- Email: [email protected]
Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy
Radiotherapy and Oncology xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy Seung Yeun Chung a, Jee Suk Chang a, Byung Min Lee a, Kyung Hwan Kim a, Kyong Joo Lee b, Jinsil Seong a,⇑ a
Department of Radiation Oncology; and b Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 14 January 2017 Received in revised form 30 March 2017 Accepted 5 April 2017 Available online xxxx Keywords: Dose escalation Pancreatic cancer Chemoradiotherapy
a b s t r a c t Purpose: To investigate whether radiotherapy (RT) dose escalation would improve treatment outcomes without increasing severe toxicity in locally advanced pancreatic cancer patients. Methods: From 2005 to 2015, 497 locally advanced pancreatic cancer patients who received neoadjuvant or definitive chemoradiotherapy (CCRT) were included. Patients were divided according to the total dose (TD). Overall survival (OS), progression-free survival (PFS), local failure-free rate (LFFR), distant failurefree rate (DFFR), and toxicity rates were compared between <61 Gy (n = 345) and 61 Gy groups (n = 152). Additionally, propensity score matching was performed. Results: At a median follow-up of 19.3 months (range, 4.8–128.5 months), the 1-year OS, PFS, LFFR, and DFFR were significantly higher in the 61 Gy group. After multivariate analysis, a TD of 61 Gy remained a significant favorable factor for OS (p = 0.019), PFS (p = 0.001), LFFR (p = 0.004), and DFFR (p = 0.008). After propensity score matching, the 61 Gy group still showed higher OS, PFS, and LFFR, but not DFFR (p = 0.205). The acute and late toxicity rates showed no significant difference between the two groups. Conclusion: Patients who received a higher RT dose showed not only improved PFS and LFFR, but also improved OS without an increase in severe toxicity. Dose-escalated CCRT can be a favorable treatment option in locally advanced pancreatic cancer patients. Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx
Pancreatic cancer accounts for over 200,000 deaths per year worldwide. It is predicted to surpass breast, prostate, and colorectal cancer to become the second leading cause of death in the USA by 2030 [1,2]. At the time of diagnosis, only 20% of patients are eligible for initial resection [3]. For those ineligible for resection, chemotherapy and radiotherapy (RT) are usually performed. Although RT is considered an effective treatment modality, there are conflicting results. The ECOG 4201 trial showed an overall survival (OS) improvement from 9.2 to 11.1 months for patients who received RT with gemcitabine compared to gemcitabine alone for locally advanced pancreatic cancer [4]. In comparison, the LAP07 trial showed no survival benefit for RT with concurrent chemoradiotherapy (CCRT) after induction chemotherapy compared to chemotherapy alone [5]. However, prior trials were performed with limited RT doses due to surrounding radiation-sensitive gastrointestinal (GI) organs. With intensity-modulated radiation therapy (IMRT), dose escalation is possible without increasing the dose to organs-at-risk. In a recent comparison of IMRT with three-dimensional conformal ⇑ Corresponding author at: Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. E-mail address: [email protected] (J. Seong).
RT (3DCRT), treatment-related toxicities were significantly reduced with IMRT [6]. In our institution, CCRT has been performed with IMRT and fulldose chemotherapy since 2006 [7]. In this study, we investigated whether RT dose escalation would improve treatment outcomes and thereby improve survival, without increasing severe toxicity in locally advanced pancreatic cancer patients. Materials and methods Patients We retrospectively reviewed the medical records of pancreatic cancer patients who received RT to primary pancreatic lesions between January 2005 and December 2015. Patients who received RT alone (n = 3), received previous treatment (n = 36), had distant metastasis (n = 14), had no follow-up (n = 20), had a neuroendocrine tumor (n = 13), received RT below 20 Gy (n = 3), or had double primary malignancy (n = 10) were excluded. Finally, 497 locally advanced pancreatic cancer patients who received primary neoadjuvant or definitive CCRT were included. No patients received neoadjuvant chemotherapy. We included borderline resectable patients with unresectable patients, and used the term ‘‘locally advanced pancreatic cancer” to encompass all CCRT cases.
http://dx.doi.org/10.1016/j.radonc.2017.04.010 0167-8140/Ó 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
2
Dose escalation in pancreatic cancer patients
Resectability of the tumor was determined by the radiologist and/or the surgeon using radiologic findings based on the National Comprehensive Cancer Network (NCCN) criteria. Borderline resectable patients included in this study were recommended to receive CCRT in the multidisciplinary meeting due to the location and extent of the tumor. Radiotherapy Computed tomography (CT) simulation with diluted oral contrast and intravenous contrast was performed. All patients received respiration training to minimize respiratory motion, which was to be told to breathe as shallowly as possible before CT simulation and each treatment session. Four-dimensional CT was performed since 2014. Patients fasted for at least 4 h prior to treatment. For IMRT patients, daily megavoltage or cone-beam CT was performed. Gross tumor volume (GTV) encompassed the primary tumor and involved regional lymph nodes. Internal target volume (ITV) was delineated when possible. Planning target volume (PTV) was defined as GTV or ITV with a 5-mm margin. Prophylactic lymph nodes were not intentionally included, but when the PTV included part of celiac or superior mesenteric lymph node area, the PTV was extended to include the nodal area at that level. The PTV was not extended cranio-caudally in such cases. The primary aim was to achieve the volume of the GTV receiving 95% of the prescription dose (V95) >99.0%. For the duodenum, the maximum dose to contiguous 2 mL was limited to Equivalent Dose in 2 Gy fractions (EQD2) 45 Gy. For equal comparisons of the dose effects of various fractionation schedules, the TD was calculated as EQD2 with an a/b value of 3 for normal tissue and 10 for tumors. The TD used for analysis was based on the intended RT dose. A total of 281 (56.5%) patients received 3DCRT; 50.4 Gy in 28 fractions (EQD2 49.56 Gy) was the most common dose scheme. IMRT patients accounted for 43.5% (n = 216), and most received 58.42 Gy in 23 fractions (EQD2 61.05 Gy) or 57 Gy in 20 fractions (EQD2 61.04 Gy). Since the aim of this study was to show that dose escalation via IMRT is feasible without increased toxicity and can even lead to beneficial treatment outcomes, the cut-off value was determined clinically, with the major dose scheme for IMRT patients as the cut-off value. Thus, patients were divided into 2 groups according to the TD: below EQD2 61 Gy (<61 Gy group, n = 345) and equal to or above EQD2 61 Gy (61 Gy group, n = 152).
