|Year : 2022 | Volume
| Issue : 3 | Page : 112-117
A comparative study on sequential single-agent chemotherapy followed by radiation versus single-agent chemotherapy alone in elderly patients of metastatic non-small cell lung cancer
Adhikarimayum Ambika Devi1, Laishram Purnima Devi1, Yengkhom Indibor Singh2, Thangjam Nirpendra1, Ram Kamei1, Manirathinam Ramalingam3
1 Department of Radiation Oncology, Jawaharlal Nehru Institute of Medical Sciences, Imphal, Manipur, India
2 Department of Radiation Oncology, Regional Institute of Medical Sciences, Imphal, Manipur, India
3 Meenakshi Mission Hospital and Research Centre, Madurai, Tamil Nadu, India
|Date of Submission||04-Sep-2022|
|Date of Acceptance||19-Oct-2022|
|Date of Web Publication||25-Feb-2023|
Dr. Laishram Purnima Devi
Department of Radiation Oncology, Jawaharlal Nehru Institute of Medical Sciences, Porompat, Imphal, Manipur
Source of Support: None, Conflict of Interest: None
Background: Stage IV non-small cell lung cancer (NSCLC) in elderly patients typically has a poor prognosis and addition of aggressive local therapy to the systemic therapy could provide encouraging outcomes with prolonged survival in certain patients with stage IV NSCLC.
Objectives: The aim of this study is to compare the treatment response and progression-free survival (PFS) between single-agent chemotherapy (CT) followed by external-beam radiotherapy versus single-agent CT alone in elderly patients with metastatic NSCLC.
Materials and Methods: In a randomized prospective study, after taking Ethical committees approval, 40 patients aged from 60 to 82 years were enrolled and divided into two equal groups: Arm A and Arm B. Both the arms received Gemcitabine 1 g/m2/dose as 30 min intravenous infusion on D1, D8, and D15 of 28-day cycle or D1 and D8 of a 21-day cycle for a total of 3–4 cycles, whereas Arm A received radiation 45–55 Gy @ 180 cgy/fraction after CT. Treatment response and PFS against time were analyzed using Friedman's test and Kaplan − Meier method. P < 0.05 was considered statistically significant.
Results: The demographic profiles of the patients were comparable between the two groups. Most patients have Stage IV M1b disease and squamous cell carcinoma subtype and bone metastasis. There were marked symptomatic improvements in both the arms. The overall treatment response was 70.0% in Arm A and 50.0% in Arm B with median follow-up was 8 months. Median PFS and overall survival were 5 months and 8 months for arm A, respectively whereas it was 4 months and 7 months for Arm B (P = 0.03).
Conclusion: In this study, it was found that sequential single agent CT followed by radiation has shown survival advantage in certain patients with Stage IV NSCLC.
Keywords: Elderly, lung cancer, radiation therapy, sequential chemotherapy
|How to cite this article:|
Devi AA, Devi LP, Singh YI, Nirpendra T, Kamei R, Ramalingam M. A comparative study on sequential single-agent chemotherapy followed by radiation versus single-agent chemotherapy alone in elderly patients of metastatic non-small cell lung cancer. J Med Soc 2022;36:112-7
|How to cite this URL:|
Devi AA, Devi LP, Singh YI, Nirpendra T, Kamei R, Ramalingam M. A comparative study on sequential single-agent chemotherapy followed by radiation versus single-agent chemotherapy alone in elderly patients of metastatic non-small cell lung cancer. J Med Soc [serial online] 2022 [cited 2023 Mar 28];36:112-7. Available from: https://www.jmedsoc.org/text.asp?2022/36/3/112/370594
| Introduction|| |
Lung cancer remains the leading cause of cancer-related mortality all over the world. About 80% of all lung cancer cases are non-small cell lung cancer (NSCLC) and about half of these cases (55%) present with metastatic disease (Stage IV) at initial diagnosis.
