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Asia-Pacific Journal of Clinical Oncology 2014
doi: 10.1111/ajco.12262
ORIGINAL ARTICLE
A decade of community-based outcomes of patients treated with curative radiotherapy with or without chemotherapy for non-small cell lung cancer Ariyanto PRAMANA,1 Joseph DESCALLAR2,4 and Shalini K VINOD2,3,4,5 1 Radiation Oncology Department, St George Cancer Care Centre, 2Ingham Institute of Applied Medical Research, Liverpool Hospital, and 3Liverpool and Macarthur Cancer Therapy Centres, and 4University of NSW, 5University of Western Sydney, Sydney, New South Wales, Australia
Abstract Aim: Clinical trials have reported good outcomes for non-small cell lung cancer (NSCLC) patients treated with curative radiotherapy. These populations are highly selected and may not be representative of lung cancer population. We aim to evaluate the outcomes of NSCLC patients treated with radiotherapy ± chemotherapy in Australian community setting and to assess the effect of comorbidity on outcomes. Method: Oncology records at Liverpool and Macarthur Cancer Therapy Centres, Sydney, Australia, were queried to retrieve patient, tumor and treatment data for stage I–III NSCLC patients who were treated with radiotherapy (minimum dose 60 Gy) between 1 January 2000 and 31 December 2010. Simplified comorbidity score (SCS) was used to score comorbidity. Kaplan–Meier and Cox hazards models were used for survival analysis. Results: A total of 160 patients were identified with median follow-up of 22 months. Median age was 69 years (range 36–89); 76 patients received radiotherapy alone, 25 received sequential chemoradiation and 59 received concurrent chemoradiation. Median overall survivals for stages I, II and III were 29, 26 and 18 months, respectively. On multivariate analysis, stage II or III and weight loss > 5% were predictive of cancer-specific survival with hazard ratios of 4.47 (1.08–18.55, P = 0.04) and 2.23 (1.13–4.39, P = 0.02), respectively. Toxicities were grade ≥ 3 pneumonitis in 2% of patients, grade ≥ 3 esophagitis in 6% and grade ≥ 3 febrile neutropenia in 2%. There were no treatment-related deaths. SCS was neither prognostic nor predictive of toxicity or survival. Conclusion: Curative radiotherapy ± chemotherapy is a well-tolerated and effective treatment for inoperable or locally advanced NSCLC. Patients should not be excluded from radiotherapy on basis of comorbidity since higher SCS was not correlated with worse survival. Key words: chemotherapy, community, comorbidity, lung cancer, radiotherapy.
INTRODUCTION
Correspondence: Dr Ariyanto Pramana BSc (Med) MBBS FRANZCR, St George Cancer Care Centre, 1 Short Street Kogarah, NSW 2217, Australia. Email: [email protected] Conflict of interest: The authors declare no conflict of interest or financial support for this study. Accepted for publication 30 June 2014.
© 2014 Wiley Publishing Asia Pty Ltd
In Australia, lung cancer is the fourth most commonly diagnosed cancer.1 It is the leading cause of cancer deaths for both sexes. Non-small cell lung cancer (NSCLC) is the predominant histology with 60%. There are many international trials reporting good outcomes with curative radiotherapy. These populations are highly selected and there are limited data on whether these outcomes are seen in community practice.2,3
2
Radiotherapy is indicated for inoperable stage I–III NSCLC.4 For stages I and II, overall survival (OS) at 2 and 5 years was 22–72% and 0–42%, respectively; cancer-specific survival (CSS) was 54–93% and 13–39%, correspondingly.5 Between 11 and 43%, patients die from non-cancer causes, reflecting their poor health status. Nonsurgical patients are staged clinically and lack of pathologic staging contributes to poorer outcomes. Chemoradiation is the standard of care for inoperable stage III NSCLC.6,7 In NPC 95-01 study, where stage III patients had good performance status and minimal weight loss (5% were found to be predictive on multivariate analysis with hazard ratios (HRs) of 4.47 (1.08–18.55, P = 0.04) and 2.23 (1.13–4.39, P = 0.02), respectively. Univariate analysis showed increased weight loss >5% (HR = 2.28 [1.23–4.23]) and radiotherapy interruption (HR = 2.42 [1.45–4.06]) was predictive of OS. However, on multivariate analysis, none of these were significant for OS. Other factors considered a priori such as performance status, age, SCS, respiratory function, pathology and grades were not predictive of OS.
Toxicity Table 4 summarizes the toxicity from radiotherapy ± chemotherapy. Overall, severe toxicities of grade ≥3 pneumonitis, esophagitis and febrile neutropenia were 2, 6 and 2%, respectively, for whole cohort and 2, 10 and 2% for the concurrent chemoradiation group. Rate of esophagitis increased with use of chemotherapy. No patients died as a result of radiotherapy/ chemotherapy-related toxicity and there have been no episodes of myelopathy. SCS > 9 was not predictive of toxicity from treatments, with only 4/25 (16%) patients with grade ≥3 radiation toxicity have SCS > 9 and 0/7
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Table 1
A Pramana et al.