rence of disease in regional lymph nodes and soft tissues located near the primary tumor. Distant failure was defined as the development of distant metastasis. Toxicity assessment Acute and late toxicity was each defined as a toxicity event occurring within and after 90 days from the start of RT, respectively. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) were used to grade toxicity events; toxicities equal to or higher than grade 3 were defined as severe events. Statistical analysis Baseline characteristics between the 2 groups were compared using the v2 and Fisher’s exact tests. The cumulative probabilities of OS, PFS, LFFR, and DFFR rates were calculated using the Kaplan– Meier method and compared using a log rank test. Univariate and multivariate analyses were performed using Cox’s regression. For multivariate analysis, statistically significant factors proven using univariate analysis were included. To reduce bias arising from the retrospective nature of this study, propensity score matching (PSM) was used with the nearest-neighbor matching method. The dose–response relationship was analyzed using logistic regression. All analyses were performed using SPSS version 23.0 (IBM Inc., Armonk, NY, USA) and R version 2.12.1. (R Foundation for Statistical Computing, Vienna, Austria). Results Patients and tumor characteristics Patient and tumor characteristics such as age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, pathology, subsite, T stage, N stage, tumor size, resectability, post-CCRT surgery and concurrent chemotherapy regimen were well balanced between the 2 groups (all p > 0.05) (Table 1). More patients received maintenance chemotherapy in the 61 Gy group (69.7%) than in the <61 Gy group (55.7%). Initial CA 19-9 was significantly higher in the <61 Gy group. All patients in the 61 Gy group received IMRT. Overall survival and progression-free survival
Chemotherapy Chemotherapy regimens were chosen by the physician and were as follows: (1) 1000 mg/m2 gemcitabine weekly (days 1, 8, and 15) followed by a 1-week rest period; (2) 75 mg/m2 cisplatin on day 1 of each 28-day cycle combined with weekly 1000 mg/ m2 gemcitabine; (3) 500 mg/m2 fluorouracil weekly; (4) 850 mg/ m2 capecitabine twice a day; (5) 40 mg/m2 titanium silicate-1 twice a day from days 1 to 14 and from days 22 to 35; and (6) 0.5 g tegafur/uracil 3 times a day. The primary aim was to administer full dose chemotherapy. Patients without progression after the first response evaluation and those who underwent surgery generally received maintenance chemotherapy. Response assessment Treatment response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST). Follow-up evaluation was performed at 1 and 3 months post-CCRT, and routinely thereafter. Local failure was defined as progression of the primary tumor or recurrence at the primary tumor bed, generally suggesting infield failure. Regional failure was defined as progression or recur-
The median follow-up was 19.3 months (range, 4.8– 128.5 months). The median OS was 15.7 months for all patients. For the 61 Gy and <61 Gy groups, the median OS was 21.9 and 14.8 months, and the 1-year OS rates were 74.7% and 60.6%, respectively (p = 0.001) (Fig. 1A). In multivariate analysis, factors such as age >64 years (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.01–1.51; p = 0.040), male sex (HR 1.28, CI 1.05– 1.58; p = 0.017), initial CA 19-9 >304.5 U/mL (HR 1.31, CI 1.07– 1.60; p = 0.008), and tumor size >3.1 cm (HR 1.24, CI 1.00–1.55; p = 0.049) showed a significantly adverse effect on OS. Favorable factors were borderline resectable tumors (HR 0.70, CI 0.52–0.93; p = 0.015) and TD 61 Gy (HR 0.68, CI 0.49–0.94; p = 0.019) (Table 2). The median OS was also evaluated in different subgroups. In unresectable disease, the median OS was 21.4 months and 13.6 months for the 61 Gy and <61 Gy groups, respectively (p < 0.001), while it was 23.2 months and 18.3 months, respectively, in borderline resectable disease (p = 0.013). Patients who underwent post-CCRT surgery showed a median OS of 30.0 months compared to that of 13.7 months in patients who did not undergo surgery (p < 0.001). For post-CCRT surgery patients, median OS was
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
3
S.Y. Chung et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx Table 1 Patient and tumor characteristics. Total N = 497 n Age, median (range) 64 >64 Sex Female Male ECOG performance status 0 1 2 Pathology Adenoca Adenosquamous Poorly differentiated Failed to confirm Subsite Head Other T stage 1 2 3 4 N stage 0 1 Tumor size, median (range) 3.1 cm >3.1 cm Resectability Unresectable Borderline Post-CCRT surgery No Yes Concurrent chemotherapy Gem-based Other Maintenance chemotherapy No Yes Initial CA 19–9, median (range) 304.5 U/mL >304.5 U/mL RT technique 3DCRT IMRT Total dose in EQD2, median (Gy, range)
61 Gy
<61 Gy N = 345 %
n
64 (35–88) 272 225
p
N = 152 %
n
%
54.7 45.3
64 (35–87) 188 157
54.5 45.5
64 (39–88) 84 68
55.3 44.7
0.874
202 295
40.6 59.4
135 210
39.1 60.7
67 85
44.1 55.9
0.301
131 358 8
26.4 72 1.6
100 239 6
29 69.3 1.7
31 119 2
20.4 78.3 1.3
0.119
413 5 5 74
83.1 1 1 14.9
284 3 5 53
82.3 0.9 1.4 15.4
129 2 0 21
84.9 1.3 0 13.8
0.512*
345 152
69.4 30.6
239 106
69.3 30.7
106 46
69.7 30.3
0.918
7 33 204 253
1.4 6.6 41 50.9
6 26 143 170
1.7 7.5 41.4 49.3
1 7 61 83
0.7 4.6 40.1 54.6
0.479*
297 200 3.1 (1.2–9.0) 251 246
59.8 40.2
57.7 42.3
0.155
49.3 50.7
98 54 3.00 (1.2–9.0) 81 71
64.5 35.5
50.5 49.5
199 146 3.2 (1.3–9.0) 170 175
53.3 46.7
0.410
378 119
76.1 23.9
271 74
78.6 21.4
107 45
70.4 29.6
0.053*
392 105
78.9 21.1
268 77
77.7 22.3
124 28
81.6 18.4
0.327
251 246
50.5 49.5
180 165
52.2 47.8
71 81
46.7 53.3
0.262
199 40 298 60 304.5 (0.0–20000) 247 49.9 248 50.1
153 44.3 192 55.7 371 (0.0–20000) 161 46.9 182 53.1
46 30.3 106 69.7 169 (0.10–20000) 86 56.6 66 43.4
0.003
281 56.5 216 43.5 49.56 (24.42–64.31)
281 81.4 64 18.6 49.56 (24.42–60.95)
0 0 152 100 61.05 (61.04–64.31)
<0.001
0.048
*
Fisher’s exact test. Abbreviations: ECOG, Eastern Cooperative Oncology Group; CCRT, concurrent chemoradiotherapy; Gem, gemcitabine; RT, radiotherapy; 3DCRT, 3D conformal radiotherapy; IMRT, intensity-modulated radiation therapy; EQD2, equivalent dose in 2 Gy fractions.
44.0 months and 24.0 months for 61 Gy and <61 Gy groups, respectively (p = 0.036). For those who did not receive post-CCRT surgery, median OS was 18.1 months and 12.8 months, respectively (p = 0.001). Although the percentages of patients who underwent post-CCRT surgery did not differ significantly, the pathologic reports were different between the 2 groups. The pathologic complete response rates were 17.9% and 5.2%, and the down-staging rates were 67.9% and 41.6%, in the 61 Gy and <61 Gy groups, respectively. The median PFS was 11.1 months and 8.0 months, and the 1year PFS rates were 46.2% and 30.9% for the 61 Gy and <61 Gy groups, respectively (p < 0.001) (Fig. 1B). When other factors were adjusted, TD 61 Gy (HR 0.69, CI 0.56–0.86; p = 0.001) remained a favorable predictor of PFS. Adverse factors were initial CA 19-9 >304.5 U/mL (HR 1.33, CI 1.10–1.60; p = 0.003) and tumor size
>3.1 cm (HR 1.38, CI 1.14–1.67; p = 0.001) (Supplementary Table 1). Local failure The median LFF period was 26.2 months and 21.2 months, and the 1-year LFFR was 86.9% and 70.9% for the 61 Gy and <61 Gy groups, respectively (p = 0.001) (Fig. 1C). Other chemotherapy regimens besides gemcitabine were poor predictors for LFFR (HR 1.82, CI 1.33–2.50; p < 0.001). TD 61 Gy remained a favorable predictor (HR 0.47, CI 0.28–0.79; p = 0.004) using multivariate analysis (Table 2). As for regional failure, regional failure only as the first site of failure occurred in 6 patients (1.2%), with 3 patients in each group. Overall proportion of regional failure alone as first site of failure and also including those accompanied with local or distant failure was 9.5% (n = 47).
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
4
Dose escalation in pancreatic cancer patients
Fig. 1. Kaplan–Meier estimates of overall survival (A), progression-free survival (B), local failure-free survival (C), and distant failure-free survival (D), according to total dose 61 Gy or <61 Gy.
Distant failure The median DFF period was 16.0 months and 9.9 months, and the 1-year DFFR was 56.4% and 45.8% for the 61 Gy and <61 Gy groups, respectively (p = 0.007) (Fig. 1D). In multivariate analysis, initial CA 19-9 >304.5 U/mL, tumor size >3.1 cm, and subsite other than the pancreas head were adverse predictors of distant metastasis. TD 61 Gy was a positive predictor (Supplementary Table 1).