NSCLC is predominantly a disease of elderly with a median age of diagnosis of approximately 68 years. Elderly patients with Stage IV NSCLC typically have a poorer prognosis. Historically, palliative treatment with single-agent CT and palliative radiotherapy (RT) given to appropriate metastatic sites in selected patients have been the standard of care in elderly metastatic NSCLC but outcomes with this approach have been dismal with a median overall survival (OS) of only 8–10 months. In recent years, increasing data have shown that addition of aggressive local therapy to the systemic therapy could provide encouraging outcomes with prolonged survival in certain patients with stage IV NSCLC. However, such treatment protocols in elderly patients are still not well defined, in part because of treatment dilemma to maintain a balance between appropriate disease control which translates to improved survival and lower tolerance to treatment toxicity due to age-related impairment of organ function and presence of potentially complicating comorbidities.
It is well-established that the standard treatment for elderly patients with stage IV NSCLC is single-agent CT. However, there are limited data on the role of local thoracic radiation given along with CT. In this context, we have performed a study to determine whether sequential addition of radiation to standard single-agent CT improves survival in elderly patients presenting with metastatic NSCLC.
| Materials and Methods|| |
A randomized prospective study was conducted in the Department of RT, Regional Institute of Medical Sciences, Imphal, Manipur from August 2016 to July 2018. The primary study objective was to compare the survival in the two treatment groups. The secondary objectives of the study included the assessment of tumour response and treatment toxicities.
Study population/eligibility/patient selection
Patients who were cytologically/histopathologically confirmed case of NSCLC AJCC stage IV (M1a and M1b) (7th edition, 2010) in the age group of 60–85 years were eligible for the study. Additional inclusion criteria include Karnofsky Performance Status ≥50%, a normal kidney function test, liver function test and blood sugar, pulmonary function test >50% (forced expiratory volume 1 and forced vital capacity), and a normal echocardiography (left ventricular ejection fraction ≥60%). Patients were excluded if they have the presence of brain metastasis, massive pleural effusion, associated major comorbid medical conditions, oncologic emergencies, and a previous treatment history with CT, RT, and/or thoracic surgery.
Randomization was done using random table method into two arms: Arm A (study arm) and Arm B (control arm). On the selection of patients, particulars of the patients, a complete history and physical examination findings were recorded. Pretreatment evaluation included complete blood count (CBC), blood chemistry, echocardiogram, urine R/E, blood sugar, chest X-ray (CXR) (PA view), ultrasound whole abdomen, CT scan thorax, fiberoptic bronchoscopy, spirometry, and other investigations as indicated were performed. Informed written consent was taken from all eligible patients.
Ethical approval was obtained from the Research Ethics Board, RIMS, Imphal, Manipur.
Both the arms received CT. Choice of CT was one of the front line recommended agent in elderly-Gemcitabine as it has a lower toxicity profile. The recommended standard dose and schedule was followed, i.e., Injection Gemcitabine 1 g/m2/dose as 30 min intravenous infusion along with premedications on D1, D8 and D15 of 28-day cycle or D1 and D8 of a 21-day cycle for a total of 3–4 cycles.
Arm A received radiation 2–4 weeks after the completion of last CT cycle. Radiation was delivered to the primary site with external-beam radiotherapy by Cobalt-60 teletherapy machine with a source to skin distance of 80 cm to a total dose range of 45–55 Gy @ 180cgy/fraction (5 days in a week) for 25–30 fractions. Radiation was delivered based on the location of the primary tumor and the associated nodal regions in the lung by two opposing postero-anterior fields or multiple fields as required. Treatment planning was done in the conventional method by using chest radiographs and contrast enhanced CT (CECT). The gross tumor volume (GTV) includes thoracic primary tumors and the visible mediastinal lymph nodes on the CT scan; the planning target volume was defined by the GTV plus a 1.5–2 cm margin for setup uncertainty and respiratory motion. Portal verification was done by taking orthogonal X-rays. Wedge filters as beam modifying devices were used as and when required. Manual dosimetry for depth dose calculation was done. Treatment was done in the supine position with appropriate immobilization. The spinal cord was spared after 46 Gy and remaining radiation dose was given for the reduced field.
Radiation to appropriate metastatic site was given by short-course palliative radiation therapy with a dose of 20 Gy for 5 fractions taking a reasonable margin.
Supportive care and blood product transfusions and bone marrow stimulants were given whenever indicated. Other comedications, symptom control, and supportive care such as nutritional therapy, control of infection, nausea, and vomiting were done.
