Lung (2014) 192:151–158 DOI 10.1007/s00408-013-9518-9
LUNG CANCER
Comparison of Once and Twice Daily Radiotherapy for Limited Stage Small-Cell Lung Cancer Abhilash Gazula • Elizabeth H. Baldini Aileen Chen • David Kozono
•
Received: 25 June 2013 / Accepted: 2 October 2013 / Published online: 27 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Purpose This study was designed to review outcomes of once- (QD) versus twice-daily (BID) radiotherapy (RT) for limited stage small-cell lung cancer (L-SCLC) treated at Dana-Farber Cancer Institute/Brigham and Women’s Hospital. Methods We reviewed records for all patients with L-SCLC treated with radical chemoradiotherapy at our institution between January 2005 and December 2010. Differences in patient, tumor, and treatment characteristics were assessed by Student’s t test and Fisher exact test. Outcomes were compared using Kaplan–Meier estimates and Cox proportional hazards regression. Results Twenty patients received QD RT to a median dose of 61.2 Gy, and 26 patients received BID RT to a dose of 45 Gy. Median follow-up was 2.8 years. Overall survival (OS) was similar in both groups. 5-year locoregional control (LC) for all patients was 67 %: 80 % for the QD group and 57 % for the BID group (log-rank, P = 0.16). Grade 2 or higher dermatitis and pneumonitis were significantly higher in the QD group (15 vs. 0 %, P = 0.0014 and 13 vs. 4 %, P = 0.048, respectively), whereas Grade 2
A. Gazula E. H. Baldini A. Chen D. Kozono (&) Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, 450 Brookline Avenue, Boston, MA 02215, USA e-mail: [email protected] A. Gazula e-mail: [email protected] E. H. Baldini e-mail: [email protected] A. Chen e-mail: [email protected]
or higher esophagitis trended higher in the BID group (44 vs. 24 %, P = 0.076). Conclusions Although there were no differences in OS with QD versus BID RT, there was a trend toward increased LC in the QD group. Dermatitis and pneumonitis were more common for QD RT, and esophagitis was somewhat more common for BID RT. Possible differences in toxicities depending on RT regimen may be worth further investigation, until results from CALGB 30610 become available. Keywords Small cell lung carcinoma (SCLC) Lung neoplasms Humans Radiotherapy Dose fractionation Outcome assessment
Background Of the estimated 226,160 new diagnoses of lung cancer in the United States in 2012, *14 % were small-cell lung cancer (SCLC) [1]. Of these, *40 % were of limited stage small-cell lung cancer (L-SCLC) that may be contained in a tolerable radiotherapy (RT) volume [2]. Two meta-analyses in 1992 showed that the addition of RT to chemotherapy increases survival, establishing combined modality therapy for L-SCLC [3, 4]. Optimal RT timing, dose, volume, and fractionation regimens however remain widely contested. In 1999, Turrisi et al. [5] published results from INT 0096, in which 417 L-SCLC patients were randomized to receive 45 Gy in either twice daily (BID) fractions over 3 weeks or once daily (QD) fractions over 5 weeks, demonstrating superior survival with BID RT. Choi et al. [6] (CALGB 8837) determined the maximum tolerated doses (MTD) for QD and BID RT as 70 Gy in 35 fractions and 45 Gy in 30 fractions,
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respectively, based on the highest doses that produced no more than 33 % Grade 4 or higher acute esophagitis and/or Grade 3 or higher pulmonary toxicity. Bogart et al. [7] (CALGB 39808) confirmed the safety of 70 Gy in 35 daily fractions. Turrisi et al. [5] found that Grade 3–4 esophagitis was twice as frequent in the BID versus QD arm. Despite the increased survival rate, only an estimated 25 % of centers treat L-SCLC patients with BID RT [8], in part due to perceived severe acute toxicities, beliefs about efficacy of higher doses with QD RT, or logistical issues. The Cancer and Leukemia Group B (CALGB 30610) is conducting a Phase III trial comparing 45 Gy BID and 70 Gy QD. A third arm comparing these to 61.2 Gy given with a concomitant boost was dropped after interim analysis [9]. Results, however, will not be available for several years. We analyzed outcomes of patients treated at our institution with QD or BID RT to obtain insights while awaiting results from CALGB 30610 [9].
Methods Patient Selection Under an Institutional Review Board approved protocol, records of L-SCLC patients treated with thoracic RT at Dana-Farber Cancer Institute/Brigham and Women’s Hospital between January 2005 and December 2010 were reviewed. Patients were excluded if they were treated with palliative intent, underwent surgical resection of their SCLC, had any other active cancers at the time of treatment, or had a diagnosis of mixed SCLC and NSCLC. Patients with a history of prior cancers that were in remission, who had received previous chemotherapy for other diagnoses, or who had undergone resection for NSCLC prior to diagnosis of SCLC were not excluded. Forty-six patients met inclusion criteria. Four patients received RT for L-SCLC but were not included due to treatment to a dose \45 Gy or palliative intent (n = 2), surgical resection of the SCLC (n = 2), and/or a mixed SCLC and NSCLC diagnosis (n = 1); one patient had a lobectomy and a mixed diagnosis. Patient Data All available physician notes, radiation records, radiology reports, and pulmonary function tests (PFTs) were reviewed to assess stage, treatment intent, RT details, and outcomes. RT tumor volumes were assessed retrospectively to determine whether elective nodal irradiation (ENI) was delivered. ENI was defined as explicit inclusion of mediastinal and/or supraclavicular nodal stations in the CTV that were not included in the GTV and not included
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via uniform margin expansion. RT plans also were reviewed to determine tumor volumes, lung V5, V20 and mean dose (MLD), esophagus and heart MLD, and spinal cord maximal dose. Smoking history and Eastern Cooperative Oncology Group (ECOG) performance status (PS) [10] were determined from physician notes. PFTs, including forced expiratory volume in 1 s (FEV1) and diffusion capacity for carbon monoxide (DLCO) within 2 months before treatment, were recorded. Tumor and nodal staging was determined from physician notes or based on evaluation of positron emission tomography (PET) and/or chest computed tomography (CT) scans at diagnosis. Physician and radiology notes were translated for uniform staging according to the American Joint Committee on Cancer (AJCC), 7th edition, 2010 guidelines [11]. Total number of chemotherapy cycles, agents used, and the timing of RT relative to chemotherapy were recorded. Treatment with prophylactic cranial irradiation (PCI) was recorded. Toxicities were evaluated by the research team retrospectively from physician and nursing notes and radiology records according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [12] for uniform toxicity assessment. Tumor response was evaluated by the research team retrospectively according to Response Evaluation Criteria in Solid Tumors (RECIST) [13]. The last follow-up date was recorded as the last date on which the patient was examined for evaluation of SCLC status. Cause of death was noted as SCLC if there was evidence of active disease within 3 months of death. The Social Security Death Index was searched for patients lost to follow-up.