Propensity score matching analysis Although the percentage of patients who received maintenance chemotherapy was significantly different between the 2 groups, it was excluded from multivariate analysis to avoid leading time bias. Therefore, PSM was performed to elaborate further on the current results. The 2 groups were matched for maintenance chemotherapy and initial CA 19-9, as well as for age, sex, subsite, T stage, N stage, tumor size, resectability, and concurrent chemotherapy regimen. As a result, 152 patients were matched in each group (Supplementary Table 2). After PSM, the 1-year OS rates were 74.7% and 62.4% for the 61 Gy and <61 Gy groups, respectively (p = 0.011) (Fig. 2A). The 1-year PFS rates were 46.2% and 34.6% (p = 0.016), and the 1-year LFFR were 86.9% and 71.9% (p = 0.002) for the 61 Gy and <61 Gy groups, respectively (Figs. 2B and C). The DFFRs were different from previous results, with 1-year DFFRs
of 56.4% and 50.5% for the 61 Gy and <61 Gy groups, respectively (p = 0.205) (Fig. 2D). Dose–response relationship When multivariate analysis was performed for OS, PFS, and LFFR with RT dose as a continuous variable, TD still proved to be a beneficial factor for all OS, PFS, and LFFR (Supplementary Table 3). Thus, the dose–response relationship was additionally analyzed and as shown in Fig. 3A and B, the probability of local recurrence and death decreased as the TD increased. Toxicity For both acute and late toxicities, there were no significant differences between the 2 groups (Table 3). Leukopenia was the most common acute hematologic toxicity in both groups. Grade 4 acute hematologic toxicities were observed; however, there was no acute GI toxicity higher than grade 3 in both groups. Although not shown in Table 3, acute toxicities such as constipation, diarrhea, and epigastric discomfort were also reviewed; no patients had severe toxicity except for 1 patient with grade 3 diarrhea. For late toxicity, the rate of severe GI bleeding was no higher in the 61 Gy group than in the <61 Gy group. At the time of diagnosis, the rates of bowel invasion did not differ between the 2 groups (p = 0.450). Bleeding due to cancer invasion was excluded. Severe
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
<0.001 0.562
0.004
1.33–2.50 0.73–1.79
0.28–0.79
1.82 1.14
0.47
0.04–1.90 0.51–1.83 0.94–1.77 0.78–1.46 0.89–1.76 1.30–2.42 0.48–0.90 0.83–1.54 0.86–1.58 0.36–0.77 0.76–1.37 1.07–1.60 1.00–1.55 0.49–0.94 1.02 1.31 1.24 0.68
0.873 0.008 0.049 0.019
0.52–0.93 0.70
0.015
0.15–1.12 0.78–1.79 0.74–1.20 0.41 1.18 0.94
0.234 0.082 0.430 0.625
0.26 0.97 1.29 1.06 1.25 1.77 0.66 1.13 1.16 0.53
0.663–1.29 0.00–1.06 0.80–1.54 0.92 0.00 1.11 0.86–1.35 1.24–5.27 0.94–1.43
0.13–0.93 0.67–1.46 0.66–1.00 0.81–1.21 0.48–0.80 0.84–1.26 0.67–0.995 1.11–1.64 1.16–1.73 0.53–0.85
1.08 2.56 1.16
0.34 0.99 0.81 0.99 0.62 1.03 0.81 1.35 1.42 0.67
Abbreviations: ECOG, Eastern Cooperative Oncology Group; Gem, gemcitabine; RT, radiotherapy; 3DCRT, 3D conformal radiotherapy; IMRT, intensity-modulated radiation therapy; EQD2, equivalent dose in 2 Gy fractions.
p 95% CI 0.78–1.45 0.87–1.63 1.07 1.19 0.040 0.017 1.01–1.51 1.05–1.58 1.23 1.28
0.021 0.006 0.077 0.513 0.011 0.175 0.026 0.035 0.947 0.052 0.897 <0.001 0.783 0.045 0.003 0.001 <0.001 1.04–1.54 1.09–1.63
HR p 95% CI p 95% CI
1.26 1.33
Age (64 vs. >64) Sex (Female vs. Male) ECOG performance status ECOG 0 vs. ECOG 1 ECOG 0 vs. ECOG 2 Subsite (Head vs. Other) T stage T4 vs.T1 T4 vs. T2 T4 vs. T3 N stage (N0 vs. N1) Resectability (Unresectable vs. Borderline) Concurrent Chemotherapy (Gem based vs. Other) RT modality (3DCRT vs. IMRT) Initial CA19-9 (304.5 U/mL vs. >304.5 U/mL) Tumor size (3.1 cm vs. >3.1 cm) Total dose in EQD2 (<61 Gy vs. 61 Gy)
HR
Table 2 Univariate and multivariate Cox regression models for overall survival and local failure-free rate.
0.686 0.271 0.894 0.638 0.951 0.552 0.186 0.186 0.923 0.117 0.697 0.196 <0.001 0.010 0.425 0.336 0.001
HR
UVA
HR
UVA
95% CI
Local failure-free rate
MVA Overall Survival
p
MVA
S.Y. Chung et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
5
GI bleeding occurred in 19 patients (5.5%) in the <61 Gy group and 7 patients (4.6%) in the 61 Gy group. Grade 5 toxicity occurred in 2 patients (1.3%) in the 61 Gy group.
Discussion Currently, borderline pancreatic cancer patients are usually recommended for neoadjuvant CCRT and unresectable pancreatic cancer patients are recommended for either chemotherapy, induction chemotherapy with RT, or definitive CCRT. In our institution, CCRT with full dose chemotherapy is performed to optimize RT and chemotherapy for local and distant control. Although gemcitabine is considered a difficult factor for dose escalation due to increased toxicity rates, around half of the patients in this study received gemcitabine, and dose escalation was possible without any increased severe toxicity [8]. There have been many studies reporting the effectiveness of RT for local control and advocating its effectiveness of dose escalation. A study of unresectable pancreatic cancer patients treated with gemcitabine and concurrent RT with a median of 36 Gy in 15 fractions showed a median OS of 11.2 months [9]. In comparison, a phase I/II trial of dose escalation from 50 to 60 Gy in 25 fractions from the same institution reported a median OS of 14.8 months [10]. Another report of both unresectable and borderline resectable cases with induction chemotherapy followed by gemcitabine and RT of 55 Gy in 25 fractions showed a median OS of 23.1 months [11]. Thus, compared to RT at 36 Gy, higher RT doses have shown better treatment outcomes. However, compared to chemotherapy alone, there have been conflicting results regarding OS in randomized trials such as ECOG 4201 and LAP07, which used 3DCRT with RT dose schemes of 50.4 Gy in 28 fractions and 54 Gy in 30 fractions, respectively [4,5]. Nowadays, RT dose can further be escalated with IMRT. Recently, MD Anderson Cancer Center (MDACC) showed better outcomes for those receiving biologically effective dose (BED) >70 Gy in a study of 200 unresectable pancreatic cancer patients. The median OS was 17.8 months versus 15.0 months for the BED > 70 Gy and 70 Gy groups, respectively [12]. In addition, a Japanese study reported better histopathological effects for preoperative CCRT patients receiving 60 Gy than those receiving 50 Gy [13]. Similarly, our study showed better treatment outcomes in the 61 Gy group, with a median OS of 21.4 months for unresectable disease and 23.2 months for borderline resectable disease. Apart from dose-escalated CCRT, stereotactic body radiotherapy (SBRT) has emerged as a feasible option for locally advanced pancreatic cancer patients. Based on radiobiological advantage as well as shorter treatment time period, its efficacy has been reported [14]. However SBRT needs to be applied to highly selected patients due to the high risk of critical GI toxicity. Currently only retrospective series and some phase I-II studies are available [15–18]. While SBRT seems to be an attractive approach, further studies are necessary to show its effectiveness and toxicity. For distant metastasis, although dose escalation seemed to have a positive effect on the DFFR, it did not remain a significant factor when PSM was performed. Nowadays, the idea of dividing pancreatic cancer into locally destructive or metastatic groups according to the status of DPC4 is gaining much attention [19]. Thus, one hypothesis is that the locally destructive group gained local control or delayed progression through dose escalation, which resulted in improved survival [20]. But dose escalation could have been ineffective for distant metastasis in the metastatic group, and therefore showed no significant results. However, as shown in Fig. 2D, after approximately 6 months, the DFFR was higher in the 61 Gy group. Distant metastasis may
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
6
Dose escalation in pancreatic cancer patients
Fig. 2. Kaplan–Meier estimates of overall survival (A), progression-free survival (B), local failure-free survival (C), distant failure-free survival (D), according to total dose 61 Gy or <61 Gy after propensity score matching.
