Review
Stereotactic body radiation therapy in pancreatic cancer: the new frontier Expert Review of Anticancer Therapy 2014.14:1461-1475. Downloaded from informahealthcare.com by Emory University on 04/19/15. For personal use only.
Expert Rev. Anticancer Ther. 14(12), 1461–1475 (2014)
Shalini Moningi1, Ariel E Marciscano1, Lauren M Rosati1, Sook Kien Ng1, Roland Teboh Forbang1, Juan Jackson1, Daniel T Chang2, Albert C Koong2 and Joseph M Herman*1 1
Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 401 N. Broadway, Weinberg Suite 1440, Baltimore, MD 21231, USA 2 Department of Radiation Oncology, Stanford University, Stanford, CA, USA *Author for correspondence: Tel.: +1 410 955 6980 Fax: +1 410 502 1419 [email protected]
informahealthcare.com
Pancreatic cancer (PCA) remains a disease with a poor prognosis. The majority of PCA patients are unable to undergo surgical resection, which is the only potentially curative option at this time. A combination of chemotherapy and chemoradiation (CRT) are standard options for patients with locally advanced, unresectable disease, however, local control and patient outcomes remains poor. Stereotactic body radiation therapy (SBRT) is an emerging treatment option for PCA. SBRT delivers potentially ablative doses to the pancreatic tumor plus a small margin over a short period of time. Early studies with single-fraction SBRT demonstrated excellent tumor control with high rates of toxicity. The implementation of SBRT (3–5 doses) has demonstrated promising outcomes with favorable tumor control and toxicity rates. Herein we discuss the evolving role of SBRT in PCA treatment. KEYWORDS: locally advanced • pancreatic cancer • radiation oncology • radiation therapy • stereotactic body radiation therapy
Pancreatic cancer (PCA) is one of the most lethal cancers in the USA, contributing to more than 37,500 deaths in 2013 [1]. In developed countries, it is the fourth leading cause of cancer death in both men and women [2]. Despite aggressive combined modality treatment, 5-year survival remains poor at less than 5% [1,3]. PCA can manifest as aggressive local and/or systemic disease; therefore, local and systemic therapies should be considered. However, the optimal role and sequencing of these therapies in the management of PCA remains unclear. In 2009, a study by Iacobuzio-Donahue et al. reported that up to 30% of patients with PCA died from isolated local progression of disease [4]. This study importantly highlighted that although the majority of patients with PCA end up with metastatic disease, a significant proportion of patients (~30%) die as a result of isolated local tumor progression. This finding supports the role of local radiation therapy (RT) in select patients. Along with efforts to advance local therapy, there has also been progress with regard to systemic therapy. Recent studies have demonstrated that aggressive regimens such as FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and
10.1586/14737140.2014.952286
oxaliplatin; FFX) or gemcitabine and nabpaclitaxel improve survival when compared with gemcitabine alone [5,6]. As advances in systemic therapy continue to improve patient outcomes, the occurrence of morbidity and mortality from local progression of disease will likely increase. History of RT & the evolution of stereotactic body radiation therapy
Chemoradiation (CRT) has played a role in the management of patients with PCA for the past four decades, particularly among patients with borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC). In LAPC, the role of standard CRT remains unclear due to conflicting results from previous clinical trials. Although three trials, the Gastrointestinal Tumor Study Group 9283, the Eastern Cooperative Oncology Group 4201 and the Groupe Coope´rateur Multidisciplinaire en Oncologie trials, confirmed an increase in overall survival (OS) with CRT compared with chemotherapy alone, there was also a substantial increase in toxicity in the CRT arms of the first two studies [7,8]. In contrast, patients undergoing CRT in the Fe´de´ration Francophone de Cance´rologie Digestive and Socie´te´ Francophone de Radiothe´rapie Oncologique study
2014 Informa UK Ltd
ISSN 1473-7140
1461
Expert Review of Anticancer Therapy 2014.14:1461-1475. Downloaded from informahealthcare.com by Emory University on 04/19/15. For personal use only.