Treatment All patients received external beam RT, including threedimensional conformal RT (3D-CRT) (n = 38) and intensity modulated RT (IMRT) (n = 8). The majority of patients underwent planning with four-dimensional respiratory gated CT. Treatment volumes were individualized for each patient and typically included a gross or internal tumor volume (GTV or ITV). To create a clinical tumor volume (CTV), the GTV or ITV was typically expanded by 7 mm and edited for anatomy. Adjacent mediastinal nodal areas often were included. The CTV was expanded most often by 5 mm to delineate the planning target volume (PTV). The RT prescription was 45 Gy in 1.5 Gy BID fractions for all patients treated with BID RT. Those treated with QD RT received a median dose of 61.2 (range 50–66.6) Gy in 1.8- or 2-Gy fractions. The biologically equivalent dose (BED) using an a/b ratio of 10 was 51.8 and 72.2 Gy for the BID and QD regimens, respectively; taking into account overall treatment time and accelerated
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Thirty-three patients (72 %) received four cycles of cisplatin/etoposide; of the remainder, five (11 %) received varying numbers of cycles of cisplatin/etoposide, six (13 %) received carboplatin/etoposide, and one (2 %) each received cisplatin/irinotecan or carboplatin/irinotecan. Forty patients (87 %) received chemotherapy and RT concurrently, and six received sequential chemotherapy followed by RT. After completion of chemotherapy and thoracic RT, patients were reimaged with chest and head CTs or magnetic resonance imaging (MRI). Patients who had complete or substantial partial radiographic responses to treatment were offered PCI. Twenty-five patients (54 %) received PCI; of these, 16 (64 %) received a regimen of 30 Gy in 2-Gy fractions; the remainder received regimens ranging from 25 to 36 Gy in 2- to 3-Gy fractions.
Statistical Analysis
Fig. 1 Overall (a) and progression-free (b) survival following oncedaily compared with twice-daily RT for patients with L-SCLC. Kaplan–Meier analysis and the log-rank test with a significance value of 0.05 were performed
Fig. 2 LC following once-daily compared with twice-daily RT for patients with L-SCLC. Kaplan–Meier analysis and the log-rank test with a significance value of 0.05 were performed
repopulation using Teff = 5 days, Tko = 14 days and a = 0.35 [14], the tBED was 49.0 and 58.9 Gy for the BID and QD regimens, respectively Figs. 1 and 2.
Overall survival (OS) was measured from the date of diagnosis, defined as the date of first histopathological material showing SCLC. Locoregional control (LC) was measured as the interval between the date of diagnosis and the date of first evidence of primary or thoracic nodal disease progression or last follow-up. Radiographic scarring and changes were not scored as failure unless disease progression was shown, in which case the failure was recorded as the first time the lesion was noted. Distant metastasis-free survival (DMFS) was measured as the interval between the date of diagnosis and the date of first evidence of metastatic disease progression or last followup. The site of first metastatic failure was recorded. Concurrent local and metastatic failures were noted as separate occurrences. Progression-free survival (PFS) was measured as the interval between the date of diagnosis and the date of first evidence of either locoregional or distant metastatic disease progression or last follow-up. OS, LC, DMFS, and PFS were all obtained using Kaplan–Meier estimates. Subgroup analyses were performed to compare patients treated with BID versus QD RT. Differences between the two subgroups in patient, tumor, or treatment characteristics were assessed using Student’s t tests for numerical data and Fisher exact test for categorical data. Differences in rates of toxicities were assessed using the Fisher exact test. Grade 2 or higher toxicities were compared due to the small amount of patients experiencing Grade 3 or higher toxicities. Hazard ratios for death were determined using a Cox proportional hazards model. All tests were performed two-sided using a significance value of 0.05. Statistical calculations were performed using JMP Pro 10 (SAS, Cary, NC, USA).