Evaluation of treatment-related toxicity, response assessment, and follow-up
Treatment-related acute toxicity was scored according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTC) version 3.0. During the CT period, patients were checked weekly to note any adverse or untoward side effects and the subjective response. Patients were subjected to CBC before every CT and biochemical profile before every CT cycle. Treatment was deferred if hemoglobin is <10 g%, TLC <4000/mm3 or platelet count <1 lakh/mm3 and treatment was resumed upon bone marrow recovery as indicated by recovery of hematological parameters to normal levels. After the completion of CT, the patients were followed up monthly for a minimum period of 6 months.
During RT, patients were evaluated weekly for the development of any skin, pulmonary, or esophageal toxicity. CBC and biochemical parameters were checked before the start of radiation and weekly during treatment.
The early treatment response was assessed at 1 month following the completion of treatment in accordance with RECIST criteria using CXR and CECT thorax. After the completion of RT, the patient was followed up at monthly intervals, till the completion of the study.
The primary end point was progression-free survival (PFS). PFS was defined as the duration between the commencement of treatment to the first site of tumor progression, death of any cause, or date of last follow-up. The secondary end points included OS, tumor response, and toxicity. OS was measured from the day of commencement of treatment to day of last follow-up or death of any cause. Descriptive statistics such as mean, standard deviation, median, percentages, and interferential statistics such as Chi-square test, Fisher's exact test, and nonparametric test were used. Survival was analyzed using the Kaplan–Meier method and log-rank test. P < 0.05 was considered statistically significant.
| Results|| |
A total of 40 cases of confirmed metastatic NSCLC staged according to AJCC, 2010 were included in the study after randomization into two arms namely Arm A and Arm B of 20 patients each. The age of the patient ranges from 60 to 82 years (median-71 years). The male-to-female ratio for the study sample was 1.1:1. Patient characteristics and disease characteristics are given in [Table 1] and [Table 2], respectively. Most patients have Stage IV M1b disease and squamous cell carcinoma (SCC) histological subtype and bone metastasis. Majority of patients with bone metastasis were localized to the dorsolumbar spine at multiple vertebral levels (92.8%) and only one patient (7.14%) had right humeral metastasis. Other site metastasis included adrenal metastasis (80.0%), distant lymph nodes (20.0%), and subcutaneous nodules (20.0%). Two patients (5.0%) in Arm B had metastasis at multiple sites.
Four different common symptoms were taken into account, namely cough, chest pain, dyspnea, and hemoptysis. Pretreatment symptoms show that Grade 1 cough was the most common presentation in 23 patients (57.5%) with 55.0% in Arm A and 60.0% in Arm B. This was followed by chest pain, dyspnea, and haemoptysis in both Arm A and arm B. After 1 month of treatment, the result shows a mark improvement of all the symptoms in both the Arms. Arm A shows most significant improvement of symptom in hemoptysis (85.0%) and chest pain (40.0%) followed by dyspnea (35.0%) and cough (20.0%). Whereas arm B shows improvement in hemoptysis (60.0%), dyspnea (55.0%), chest pain (55.0%), and cough (30.0%).
The overall treatment response (CR + PR) was 70.0% in Arm A and 50.0% in Arm B (P = 0.55), as shown in [Figure 1]. The response rates of adenocarcinoma were 75.0% in arm A and 60.0% in arm B while that for SCC was 66.6% in Arm A and 40.0% in Arm B (P = 0.48). Hematologic toxicity including acute Grade 3-4 neutropenia, thrombocytopenia, and anemia was observed in 45.0%, 14.0%, and 12.0% in Arm A and 34.0%, 19.0%, and 12.0% in Arm B, respectively. The most frequently observed acute pneumonitis or esophagitis was mainly Grade 0 or Grade 1as seen in 75.0% in Arm A. No Grade 3-4 acute pneumonitis or esophagitis was observed (P = −0.62).
|Figure 1: Early treatment response of primary site at the end of 1 month|
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Median follow-up was 8 months (range – 4–16 months) with a PFS and OS range of 2–14 months and 3–16 months, respectively. Survival functions (PFS and OS) are shown in [Figure 2].
|Figure 2: PFS and OS between the two arms. PFS: progression-free survival, OS: Overall survival, SD: Standard deviation, CI: Confidence interval|
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| Discussion|| |
More than 50% of cases of advanced NSCLC are diagnosed in patients over the age of 65 years. The selection of optimal treatment in elderly cancer patients is challenging owing to their medical and physiological changes. This patient population is at risk of both excessive toxicity from standard therapy or empirical under treatment. Historically, in this clinical setting, palliative CT with a single-agent is considered the routine standard of care. However, outcomes with palliative CT have been dismal., We gave sequential treatment of CT followed by local RT which resulted in an improved OS and tumor response compared to CT alone with tolerable toxicity profile.
