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.

Both arms were well balanced regarding age, sex, smoking habit, co morbidity, weight loss before radiation, HB level and PS (Table 1).

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 (Table 2 and Table 3).

Both arms were well balanced regarding pathology, stage and the field size.

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

arms regarding the response to chemotherapy (P value = 0.73) (Table 4).

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

not reach statistical significance for any symptom (Table 5).

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) (Table 6).

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 (Table 7).

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 (Table 8). Post treatment mean values of FVC and FEV1 were higher in arm B than arm A without significant difference (Table 9).

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.

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 [14] [21] .

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 [11] [14] [15] [21] [22] who found that the most effectively palliated symptoms were chest pain and haemoptysis. Dyspnea was the least effectively palliated symptom in our study and this is similar to [15] [22] due to irreversible lung damage caused by pulmonary collapse or consolidation. This is in contrast to Attia and Abdelgawad [23] who reported that the most effectively palliated symptoms were dyspnea and cough.

Sundstrøm et al. [14] reported equality of 3 arms in thoracic palliation of lung cancer. The arms were: A, 17 Gy in 2 fractions, day 1 and 8 (n = 146); B, 42 Gy in 15 fractions in 3 weeks (n = 145); and C, 50 Gy in 25 fractions in 5 weeks (n = 130). In contrast of our study, there was no limitation of age and PS was 0 - 3. Clinicians’ assessments of symptom improvement were at 2, 6, and 14 weeks after completion of treatment. Also Macbeth et al. [13] reported that no strong evidence for the superiority of any particular regimen in spite of differences in the radiotherapy regimens, patient characteristics and outcome measures. Senkus-Konefka, et al. [19] randomized 100 patients into 2 arms: 20 Gy in 5 daily fractions (arm A: 55 patients) or 16 Gy in 2 fractions, day 1 and 8 (arm B: 45 patients). The grading of symptom intensity was performed using a 4-point scale (none, mild, moderate, severe). No significant differences between study arms were observed.

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 [8] .

Van den Hout et al. [24] compared two fractionation arms (30 Gy in 10 fraction in 2 weeks and 17 Gy in 2 fractions 1week apart) and reported that arms were equally effective regarding palliation. This is similar to Rees et al. [11] who also found that 17 Gy in 2 fractions, day 1 and 8 or 22.5 Gy in five daily fractions had no clinically important differences in efficacy between the two regimens. Similarly, Sourav et al. [25] randomly assigned patients to three treatments arms: 1) 17 Gy in 2 fractions, day 1 and 8; 2) 20 Gy in five fractions in one week and 3) 30 Gy in 10 fractions in two weeks. Symptomatic relief was equivalent in all the three arms.

Limited number of studies reported better symptom control between compared regimens. Besjak [18] compared 10 Gy single fraction with 20 Gy in 5 daily fractions and reported that highly significant improvement in symptoms control with the fractionated schedule (five fractions). Erridge et al. [26] reported that the 30 Gy in 10 fractions over 2 weeks regimen was significantly better at reducing chest pain and dyspnea compared to 10 Gy single fraction regimen. In addition, a significant improvement in PS with fractionated regimen.

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. [16] in which 22% of arm A (17 Gy in 2 fractions, day 1 and 8) and 25% of arm B (30 Gy in 10 fractions in 2 weeks or 27 Gy in 6 fractions in 8 days) achieved PR without statistical significant. Senkus-Konefka et al. [19] also reported equality between two compared arms (20 Gy in 5 fractions in 1 week and 16 Gy in 2 fractions, day 1 and 8) regarding radiological assessment of primary thoracic lesion by chest X ray 2 weeks after treatment. In this study, 52% and 54% achieved PR in the 5 fractions regimen and the single fraction regimen respectively without significant difference.

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 [18] who reported mild esophagitis and skin reaction without significant difference between the two treatment arms. This is similar to Lupatelli et al. [27] study in which short course palliative radiotherapy in advanced NSCLC was carried out. The regimen was 16 Gy given in 2 fractions, day 1 and 8. Treatment was generally well tolerated, only 4 patients (5%) experienced World Health Organization grade III dysphagia. No reported cases of skin reaction. This is similar to Cross et al. [22] who reported no cases of radiation esophagitis or skin reaction in 16 Gy in 2 fractions, day 1 and 8 regimen.

This is in contrast to Rees et al. [11] who found that 50% of patients receiving two fractions (17 Gy over 2 fractions, day 1 and 8) and 38% of those having five fractions (22.5 Gy in 5 fractions in 1 week) experienced moderate or severe dysphagia at some time shortly after treatment. Two weeks after treatment, moderate or severe dysphagia was reported by 28% of those receiving two fractions and by 15% of those given five fractions. At 3 weeks after treatment, only 7% of all patients reported moderate/severe dysphagia. Also Tomasz et al. [28] reported 100% dysphagia and odonophagia in 125 patients with advanced NSCLC received 20 Gy in 5 fractions in one week. Radiation-induced esophagitis grade 4 was observed in 5 patients (4.0%) and these patients required enteral and parenteral support. This study included patients with poor PS (Karnofsky PS accounted 40% - 30%) and this may be the cause of high rates of morbidity.

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. [12] study in which 152 patients were randomized to receive conventionally fractionated (arm A: 60 Gy in 30 fractions over 6 weeks, number of patients: 79) or short- term accelerated treatment (arm B: 32 Gy, 2 Gy bid in 8 days; number of patients: 73). Sixty five % of patients had clear or equivocal radiological signs of pulmonary radiation injury 6 weeks after treatment. Such a high incidence in this study can be easily linked to much higher RT doses used.