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Results Demographic Data Median age at the time of diagnosis was 62 (range 44–87) years. Nineteen patients (41 %) were male. Thirty-eight patients (83 %) had an ECOG PS of 0–1 and eight (17 %) had a PS of 2. Six patients (13 %) had a weight loss of at least 5 % during the 6 months before consultation. Fortyfour patients (96 %) had a smoking history of at least 10 pack-years and 42 patients (91 %) had one of at least 30 pack-years; the median number of pack-years was 49 (range 1–100). All patients had an FEV1 of at least 1.18 L and a DLCO of at least 49 % predicted. AJCC stage was as follows: 2 Stage I, 6 Stage II, 23 Stage IIIA, and 15 Stage IIIB (Table 1). Both age (P = 0.0052) and chemotherapy cycle number at the time of RT (P = 0.014) were statistically significantly higher in the QD subgroup; median age was 65 versus 59 years and 50 versus 81 % had RT during chemotherapy cycle 1 or 2 in the QD versus BID subgroups, respectively. Primary tumor diameter at diagnosis was statistically significantly higher (P = 0.0062) in the BID (6.25 cm) versus QD (3 cm) subgroup. The number of T1 tumors was higher in QD versus BID (10 vs. 4, P = 0.012), and the number of T3 tumors was higher in BID versus QD (12 vs. 2, P = 0.0077). No other characteristics showed statistically significant differences between subgroups (Table 1). Radiotherapy Plans and Metrics ENI was not consistently delivered; 7 of 26 patients (27 %) in the BID subgroup received ENI compared with 1 of 20 patients (5 %) in the QD subgroup. RT metrics were tabulated (Table 2) but not analyzed for statistically significant differences due to expected biological differences inherit in the two regimens. Outcomes Median follow-up was 2.8 (range 0.18–6.94) years and was similar between groups (2.8 vs. 2.5 years for the QD vs. BID subgroups, respectively). Median OS was 1.9 (range 0.21–6.94) years with a 5-year OS rate of 30 %. Thirtynine patients (85 %) achieved a complete response (CR) or partial response (PR), 16 (35 %) versus 23 (50 %) in the QD versus BID subgroup, respectively. The 5-year LC rate was 67 % overall; it showed a trend (P = 0.16) toward an improved rate of 80 % in the QD versus 57 % in the BID subgroup. Median PFS was 1.03 years with a 5-year PFS rate of 40 %. There were no statistically significant differences in these outcomes between the QD and BID
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subgroups: the OS hazard ratio (HR) for death (BID vs. QD) was 1.01 [95 % confidence interval (CI) 0.46–2.28], the PFS HR for failure (BID vs. QD) was 1.29 (95 % CI 0.58–3.00), and the LC HR for failure (BID vs. QD) was 2.24 (95 % CI 0.65–10.25; Table 3). There were no statistically significant differences for any of the above outcomes based on age, primary tumor diameter, or ECOG PS. Toxicities Statistically significant differences were found in the rates of both Grade 2 or higher dermatitis (15 vs. 0 %, P = 0.0014) and pneumonitis (13 vs. 4 %, P = 0.048) in the QD versus BID subgroups, respectively (Table 4). One patient died of pneumonitis 6 months following four cycles of chemotherapy and an RT to a dose of 50 Gy in 25 daily fractions. The patient was a 75-year-old male with an ECOG PS of 0. Lung V5, V20, and MLD were 50.4, 31.3 %, and 16.9 Gy, respectively. Although there was no statistically significant difference, a trend (P = 0.076) was observed showing a higher rate of Grade 2 or higher esophagitis in the BID versus QD subgroup (44 vs. 24 %, respectively).
Discussion During the past several decades, numerous studies have examined various chemoradiotherapy regimens for L-SCLC [3–7, 15–17]. The optimal RT regimen remains contested. CALGB 30610 [9] is designed to determine whether daily treatment to an escalated dose of 70 Gy is superior to BID RT to a dose of 45 Gy. However, these results will not be available for several years. Meanwhile, it may be helpful to determine whether QD versus BID RT in nonrandomized patient series shows any differences in outcomes. Grade 3 or higher toxicities were rare, so we were limited to comparisons of Grade 2 or higher toxicities. Although lower grade toxicities may not be grounds to avoid a treatment regimen, it may be preferable to limit these in older, frailer patients. Our data showed statistically significant differences in Grade 2 or higher dermatitis and pneumonitis, both occurring at higher rates in the QD subgroup. Esophagitis trended toward a higher rate in the BID subgroup. This likely reflects the nature of the two regimens. The increased Grade 2 or higher esophagitis in the BID subgroup may be related to the compressed RT treatment time, reaching a dose of 45 Gy in 3 weeks rather than 5. This is in keeping with INT 0096, which showed rates of Grade 3 esophagitis of 27 versus 11 % in the BID versus QD arms, respectively [5]. Similarly, Mauguen et al. [15] found that the rates of acute esophagitis increased in
Lung (2014) 192:151–158 Table 1 Patient characteristics for patients with L-SCLC treated with once daily versus twice daily RT (n = 45)
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Characteristic
Value
QD
BID
19
26
Median
65
59
62
Range
49–87
44–73
44–87
Number of patients
Total
Age (years)
P*
0.0052
ECOG PS (n)
0.38 0–1
14
24
38
2
6
2
8
Median
2.21
1.89
2.08
Range
1.28–3.3
1.18–3.12
1.18–3.3
Median
61
70
70
Range
58–100
40–93
40–100
Median Range
91 91–91 %
62 49–86 %
63 49–91 %
Current
8
9
17
Former
11
17
28
\30
2
2
4
FEV1 (L)
0.7
FEV1 (% predicted)
0.61
\0.001
DLCO(Hb) (% predicted)
Smoking status (n)
Smoking history (pack-years)
0.91 C30
17
24
42
Median
47
49.5
49
Range
1–100
7.5–100
1–100
Median
3
6.25
4
Range
1.6–6.6
0.9–10.5
0.9–10.5
Median
3
3
3
Range
0–6
0–6
0–6
T1
10
4
14
0.012
T2
6
6
12
0.23
T3
2
12
14
0.0077
T4
2
4
6
0.3
N0
1
3
4
0.32
N1
2
3
5
0.36
N2
12
13
25
0.19
N3
5
7
12
0.26
I
0
2
2
0.31
II
3
3
6
0.32
IIIA
11
12
23
0.2
IIIB
6
9
15
0.24
1–2
10
21
31
