Background: The optimal dose of palliative radiotherapy (RT) in symptomatic advanced lung cancer is unclear. Patients and methods: Patients with advanced NSCLC who were indicated for thoracic palliative RT with age up to 65 y and Performance Status (PS) 0 - 2 and no significant cardiac or lung co-morbidities were randomized into two fractionation arms: arm A: 30 Gy/10 over 2 weeks and arm B: 27 Gy/6 over 3 weeks (2 fractions per week) using 2 anterior posterior (AP-PA) fields in both arms. Primary end points were symptomatic and radiological tumor response, respiratory functions assessment. Secondary end point was toxicity. Results: From December 2014 to October 2015, 40 patients were randomized, 20 patients in each arm. There was statistically insignificant higher symptomatic improvement in arm B. Four weeks after treatment, 12 out of 40 patients (30%), 6 patients in each arm, had radiological Partial Response (PR) of the primary thoracic lesion without significant difference between the two arms. There was a tendency for improvement in the post treatment mean Forced Vital Capacity (FVC) and Forced Expiratory Volume in one second (FEV1) in each arm without statistical significance. There were no reported skin reaction s or esophagitis in both arms up to 4 weeks after treatment. Eleven out of the 40 patients (27.5%), 6 in arm B and 5 in arm A, had radiological signs of radiation pneumonitis without significant difference between both arms. Conclusion: The two RT fractionation schedules showed equal efficacy in terms of symptoms relief, radiological response of the primary thoracic tumor, respiratory functions and toxicity. Thus the 27 Gy/6 fractionation arm appears preferable compared to 30 Gy/10 arm to minimize the patients ’ visits and load on the machines.
According to World Health Organization (WHO), lung cancer is the most common cancer worldwide, accounting for 1.8 million new cases and 1.6 million deaths in 2012. In Egypt in 2013, the estimated number of lung cancer cases constituted 4.2% from total cancer cases in combined gender. In males, lung cancer cases constituted about 5.7% of total malignancies compared to 2.7% in females [
Primary carcinomas of the lung are traditionally classified as either Small Cell Lung Cancer )SCLC) or Non-Small Cell Lung Cancer (NSCLC). NSCLC constitutes approximately 80% of all primary lung cancers. Adenocarcinoma, Squamous Cell Carcinoma (SCC) and Large Cell Carcinoma (LCC) constitute the major histological types [
The main goals of treatment in advanced NSCLC patients are prolongation of life, palliation of symptoms and improvement of Quality Of Life (QOL) [
Treatment decisions should ideally be discussed within a multidisciplinary tumor board. Systemic therapy should be offered to all stage IV NSCLC patients with a PS 0 - 2. In any stage of NSCLC, smoking cessation should be highly encouraged because it improves the outcome [
A comprehensive review involving 14 randomized clinical trials, all related to different dose schedules to palliate the symptomatic primary lung cancer, was performed by the Cochrane Collaboration [
This study is a prospective randomized study to compare the effect of two RT schedules for thoracic palliation in advanced NSCLC patients (30 Gy in 10 fractions over two weeks and 27 Gy in 6 fractions over three weeks, 2 fractions per week) on improvement of pulmonary symptoms, respiratory functions, radiological response of the primary thoracic tumor and toxicity.
Patients with advanced NSCLC who presented to radiation oncology department, National Cancer Institute, Cairo University for palliative irradiation to the lung From December 2014 to October 2015 were studied for eligibility. Patients younger than 65 years with World Health Organization (WHO) PS up to 2 and expected survival of at least 3 months were eligible. Patients with significant cardiac disease, pleural effusion and known asthmatic patients or those with history of previous radiotherapy to chest region were excluded.
Eligible patients were randomized into two fractionation arms: 30 Gy in 10 fractions over two weeks and 27 Gy in 6 fractions over three weeks (two fractions per week).