Patient demographics Group Radiotherapy alone (n = 76), n (%)
Sequential chemoradiation (n = 25), n (%)
Concurrent chemoradiation (n = 59), n (%)
All patients (n = 160), n (%)
72.5 36–87
73 39–88
65 41–89
69 36–89
53 (70) 23 (30)
18 (72) 7 (18)
48 (81) 11 (19)
119 (74) 41 (26)
38 (50) 38 (50)
10 (40) 15 (60)
30 (51) 29 (49)
78 (49) 82 (51)
58 (76) 14 (19) 4 (5)
21 (84) 3 (12) 1 (4)
55 (93) 4 (7) 0 (0)
134 (84) 21 (13) 5 (3)
51 (67) 22 (29) 3 (4)
15 (60) 10 (40) 0 (0)
44 (75) 15 (25) 0 (0)
110 (69) 47 (29) 3 (2)
67 (88) 6 (8) 3 (4)
22 (88) 3 (12) 0 (0)
56 (95) 3 (5) 0 (0)
145 (91) 12 (7) 3 (2)
8 (10) 43 (57) 25 (33)
3 (12) 16 (64) 6 (24)
4 (7) 24 (41) 31 (52)
15 (9) 83 (52) 62 (39)
38 (50) 6 (8) 32 (42)
18 (72) 3 (12) 4 (16)
18 (30) 8 (14) 33 (56)
74 (46) 17 (11) 69 (43)
24 (32) 11 (14) 41 (54)
5 (20) 6 (24) 14 (56)
0 (0) 11 (19) 48 (81)
29 (18) 28 (18) 103 (64)
32 (42) 31 (41) 11 (14) 2 (3)
6 (24) 11 (44) 7 (28) 1 (4)
25 (43) 15 (25) 13 (22) 6 (10)
63 (39) 57 (36) 31 (19) 9 (6)
Age (years) Median Range Gender Male Female Country of birth Australia Overseas ECOG 0–1 >1 Unknown Simplified comorbidity score ≤9 >9 Unknown Smoking Yes No Unknown Respiratory function (FEV1) 5% Unknown Stage I II III Histology Large cell Squamous cell Adenocarcinoma Carcinoma, NOS
P value 0.02
0.30
0.29
0.10
0.58
0.27
1.0
0.17
9.
SCS and survival All except three patients in this cohort had at least one SCS. Median SCS was 8 (1–16). Smoking was prevalent
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in 145/157 (92%), followed by respiratory comorbidity (63/157 [40%]), cardiovascular disease (62/157 [39%]), diabetes (18/157 [11%]), prior neoplastic condition >5 years prior to NSCLC (13/157 [8%]), alcoholism (8/157 [5%]) and renal impairment (5/157 [3%]). Univariate analysis (reference of SCS ≤ 9) revealed HR for CSS of 0.44 (0.25–0.78, P = 0.005) and HR for OS of 1.30
Asia-Pac J Clin Oncol 2014
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Outcomes of chemoradiation for lung cancer
Table 2
First site of recurrence Stage I
Treatment group
Stages II–III
Radiation alone (n = 24) Sequential chemoradiation (n = 5) Concurrent chemoradiation (n = 0), n (%)
Radiation alone (n = 52)
Sequential chemoradiation (n = 20)
Concurrent chemoradiation (n = 59)
8 (28) 5 (17) 0 (0) 16 (55)
17 (33) 16 (31) 1 (2) 18 (35)
12 (60) 6 (30) 0 (0) 2 (10)
18 (31) 21 (36) 3 (5) 17 (29)
Recurrence pattern Local Distant Both None
Table 3 Median OS and 2-year OS by treatment groups Median OS (months)
Stage I
Stage II
Stage III
31.7 9.7 –
27.6 15.5 29.3
17.1 15.6 17.9
Stage I
Stage II
Stage III
63% 20% –
60% 17% 64%
44% 38% 42%
Radiation alone Sequential chemoradiation Concurrent chemoradiation 2-year OS (%) Radiation alone Sequential chemoradiation Concurrent chemoradiation OS, overall survival.
Table 4
Severe toxicity summary Group Radiation alone (n = 76), n (%)
Sequential chemoradiation (n = 25)
Concurrent chemoradiation (n = 59)
All patients (n = 160)
12 (16) 1 (1)
7 (28) 1 (4)
13 (22) 1 (2)
32 (20) 3 (2)
2 (3) 3 (4)
1 (4) 1 (4)
2 (3) 6 (10)
– –
1 (4) 1 (4)
4 (7) 1 (2)
Pneumonitis Grade 2 Grade 3 Esophagitis Grade 2 Grade 3
Febrile neutropenia Grade 2 Grade 3
(0.89–1.89, P = 0.18). On multivariate analysis, SCS was not a statistically significant prognostic variable for CSS or OS.
DISCUSSION Patient demographics Demographic of community NSCLC patients is different from those enrolled in clinical trials, which tend to
Asia-Pac J Clin Oncol 2014
5 (3) 10 (6) Patients who received chemotherapy (n = 84) 5 (6) 2 (2)
include fit patients without any significant comorbidity. Fournel et al.’s study in unresectable stage III NSCLC had eligibility criteria of age 70 and two trials required 1 in 13%, FEV1 5% in 11% and SCS >9 in 29%. Acknowledging that there are missing data, it appears that our patients have slightly worse health compared from trials population.
Radiotherapy for stage I NSCLC Radiotherapy is the standard of care for stage I NSCLC patients who are medically inoperable or who refuse surgery. In our cohort, median CSS and OS for stage I were 51 and 29 months and 2-year CSS and OS of 71 and 55%, respectively. These results are similar to data from a systematic review: radiotherapy for stage I/II patients who were unfit or declining surgery, and yielded 2-year OS of 22–72% and median OS of 15–33 months. Fiveyear OS was better for T1 than for T2 tumors (29–37% vs 4–24%), and 2-year CSS was 54–93%.5 Between 11% and 43% (median 25%) of patients died from non-cancer causes, reflecting their poor health status. In our cohort, around 16% of patients are dying of non-cancer causes at 2 years. This is less than the median 25% obtained from Rowell et al., which may be related to different patient demographic and selection factor. Stereotactic body radiotherapy (SBRT) is currently being investigated for definitive management of stage I NSCLC. SBRT provides greater local control than standard radiotherapy for high-risk and medically inoperable patients.17 A meta-analysis revealed 2-year OS of 3201 patients with localized stage I NSCLC treated with SBRT was 70% and 2-year local control of 91%. Our data showed 2-year OS of 63% for stage I NSCLC patients who received radiotherapy alone, which is comparable to radiotherapy data from Rowell et al.; however, inferior outcomes were compared with SBRT.