3–6
5
4
9
Sequential
5
1
6
Primary tumor diameter (cm)
0.0062
Nodal stations (n)
0.22
T stage (n)
N stage (n)
ECOG Eastern Cooperative Oncology Group, PS Performance Status, FEV1 forced expiratory volume in 1 s, DLCO(Hb) diffusion capacity for carbon monoxide corrected for blood hemoglobin concentration * P values were calculated using the Student’s t test for numerical data and the Fisher exact test for categorical data
AJCC 7 stage (n)
Chemotherapy cycle at start of radiation
0.014
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156 Table 2 RT metrics for patients with L-SCLC treated with once daily versus twice daily RT (n = 45)
Lung (2014) 192:151–158
Metric
P*
Value
QD
BID
Total
Median
84
132
114
Range
5–518
7–321
5–518
GTV (cc)
0.23
CTV (cc)
0.21 Median
227
346
301
Range
67–812
33–582
33–812
Median
357
583
503
Range
108–1,143
75–929
75–1,143
1 (5)
7 (27)
8 (17)
Median
3,642
3,545
3,630
Range
2,290–6,265
2,018–5,585
2,018–6,265
Median Range
50 28–72
41 20–71
45 20–72
Median
29
26
26
Range
15–37
9–33
9–37
Median
16.8
12.7
13.5
Range
9.4–20.0
3.8–17.6
3.8–20
Median
29.2
21.6
24.1
Range
19.8–49.5
8.9–43.7
8.9–49.5
Median
11.0
6.9
9.2
Range
1.3–30.1
0.7–27.8
0.7–30.1
Median
45.4
34.5
36
Range
32.5–50
2.4–38.3
2.4–50
PTV (cc)
0.26
ENI, n (%) Total lung volume (cc)
0.85
Lung V5 (%)
Lung V20 (%)
MLD (Gy)
Esophagus, mean (Gy)
Heart, mean (Gy) GTV gross or internal tumor volume, CTV clinical tumor volume, PTV planning target volume, MLD mean lung dose
Cord, max (Gy)
* P values were calculated using Student’s t test
Table 3 Outcomes for patients with L-SCLC treated with once daily versus twice daily RT (n = 45) Survival
Value
BID
QD
Total
Overall Median (years)
1.98
1.92
1.92
5-year (%)
28
32
30
5-year (%)
57
80
67
Locoregional Distant metastatic free Median (years) 5-year (%)
1.16 38
NR 52
1.16 44
Median (years)
0.85
1.04
1.03
5-year (%)
39
43
40
Progression free
*
P values were calculated using the Chi square test
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P*
Risk ratio BID/ QD (95 % CI)
0.99
1.01 (0.46–2.28)
0.16
2.24 (0.65–10.25)
0.6
1.27 (0.53–3.2)
0.54
1.29 (0.58–3.00)
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Table 4 Toxicities for patients with L-SCLC treated with once daily versus twice daily RT (n = 45) Toxicity
Grade
QD
BID
Total
P*
Fatigue C2
2
2
4
C3
0
0
0
0.38
Dermatitis C2
7
0
7
C3
0
0
0
C2
11
20
31
C3
0
0
0
C2
6
2
8
C3
1
0
1
0.0014
Esophagitis 0.076
Pneumonitis/fibrosis
*
0.048
P values were calculated using the Fisher exact test
both NSCLC and SCLC patients treated with BID RT. On the other hand, dermatitis and pneumonitis may occur at higher rates in the QD versus BID subgroup due to overall higher dose. This is in keeping with Tsujino et al. [16], which showed higher rates of pneumonitis among predominantly NSCLC patients treated to a median dose of 60 (range 48–66) Gy in 1.8–2.0 Gy QD fractions compared with SCLC patients treated with 45 Gy in 1.5 Gy BID fractions. Given the subacute timing of pneumonitis, which typically peaks 3–6 months after treatment, it may be the total dose, rather than the overall treatment time, that may impact its probability [18]. We did not observe statistically significant differences in survival or local control outcomes. This may be due to the small patient sample size as well as to potential confounding variables, including patient, tumor, and/or radiation treatment characteristics. Any improvements with the higher BED of QD treatment may have been offset by the poorer health of these patients. Likewise, higher tumor size at diagnosis and T stage of the BID subgroup may have offset any improvements with treatment. There appeared to be a trend in our study toward decreased LC in the BID versus QD subgroup. This may be due to poorer LC in the BID subgroup of our study compared with other studies. Our actuarial 5-year LC rate of 57 % appears lower than the absolute LC rate of 64 % reported after an 8-year median follow-up by Turrisi et al. Of note, patients in Turrisi et al. were consistently treated with ENI of the bilateral mediastinum, whereas our patients were not. This may explain the differences seen in LC, as may other confounding variables. ENI may conceivably be more crucial for the BID compared to the QD regimen, which may be worth further investigation. On the other hand, the trend toward increased LC in the QD subgroup
may be related to the higher BED of the QD regimen. Tomita et al. [17] found that with daily treatment, patients receiving C54 Gy compared with \54 Gy had median survivals of 41.0 and 14.0 months, respectively. In this retrospective patient series, there was likely selection bias regarding the choice of QD or BID treatment. Such factors as age, ECOG PS, and tumor size may have guided physician preferences, and the logistics of BID versus QD treatment may have guided some patient preferences. Indeed, QD treated patients were older, and this may reflect a belief that daily fractionation is associated with less acute toxicity. It also is plausible that older patients are less willing or unable to come in for treatment twice per day. It is conceivable that CALGB 30610 will show no statistically significant differences in outcomes between treatment arms. If so, then patient-specific factors may guide regimen selection, based on differences in expected toxicities. For example, if a patient has poor nutrition and severe weight loss at baseline, then one may opt for a QD regimen to avoid severe esophagitis, whereas if a patient has poor pulmonary function, one may opt for a BID regimen to decrease risk of pneumonitis. These possible differences in toxicities due to treatment regimen should be explored prospectively, as these may help guide regimen selection if confirmed. Acknowledgments This work was supported by internal funds of the Department of Radiation Oncology at the Dana-Farber Cancer Institute/Brigham and Women’s Hospital. Conflict of interest
None.