Was done pretreatment and 4 weeks after end of RT in the form of:
1) Full history taking and complete physical examination. Symptomatic assessment according to a 4-point scale (none, mild, moderate, severe). Palliation of a symptom was defined as disappearance or improvement of the initial symptom one or more degree along the scale. Acute Toxicity (esophagitis and skin reaction) assessment according to Radiotherapy Oncology Group (RTOG) Acute Radiation Morbidity.
2) Complete blood count (CBC).
3) Respiratory function testing: FVC and FEV1.
4) CT chest with contrast: to assess radiological tumor extent initially and response to RT (longest diameter was recorded) and radiation pneumonitis. Assessment of tumor response was done according to: New Response Evaluation Criteria In Solid Tumors: Revised (RECIST) guideline version 1.1 [
The patients in both arms were simulated in the supine position with arms up. Geeral Electric computerized tomography simulator (CT-simulator) light speed 1017CT02 was used for the simulation. All patients were treated with 2 dimensional (2D) RT technique with two parallel opposing (AP-PA) iso-centeric fields. The treatment portals were extended 2 cm around the gross disease.
Primary end points encompassing palliation of chest tumor related symptoms, respiratory functions: FVC and FEV1 and radiological response of the primary thoracic tumor. Whereas the secondary end point aimed at comparing the treatment side effects relative to each fractionation arm.
The continuous variables were summarized by descriptive data (i.e., mean, standard deviation (SD), frequencies). Mean values were compared using simple t test. Percentages were compared using Chi-square test. P value less than 0.05 was considered statistically significant.
This study included forty Patients with advanced NSCLC who presented to the radiation oncology department, National Cancer Institute, Cairo University-from December 2014 to October 2015 for palliative irradiation to the lung. The patients were randomized into two fractionation arms 20 patients in each arm: 30 Gy in 10 fractions over two weeks (arm A) and 27 Gy in 6 fractions over three weeks, two fractions per week (arm B).
Both arms were well balanced regarding age, sex, smoking habit, co morbidity, weight loss before radiation, HB level and PS (
Cough was the most common complaint (90%) followed by pain (85%), dyspnea (60%) and haemoptysis (50%). There was no significant difference between the two treatment arms in the incidence or the degree of thoracic symptoms (
Both arms were well balanced regarding pathology, stage and the field size.
Adenocarcinoma was the most common pathology type, followed by SCC and lastly large cell carcinoma (
Majority of patients in both arms were stage IV representing all patients in arm A compared to 18 patients (90%) in arm B while the remaining 2 patients (10%) were stage IIIB without significant difference (P value = 0.49) (
No significant difference was found in the mean field size between both arms (arm A:
Criteria | No. of Patients (%) | P value | ||
---|---|---|---|---|
Arm A (20 pts ) | Arm B (20 pts) | Total pts (40 pts) | ||
Age Range Mean | 50 - 65 y 59.80 y | 40 - 64 y 57 y | 40 - 65 y 58.40 y | 0.15 |
Sex Male Female | 20 (100%) 0 (0%) | 18 (90%) 2 (10%) | 38 (95%) 2 (5%) | 0.49 |
Smoking habit Smoker Median years of smoking Cessation of smoking | 20 (100%) 30 y 19 (95%) | 18 (90%) 30 y 17 (94.4%) | 38 (95%) 30 y 36 (90%) | 0.49 0.61 0.41 |
Diabetes Mellitus (DM) DM | 2 (10%) 2 (10 %) | 3 (15%) 3 (15%) | 5 (25%) 5 (12.5%) | ------- |
Hypertension (HTN) | 3 (15%) | 4 (20%) | 7 (17.5%) | |
Weight loss more than 5% before radiation | 12 (60%) | 10 (50%) | 22 (55%) | 0.75 |
Hemoglobin (HB) Range Mean | 9.8 - 13.7 mg/dl 12.3 mg/dl 12.3 mg/dl | 10.3 - 13.9 mg/dl 12.7 mg/dl | 9.8 - 14.6 mg/dl 12.52 mg/dl | 0.12 |
World Health Organization (WHO) Performance Status (PS) 1 2 | 11 (55%) 9 (45%) | 10 (50%) 10 (50%) | 21 (52.5%) 19 (47.5%) | 0.75 |
Arm A No. of pt (%) | Arm B No. of pt (%) | Total No. of pt(%) | P value | ||
---|---|---|---|---|---|
Clinical presentation | Cough | 17 (85%) | 19 (95%) | 36 (90%) | 0.29 |
Pain | 18 (90%) | 16 (80%) | 34 (85%) | 0.38 | |
Dyspnea | 12 (60%) | 12 (60%) | 24 (60%) | 1 | |
Haemoptysis | 8 (40%) | 12 (60%) | 20 (50%) | 0.21 |
mean 148 cm2, with range 100 - 220 cm2; arm B: mean142 cm2, with range 85 - 215 cm2; P value = 0.48).