Radiotherapy or combined modality therapy for stage II and III NSCLC The optimal treatment recommendation for stage III NSCLC is not clearly defined and some aspects currently remain controversial due to heterogeneity in NSCLC. Patients with stage II NSCLC who are medically inoperable are being increasingly treated as stage III, extrapolating the benefits of adjuvant chemotherapy in the postoperative setting to concurrent chemoradiation in the nonoperative setting. Furthermore, radiotherapy alone may be used as definitive modality for stage II–III NSCLC patients who are not candidates for chemotherapy.
© 2014 Wiley Publishing Asia Pty Ltd
A Pramana et al.
Zierhut et al. analyzed 60 inoperable stage I (35%) and II (65%) NSCLC treated with median radiotherapy dose of 60 Gy.18 The median progression-free survival and median OS were 18 and 21 months, respectively. Our stage II cohort who was treated with radiotherapy alone had a median OS of 28 months and 2-year OS of 60%. In contrast, radiotherapy alone for patients with stage III NSCLC resulted in a median OS of approximately 10 months and 2-year OS of 13–23%.5,19–21 Our results for these stage III patients were median OS of 17 months and 2-year OS of 44%. The slightly better outcomes in our cohort could be related to patient selection factors. Randomized trials have established the advantage of concurrent chemoradiation approach (with platinum doublet), which is the standard of care for unresected stage III NSCLC.22 Our data for stage III patients treated with concurrent chemoradiation have revealed median OS of 18 months and 2-year OS of 42%. These are comparable to NPC-95-01 with 16 months of median survival and 2-year OS of 39%.6 Similarly, RTOG-9410 has also shown 17 months of median survival and 5-year OS of 16%.23 Other studies utilizing altered fractionation concurrent chemoradiation have resulted in 17–22 months of median survival and 2-year OS between 23 and 35%.24–26 Sequential chemotherapy followed by radiotherapy was initially used to avoid overlapping toxicities from each modality.20,27,28 Dillman et al. were one of the first authors who initially established the benefits of this approach compared to radiotherapy alone. They reported a significantly higher long-term survival with additional 4 months of median survival and improved distant failure-free survival, but without impact on LR.19 Their median survival and 2-year OS were 13.7 months and 26% with sequential chemoradiation for stage III NSCLC. Our result for stage III NSCLC with sequential approach is slightly better with median survival and 2-year OS of 15.6 months and 38%, respectively. An updated meta-analysis exploring sequential versus concurrent chemoradiation has demonstrated a survival benefit for concurrent approach due to potential radiosensitization and reduced systemic micrometastatic disease.22 A significant OS benefit of concurrent treatment was evident with HR 0.74 (0.62–0.89) and 10% absolute OS benefit at 2 years. However, there was increased severe esophagitis in the concurrent group with risk ratio of 4.96 (2.17–11.37). Therefore, patient selection is an important consideration in view of the potential added toxicity of concurrent regimen. It is unclear whether similar benefits could be achieved using
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Outcomes of chemoradiation for lung cancer
modern radiotherapy techniques, and accelerated or hyperfractionated regimens. In our stage II–III cohort in sequential chemoradiation group, LR rate was inferior compared to either radiation alone or chemoradiation group. Possible explanations for this include, firstly, patient selection bias, which was inherent within the context of a retrospective study. It is possible that due to large tumor volume, safe radiotherapy was not able to be delivered either alone or with concurrent approach. Therefore, chemotherapy is initiated first for 10 of 25 patients (40%) in sequential chemoradiation group. We argued that these patients were categorized as patients with higher risk and poorer prognosis for recurrence and survival. Secondly, due to prolonged overall treatment time with sequential approach, it is possible that accelerated repopulation may have been initiated post chemotherapy. This highlighted the importance of optimizing chemoradiation temporal relationship with concurrent chemoradiation
Table 5
as the preferred treatment for locally advanced NSCLC. Thirdly, due to the small number of sequential chemoradiation cohort, it is possible that this finding occurred due to chance. Nguyen et al. have reported LR rates for locally advanced NSCLC treated with chemoradiation which range from 43 to 71%.29 Distant metastasis was 25–71%. It was postulated that poor local control contributed to higher rates of distant metastasis. On contrary, it is also possible that these patients may have had micro metastases at diagnosis. OS for sequential chemotherapy cohort follows the pattern of LR rate with inferior median OS and 2-year OS compared to either radiation alone or concurrent chemoradiation as shown in Table 3. Interestingly, higher LR rate in sequential chemoradiation cohort did not correspond to higher DR, which could be due to small number of events. Table 5 summarizes comparisons between landmark local and international studies with respect to outcomes
Curative radiotherapy ± chemotherapy result for inoperable non-small cell Lung cancer
Study Present study Retrospective 2013 Local Ball et al. (1999)3 RCT Graham et al. (2006)2 Prospective
International EORTC Schaake-Koning et al. (1990)28 RCT RTOG Byhardt et al. (1998)7 Pooled data
Stage
Treatments
Number
Median age
I–III
60 Gy RT ± CT
160
69
Median OS: 21 months 2-year OS CRT stage III: 38%
RTOG Pneumonitis Gd 2: 20% Pneumonitis Gd 3: 2% Esophagitis Gd 3: 6%
I–III
60 Gy RT versus accelerated RT ± carboplatin Concurrent end phase boost RT (45 Gy + 20 Gy) ± cisplatin
204
62–68†
WHO Pneumonitis: NR Esophagitis Gd 3/4: 21%
121
66‡
Median OS: 15.7 months 2-year OS CRT: 31% Median OS: 23 months 2-year OS CRT stage II + III: 52%
331
59–61†
2-year OS RT + daily cisplatin: 26%
WHO “Late dyspnoea”: 12% Esophagitis: 4%
2-year OS sequential CT → CRT: 35%
RTOG Lung ≥Gd 3: 4% Esophagitis ≥Gd 3: 6%
I–III
I–III
Split RT (30 Gy + 25 Gy) ± cisplatin
II–III
461 Sequential CT → RT or CRT CT + hyper-fractionated RT Minimum 60 Gy RT
59.9‡
Outcomes
Toxicity
RTOG Pneumonitis Gd >1: 9% Esophagitis Gd 3/4: 7%
† Median age between treatment arms. ‡Mean age. →, followed by; CRT, concurrent chemoradiation; CT, chemotherapy; EORTC, European Organization for Research and Treatment of Cancer; Gd, grade; NR, not recorded; OS, overall survival; RCT, randomized controlled trial; RT, radiotherapy; RTOG, Radiation Therapy Oncology Group.