Fig. 3. Dose–response relationship for local recurrence (A) and death (B).
have occurred within 6 months in the metastatic group, and further distant metastasis may have been prevented in the locally destructive group. Dose escalation may have led to controlled or delayed local disease, thus preventing further progression or allowing patients to receive maintenance chemotherapy. As shown in Table 1, more patients in the 61 Gy group received maintenance chemotherapy. However, these hypotheses must be tested
in further studies since the status of DPC4 was unknown in this study. Acute and late toxicity rates did not differ between the 2 groups and the rates were acceptable. However, 2 grade 5 severe bleeding events occurred in the 61 Gy group. In these cases, it was hard to identify the exact bleeding location, and thus difficult to conclude that the events were radiation-induced. The primary tumor was in
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
7
S.Y. Chung et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx Table 3 Acute and late toxicities. Total N = 497
Acute toxicity Leukopenia Grade 0–2 Grade 3–4 Anemia Grade 0–2 Grade 3–4 Thrombocytopenia Grade 0–2 Grade 3–4 Nausea Grade 0–2 Grade 3 Vomiting Grade 0–2 Grade 3 Anorexia Grade 0–2 Grade 3 Fatigue Grade 0–2 Grade 3 Late toxicity GI bleeding Grade 0–2 Grade 3–5
61 Gy N = 152
<61 Gy N = 345
p
n
%
n
%
n
%
391 106
78.7 21.3
267 78
77.4 22.6
124 28
81.6 18.4
476 21
95.8 4.2
331 14
95.9 4.1
145 7
95.4 4.6
460 37
92.6 7.4
316 29
91.6 8.4
144 8
94.7 5.3
491 6
98.8 1.2
341 4
98.8 1.2
150 2
98.7 1.3
493 4
99.2 0.8
342 3
99.1 0.9
151 1
99.3 0.7
492 5
99.0 1.0
340 5
98.6 1.4
152 0
100.0 0.0
493 4
99.2 0.8
341 4
98.8 1.2
152 0
100.0 0.0
471 26
94.8 5.2
326 19
94.5 5.5
145 7
95.4 4.6
0.294
0.780
0.219
1.000*
1.000*
0.330*
0.318*
0.677
*
Fisher’s exact test. Abbreviations: GI, gastrointestinal. Toxicity graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.03).
a progressive status prior to the events in both patients, and the events occurred 2 and 10 months post-RT, respectively. In a recent study from the MDACC, acute severe toxicity was acceptable in dose-escalated patients, which was concordant with our study. However, only 1 episode of treatment-related GI bleeding occurred in a total of 200 patients, compared to 26 events in 497 patients in our study. This may be due to the retrospective toxicity assessment or the continuous follow-up in our institution resulting from geographic accessibility. Furthermore, only patients with tumors more than 1 cm from the closest GI mucosa were selected for dose escalation at the MDACC [12]. There are several limitations of this study owing to its retrospective nature. Firstly, heterogeneous chemotherapy regimens were used. Secondly, there may have been late toxicity events in the patients lost to follow-up. Finally, we were unable to evaluate molecular markers related to the DPC4 gene, since fine needle aspiration was performed for pathologic diagnosis in most patients. A prospective trial, Radiation Therapy Oncology Group/NRG Oncology 1201, which aimed to investigate both dose escalation and DPC4 genetic status, was started in 2013, but closed due to poor accrual. But another trial, Systemic Therapy and Chemoradiation in Advanced Localized Pancreatic Cancer–2 (SCALOP-2), which will evaluate the role of RT dose escalation and addition of nelfinavir to CCRT is currently recruiting patients. This study also has several strengths. Reports of dose escalation in pancreatic cancer are rare, and to the best of our knowledge, this is the study with the largest number of patients. Furthermore, all patients were treated with CCRT initially, thereby reducing the selection bias that is possible in other studies of patients receiving induction chemotherapy. In summary, our data suggest that dose escalation is feasible with IMRT in locally advanced pancreatic cancer patients. Patients who received higher RT dose showed not only improved PFS and LFFR, but also improved OS, without an increase in severe toxicity.
Therefore, dose-escalated CCRT can be a favorable treatment option in locally advanced pancreatic cancer patients. Conflict of interest statement The authors have no conflicts of interest to declare. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2017.04. 010. References [1] Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet 2016;388:73–85. [2] Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913–21. [3] Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med 2010;7: e1000267. [4] Loehrer Sr PJ, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 2011;29:4105–12. [5] Hammel P, Huguet F, van Laethem JL, et al. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA 2016;315:1844–53. [6] Bittner MI, Grosu AL, Brunner TB. Comparison of toxicity after IMRT and 3Dconformal radiotherapy for patients with pancreatic cancer – a systematic review. Radiother Oncol 2015;114:117–21. [7] Chang JS, Wang ML, Koom WS, et al. High-dose helical tomotherapy with concurrent full-dose chemotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2012;83:1448–54.
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
8
Dose escalation in pancreatic cancer patients
[8] Mukherjee S, Hurt CN, Bridgewater J, et al. Gemcitabine-based or capecitabinebased chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol 2013;14:317–26. [9] Murphy JD, Adusumilli S, Griffith KA, et al. Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2007;68:801–8. [10] Ben-Josef E, Schipper M, Francis IR, et al. A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2012;84:1166–71. [11] Badiyan SN, Olsen JR, Lee AY, et al. Induction chemotherapy followed by concurrent full-dose gemcitabine and intensity-modulated radiation therapy for borderline resectable and locally advanced pancreatic adenocarcinoma. Am J Clin Oncol 2016;39:1–7. [12] Krishnan S, Chadha AS, Suh Y, et al. Focal radiation therapy dose escalation improves overall survival in locally advanced pancreatic cancer patients receiving induction chemotherapy and consolidative chemoradiation. Int J Radiat Oncol Biol Phys 2016;94:755–65. [13] Hirata T, Teshima T, Nishiyama K, et al. Histopathological effects of preoperative chemoradiotherapy for pancreatic cancer: an analysis for the impact of radiation and gemcitabine doses. Radiother Oncol 2015;114:122–7.
[14] Wei Q, Yu W, Rosati LM, Herman JM. Advances of stereotactic body radiotherapy in pancreatic cancer. Chin J Cancer Res 2015;27:349–57. [15] Schellenberg D, Kim J, Christman-Skieller C, et al. Single-fraction stereotactic body radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2011;81:181–8. [16] Hoyer M, Roed H, Sengelov L, et al. Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother Oncol 2005;76:48–53. [17] Mahadevan A, Jain S, Goldstein M, et al. Stereotactic body radiotherapy and gemcitabine for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2010;78:735–42. [18] Chuong MD, Springett GM, Freilich JM, et al. Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys 2013;86:516–22. [19] Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009;27:1806–13. [20] Gutt R, Liauw SL, Weichselbaum RR. The role of radiotherapy in locally advanced pancreatic carcinoma. Nat Rev Gastroenterol Hepatol 2010;7:437–47.