The Mean number of chemotherapy cycles in each arm was 5. Platinum based regimens were the most frequent regimens, 3 patients in arm A didn’t receive chemotherapy because of impaired renal functions. No significant difference was found between both
Symptom | Arm A No. of patients (%) | Arm B No. of patients (%) | P value |
---|---|---|---|
Cough non mild moderate severe | 3 (15%) 9 (45%) 6 (30%) 2 (10%) | 1 (5%) 8 (40%) 8 (40%) 3 (15%) | 0.67 |
Pain non mild moderate severe | 2 (10%) 8 (40%) 6 (30%) 4 (20%) | 4 (20%) 6 (30%) 7 (35%) 3 (15%) | 0.76 |
Dyspnea non mild moderate severe | 8 (40%) 5 (25%) 5 (25%) 2 (10%) | 8 (40%) 4 (20%) 7 (35%) 1 (5%) 1 (5%) | 0.85 |
Hemoptysis non mild moderate severe | 12 (60%) 4 (20%) 4 (20%) 0 (0%) | 8 (40%) 6 (30%) 5 (25%) 1 (5%) | 0.51 |
arms regarding the response to chemotherapy (P value = 0.73) (
The number of patients achieving improvement in symptoms (namely cough chest pain, dyspnea or hemoptysis) or in performance status was higher in the arm B, but did
Criteria | Arm A No. of pts (%) | Arm B No. of pts (%) | Total pts No. of pts (%) | P value |
---|---|---|---|---|
Chemotherapy given | 17 (85%) | 20 (100%) | 37 (92.5%) | 0.072 |
Response to chemotherapy Progressive Disease (PD) Stable Disease (SD) | 11 (64.7%) 6 (35.2%) | 14 (70%) 6 (30%) | 25 (67.5%) 12 (32.5%) | 0.73 |
not reach statistical significance for any symptom (
The mean longest tumor diameter recorded in pre treatment CT was 7.12 cm in arm A compared to 7.45 cm in arm B without significant difference (P value = 0.68).
Four weeks after treatment, no significant difference was found between both arms in radiological response of the primary thoracic tumor (P value = 0.64) (
FVC and FEV1 were presented as percentage (%) of actual from predicted value (actual/predicted).