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LUNG CANCER
Comparison of Once and Twice Daily Radiotherapy for Limited Stage Small-Cell Lung Cancer Abhilash Gazula • Elizabeth H. Baldini Aileen Chen • David Kozono
•
Received: 25 June 2013 / Accepted: 2 October 2013 / Published online: 27 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Purpose This study was designed to review outcomes of once- (QD) versus twice-daily (BID) radiotherapy (RT) for limited stage small-cell lung cancer (L-SCLC) treated at Dana-Farber Cancer Institute/Brigham and Women’s Hospital. Methods We reviewed records for all patients with L-SCLC treated with radical chemoradiotherapy at our institution between January 2005 and December 2010. Differences in patient, tumor, and treatment characteristics were assessed by Student’s t test and Fisher exact test. Outcomes were compared using Kaplan–Meier estimates and Cox proportional hazards regression. Results Twenty patients received QD RT to a median dose of 61.2 Gy, and 26 patients received BID RT to a dose of 45 Gy. Median follow-up was 2.8 years. Overall survival (OS) was similar in both groups. 5-year locoregional control (LC) for all patients was 67 %: 80 % for the QD group and 57 % for the BID group (log-rank, P = 0.16). Grade 2 or higher dermatitis and pneumonitis were significantly higher in the QD group (15 vs. 0 %, P = 0.0014 and 13 vs. 4 %, P = 0.048, respectively), whereas Grade 2
A. Gazula E. H. Baldini A. Chen D. Kozono (&) Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women’s Hospital, 450 Brookline Avenue, Boston, MA 02215, USA e-mail: [email protected] A. Gazula e-mail: [email protected] E. H. Baldini e-mail: [email protected] A. Chen e-mail: [email protected]
or higher esophagitis trended higher in the BID group (44 vs. 24 %, P = 0.076). Conclusions Although there were no differences in OS with QD versus BID RT, there was a trend toward increased LC in the QD group. Dermatitis and pneumonitis were more common for QD RT, and esophagitis was somewhat more common for BID RT. Possible differences in toxicities depending on RT regimen may be worth further investigation, until results from CALGB 30610 become available. Keywords Small cell lung carcinoma (SCLC) Lung neoplasms Humans Radiotherapy Dose fractionation Outcome assessment
Background Of the estimated 226,160 new diagnoses of lung cancer in the United States in 2012, *14 % were small-cell lung cancer (SCLC) [1]. Of these, *40 % were of limited stage small-cell lung cancer (L-SCLC) that may be contained in a tolerable radiotherapy (RT) volume [2]. Two meta-analyses in 1992 showed that the addition of RT to chemotherapy increases survival, establishing combined modality therapy for L-SCLC [3, 4]. Optimal RT timing, dose, volume, and fractionation regimens however remain widely contested. In 1999, Turrisi et al. [5] published results from INT 0096, in which 417 L-SCLC patients were randomized to receive 45 Gy in either twice daily (BID) fractions over 3 weeks or once daily (QD) fractions over 5 weeks, demonstrating superior survival with BID RT. Choi et al. [6] (CALGB 8837) determined the maximum tolerated doses (MTD) for QD and BID RT as 70 Gy in 35 fractions and 45 Gy in 30 fractions,
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respectively, based on the highest doses that produced no more than 33 % Grade 4 or higher acute esophagitis and/or Grade 3 or higher pulmonary toxicity. Bogart et al. [7] (CALGB 39808) confirmed the safety of 70 Gy in 35 daily fractions. Turrisi et al. [5] found that Grade 3–4 esophagitis was twice as frequent in the BID versus QD arm. Despite the increased survival rate, only an estimated 25 % of centers treat L-SCLC patients with BID RT [8], in part due to perceived severe acute toxicities, beliefs about efficacy of higher doses with QD RT, or logistical issues. The Cancer and Leukemia Group B (CALGB 30610) is conducting a Phase III trial comparing 45 Gy BID and 70 Gy QD. A third arm comparing these to 61.2 Gy given with a concomitant boost was dropped after interim analysis [9]. Results, however, will not be available for several years. We analyzed outcomes of patients treated at our institution with QD or BID RT to obtain insights while awaiting results from CALGB 30610 [9].
Methods Patient Selection Under an Institutional Review Board approved protocol, records of L-SCLC patients treated with thoracic RT at Dana-Farber Cancer Institute/Brigham and Women’s Hospital between January 2005 and December 2010 were reviewed. Patients were excluded if they were treated with palliative intent, underwent surgical resection of their SCLC, had any other active cancers at the time of treatment, or had a diagnosis of mixed SCLC and NSCLC. Patients with a history of prior cancers that were in remission, who had received previous chemotherapy for other diagnoses, or who had undergone resection for NSCLC prior to diagnosis of SCLC were not excluded. Forty-six patients met inclusion criteria. Four patients received RT for L-SCLC but were not included due to treatment to a dose \45 Gy or palliative intent (n = 2), surgical resection of the SCLC (n = 2), and/or a mixed SCLC and NSCLC diagnosis (n = 1); one patient had a lobectomy and a mixed diagnosis. Patient Data All available physician notes, radiation records, radiology reports, and pulmonary function tests (PFTs) were reviewed to assess stage, treatment intent, RT details, and outcomes. RT tumor volumes were assessed retrospectively to determine whether elective nodal irradiation (ENI) was delivered. ENI was defined as explicit inclusion of mediastinal and/or supraclavicular nodal stations in the CTV that were not included in the GTV and not included
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via uniform margin expansion. RT plans also were reviewed to determine tumor volumes, lung V5, V20 and mean dose (MLD), esophagus and heart MLD, and spinal cord maximal dose. Smoking history and Eastern Cooperative Oncology Group (ECOG) performance status (PS) [10] were determined from physician notes. PFTs, including forced expiratory volume in 1 s (FEV1) and diffusion capacity for carbon monoxide (DLCO) within 2 months before treatment, were recorded. Tumor and nodal staging was determined from physician notes or based on evaluation of positron emission tomography (PET) and/or chest computed tomography (CT) scans at diagnosis. Physician and radiology notes were translated for uniform staging according to the American Joint Committee on Cancer (AJCC), 7th edition, 2010 guidelines [11]. Total number of chemotherapy cycles, agents used, and the timing of RT relative to chemotherapy were recorded. Treatment with prophylactic cranial irradiation (PCI) was recorded. Toxicities were evaluated by the research team retrospectively from physician and nursing notes and radiology records according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 [12] for uniform toxicity assessment. Tumor response was evaluated by the research team retrospectively according to Response Evaluation Criteria in Solid Tumors (RECIST) [13]. The last follow-up date was recorded as the last date on which the patient was examined for evaluation of SCLC status. Cause of death was noted as SCLC if there was evidence of active disease within 3 months of death. The Social Security Death Index was searched for patients lost to follow-up.