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
Contents lists available at ScienceDirect
Radiotherapy and Oncology journal homepage: www.thegreenjournal.com
Original article
Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy Seung Yeun Chung a, Jee Suk Chang a, Byung Min Lee a, Kyung Hwan Kim a, Kyong Joo Lee b, Jinsil Seong a,⇑ a
Department of Radiation Oncology; and b Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
a r t i c l e
i n f o
Article history: Received 14 January 2017 Received in revised form 30 March 2017 Accepted 5 April 2017 Available online xxxx Keywords: Dose escalation Pancreatic cancer Chemoradiotherapy
a b s t r a c t Purpose: To investigate whether radiotherapy (RT) dose escalation would improve treatment outcomes without increasing severe toxicity in locally advanced pancreatic cancer patients. Methods: From 2005 to 2015, 497 locally advanced pancreatic cancer patients who received neoadjuvant or definitive chemoradiotherapy (CCRT) were included. Patients were divided according to the total dose (TD). Overall survival (OS), progression-free survival (PFS), local failure-free rate (LFFR), distant failurefree rate (DFFR), and toxicity rates were compared between <61 Gy (n = 345) and 61 Gy groups (n = 152). Additionally, propensity score matching was performed. Results: At a median follow-up of 19.3 months (range, 4.8–128.5 months), the 1-year OS, PFS, LFFR, and DFFR were significantly higher in the 61 Gy group. After multivariate analysis, a TD of 61 Gy remained a significant favorable factor for OS (p = 0.019), PFS (p = 0.001), LFFR (p = 0.004), and DFFR (p = 0.008). After propensity score matching, the 61 Gy group still showed higher OS, PFS, and LFFR, but not DFFR (p = 0.205). The acute and late toxicity rates showed no significant difference between the two groups. Conclusion: Patients who received a higher RT dose showed not only improved PFS and LFFR, but also improved OS without an increase in severe toxicity. Dose-escalated CCRT can be a favorable treatment option in locally advanced pancreatic cancer patients. Ó 2017 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2017) xxx–xxx
Pancreatic cancer accounts for over 200,000 deaths per year worldwide. It is predicted to surpass breast, prostate, and colorectal cancer to become the second leading cause of death in the USA by 2030 [1,2]. At the time of diagnosis, only 20% of patients are eligible for initial resection [3]. For those ineligible for resection, chemotherapy and radiotherapy (RT) are usually performed. Although RT is considered an effective treatment modality, there are conflicting results. The ECOG 4201 trial showed an overall survival (OS) improvement from 9.2 to 11.1 months for patients who received RT with gemcitabine compared to gemcitabine alone for locally advanced pancreatic cancer [4]. In comparison, the LAP07 trial showed no survival benefit for RT with concurrent chemoradiotherapy (CCRT) after induction chemotherapy compared to chemotherapy alone [5]. However, prior trials were performed with limited RT doses due to surrounding radiation-sensitive gastrointestinal (GI) organs. With intensity-modulated radiation therapy (IMRT), dose escalation is possible without increasing the dose to organs-at-risk. In a recent comparison of IMRT with three-dimensional conformal ⇑ Corresponding author at: Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. E-mail address: [email protected] (J. Seong).
RT (3DCRT), treatment-related toxicities were significantly reduced with IMRT [6]. In our institution, CCRT has been performed with IMRT and fulldose chemotherapy since 2006 [7]. In this study, we investigated whether RT dose escalation would improve treatment outcomes and thereby improve survival, without increasing severe toxicity in locally advanced pancreatic cancer patients. Materials and methods Patients We retrospectively reviewed the medical records of pancreatic cancer patients who received RT to primary pancreatic lesions between January 2005 and December 2015. Patients who received RT alone (n = 3), received previous treatment (n = 36), had distant metastasis (n = 14), had no follow-up (n = 20), had a neuroendocrine tumor (n = 13), received RT below 20 Gy (n = 3), or had double primary malignancy (n = 10) were excluded. Finally, 497 locally advanced pancreatic cancer patients who received primary neoadjuvant or definitive CCRT were included. No patients received neoadjuvant chemotherapy. We included borderline resectable patients with unresectable patients, and used the term ‘‘locally advanced pancreatic cancer” to encompass all CCRT cases.
http://dx.doi.org/10.1016/j.radonc.2017.04.010 0167-8140/Ó 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
2
Dose escalation in pancreatic cancer patients
Resectability of the tumor was determined by the radiologist and/or the surgeon using radiologic findings based on the National Comprehensive Cancer Network (NCCN) criteria. Borderline resectable patients included in this study were recommended to receive CCRT in the multidisciplinary meeting due to the location and extent of the tumor. Radiotherapy Computed tomography (CT) simulation with diluted oral contrast and intravenous contrast was performed. All patients received respiration training to minimize respiratory motion, which was to be told to breathe as shallowly as possible before CT simulation and each treatment session. Four-dimensional CT was performed since 2014. Patients fasted for at least 4 h prior to treatment. For IMRT patients, daily megavoltage or cone-beam CT was performed. Gross tumor volume (GTV) encompassed the primary tumor and involved regional lymph nodes. Internal target volume (ITV) was delineated when possible. Planning target volume (PTV) was defined as GTV or ITV with a 5-mm margin. Prophylactic lymph nodes were not intentionally included, but when the PTV included part of celiac or superior mesenteric lymph node area, the PTV was extended to include the nodal area at that level. The PTV was not extended cranio-caudally in such cases. The primary aim was to achieve the volume of the GTV receiving 95% of the prescription dose (V95) >99.0%. For the duodenum, the maximum dose to contiguous 2 mL was limited to Equivalent Dose in 2 Gy fractions (EQD2) 45 Gy. For equal comparisons of the dose effects of various fractionation schedules, the TD was calculated as EQD2 with an a/b value of 3 for normal tissue and 10 for tumors. The TD used for analysis was based on the intended RT dose. A total of 281 (56.5%) patients received 3DCRT; 50.4 Gy in 28 fractions (EQD2 49.56 Gy) was the most common dose scheme. IMRT patients accounted for 43.5% (n = 216), and most received 58.42 Gy in 23 fractions (EQD2 61.05 Gy) or 57 Gy in 20 fractions (EQD2 61.04 Gy). Since the aim of this study was to show that dose escalation via IMRT is feasible without increased toxicity and can even lead to beneficial treatment outcomes, the cut-off value was determined clinically, with the major dose scheme for IMRT patients as the cut-off value. Thus, patients were divided into 2 groups according to the TD: below EQD2 61 Gy (<61 Gy group, n = 345) and equal to or above EQD2 61 Gy (61 Gy group, n = 152).