Asia-Pac J Clin Oncol 2014
© 2014 Wiley Publishing Asia Pty Ltd
8
and toxicities in treatment of inoperable NSCLC. Comparison with these highly selected populations enrolled in clinical trials shows comparable survival and toxicity outcomes. Evidence generated from clinical trials can be applied to community NSCLC population with acceptable outcomes.
Comorbidity Comorbidity plays a significant clinical decision-making role in NSCLC patients whose outcomes are considered unfavorable, and they are usually selected for nonsurgical management. Comorbidities are frequent in NSCLC, especially with increasing age and high frequency of smokers. The most frequent concomitant diseases were cardiovascular (23%), COPD (22%), other malignancies (15%) and hypertension/diabetes (40 years. CCI’s strength includes the incorporation of patient’s age to predict patient’s mortality rate. However, the severity of diseases is not measured, as well as absence of stages for different comorbidities.30 More recently, Colinet et al. have constructed SCS specific for NSCLC patients, which appears to be more prognostic than CCI.13,14 SCS threshold has been chosen taking into account the value of >9 for those patients with poorer prognosis. An advantage of SCS over CCI is the reduced number of items taken into account allowing score calculation in only a few minutes. On contrary, not all comorbidities assessed in CCI were checked in SCS. It is argued that CCI provides a more robust and extensive assessment of comorbidity. CCI has also been validated in many thoracic or nonthoracic cancer studies to be a better predictor of OS,12 including in elderly patients.10 Moreover, comorbidity may have multiplicative rather than additive effect in patient’s overall health. SCS deserves further prospective study to determine whether or not these findings have clinical impact on treatment recommendation. Literature has reaffirmed the prognostic impact of comorbidity on survival both in operable and inoperable NSCLCs.8,31 Firat et al. have also shown that the pres-
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A Pramana et al.
ence of significant comorbidity and KPS < 70 are both important prognostic factors, which are independent of each other in stage I NSCLC treated with surgery or radiotherapy12 and stage III NSCLC treated with radiotherapy alone.32 They utilized Cumulative Illness Rating Scale for Geriatrics and CCI, which graded the severity of 13 organs from 0 (normal) to 4 (severe impairment) and 19 clinical conditions, respectively. SCS was neither prognostic nor predictive for survival in our cohort. This could be related to several factors, including study’s retrospective nature and different patient baseline characteristic between studies, with nearly half of their cohort having metastatic disease, compared to none in our cohort. It may also be that patient selection criteria for treatment in our cohort were responsible, as patients with more significant comorbidities may have received only palliative treatment. We observed no difference in survival of our patients with SCS ≤ 9 versus SCS > 9, which is similar with experience from Phernambucq et al. which showed no difference in survival for patients with ≥1 comorbidities versus those without comorbidities.33 Similarly, a Netherlands study investigating the effect of comorbidity on treatment and prognosis of elderly NSCLC patients has concluded that comorbidity assessed by modified CCI had no independent prognostic effect, and hence questioned whether less aggressive treatment is justified.34 We acknowledged the usual deficiencies of a retrospective analysis, which includes inherent selection bias (known or unknown), uncontrolled patient and tumor factors and physician treatment bias. Efforts were made to minimize bias. In the accession phase, we established appropriate defined inclusion and exclusion criteria, and inclusion of all consecutive patients meeting these to reduce the risk of selection bias. For statistical analysis, a statistician who did not collect raw data performed analysis independently with preset statistical plan. Despite these limitations, this study is one of the few studies that report the outcomes of NSCLC patients treated with radiotherapy ± chemotherapy in the Australian setting.2,3
Conclusion Curative intent radiotherapy ± chemotherapy is a welltolerated and effective treatment for inoperable or locally advanced NSCLC. The benefits seen with treatment techniques reported in clinical trials are able to be translated into clinical practice. Patients should not be excluded from radiotherapy on basis of comorbidity alone since higher SCS was not prognostic of survival in this cohort.
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Outcomes of chemoradiation for lung cancer
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30 Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40 (5): 373–83. 31 Lopez-Encuentra A, Astudillo J, Cerezal J et al. Prognostic value of chronic obstructive pulmonary disease in 2994 cases of lung cancer. Eur J Cardiothorac Surg 2005; 27 (1): 8–13. 32 Firat S, Byhardt RW, Gore E. Comorbidity and Karnofsky performance score are independent prognostic factors in stage III non-small-cell lung cancer: an institutional analysis of patients treated on four RTOG studies. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2002; 54 (2): 357–64. 33 Phernambucq E, Spoelstra F, Verbakel W et al. Outcomes of concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer and significant comorbidity. Ann Oncol 2011; 22 (1): 132–8. 34 Janssen-Heijnen ML, Smulders S, Lemmens VE, Smeenk FW, van Geffen HJ, Coebergh JW. Effect of comorbidity on the treatment and prognosis of elderly patients with non-small cell lung cancer. Thorax 2004; 59 (7): 602– 7.