The Central Statistics Office, Government of India documented elderly population as people aged 60 years and above. Hence, for this study, we have used 60 years of age and older as the general definition of an elderly person. Most patients fall in the age group range of 60–69 years with a mean age of 71.75 ± 7.08 years. In a prospective study in patients with newly diagnosed metastatic NSCLC, the mean age at the diagnosis was 64.87 ± 9.41 years and metastatic NSCLC accounts for 51% and 49% in males and females, respectively. In contrast to most other studies,, SCC (55.0%) is the predominant histologic subtype in our study accounting for 60.0% and 50.0% in Arm A and B, respectively.
Single-agent gemcitabine has shown acceptable activity and favorable toxicity profile in elderly patients with advanced NSCLC. In a phase II trial with single-agent gemcitabine in elderly population (median age–73 years), median duration of PR and SD was 8 months and 4 months, respectively. The median time to progression was 4 months, the median survival was 9 months, and 1-year survival was 44%.
Recent studies on the implications of locoregional failure in elderly patients with advanced NSCLC have found that the disease course after progression following first-line single-agent CT markedly influence the OS. Observational studies report that the predominant pattern of recurrence in patients with metastatic NSCLC treated with first-line systemic therapy appears to be local only. Metastatic NSCLC patients (65%) had stable or progressive disease in initially involved sites without developing new metastases which implies that some form of aggressive local therapy to thoracic primary combined with systemic therapy might support the potential PFS benefit.
In this study, the response rates were better in the radiation arm (70.0%) compared to CT alone (50.0%) The median PFS and OS were significantly longer in those who received radiation in addition to systemic CT.
Similarly, Moumtzi et al., in a retrospective analysis observed that in Stage IV patients, the OS and PFS of irradiated patients is significantly longer than that of nonirradiated patient (P < 0.001). Furthermore, the number of distant metastases does not statistically significantly affect OS, neither the PFS.
Hematologic toxicity was almost comparable in both arms. Acute esophagitis and pneumonitis observed in the study arm were generally low grade. The acceptable adverse effects demonstrated in our study could be a result of the strict eligibility criteria taken for this study. Gomez et al. in a randomized phase II trial in oligometastatic NSCLC gave local therapy (RT) as an additional treatment demonstrating a significantly improved PFS (11.9 months) compared to maintenance CT alone (3.9 months) with similar toxicity between groups, with no Grade 4-5 events.
The most efficient therapeutic strategy for stage IV NSCLC involves both control of the primary tumor and treatment of metastatic lesions. A systematic review has shown prolonged survival by increasing fractionation and total radiation dose to primary tumors. A study on radiation dose escalation found that increasing the dose improved the control rate of local tumors in locally advanced NSCLC. A primary tumor radiation dose ≥63 Gy provided better OS and LRPFS, although of borderline significance. These data indicate that survival benefit may be received from administrating local RT in elderly metastatic NSCLC integrated with systemic therapy sequentially. Although the radiation treatment administered in our study was not optimal owing to the use of two-dimensional radiation planning and a small sample size, further optimization of radiation treatment using newer three-dimensional techniques and large samples may facilitate a more prolonged survival, improved treatment response, and reduced toxicities in this population group.
| Conclusion|| |
Elderly patients with stage IV NSCLC can benefit from higher radiation doses (45–55 Gy) delivered to the primary tumor after systemic CT resulting in improved response rates and survival outcomes with an acceptable toxicity profile. Thus, in addition to systemic CT, thoracic RT beyond palliative intent can be considered. Further trials with larger samples and more lenient eligibility criteria may be required to explore aggressive local therapies in this patient group.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]