rence of disease in regional lymph nodes and soft tissues located near the primary tumor. Distant failure was defined as the development of distant metastasis. Toxicity assessment Acute and late toxicity was each defined as a toxicity event occurring within and after 90 days from the start of RT, respectively. The National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.03) were used to grade toxicity events; toxicities equal to or higher than grade 3 were defined as severe events. Statistical analysis Baseline characteristics between the 2 groups were compared using the v2 and Fisher’s exact tests. The cumulative probabilities of OS, PFS, LFFR, and DFFR rates were calculated using the Kaplan– Meier method and compared using a log rank test. Univariate and multivariate analyses were performed using Cox’s regression. For multivariate analysis, statistically significant factors proven using univariate analysis were included. To reduce bias arising from the retrospective nature of this study, propensity score matching (PSM) was used with the nearest-neighbor matching method. The dose–response relationship was analyzed using logistic regression. All analyses were performed using SPSS version 23.0 (IBM Inc., Armonk, NY, USA) and R version 2.12.1. (R Foundation for Statistical Computing, Vienna, Austria). Results Patients and tumor characteristics Patient and tumor characteristics such as age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, pathology, subsite, T stage, N stage, tumor size, resectability, post-CCRT surgery and concurrent chemotherapy regimen were well balanced between the 2 groups (all p > 0.05) (Table 1). More patients received maintenance chemotherapy in the 61 Gy group (69.7%) than in the <61 Gy group (55.7%). Initial CA 19-9 was significantly higher in the <61 Gy group. All patients in the 61 Gy group received IMRT. Overall survival and progression-free survival
Chemotherapy Chemotherapy regimens were chosen by the physician and were as follows: (1) 1000 mg/m2 gemcitabine weekly (days 1, 8, and 15) followed by a 1-week rest period; (2) 75 mg/m2 cisplatin on day 1 of each 28-day cycle combined with weekly 1000 mg/ m2 gemcitabine; (3) 500 mg/m2 fluorouracil weekly; (4) 850 mg/ m2 capecitabine twice a day; (5) 40 mg/m2 titanium silicate-1 twice a day from days 1 to 14 and from days 22 to 35; and (6) 0.5 g tegafur/uracil 3 times a day. The primary aim was to administer full dose chemotherapy. Patients without progression after the first response evaluation and those who underwent surgery generally received maintenance chemotherapy. Response assessment Treatment response was evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST). Follow-up evaluation was performed at 1 and 3 months post-CCRT, and routinely thereafter. Local failure was defined as progression of the primary tumor or recurrence at the primary tumor bed, generally suggesting infield failure. Regional failure was defined as progression or recur-
The median follow-up was 19.3 months (range, 4.8– 128.5 months). The median OS was 15.7 months for all patients. For the 61 Gy and <61 Gy groups, the median OS was 21.9 and 14.8 months, and the 1-year OS rates were 74.7% and 60.6%, respectively (p = 0.001) (Fig. 1A). In multivariate analysis, factors such as age >64 years (hazard ratio [HR] 1.23, 95% confidence interval [CI] 1.01–1.51; p = 0.040), male sex (HR 1.28, CI 1.05– 1.58; p = 0.017), initial CA 19-9 >304.5 U/mL (HR 1.31, CI 1.07– 1.60; p = 0.008), and tumor size >3.1 cm (HR 1.24, CI 1.00–1.55; p = 0.049) showed a significantly adverse effect on OS. Favorable factors were borderline resectable tumors (HR 0.70, CI 0.52–0.93; p = 0.015) and TD 61 Gy (HR 0.68, CI 0.49–0.94; p = 0.019) (Table 2). The median OS was also evaluated in different subgroups. In unresectable disease, the median OS was 21.4 months and 13.6 months for the 61 Gy and <61 Gy groups, respectively (p < 0.001), while it was 23.2 months and 18.3 months, respectively, in borderline resectable disease (p = 0.013). Patients who underwent post-CCRT surgery showed a median OS of 30.0 months compared to that of 13.7 months in patients who did not undergo surgery (p < 0.001). For post-CCRT surgery patients, median OS was
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
3
S.Y. Chung et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx Table 1 Patient and tumor characteristics. Total N = 497 n Age, median (range) 64 >64 Sex Female Male ECOG performance status 0 1 2 Pathology Adenoca Adenosquamous Poorly differentiated Failed to confirm Subsite Head Other T stage 1 2 3 4 N stage 0 1 Tumor size, median (range) 3.1 cm >3.1 cm Resectability Unresectable Borderline Post-CCRT surgery No Yes Concurrent chemotherapy Gem-based Other Maintenance chemotherapy No Yes Initial CA 19–9, median (range) 304.5 U/mL >304.5 U/mL RT technique 3DCRT IMRT Total dose in EQD2, median (Gy, range)
61 Gy
<61 Gy N = 345 %
n
64 (35–88) 272 225
p
N = 152 %
n
%
54.7 45.3
64 (35–87) 188 157
54.5 45.5
64 (39–88) 84 68
55.3 44.7
0.874
202 295
40.6 59.4
135 210
39.1 60.7
67 85
44.1 55.9
0.301
131 358 8
26.4 72 1.6
100 239 6
29 69.3 1.7
31 119 2
20.4 78.3 1.3
0.119
413 5 5 74
83.1 1 1 14.9
284 3 5 53
82.3 0.9 1.4 15.4
129 2 0 21
84.9 1.3 0 13.8
0.512*
345 152
69.4 30.6
239 106
69.3 30.7
106 46
69.7 30.3
0.918
7 33 204 253
1.4 6.6 41 50.9
6 26 143 170
1.7 7.5 41.4 49.3
1 7 61 83
0.7 4.6 40.1 54.6
0.479*
297 200 3.1 (1.2–9.0) 251 246
59.8 40.2
57.7 42.3
0.155
49.3 50.7
98 54 3.00 (1.2–9.0) 81 71
64.5 35.5
50.5 49.5
199 146 3.2 (1.3–9.0) 170 175
53.3 46.7
0.410
378 119
76.1 23.9
271 74
78.6 21.4
107 45
70.4 29.6
0.053*
392 105
78.9 21.1
268 77
77.7 22.3
124 28
81.6 18.4
0.327
251 246
50.5 49.5
180 165
52.2 47.8
71 81
46.7 53.3
0.262
199 40 298 60 304.5 (0.0–20000) 247 49.9 248 50.1
153 44.3 192 55.7 371 (0.0–20000) 161 46.9 182 53.1
46 30.3 106 69.7 169 (0.10–20000) 86 56.6 66 43.4
0.003
281 56.5 216 43.5 49.56 (24.42–64.31)
281 81.4 64 18.6 49.56 (24.42–60.95)
0 0 152 100 61.05 (61.04–64.31)
<0.001
0.048
*
Fisher’s exact test. Abbreviations: ECOG, Eastern Cooperative Oncology Group; CCRT, concurrent chemoradiotherapy; Gem, gemcitabine; RT, radiotherapy; 3DCRT, 3D conformal radiotherapy; IMRT, intensity-modulated radiation therapy; EQD2, equivalent dose in 2 Gy fractions.
44.0 months and 24.0 months for 61 Gy and <61 Gy groups, respectively (p = 0.036). For those who did not receive post-CCRT surgery, median OS was 18.1 months and 12.8 months, respectively (p = 0.001). Although the percentages of patients who underwent post-CCRT surgery did not differ significantly, the pathologic reports were different between the 2 groups. The pathologic complete response rates were 17.9% and 5.2%, and the down-staging rates were 67.9% and 41.6%, in the 61 Gy and <61 Gy groups, respectively. The median PFS was 11.1 months and 8.0 months, and the 1year PFS rates were 46.2% and 30.9% for the 61 Gy and <61 Gy groups, respectively (p < 0.001) (Fig. 1B). When other factors were adjusted, TD 61 Gy (HR 0.69, CI 0.56–0.86; p = 0.001) remained a favorable predictor of PFS. Adverse factors were initial CA 19-9 >304.5 U/mL (HR 1.33, CI 1.10–1.60; p = 0.003) and tumor size
>3.1 cm (HR 1.38, CI 1.14–1.67; p = 0.001) (Supplementary Table 1). Local failure The median LFF period was 26.2 months and 21.2 months, and the 1-year LFFR was 86.9% and 70.9% for the 61 Gy and <61 Gy groups, respectively (p = 0.001) (Fig. 1C). Other chemotherapy regimens besides gemcitabine were poor predictors for LFFR (HR 1.82, CI 1.33–2.50; p < 0.001). TD 61 Gy remained a favorable predictor (HR 0.47, CI 0.28–0.79; p = 0.004) using multivariate analysis (Table 2). As for regional failure, regional failure only as the first site of failure occurred in 6 patients (1.2%), with 3 patients in each group. Overall proportion of regional failure alone as first site of failure and also including those accompanied with local or distant failure was 9.5% (n = 47).
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
4
Dose escalation in pancreatic cancer patients
Fig. 1. Kaplan–Meier estimates of overall survival (A), progression-free survival (B), local failure-free survival (C), and distant failure-free survival (D), according to total dose 61 Gy or <61 Gy.
Distant failure The median DFF period was 16.0 months and 9.9 months, and the 1-year DFFR was 56.4% and 45.8% for the 61 Gy and <61 Gy groups, respectively (p = 0.007) (Fig. 1D). In multivariate analysis, initial CA 19-9 >304.5 U/mL, tumor size >3.1 cm, and subsite other than the pancreas head were adverse predictors of distant metastasis. TD 61 Gy was a positive predictor (Supplementary Table 1).
