⁴ We saw better survival in stage IIIA (mean of 21 months) than in stages IIIB, C, and IVa (mean of 13 months) which is expected. In our previous publication, we showed that concurrent chemotherapy and radiation therapy (CTRT) and sequential CTRT gave similar results, that concurrent CTRT caused considerable weight loss and decreased KPS, and hence was discontinued.² Similar toxicity studies with CTRT have been reported by a tertiary care center in India.¹⁵ In fact, in the Western literature, it is reported that the possibility of concurrent CTRT is only around 50%, and the remaining 50% have been excluded from such an approach owing to comorbidities or age-related poor tolerance. In this study, 15% of the patients had poor KPS, 30% were over 65 years of age, 20% had comorbidities, 84% were stage IIIB and above, 70% were smokers, and the median PTV was above 500 cc. Most smokers could have been undiagnosed chronic obstructive pulmonary disease (COPD), which affects tolerance and outcome of treatment in many ways. Evidence-based recommendations derived from research data from developing countries may not be generalizable to countries with limited resources, and therefore recommendations from developing countries mention sequential CTRT in patients with poor KPS, elderly age, and large tumors.¹⁶ Additionally, the use of combined modality treatment may increase the burden on existing supportive care facilities in resource-limited settings.

Among the dosimetric factors, V20 > 25% indicates a correlation with the degree of pneumonitis. The lack of association between mean lung dose (MLD) and V5 with lung disease may be due to different treatment methods (concurrent CTRT and sequential CTRT) and different dose constraints in each technique. We have previously found that V5 greater than 50%, V20 greater than 33%, and MLD greater than 18 Gy are associated with pneumonitis, and within these parameters, the incidence of pneumonitis with concurrent CTRT is higher.¹⁷ Meta-analysis on radiation pneumonitis was also consistent with the observation that concurrent CTRT causes a higher incidence of radiation pneumonitis.¹⁸ Our data showed that patients with grade I or less esophagitis were treated with a mean esophagus dose of 32 Gy, and patients with grade II or more esophagitis were treated with 60 Gy, and this impacted survival in both univariate and multivariate analysis. Although the median PTV was different between the two groups, the incidence of grade II or higher pneumonitis or esophagitis was not higher in the M1a group, suggesting that radical radiation was tolerated well in this group. A total dose of 60–66 Gy is effective in LALC, and we observed similar results in both the groups consisting of M1a and M0 subpopulations. Median OS in patients with EGFR mutation was 22 months (IQR, 8–38 months) while it was 14 months (IQR, 10–21 months) in those without mutation, confirming that outcomes are better for EGFR mutated subsets.¹⁹ Since this test was not performed on all patients in the early period due to its nonavailability at our organization and the high cost, we did not analyze outcomes separately for the two groups of patients.

Our study has several limitations. First, because this was a retrospective study of patients treated with radical RT, the patients included in the analysis were carefully selected and are not representative of all patients with pleural carcinomatosis. Second, because our dataset is not specific to pleural carcinomatosis, more detailed information such as MPE outcomes with the use of intraoperative intrapleural chemotherapy and with TKIs or chemotherapy alone is not addressed. Since PET–CT is expensive in our country and there are long waiting lists, some of these patients could have been undiagnosed M1b or M1c, and accurate staging was not possible before starting treatment.

CONCLUSION

Radical RT is feasible and effective for NSCLC M1a patients responding to chemotherapy. Their outcomes are similar to patients with locally advanced disease (M0), even with larger tumor volumes in M1a patients. To benefit this subset of patients who present in large numbers in our country the potential of RT needs to be further investigated in a larger database.

ORCID

Zia Hashim https://orcid.org/0000-0002-1707-4554

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