Treatment All patients received external beam RT, including threedimensional conformal RT (3D-CRT) (n = 38) and intensity modulated RT (IMRT) (n = 8). The majority of patients underwent planning with four-dimensional respiratory gated CT. Treatment volumes were individualized for each patient and typically included a gross or internal tumor volume (GTV or ITV). To create a clinical tumor volume (CTV), the GTV or ITV was typically expanded by 7 mm and edited for anatomy. Adjacent mediastinal nodal areas often were included. The CTV was expanded most often by 5 mm to delineate the planning target volume (PTV). The RT prescription was 45 Gy in 1.5 Gy BID fractions for all patients treated with BID RT. Those treated with QD RT received a median dose of 61.2 (range 50–66.6) Gy in 1.8- or 2-Gy fractions. The biologically equivalent dose (BED) using an a/b ratio of 10 was 51.8 and 72.2 Gy for the BID and QD regimens, respectively; taking into account overall treatment time and accelerated
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Thirty-three patients (72 %) received four cycles of cisplatin/etoposide; of the remainder, five (11 %) received varying numbers of cycles of cisplatin/etoposide, six (13 %) received carboplatin/etoposide, and one (2 %) each received cisplatin/irinotecan or carboplatin/irinotecan. Forty patients (87 %) received chemotherapy and RT concurrently, and six received sequential chemotherapy followed by RT. After completion of chemotherapy and thoracic RT, patients were reimaged with chest and head CTs or magnetic resonance imaging (MRI). Patients who had complete or substantial partial radiographic responses to treatment were offered PCI. Twenty-five patients (54 %) received PCI; of these, 16 (64 %) received a regimen of 30 Gy in 2-Gy fractions; the remainder received regimens ranging from 25 to 36 Gy in 2- to 3-Gy fractions.
Statistical Analysis
Fig. 1 Overall (a) and progression-free (b) survival following oncedaily compared with twice-daily RT for patients with L-SCLC. Kaplan–Meier analysis and the log-rank test with a significance value of 0.05 were performed
Fig. 2 LC following once-daily compared with twice-daily RT for patients with L-SCLC. Kaplan–Meier analysis and the log-rank test with a significance value of 0.05 were performed
repopulation using Teff = 5 days, Tko = 14 days and a = 0.35 [14], the tBED was 49.0 and 58.9 Gy for the BID and QD regimens, respectively Figs. 1 and 2.
Overall survival (OS) was measured from the date of diagnosis, defined as the date of first histopathological material showing SCLC. Locoregional control (LC) was measured as the interval between the date of diagnosis and the date of first evidence of primary or thoracic nodal disease progression or last follow-up. Radiographic scarring and changes were not scored as failure unless disease progression was shown, in which case the failure was recorded as the first time the lesion was noted. Distant metastasis-free survival (DMFS) was measured as the interval between the date of diagnosis and the date of first evidence of metastatic disease progression or last followup. The site of first metastatic failure was recorded. Concurrent local and metastatic failures were noted as separate occurrences. Progression-free survival (PFS) was measured as the interval between the date of diagnosis and the date of first evidence of either locoregional or distant metastatic disease progression or last follow-up. OS, LC, DMFS, and PFS were all obtained using Kaplan–Meier estimates. Subgroup analyses were performed to compare patients treated with BID versus QD RT. Differences between the two subgroups in patient, tumor, or treatment characteristics were assessed using Student’s t tests for numerical data and Fisher exact test for categorical data. Differences in rates of toxicities were assessed using the Fisher exact test. Grade 2 or higher toxicities were compared due to the small amount of patients experiencing Grade 3 or higher toxicities. Hazard ratios for death were determined using a Cox proportional hazards model. All tests were performed two-sided using a significance value of 0.05. Statistical calculations were performed using JMP Pro 10 (SAS, Cary, NC, USA).