Asia-Pac J Clin Oncol 2014
Asia-Pacific Journal of Clinical Oncology 2014
doi: 10.1111/ajco.12262
ORIGINAL ARTICLE
A decade of community-based outcomes of patients treated with curative radiotherapy with or without chemotherapy for non-small cell lung cancer Ariyanto PRAMANA,1 Joseph DESCALLAR2,4 and Shalini K VINOD2,3,4,5 1 Radiation Oncology Department, St George Cancer Care Centre, 2Ingham Institute of Applied Medical Research, Liverpool Hospital, and 3Liverpool and Macarthur Cancer Therapy Centres, and 4University of NSW, 5University of Western Sydney, Sydney, New South Wales, Australia
Abstract Aim: Clinical trials have reported good outcomes for non-small cell lung cancer (NSCLC) patients treated with curative radiotherapy. These populations are highly selected and may not be representative of lung cancer population. We aim to evaluate the outcomes of NSCLC patients treated with radiotherapy ± chemotherapy in Australian community setting and to assess the effect of comorbidity on outcomes. Method: Oncology records at Liverpool and Macarthur Cancer Therapy Centres, Sydney, Australia, were queried to retrieve patient, tumor and treatment data for stage I–III NSCLC patients who were treated with radiotherapy (minimum dose 60 Gy) between 1 January 2000 and 31 December 2010. Simplified comorbidity score (SCS) was used to score comorbidity. Kaplan–Meier and Cox hazards models were used for survival analysis. Results: A total of 160 patients were identified with median follow-up of 22 months. Median age was 69 years (range 36–89); 76 patients received radiotherapy alone, 25 received sequential chemoradiation and 59 received concurrent chemoradiation. Median overall survivals for stages I, II and III were 29, 26 and 18 months, respectively. On multivariate analysis, stage II or III and weight loss > 5% were predictive of cancer-specific survival with hazard ratios of 4.47 (1.08–18.55, P = 0.04) and 2.23 (1.13–4.39, P = 0.02), respectively. Toxicities were grade ≥ 3 pneumonitis in 2% of patients, grade ≥ 3 esophagitis in 6% and grade ≥ 3 febrile neutropenia in 2%. There were no treatment-related deaths. SCS was neither prognostic nor predictive of toxicity or survival. Conclusion: Curative radiotherapy ± chemotherapy is a well-tolerated and effective treatment for inoperable or locally advanced NSCLC. Patients should not be excluded from radiotherapy on basis of comorbidity since higher SCS was not correlated with worse survival. Key words: chemotherapy, community, comorbidity, lung cancer, radiotherapy.
INTRODUCTION
Correspondence: Dr Ariyanto Pramana BSc (Med) MBBS FRANZCR, St George Cancer Care Centre, 1 Short Street Kogarah, NSW 2217, Australia. Email: [email protected] Conflict of interest: The authors declare no conflict of interest or financial support for this study. Accepted for publication 30 June 2014.
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In Australia, lung cancer is the fourth most commonly diagnosed cancer.1 It is the leading cause of cancer deaths for both sexes. Non-small cell lung cancer (NSCLC) is the predominant histology with 60%. There are many international trials reporting good outcomes with curative radiotherapy. These populations are highly selected and there are limited data on whether these outcomes are seen in community practice.2,3
2
Radiotherapy is indicated for inoperable stage I–III NSCLC.4 For stages I and II, overall survival (OS) at 2 and 5 years was 22–72% and 0–42%, respectively; cancer-specific survival (CSS) was 54–93% and 13–39%, correspondingly.5 Between 11 and 43%, patients die from non-cancer causes, reflecting their poor health status. Nonsurgical patients are staged clinically and lack of pathologic staging contributes to poorer outcomes. Chemoradiation is the standard of care for inoperable stage III NSCLC.6,7 In NPC 95-01 study, where stage III patients had good performance status and minimal weight loss (5% were found to be predictive on multivariate analysis with hazard ratios (HRs) of 4.47 (1.08–18.55, P = 0.04) and 2.23 (1.13–4.39, P = 0.02), respectively. Univariate analysis showed increased weight loss >5% (HR = 2.28 [1.23–4.23]) and radiotherapy interruption (HR = 2.42 [1.45–4.06]) was predictive of OS. However, on multivariate analysis, none of these were significant for OS. Other factors considered a priori such as performance status, age, SCS, respiratory function, pathology and grades were not predictive of OS.
Toxicity Table 4 summarizes the toxicity from radiotherapy ± chemotherapy. Overall, severe toxicities of grade ≥3 pneumonitis, esophagitis and febrile neutropenia were 2, 6 and 2%, respectively, for whole cohort and 2, 10 and 2% for the concurrent chemoradiation group. Rate of esophagitis increased with use of chemotherapy. No patients died as a result of radiotherapy/ chemotherapy-related toxicity and there have been no episodes of myelopathy. SCS > 9 was not predictive of toxicity from treatments, with only 4/25 (16%) patients with grade ≥3 radiation toxicity have SCS > 9 and 0/7
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Table 1
A Pramana et al.