At base line, patients in both arms had comparable mean FVC and FEV1 (
Four weeks after treatment, there was a tendency for improvement in the mean of FVC and FEV1 compared to the pre treatment mean values, however this improvement didn’t reach statistical significance in each arm (
Arm A No. of pts (%) | Arm B No. of pts (%) | P value | |
---|---|---|---|
Cough Improvement | 10/17 (58.82%) | 13/19 (68.42%) | 0. 41 |
Progression | 4/17 (23.5 %) | 3/19 (15.7%) | |
SD | 3/17 (17.6%) | 3/19 (15.7%) | |
Pain | |||
Improvement | 13/18 (72.2%) | 15/16 (93.75%) | 0.27 |
Progression | 3/18 (16.6%) | 1/16 (6.2%) | |
SD | 2/18 (11.11%) | 0/16 (0.0%) | |
Dyspnea Improvement | 5/12 (41.66%) | 6/12 (50%) | 0.57 |
Progression | 4/12 (33.33%) | 3/12 (25%) | |
SD | 3/12 (25%) | 3/12 (25%) | |
Haemoptysis | |||
Improvement | 6/8 (75%) | 10/12 (83.33%) | 0.81 |
Progression | 1/8 (12.5%) | 0/12 (0.0%) | |
SD | 1/8 (12.5%) | 2/12 (16.66%) | |
Performance Status (PS) | |||
Improvement | 10/20 (50%) | 12/20 (60%) | 0.75 |
Stable | 10/20 (50%) | 8/20 (40%) | 0.19 |
Arm | Total No. of pts (%) No. of pts (%) | P value | |||
---|---|---|---|---|---|
Arm A No. of pts (%) | Arm B No. of pts (%) 6 (30%) | ||||
Radiological response of chest tumor 4 weeks after treatment | PR | 6 (30%) | 6 (30%) | 12 (30%) | 0.64 |
SD | 12 (60%) | 14 (70%) | 26 (65%) | ||
PD | 2 (10%) | 0 (0.0%) | 2 (5%) |
Pre treatment FVC (%) | Pre treatment FEV1 (%) | |||||
---|---|---|---|---|---|---|
Arm A | Arm B | P value | Arm A | Arm B | P value | |
Mean | 56.80 | 56.60 | 0.96 | 53.90 | 54.40 | 0.95 |
Minimum | 33 | 30 | 32 | 30 | ||
Maximum | 89 | 92 | 92 | 86 |
Pretreatment Mean FVC (%) | Post treatment Mean FVC (%) | p value | Pretreatment Mean FEV1 (%) | Post treatment Mean FEV1 (%) | P value | |
---|---|---|---|---|---|---|
Arm A Arm B | 56.80 56.60 | 59.45 61.45 | 0.24 0.11 | 53.90 54.40 | 56.10 56.40 | 0.23 0.09 |
Post treatment FVC (%) | Post treatment FEV1 (%) | |||||
---|---|---|---|---|---|---|
Arm A Arm A | Arm B | P value | Arm A | Arm B | P value | |
Mean | 59.45 | 61.45 | 0.73 | 56.10 | 56.40 | 0.79 |
Minimum | 33 | 30 | 32 | 30 | ||
Maximum | 89 | 92 | 92 | 86 |
Treatment was generally well tolerated in the two treatment arms. According to RTOG Acute Radiation Morbidity, no reported cases of skin reaction or esophagitis were recorded in both arms up to 4 weeks after treatment. Four weeks after treatment, 11 patients out of 40 (27.5%) had radiological signs of radiation pneumonitis through CT chest. Five patients (25%) in arm A had radiological signs of radiation pneumonitis compared to 6 patients (30%) in arm B without significant difference (P value = 0.68). The radiological finding was a diffuse haziness or fuzziness in areas of the irradiated lung.
The issue of optimal palliative irradiation schedule in advanced symptomatic NSCLC has been a subject of numerous randomized studies (
In our study the fractionation in arm B 27 Gy/6 over 3 weeks was not used in previous randomized trials and the long overall treatment time was intended to minimize toxicity of short fractionation schedules and it proved same palliation.