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Results Demographic Data Median age at the time of diagnosis was 62 (range 44–87) years. Nineteen patients (41 %) were male. Thirty-eight patients (83 %) had an ECOG PS of 0–1 and eight (17 %) had a PS of 2. Six patients (13 %) had a weight loss of at least 5 % during the 6 months before consultation. Fortyfour patients (96 %) had a smoking history of at least 10 pack-years and 42 patients (91 %) had one of at least 30 pack-years; the median number of pack-years was 49 (range 1–100). All patients had an FEV1 of at least 1.18 L and a DLCO of at least 49 % predicted. AJCC stage was as follows: 2 Stage I, 6 Stage II, 23 Stage IIIA, and 15 Stage IIIB (Table 1). Both age (P = 0.0052) and chemotherapy cycle number at the time of RT (P = 0.014) were statistically significantly higher in the QD subgroup; median age was 65 versus 59 years and 50 versus 81 % had RT during chemotherapy cycle 1 or 2 in the QD versus BID subgroups, respectively. Primary tumor diameter at diagnosis was statistically significantly higher (P = 0.0062) in the BID (6.25 cm) versus QD (3 cm) subgroup. The number of T1 tumors was higher in QD versus BID (10 vs. 4, P = 0.012), and the number of T3 tumors was higher in BID versus QD (12 vs. 2, P = 0.0077). No other characteristics showed statistically significant differences between subgroups (Table 1). Radiotherapy Plans and Metrics ENI was not consistently delivered; 7 of 26 patients (27 %) in the BID subgroup received ENI compared with 1 of 20 patients (5 %) in the QD subgroup. RT metrics were tabulated (Table 2) but not analyzed for statistically significant differences due to expected biological differences inherit in the two regimens. Outcomes Median follow-up was 2.8 (range 0.18–6.94) years and was similar between groups (2.8 vs. 2.5 years for the QD vs. BID subgroups, respectively). Median OS was 1.9 (range 0.21–6.94) years with a 5-year OS rate of 30 %. Thirtynine patients (85 %) achieved a complete response (CR) or partial response (PR), 16 (35 %) versus 23 (50 %) in the QD versus BID subgroup, respectively. The 5-year LC rate was 67 % overall; it showed a trend (P = 0.16) toward an improved rate of 80 % in the QD versus 57 % in the BID subgroup. Median PFS was 1.03 years with a 5-year PFS rate of 40 %. There were no statistically significant differences in these outcomes between the QD and BID
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subgroups: the OS hazard ratio (HR) for death (BID vs. QD) was 1.01 [95 % confidence interval (CI) 0.46–2.28], the PFS HR for failure (BID vs. QD) was 1.29 (95 % CI 0.58–3.00), and the LC HR for failure (BID vs. QD) was 2.24 (95 % CI 0.65–10.25; Table 3). There were no statistically significant differences for any of the above outcomes based on age, primary tumor diameter, or ECOG PS. Toxicities Statistically significant differences were found in the rates of both Grade 2 or higher dermatitis (15 vs. 0 %, P = 0.0014) and pneumonitis (13 vs. 4 %, P = 0.048) in the QD versus BID subgroups, respectively (Table 4). One patient died of pneumonitis 6 months following four cycles of chemotherapy and an RT to a dose of 50 Gy in 25 daily fractions. The patient was a 75-year-old male with an ECOG PS of 0. Lung V5, V20, and MLD were 50.4, 31.3 %, and 16.9 Gy, respectively. Although there was no statistically significant difference, a trend (P = 0.076) was observed showing a higher rate of Grade 2 or higher esophagitis in the BID versus QD subgroup (44 vs. 24 %, respectively).
Discussion During the past several decades, numerous studies have examined various chemoradiotherapy regimens for L-SCLC [3–7, 15–17]. The optimal RT regimen remains contested. CALGB 30610 [9] is designed to determine whether daily treatment to an escalated dose of 70 Gy is superior to BID RT to a dose of 45 Gy. However, these results will not be available for several years. Meanwhile, it may be helpful to determine whether QD versus BID RT in nonrandomized patient series shows any differences in outcomes. Grade 3 or higher toxicities were rare, so we were limited to comparisons of Grade 2 or higher toxicities. Although lower grade toxicities may not be grounds to avoid a treatment regimen, it may be preferable to limit these in older, frailer patients. Our data showed statistically significant differences in Grade 2 or higher dermatitis and pneumonitis, both occurring at higher rates in the QD subgroup. Esophagitis trended toward a higher rate in the BID subgroup. This likely reflects the nature of the two regimens. The increased Grade 2 or higher esophagitis in the BID subgroup may be related to the compressed RT treatment time, reaching a dose of 45 Gy in 3 weeks rather than 5. This is in keeping with INT 0096, which showed rates of Grade 3 esophagitis of 27 versus 11 % in the BID versus QD arms, respectively [5]. Similarly, Mauguen et al. [15] found that the rates of acute esophagitis increased in
Lung (2014) 192:151–158 Table 1 Patient characteristics for patients with L-SCLC treated with once daily versus twice daily RT (n = 45)
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Characteristic
Value
QD
BID
19
26
Median
65
59
62
Range
49–87
44–73
44–87
Number of patients
Total
Age (years)
P*
0.0052
ECOG PS (n)
0.38 0–1
14
24
38
2
6
2
8
Median
2.21
1.89
2.08
Range
1.28–3.3
1.18–3.12
1.18–3.3
Median
61
70
70
Range
58–100
40–93
40–100
Median Range
91 91–91 %
62 49–86 %
63 49–91 %
Current
8
9
17
Former
11
17
28
\30
2
2
4
FEV1 (L)
0.7
FEV1 (% predicted)
0.61
\0.001
DLCO(Hb) (% predicted)
Smoking status (n)
Smoking history (pack-years)
0.91 C30
17
24
42
Median
47
49.5
49
Range
1–100
7.5–100
1–100
Median
3
6.25
4
Range
1.6–6.6
0.9–10.5
0.9–10.5
Median
3
3
3
Range
0–6
0–6
0–6
T1
10
4
14
0.012
T2
6
6
12
0.23
T3
2
12
14
0.0077
T4
2
4
6
0.3
N0
1
3
4
0.32
N1
2
3
5
0.36
N2
12
13
25
0.19
N3
5
7
12
0.26
I
0
2
2
0.31
II
3
3
6
0.32
IIIA
11
12
23
0.2
IIIB
6
9
15
0.24
1–2
10
21
31
3–6
5
4
9
Sequential
5
1
6