Propensity score matching analysis Although the percentage of patients who received maintenance chemotherapy was significantly different between the 2 groups, it was excluded from multivariate analysis to avoid leading time bias. Therefore, PSM was performed to elaborate further on the current results. The 2 groups were matched for maintenance chemotherapy and initial CA 19-9, as well as for age, sex, subsite, T stage, N stage, tumor size, resectability, and concurrent chemotherapy regimen. As a result, 152 patients were matched in each group (Supplementary Table 2). After PSM, the 1-year OS rates were 74.7% and 62.4% for the 61 Gy and <61 Gy groups, respectively (p = 0.011) (Fig. 2A). The 1-year PFS rates were 46.2% and 34.6% (p = 0.016), and the 1-year LFFR were 86.9% and 71.9% (p = 0.002) for the 61 Gy and <61 Gy groups, respectively (Figs. 2B and C). The DFFRs were different from previous results, with 1-year DFFRs
of 56.4% and 50.5% for the 61 Gy and <61 Gy groups, respectively (p = 0.205) (Fig. 2D). Dose–response relationship When multivariate analysis was performed for OS, PFS, and LFFR with RT dose as a continuous variable, TD still proved to be a beneficial factor for all OS, PFS, and LFFR (Supplementary Table 3). Thus, the dose–response relationship was additionally analyzed and as shown in Fig. 3A and B, the probability of local recurrence and death decreased as the TD increased. Toxicity For both acute and late toxicities, there were no significant differences between the 2 groups (Table 3). Leukopenia was the most common acute hematologic toxicity in both groups. Grade 4 acute hematologic toxicities were observed; however, there was no acute GI toxicity higher than grade 3 in both groups. Although not shown in Table 3, acute toxicities such as constipation, diarrhea, and epigastric discomfort were also reviewed; no patients had severe toxicity except for 1 patient with grade 3 diarrhea. For late toxicity, the rate of severe GI bleeding was no higher in the 61 Gy group than in the <61 Gy group. At the time of diagnosis, the rates of bowel invasion did not differ between the 2 groups (p = 0.450). Bleeding due to cancer invasion was excluded. Severe
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
<0.001 0.562
0.004
1.33–2.50 0.73–1.79
0.28–0.79
1.82 1.14
0.47
0.04–1.90 0.51–1.83 0.94–1.77 0.78–1.46 0.89–1.76 1.30–2.42 0.48–0.90 0.83–1.54 0.86–1.58 0.36–0.77 0.76–1.37 1.07–1.60 1.00–1.55 0.49–0.94 1.02 1.31 1.24 0.68
0.873 0.008 0.049 0.019
0.52–0.93 0.70
0.015
0.15–1.12 0.78–1.79 0.74–1.20 0.41 1.18 0.94
0.234 0.082 0.430 0.625
0.26 0.97 1.29 1.06 1.25 1.77 0.66 1.13 1.16 0.53
0.663–1.29 0.00–1.06 0.80–1.54 0.92 0.00 1.11 0.86–1.35 1.24–5.27 0.94–1.43
0.13–0.93 0.67–1.46 0.66–1.00 0.81–1.21 0.48–0.80 0.84–1.26 0.67–0.995 1.11–1.64 1.16–1.73 0.53–0.85
1.08 2.56 1.16
0.34 0.99 0.81 0.99 0.62 1.03 0.81 1.35 1.42 0.67
Abbreviations: ECOG, Eastern Cooperative Oncology Group; Gem, gemcitabine; RT, radiotherapy; 3DCRT, 3D conformal radiotherapy; IMRT, intensity-modulated radiation therapy; EQD2, equivalent dose in 2 Gy fractions.
p 95% CI 0.78–1.45 0.87–1.63 1.07 1.19 0.040 0.017 1.01–1.51 1.05–1.58 1.23 1.28
0.021 0.006 0.077 0.513 0.011 0.175 0.026 0.035 0.947 0.052 0.897 <0.001 0.783 0.045 0.003 0.001 <0.001 1.04–1.54 1.09–1.63
HR p 95% CI p 95% CI
1.26 1.33
Age (64 vs. >64) Sex (Female vs. Male) ECOG performance status ECOG 0 vs. ECOG 1 ECOG 0 vs. ECOG 2 Subsite (Head vs. Other) T stage T4 vs.T1 T4 vs. T2 T4 vs. T3 N stage (N0 vs. N1) Resectability (Unresectable vs. Borderline) Concurrent Chemotherapy (Gem based vs. Other) RT modality (3DCRT vs. IMRT) Initial CA19-9 (304.5 U/mL vs. >304.5 U/mL) Tumor size (3.1 cm vs. >3.1 cm) Total dose in EQD2 (<61 Gy vs. 61 Gy)
HR
Table 2 Univariate and multivariate Cox regression models for overall survival and local failure-free rate.
0.686 0.271 0.894 0.638 0.951 0.552 0.186 0.186 0.923 0.117 0.697 0.196 <0.001 0.010 0.425 0.336 0.001
HR
UVA
HR
UVA
95% CI
Local failure-free rate
MVA Overall Survival
p
MVA
S.Y. Chung et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx
5
GI bleeding occurred in 19 patients (5.5%) in the <61 Gy group and 7 patients (4.6%) in the 61 Gy group. Grade 5 toxicity occurred in 2 patients (1.3%) in the 61 Gy group.
Discussion Currently, borderline pancreatic cancer patients are usually recommended for neoadjuvant CCRT and unresectable pancreatic cancer patients are recommended for either chemotherapy, induction chemotherapy with RT, or definitive CCRT. In our institution, CCRT with full dose chemotherapy is performed to optimize RT and chemotherapy for local and distant control. Although gemcitabine is considered a difficult factor for dose escalation due to increased toxicity rates, around half of the patients in this study received gemcitabine, and dose escalation was possible without any increased severe toxicity [8]. There have been many studies reporting the effectiveness of RT for local control and advocating its effectiveness of dose escalation. A study of unresectable pancreatic cancer patients treated with gemcitabine and concurrent RT with a median of 36 Gy in 15 fractions showed a median OS of 11.2 months [9]. In comparison, a phase I/II trial of dose escalation from 50 to 60 Gy in 25 fractions from the same institution reported a median OS of 14.8 months [10]. Another report of both unresectable and borderline resectable cases with induction chemotherapy followed by gemcitabine and RT of 55 Gy in 25 fractions showed a median OS of 23.1 months [11]. Thus, compared to RT at 36 Gy, higher RT doses have shown better treatment outcomes. However, compared to chemotherapy alone, there have been conflicting results regarding OS in randomized trials such as ECOG 4201 and LAP07, which used 3DCRT with RT dose schemes of 50.4 Gy in 28 fractions and 54 Gy in 30 fractions, respectively [4,5]. Nowadays, RT dose can further be escalated with IMRT. Recently, MD Anderson Cancer Center (MDACC) showed better outcomes for those receiving biologically effective dose (BED) >70 Gy in a study of 200 unresectable pancreatic cancer patients. The median OS was 17.8 months versus 15.0 months for the BED > 70 Gy and 70 Gy groups, respectively [12]. In addition, a Japanese study reported better histopathological effects for preoperative CCRT patients receiving 60 Gy than those receiving 50 Gy [13]. Similarly, our study showed better treatment outcomes in the 61 Gy group, with a median OS of 21.4 months for unresectable disease and 23.2 months for borderline resectable disease. Apart from dose-escalated CCRT, stereotactic body radiotherapy (SBRT) has emerged as a feasible option for locally advanced pancreatic cancer patients. Based on radiobiological advantage as well as shorter treatment time period, its efficacy has been reported [14]. However SBRT needs to be applied to highly selected patients due to the high risk of critical GI toxicity. Currently only retrospective series and some phase I-II studies are available [15–18]. While SBRT seems to be an attractive approach, further studies are necessary to show its effectiveness and toxicity. For distant metastasis, although dose escalation seemed to have a positive effect on the DFFR, it did not remain a significant factor when PSM was performed. Nowadays, the idea of dividing pancreatic cancer into locally destructive or metastatic groups according to the status of DPC4 is gaining much attention [19]. Thus, one hypothesis is that the locally destructive group gained local control or delayed progression through dose escalation, which resulted in improved survival [20]. But dose escalation could have been ineffective for distant metastasis in the metastatic group, and therefore showed no significant results. However, as shown in Fig. 2D, after approximately 6 months, the DFFR was higher in the 61 Gy group. Distant metastasis may
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
6
Dose escalation in pancreatic cancer patients
Fig. 2. Kaplan–Meier estimates of overall survival (A), progression-free survival (B), local failure-free survival (C), distant failure-free survival (D), according to total dose 61 Gy or <61 Gy after propensity score matching.