Patient demographics Group Radiotherapy alone (n = 76), n (%)
Sequential chemoradiation (n = 25), n (%)
Concurrent chemoradiation (n = 59), n (%)
All patients (n = 160), n (%)
72.5 36–87
73 39–88
65 41–89
69 36–89
53 (70) 23 (30)
18 (72) 7 (18)
48 (81) 11 (19)
119 (74) 41 (26)
38 (50) 38 (50)
10 (40) 15 (60)
30 (51) 29 (49)
78 (49) 82 (51)
58 (76) 14 (19) 4 (5)
21 (84) 3 (12) 1 (4)
55 (93) 4 (7) 0 (0)
134 (84) 21 (13) 5 (3)
51 (67) 22 (29) 3 (4)
15 (60) 10 (40) 0 (0)
44 (75) 15 (25) 0 (0)
110 (69) 47 (29) 3 (2)
67 (88) 6 (8) 3 (4)
22 (88) 3 (12) 0 (0)
56 (95) 3 (5) 0 (0)
145 (91) 12 (7) 3 (2)
8 (10) 43 (57) 25 (33)
3 (12) 16 (64) 6 (24)
4 (7) 24 (41) 31 (52)
15 (9) 83 (52) 62 (39)
38 (50) 6 (8) 32 (42)
18 (72) 3 (12) 4 (16)
18 (30) 8 (14) 33 (56)
74 (46) 17 (11) 69 (43)
24 (32) 11 (14) 41 (54)
5 (20) 6 (24) 14 (56)
0 (0) 11 (19) 48 (81)
29 (18) 28 (18) 103 (64)
32 (42) 31 (41) 11 (14) 2 (3)
6 (24) 11 (44) 7 (28) 1 (4)
25 (43) 15 (25) 13 (22) 6 (10)
63 (39) 57 (36) 31 (19) 9 (6)
Age (years) Median Range Gender Male Female Country of birth Australia Overseas ECOG 0–1 >1 Unknown Simplified comorbidity score ≤9 >9 Unknown Smoking Yes No Unknown Respiratory function (FEV1) 5% Unknown Stage I II III Histology Large cell Squamous cell Adenocarcinoma Carcinoma, NOS
P value 0.02
0.30
0.29
0.10
0.58
0.27
1.0
0.17
9.
SCS and survival All except three patients in this cohort had at least one SCS. Median SCS was 8 (1–16). Smoking was prevalent
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in 145/157 (92%), followed by respiratory comorbidity (63/157 [40%]), cardiovascular disease (62/157 [39%]), diabetes (18/157 [11%]), prior neoplastic condition >5 years prior to NSCLC (13/157 [8%]), alcoholism (8/157 [5%]) and renal impairment (5/157 [3%]). Univariate analysis (reference of SCS ≤ 9) revealed HR for CSS of 0.44 (0.25–0.78, P = 0.005) and HR for OS of 1.30
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Outcomes of chemoradiation for lung cancer
Table 2
First site of recurrence Stage I
Treatment group
Stages II–III
Radiation alone (n = 24) Sequential chemoradiation (n = 5) Concurrent chemoradiation (n = 0), n (%)
Radiation alone (n = 52)
Sequential chemoradiation (n = 20)
Concurrent chemoradiation (n = 59)
8 (28) 5 (17) 0 (0) 16 (55)
17 (33) 16 (31) 1 (2) 18 (35)
12 (60) 6 (30) 0 (0) 2 (10)
18 (31) 21 (36) 3 (5) 17 (29)
Recurrence pattern Local Distant Both None
Table 3 Median OS and 2-year OS by treatment groups Median OS (months)
Stage I
Stage II
Stage III
31.7 9.7 –
27.6 15.5 29.3
17.1 15.6 17.9
Stage I
Stage II
Stage III
63% 20% –
60% 17% 64%
44% 38% 42%
Radiation alone Sequential chemoradiation Concurrent chemoradiation 2-year OS (%) Radiation alone Sequential chemoradiation Concurrent chemoradiation OS, overall survival.
Table 4
Severe toxicity summary Group Radiation alone (n = 76), n (%)
Sequential chemoradiation (n = 25)
Concurrent chemoradiation (n = 59)
All patients (n = 160)
12 (16) 1 (1)
7 (28) 1 (4)
13 (22) 1 (2)
32 (20) 3 (2)
2 (3) 3 (4)
1 (4) 1 (4)
2 (3) 6 (10)
– –
1 (4) 1 (4)
4 (7) 1 (2)
Pneumonitis Grade 2 Grade 3 Esophagitis Grade 2 Grade 3
Febrile neutropenia Grade 2 Grade 3
(0.89–1.89, P = 0.18). On multivariate analysis, SCS was not a statistically significant prognostic variable for CSS or OS.
DISCUSSION Patient demographics Demographic of community NSCLC patients is different from those enrolled in clinical trials, which tend to
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5 (3) 10 (6) Patients who received chemotherapy (n = 84) 5 (6) 2 (2)
include fit patients without any significant comorbidity. Fournel et al.’s study in unresectable stage III NSCLC had eligibility criteria of age 70 and two trials required 1 in 13%, FEV1 5% in 11% and SCS >9 in 29%. Acknowledging that there are missing data, it appears that our patients have slightly worse health compared from trials population.
Radiotherapy for stage I NSCLC Radiotherapy is the standard of care for stage I NSCLC patients who are medically inoperable or who refuse surgery. In our cohort, median CSS and OS for stage I were 51 and 29 months and 2-year CSS and OS of 71 and 55%, respectively. These results are similar to data from a systematic review: radiotherapy for stage I/II patients who were unfit or declining surgery, and yielded 2-year OS of 22–72% and median OS of 15–33 months. Fiveyear OS was better for T1 than for T2 tumors (29–37% vs 4–24%), and 2-year CSS was 54–93%.5 Between 11% and 43% (median 25%) of patients died from non-cancer causes, reflecting their poor health status. In our cohort, around 16% of patients are dying of non-cancer causes at 2 years. This is less than the median 25% obtained from Rowell et al., which may be related to different patient demographic and selection factor. Stereotactic body radiotherapy (SBRT) is currently being investigated for definitive management of stage I NSCLC. SBRT provides greater local control than standard radiotherapy for high-risk and medically inoperable patients.17 A meta-analysis revealed 2-year OS of 3201 patients with localized stage I NSCLC treated with SBRT was 70% and 2-year local control of 91%. Our data showed 2-year OS of 63% for stage I NSCLC patients who received radiotherapy alone, which is comparable to radiotherapy data from Rowell et al.; however, inferior outcomes were compared with SBRT.