In our study, we restricted ECOG PS up to 2 and age up to 65 y. This facilitated respiratory function assessment. In many similar studies patients of any age or PS were included however Simpson et al. [
Reference | No. of pts | Stage or selection criteria | Dose (Gy) | No. of fractions and overall treatment period |
---|---|---|---|---|
Macbeth et al. 2004 [ | 509 | Inoperable non metastatic | 17 39 | 2F in 8 days (1 week apart) 13F over 2 weeks and half |
Sundstorm et al. 2004 [ | 421 | Stage III-IV | 17 42 50 | 2F in 8 days (1 week apart) 15F over 3 weeks 25F over 5 weeks |
Simpson et al. 1985 [ | 409 | Inoperable stage III B | 30 40 | 10F over 2 weeks 20F over 4 weeks |
MRC. 1991 [ | 369 | Inoperable including Metastases-ECOG PS up to 2 | 17 27 30 | 2F in 8 days (1 week apart) 6F in 8 days 10 F in 2 weeks |
Kramer et al. 2005 [ | 297 | Stage III-IV | 16 30 | 2F (1 week apart) 10F over 2 weeks |
MRC. 1992 [ | 235 | Locally advanced including Metastases-PS ≥ 2 | 17 10 | 2F (1 week apart) 1F |
Besjak et al. 2002 [ | 230 | Locally advanced including metastases | 10 20 | 1F 5F over 1 week |
Rees et al. 1997 [ | 216 | Locally advanced including metastases | 17 22.5 | 2F in 8 days (1 week apart) 5F over I week |
Senkus-Konfeica et al. 2005 [ | 100 | Locally advanced including metastases | 20 16 | 5F over 1 week 2F (1 week apart) |
MRC: Medical Research Council. F: fraction(s).
Like most of the previous similar studies, we used relatively simple treatment planning using two AP-PA parallel-opposed fields.
Many studies emphasized the importance of relying (as we did) more on patient self- assessment than on physicians’ evaluation, as major differences are observed between results of both these judgments [
In the current study, 4 weeks after treatment, pain, hemoptysis, cough and dyspnea had improved in 82.3%, 80%, 61.1%, 45.8%, of patients, respectively. The number of patients achieving symptomatic improvement was higher in the arm B, but did not reach statistical significance for any symptom. This was similar to other authors [
Sundstrøm et al. [
This idea of non superiority of any particular regimen in thoracic palliation of advanced lung cancer was confirmed by a Cochrane analysis of 10 randomized palliative radiotherapy trials indicated that symptomatic relief was equivalent regardless of the total radiotherapy dose [
Van den Hout et al. [
Limited number of studies reported better symptom control between compared regimens. Besjak [
In our study, 12 patients (30% - 6 patients in each arm) achieved PR of the primary thoracic lesion 4 weeks after treatment on evaluation by CT chest. This was similar to MRC. [
In our study, no dysphagia or skin reaction were reported up to 4 weeks after treatment according to RTOG Acute Radiation Morbidity. This was may be due to good PS and low biological total dose. This is similar to Bezjak [
This is in contrast to Rees et al. [
In our study, 11 patients (27.5%) had radiological signs of radiation pneumonitis. Five patients (25%) in arm A has radiological signs of radiation pneumonitis compared to 6 patients (30%) in arm B with no significant difference. This is in contrast to Nestle et al. [
Our study confirmed the equal efficacy of the two palliative lung cancer radiotherapy schedules (30 Gy/10 fractions/2 weeks regimen and 27 Gy/6 fractions/3 weeks, 2 fractions per week regimen) in terms of palliative effect, radiological response of the primary thoracic tumor, respiratory functions and toxicity. Thus we intend to implement this regimen on a bigger number of study group patients with longer follow up to validate it to become a suitable alternative in our busy department.
Small number of patients in each randomization arms and short follow up.
Lotayef, M., Elkader, Y.A., Amin, A., Taher, A., El-Kest, E. and Abdelall, M. (2016) A Prospective Study of the Effect of Different Palliative Radiotherapy Fractionation Schedules on Tumor Response and Toxicity in Advanced Non- Small Cell Lung Cancer (NSCLC) Patients. Journal of Cancer Therapy, 7, 924-938. http://dx.doi.org/10.4236/jct.2016.712090