Fig. 3. Dose–response relationship for local recurrence (A) and death (B).
have occurred within 6 months in the metastatic group, and further distant metastasis may have been prevented in the locally destructive group. Dose escalation may have led to controlled or delayed local disease, thus preventing further progression or allowing patients to receive maintenance chemotherapy. As shown in Table 1, more patients in the 61 Gy group received maintenance chemotherapy. However, these hypotheses must be tested
in further studies since the status of DPC4 was unknown in this study. Acute and late toxicity rates did not differ between the 2 groups and the rates were acceptable. However, 2 grade 5 severe bleeding events occurred in the 61 Gy group. In these cases, it was hard to identify the exact bleeding location, and thus difficult to conclude that the events were radiation-induced. The primary tumor was in
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
7
S.Y. Chung et al. / Radiotherapy and Oncology xxx (2017) xxx–xxx Table 3 Acute and late toxicities. Total N = 497
Acute toxicity Leukopenia Grade 0–2 Grade 3–4 Anemia Grade 0–2 Grade 3–4 Thrombocytopenia Grade 0–2 Grade 3–4 Nausea Grade 0–2 Grade 3 Vomiting Grade 0–2 Grade 3 Anorexia Grade 0–2 Grade 3 Fatigue Grade 0–2 Grade 3 Late toxicity GI bleeding Grade 0–2 Grade 3–5
61 Gy N = 152
<61 Gy N = 345
p
n
%
n
%
n
%
391 106
78.7 21.3
267 78
77.4 22.6
124 28
81.6 18.4
476 21
95.8 4.2
331 14
95.9 4.1
145 7
95.4 4.6
460 37
92.6 7.4
316 29
91.6 8.4
144 8
94.7 5.3
491 6
98.8 1.2
341 4
98.8 1.2
150 2
98.7 1.3
493 4
99.2 0.8
342 3
99.1 0.9
151 1
99.3 0.7
492 5
99.0 1.0
340 5
98.6 1.4
152 0
100.0 0.0
493 4
99.2 0.8
341 4
98.8 1.2
152 0
100.0 0.0
471 26
94.8 5.2
326 19
94.5 5.5
145 7
95.4 4.6
0.294
0.780
0.219
1.000*
1.000*
0.330*
0.318*
0.677
*
Fisher’s exact test. Abbreviations: GI, gastrointestinal. Toxicity graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 4.03).
a progressive status prior to the events in both patients, and the events occurred 2 and 10 months post-RT, respectively. In a recent study from the MDACC, acute severe toxicity was acceptable in dose-escalated patients, which was concordant with our study. However, only 1 episode of treatment-related GI bleeding occurred in a total of 200 patients, compared to 26 events in 497 patients in our study. This may be due to the retrospective toxicity assessment or the continuous follow-up in our institution resulting from geographic accessibility. Furthermore, only patients with tumors more than 1 cm from the closest GI mucosa were selected for dose escalation at the MDACC [12]. There are several limitations of this study owing to its retrospective nature. Firstly, heterogeneous chemotherapy regimens were used. Secondly, there may have been late toxicity events in the patients lost to follow-up. Finally, we were unable to evaluate molecular markers related to the DPC4 gene, since fine needle aspiration was performed for pathologic diagnosis in most patients. A prospective trial, Radiation Therapy Oncology Group/NRG Oncology 1201, which aimed to investigate both dose escalation and DPC4 genetic status, was started in 2013, but closed due to poor accrual. But another trial, Systemic Therapy and Chemoradiation in Advanced Localized Pancreatic Cancer–2 (SCALOP-2), which will evaluate the role of RT dose escalation and addition of nelfinavir to CCRT is currently recruiting patients. This study also has several strengths. Reports of dose escalation in pancreatic cancer are rare, and to the best of our knowledge, this is the study with the largest number of patients. Furthermore, all patients were treated with CCRT initially, thereby reducing the selection bias that is possible in other studies of patients receiving induction chemotherapy. In summary, our data suggest that dose escalation is feasible with IMRT in locally advanced pancreatic cancer patients. Patients who received higher RT dose showed not only improved PFS and LFFR, but also improved OS, without an increase in severe toxicity.
Therefore, dose-escalated CCRT can be a favorable treatment option in locally advanced pancreatic cancer patients. Conflict of interest statement The authors have no conflicts of interest to declare. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.radonc.2017.04. 010. References [1] Kamisawa T, Wood LD, Itoi T, Takaori K. Pancreatic cancer. Lancet 2016;388:73–85. [2] Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913–21. [3] Gillen S, Schuster T, Meyer Zum Buschenfelde C, Friess H, Kleeff J. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med 2010;7: e1000267. [4] Loehrer Sr PJ, Feng Y, Cardenes H, et al. Gemcitabine alone versus gemcitabine plus radiotherapy in patients with locally advanced pancreatic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol 2011;29:4105–12. [5] Hammel P, Huguet F, van Laethem JL, et al. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: the LAP07 randomized clinical trial. JAMA 2016;315:1844–53. [6] Bittner MI, Grosu AL, Brunner TB. Comparison of toxicity after IMRT and 3Dconformal radiotherapy for patients with pancreatic cancer – a systematic review. Radiother Oncol 2015;114:117–21. [7] Chang JS, Wang ML, Koom WS, et al. High-dose helical tomotherapy with concurrent full-dose chemotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2012;83:1448–54.
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010
8
Dose escalation in pancreatic cancer patients
[8] Mukherjee S, Hurt CN, Bridgewater J, et al. Gemcitabine-based or capecitabinebased chemoradiotherapy for locally advanced pancreatic cancer (SCALOP): a multicentre, randomised, phase 2 trial. Lancet Oncol 2013;14:317–26. [9] Murphy JD, Adusumilli S, Griffith KA, et al. Full-dose gemcitabine and concurrent radiotherapy for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2007;68:801–8. [10] Ben-Josef E, Schipper M, Francis IR, et al. A phase I/II trial of intensity modulated radiation (IMRT) dose escalation with concurrent fixed-dose rate gemcitabine (FDR-G) in patients with unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2012;84:1166–71. [11] Badiyan SN, Olsen JR, Lee AY, et al. Induction chemotherapy followed by concurrent full-dose gemcitabine and intensity-modulated radiation therapy for borderline resectable and locally advanced pancreatic adenocarcinoma. Am J Clin Oncol 2016;39:1–7. [12] Krishnan S, Chadha AS, Suh Y, et al. Focal radiation therapy dose escalation improves overall survival in locally advanced pancreatic cancer patients receiving induction chemotherapy and consolidative chemoradiation. Int J Radiat Oncol Biol Phys 2016;94:755–65. [13] Hirata T, Teshima T, Nishiyama K, et al. Histopathological effects of preoperative chemoradiotherapy for pancreatic cancer: an analysis for the impact of radiation and gemcitabine doses. Radiother Oncol 2015;114:122–7.
[14] Wei Q, Yu W, Rosati LM, Herman JM. Advances of stereotactic body radiotherapy in pancreatic cancer. Chin J Cancer Res 2015;27:349–57. [15] Schellenberg D, Kim J, Christman-Skieller C, et al. Single-fraction stereotactic body radiation therapy and sequential gemcitabine for the treatment of locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2011;81:181–8. [16] Hoyer M, Roed H, Sengelov L, et al. Phase-II study on stereotactic radiotherapy of locally advanced pancreatic carcinoma. Radiother Oncol 2005;76:48–53. [17] Mahadevan A, Jain S, Goldstein M, et al. Stereotactic body radiotherapy and gemcitabine for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2010;78:735–42. [18] Chuong MD, Springett GM, Freilich JM, et al. Stereotactic body radiation therapy for locally advanced and borderline resectable pancreatic cancer is effective and well tolerated. Int J Radiat Oncol Biol Phys 2013;86:516–22. [19] Iacobuzio-Donahue CA, Fu B, Yachida S, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol 2009;27:1806–13. [20] Gutt R, Liauw SL, Weichselbaum RR. The role of radiotherapy in locally advanced pancreatic carcinoma. Nat Rev Gastroenterol Hepatol 2010;7:437–47.
Please cite this article in press as: Chung SY et al. Dose escalation in locally advanced pancreatic cancer patients receiving chemoradiotherapy. Radiother Oncol (2017), http://dx.doi.org/10.1016/j.radonc.2017.04.010