Radiotherapy or combined modality therapy for stage II and III NSCLC The optimal treatment recommendation for stage III NSCLC is not clearly defined and some aspects currently remain controversial due to heterogeneity in NSCLC. Patients with stage II NSCLC who are medically inoperable are being increasingly treated as stage III, extrapolating the benefits of adjuvant chemotherapy in the postoperative setting to concurrent chemoradiation in the nonoperative setting. Furthermore, radiotherapy alone may be used as definitive modality for stage II–III NSCLC patients who are not candidates for chemotherapy.
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A Pramana et al.
Zierhut et al. analyzed 60 inoperable stage I (35%) and II (65%) NSCLC treated with median radiotherapy dose of 60 Gy.18 The median progression-free survival and median OS were 18 and 21 months, respectively. Our stage II cohort who was treated with radiotherapy alone had a median OS of 28 months and 2-year OS of 60%. In contrast, radiotherapy alone for patients with stage III NSCLC resulted in a median OS of approximately 10 months and 2-year OS of 13–23%.5,19–21 Our results for these stage III patients were median OS of 17 months and 2-year OS of 44%. The slightly better outcomes in our cohort could be related to patient selection factors. Randomized trials have established the advantage of concurrent chemoradiation approach (with platinum doublet), which is the standard of care for unresected stage III NSCLC.22 Our data for stage III patients treated with concurrent chemoradiation have revealed median OS of 18 months and 2-year OS of 42%. These are comparable to NPC-95-01 with 16 months of median survival and 2-year OS of 39%.6 Similarly, RTOG-9410 has also shown 17 months of median survival and 5-year OS of 16%.23 Other studies utilizing altered fractionation concurrent chemoradiation have resulted in 17–22 months of median survival and 2-year OS between 23 and 35%.24–26 Sequential chemotherapy followed by radiotherapy was initially used to avoid overlapping toxicities from each modality.20,27,28 Dillman et al. were one of the first authors who initially established the benefits of this approach compared to radiotherapy alone. They reported a significantly higher long-term survival with additional 4 months of median survival and improved distant failure-free survival, but without impact on LR.19 Their median survival and 2-year OS were 13.7 months and 26% with sequential chemoradiation for stage III NSCLC. Our result for stage III NSCLC with sequential approach is slightly better with median survival and 2-year OS of 15.6 months and 38%, respectively. An updated meta-analysis exploring sequential versus concurrent chemoradiation has demonstrated a survival benefit for concurrent approach due to potential radiosensitization and reduced systemic micrometastatic disease.22 A significant OS benefit of concurrent treatment was evident with HR 0.74 (0.62–0.89) and 10% absolute OS benefit at 2 years. However, there was increased severe esophagitis in the concurrent group with risk ratio of 4.96 (2.17–11.37). Therefore, patient selection is an important consideration in view of the potential added toxicity of concurrent regimen. It is unclear whether similar benefits could be achieved using
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Outcomes of chemoradiation for lung cancer
modern radiotherapy techniques, and accelerated or hyperfractionated regimens. In our stage II–III cohort in sequential chemoradiation group, LR rate was inferior compared to either radiation alone or chemoradiation group. Possible explanations for this include, firstly, patient selection bias, which was inherent within the context of a retrospective study. It is possible that due to large tumor volume, safe radiotherapy was not able to be delivered either alone or with concurrent approach. Therefore, chemotherapy is initiated first for 10 of 25 patients (40%) in sequential chemoradiation group. We argued that these patients were categorized as patients with higher risk and poorer prognosis for recurrence and survival. Secondly, due to prolonged overall treatment time with sequential approach, it is possible that accelerated repopulation may have been initiated post chemotherapy. This highlighted the importance of optimizing chemoradiation temporal relationship with concurrent chemoradiation
Table 5
as the preferred treatment for locally advanced NSCLC. Thirdly, due to the small number of sequential chemoradiation cohort, it is possible that this finding occurred due to chance. Nguyen et al. have reported LR rates for locally advanced NSCLC treated with chemoradiation which range from 43 to 71%.29 Distant metastasis was 25–71%. It was postulated that poor local control contributed to higher rates of distant metastasis. On contrary, it is also possible that these patients may have had micro metastases at diagnosis. OS for sequential chemotherapy cohort follows the pattern of LR rate with inferior median OS and 2-year OS compared to either radiation alone or concurrent chemoradiation as shown in Table 3. Interestingly, higher LR rate in sequential chemoradiation cohort did not correspond to higher DR, which could be due to small number of events. Table 5 summarizes comparisons between landmark local and international studies with respect to outcomes
Curative radiotherapy ± chemotherapy result for inoperable non-small cell Lung cancer
Study Present study Retrospective 2013 Local Ball et al. (1999)3 RCT Graham et al. (2006)2 Prospective
International EORTC Schaake-Koning et al. (1990)28 RCT RTOG Byhardt et al. (1998)7 Pooled data
Stage
Treatments
Number
Median age
I–III
60 Gy RT ± CT
160
69
Median OS: 21 months 2-year OS CRT stage III: 38%
RTOG Pneumonitis Gd 2: 20% Pneumonitis Gd 3: 2% Esophagitis Gd 3: 6%
I–III
60 Gy RT versus accelerated RT ± carboplatin Concurrent end phase boost RT (45 Gy + 20 Gy) ± cisplatin
204
62–68†
WHO Pneumonitis: NR Esophagitis Gd 3/4: 21%
121
66‡
Median OS: 15.7 months 2-year OS CRT: 31% Median OS: 23 months 2-year OS CRT stage II + III: 52%
331
59–61†
2-year OS RT + daily cisplatin: 26%
WHO “Late dyspnoea”: 12% Esophagitis: 4%
2-year OS sequential CT → CRT: 35%
RTOG Lung ≥Gd 3: 4% Esophagitis ≥Gd 3: 6%
I–III
I–III
Split RT (30 Gy + 25 Gy) ± cisplatin
II–III
461 Sequential CT → RT or CRT CT + hyper-fractionated RT Minimum 60 Gy RT
59.9‡
Outcomes
Toxicity
RTOG Pneumonitis Gd >1: 9% Esophagitis Gd 3/4: 7%
† Median age between treatment arms. ‡Mean age. →, followed by; CRT, concurrent chemoradiation; CT, chemotherapy; EORTC, European Organization for Research and Treatment of Cancer; Gd, grade; NR, not recorded; OS, overall survival; RCT, randomized controlled trial; RT, radiotherapy; RTOG, Radiation Therapy Oncology Group.