Primary tumor diameter (cm)
0.0062
Nodal stations (n)
0.22
T stage (n)
N stage (n)
ECOG Eastern Cooperative Oncology Group, PS Performance Status, FEV1 forced expiratory volume in 1 s, DLCO(Hb) diffusion capacity for carbon monoxide corrected for blood hemoglobin concentration * P values were calculated using the Student’s t test for numerical data and the Fisher exact test for categorical data
AJCC 7 stage (n)
Chemotherapy cycle at start of radiation
0.014
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156 Table 2 RT metrics for patients with L-SCLC treated with once daily versus twice daily RT (n = 45)
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Metric
P*
Value
QD
BID
Total
Median
84
132
114
Range
5–518
7–321
5–518
GTV (cc)
0.23
CTV (cc)
0.21 Median
227
346
301
Range
67–812
33–582
33–812
Median
357
583
503
Range
108–1,143
75–929
75–1,143
1 (5)
7 (27)
8 (17)
Median
3,642
3,545
3,630
Range
2,290–6,265
2,018–5,585
2,018–6,265
Median Range
50 28–72
41 20–71
45 20–72
Median
29
26
26
Range
15–37
9–33
9–37
Median
16.8
12.7
13.5
Range
9.4–20.0
3.8–17.6
3.8–20
Median
29.2
21.6
24.1
Range
19.8–49.5
8.9–43.7
8.9–49.5
Median
11.0
6.9
9.2
Range
1.3–30.1
0.7–27.8
0.7–30.1
Median
45.4
34.5
36
Range
32.5–50
2.4–38.3
2.4–50
PTV (cc)
0.26
ENI, n (%) Total lung volume (cc)
0.85
Lung V5 (%)
Lung V20 (%)
MLD (Gy)
Esophagus, mean (Gy)
Heart, mean (Gy) GTV gross or internal tumor volume, CTV clinical tumor volume, PTV planning target volume, MLD mean lung dose
Cord, max (Gy)
* P values were calculated using Student’s t test
Table 3 Outcomes for patients with L-SCLC treated with once daily versus twice daily RT (n = 45) Survival
Value
BID
QD
Total
Overall Median (years)
1.98
1.92
1.92
5-year (%)
28
32
30
5-year (%)
57
80
67
Locoregional Distant metastatic free Median (years) 5-year (%)
1.16 38
NR 52
1.16 44
Median (years)
0.85
1.04
1.03
5-year (%)
39
43
40
Progression free
*
P values were calculated using the Chi square test
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P*
Risk ratio BID/ QD (95 % CI)
0.99
1.01 (0.46–2.28)
0.16
2.24 (0.65–10.25)
0.6
1.27 (0.53–3.2)
0.54
1.29 (0.58–3.00)
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Table 4 Toxicities for patients with L-SCLC treated with once daily versus twice daily RT (n = 45) Toxicity
Grade
QD
BID
Total
P*
Fatigue C2
2
2
4
C3
0
0
0
0.38
Dermatitis C2
7
0
7
C3
0
0
0
C2
11
20
31
C3
0
0
0
C2
6
2
8
C3
1
0
1
0.0014
Esophagitis 0.076
Pneumonitis/fibrosis
*
0.048
P values were calculated using the Fisher exact test
both NSCLC and SCLC patients treated with BID RT. On the other hand, dermatitis and pneumonitis may occur at higher rates in the QD versus BID subgroup due to overall higher dose. This is in keeping with Tsujino et al. [16], which showed higher rates of pneumonitis among predominantly NSCLC patients treated to a median dose of 60 (range 48–66) Gy in 1.8–2.0 Gy QD fractions compared with SCLC patients treated with 45 Gy in 1.5 Gy BID fractions. Given the subacute timing of pneumonitis, which typically peaks 3–6 months after treatment, it may be the total dose, rather than the overall treatment time, that may impact its probability [18]. We did not observe statistically significant differences in survival or local control outcomes. This may be due to the small patient sample size as well as to potential confounding variables, including patient, tumor, and/or radiation treatment characteristics. Any improvements with the higher BED of QD treatment may have been offset by the poorer health of these patients. Likewise, higher tumor size at diagnosis and T stage of the BID subgroup may have offset any improvements with treatment. There appeared to be a trend in our study toward decreased LC in the BID versus QD subgroup. This may be due to poorer LC in the BID subgroup of our study compared with other studies. Our actuarial 5-year LC rate of 57 % appears lower than the absolute LC rate of 64 % reported after an 8-year median follow-up by Turrisi et al. Of note, patients in Turrisi et al. were consistently treated with ENI of the bilateral mediastinum, whereas our patients were not. This may explain the differences seen in LC, as may other confounding variables. ENI may conceivably be more crucial for the BID compared to the QD regimen, which may be worth further investigation. On the other hand, the trend toward increased LC in the QD subgroup
may be related to the higher BED of the QD regimen. Tomita et al. [17] found that with daily treatment, patients receiving C54 Gy compared with \54 Gy had median survivals of 41.0 and 14.0 months, respectively. In this retrospective patient series, there was likely selection bias regarding the choice of QD or BID treatment. Such factors as age, ECOG PS, and tumor size may have guided physician preferences, and the logistics of BID versus QD treatment may have guided some patient preferences. Indeed, QD treated patients were older, and this may reflect a belief that daily fractionation is associated with less acute toxicity. It also is plausible that older patients are less willing or unable to come in for treatment twice per day. It is conceivable that CALGB 30610 will show no statistically significant differences in outcomes between treatment arms. If so, then patient-specific factors may guide regimen selection, based on differences in expected toxicities. For example, if a patient has poor nutrition and severe weight loss at baseline, then one may opt for a QD regimen to avoid severe esophagitis, whereas if a patient has poor pulmonary function, one may opt for a BID regimen to decrease risk of pneumonitis. These possible differences in toxicities due to treatment regimen should be explored prospectively, as these may help guide regimen selection if confirmed. Acknowledgments This work was supported by internal funds of the Department of Radiation Oncology at the Dana-Farber Cancer Institute/Brigham and Women’s Hospital. Conflict of interest
None.
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