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and toxicities in treatment of inoperable NSCLC. Comparison with these highly selected populations enrolled in clinical trials shows comparable survival and toxicity outcomes. Evidence generated from clinical trials can be applied to community NSCLC population with acceptable outcomes.
Comorbidity Comorbidity plays a significant clinical decision-making role in NSCLC patients whose outcomes are considered unfavorable, and they are usually selected for nonsurgical management. Comorbidities are frequent in NSCLC, especially with increasing age and high frequency of smokers. The most frequent concomitant diseases were cardiovascular (23%), COPD (22%), other malignancies (15%) and hypertension/diabetes (40 years. CCI’s strength includes the incorporation of patient’s age to predict patient’s mortality rate. However, the severity of diseases is not measured, as well as absence of stages for different comorbidities.30 More recently, Colinet et al. have constructed SCS specific for NSCLC patients, which appears to be more prognostic than CCI.13,14 SCS threshold has been chosen taking into account the value of >9 for those patients with poorer prognosis. An advantage of SCS over CCI is the reduced number of items taken into account allowing score calculation in only a few minutes. On contrary, not all comorbidities assessed in CCI were checked in SCS. It is argued that CCI provides a more robust and extensive assessment of comorbidity. CCI has also been validated in many thoracic or nonthoracic cancer studies to be a better predictor of OS,12 including in elderly patients.10 Moreover, comorbidity may have multiplicative rather than additive effect in patient’s overall health. SCS deserves further prospective study to determine whether or not these findings have clinical impact on treatment recommendation. Literature has reaffirmed the prognostic impact of comorbidity on survival both in operable and inoperable NSCLCs.8,31 Firat et al. have also shown that the pres-
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ence of significant comorbidity and KPS < 70 are both important prognostic factors, which are independent of each other in stage I NSCLC treated with surgery or radiotherapy12 and stage III NSCLC treated with radiotherapy alone.32 They utilized Cumulative Illness Rating Scale for Geriatrics and CCI, which graded the severity of 13 organs from 0 (normal) to 4 (severe impairment) and 19 clinical conditions, respectively. SCS was neither prognostic nor predictive for survival in our cohort. This could be related to several factors, including study’s retrospective nature and different patient baseline characteristic between studies, with nearly half of their cohort having metastatic disease, compared to none in our cohort. It may also be that patient selection criteria for treatment in our cohort were responsible, as patients with more significant comorbidities may have received only palliative treatment. We observed no difference in survival of our patients with SCS ≤ 9 versus SCS > 9, which is similar with experience from Phernambucq et al. which showed no difference in survival for patients with ≥1 comorbidities versus those without comorbidities.33 Similarly, a Netherlands study investigating the effect of comorbidity on treatment and prognosis of elderly NSCLC patients has concluded that comorbidity assessed by modified CCI had no independent prognostic effect, and hence questioned whether less aggressive treatment is justified.34 We acknowledged the usual deficiencies of a retrospective analysis, which includes inherent selection bias (known or unknown), uncontrolled patient and tumor factors and physician treatment bias. Efforts were made to minimize bias. In the accession phase, we established appropriate defined inclusion and exclusion criteria, and inclusion of all consecutive patients meeting these to reduce the risk of selection bias. For statistical analysis, a statistician who did not collect raw data performed analysis independently with preset statistical plan. Despite these limitations, this study is one of the few studies that report the outcomes of NSCLC patients treated with radiotherapy ± chemotherapy in the Australian setting.2,3
Conclusion Curative intent radiotherapy ± chemotherapy is a welltolerated and effective treatment for inoperable or locally advanced NSCLC. The benefits seen with treatment techniques reported in clinical trials are able to be translated into clinical practice. Patients should not be excluded from radiotherapy on basis of comorbidity alone since higher SCS was not prognostic of survival in this cohort.
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30 Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40 (5): 373–83. 31 Lopez-Encuentra A, Astudillo J, Cerezal J et al. Prognostic value of chronic obstructive pulmonary disease in 2994 cases of lung cancer. Eur J Cardiothorac Surg 2005; 27 (1): 8–13. 32 Firat S, Byhardt RW, Gore E. Comorbidity and Karnofsky performance score are independent prognostic factors in stage III non-small-cell lung cancer: an institutional analysis of patients treated on four RTOG studies. Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2002; 54 (2): 357–64. 33 Phernambucq E, Spoelstra F, Verbakel W et al. Outcomes of concurrent chemoradiotherapy in patients with stage III non-small-cell lung cancer and significant comorbidity. Ann Oncol 2011; 22 (1): 132–8. 34 Janssen-Heijnen ML, Smulders S, Lemmens VE, Smeenk FW, van Geffen HJ, Coebergh JW. Effect of comorbidity on the treatment and prognosis of elderly patients with non-small cell lung cancer. Thorax 2004; 59 (7): 602– 7.
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