Review
Moningi, Marciscano, Rosati et al.
reported inferior OS when compared with chemotherapy alone [9]. In an attempt to settle the controversy regarding the role of standard CRT for LAPC patients, the Phase III Groupe Coope´rateur Multidisciplinaire en Oncologie LAP 07 study sought to evaluate the role of capecitabine-based CRT following induction chemotherapy with gemcitabine or gemcitabine/ erlotinib [10]. The preliminary results from this study suggest no significant improvement in OS with the addition of CRT compared with gemcitabine-based chemotherapy alone. In fact, patients receiving chemotherapy alone had a slightly higher median OS (16.5 months) compared with patients receiving CRT (15.3 months). It is important to stress that only 60% of patients made it to randomization due to progression and/or toxicity. For BRPC patients, CRT has shown benefit in the neoadjuvant setting. Those BRPC patients who undergo surgery have been shown to have high rates of R0 (margin-negative) resection and OS [11–15]. A review of the literature shows that resection rates in patients with BRPC have ranged from 30 to 66%, with rates of R0 resection reaching up to 98% [11–15]. Standard CRT alone has led to moderate improvements in median OS (10–16 months) among all BRPC patients; however, the greatest survival benefit is appreciated among patients who successfully undergo surgical resection following CRT (17–40 months) [11–15]. Also evaluated in the adjuvant setting, standard CRT has demonstrated a survival benefit in PCA patients when administered after resection [16–18]. However, two studies conducted by the European Organization for Research and Treatment of Cancer and the European Study Group for Pancreatic Cancer have questioned the benefit of adjuvant CRT; furthermore, the efficacy of standard CRT appears to be most beneficial in resected patients with close or positive margins [19–21]. However, with improved chemotherapy, local radiation therapy may become more important. Nevertheless, the current treatment options available for patients with PCA are suboptimal and outcomes remain poor. Standard-dose CRT results in suboptimal local control (LC, ~50–60%) and a poor median OS. Therefore, the role of standard-dose CRT has been called into question [22]. Thus, an emphasis has been placed on dose escalation to the primary tumor while limiting dose to adjacent bowel using modern techniques including intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT). Ben-Josef et al. evaluated the role of dose-escalated IMRT among patients with LAPC treated and full-dose gemcitabine to 50–60 Gy [23]. In this study, IMRT had low rates of treatment-related toxicity and achieved a favorable median OS of 14.8 months. However, freedom from local progression (FFLP) at 2 years was 59% [23]. SBRT is an alternative modality capable of delivering higher doses of radiation to the pancreatic tumor while sparing adjacent normal tissues. To date, the majority of SBRT reports have focused on patients with LAPC. Initial reports from the 1462
Stanford group explored a single-fraction SBRT (25 Gy) regimen for LAPC patients. They demonstrated excellent LC rates, but subsequent studies from the same group and Hoyer et al. showed increased rates of late gastrointestinal toxicity [24,25]. In addition, median OS was approximately 10 months, suggesting that treatment-related toxicity from SBRT may have prevented subsequent chemotherapy. Early SBRT studies likely had higher toxicity rates due to lack of fractionation, inadequate motion management (e.g., lack of fiducial placement) and/or lack of specific dose constraints for organs at risk (OARs). In the hopes of addressing these inadequacies, investigators have shifted to delivering SBRT in 2–5 fractions [26–28]. Small, retrospective reports have suggested that these SBRT regimens for unresectable LAPC result in comparable rates of LC to those of single-fraction SBRT, but with a lower incidence of high-grade toxicities [20,28,29]. Given the promising preliminary data, the role of SBRT in PCA patients is undergoing further exploration. Rationale for SBRT in PCA
In comparison to standard RT techniques, SBRT delivers highly conformal RT to smaller target volumes, which permits dose escalation and sparing of normal tissues. These dosimetric advantages have led to improvements in LC and in acute treatment-related toxicity, which may ultimately translate to improved survival outcomes for PCA patients. Although the literature on SBRT to pancreas has reported on outcomes with heterogeneous dose and fractionation schedules, it is hypothesized that the biologically effective dose delivered with SBRT is higher than conventional fractionation schedules. However, the applicability of the linear-quadratic model to hypofractionated regimens delivering ablative doses remains controversial [30–32]. A short course of SBRT (3–5 days) allows for earlier initiation or resumption of systemic therapy in addition to minimizing the delay to surgery. An Italian group reported good short-term pain control and quality of life (QoL) among patients with LAPC who received gemcitabine-based CRT with SBRT (10 Gy 3) [27]. Furthermore, a multi-institutional Phase II study reported stable QoL scores at 4 months and a significant improvement in pancreatic pain was observed 4–6 weeks post-SBRT (6.6 Gy 5) [33]. Given the significant number of PCA patients with poor performance status, further research regarding QoL outcomes and pain control in patients treated with SBRT is very much needed. Although the data are limited, SBRT also appears to be an appealing modality from a health economics perspective. If SBRT is proven to be a clinically safe and effective approach when compared with other modern RT techniques, it has the potential for cost savings for both payers and providers [33–35]. This is presumably due to the fact that despite the associated increase in technology demands, the noninvasive approach and shorter treatment duration with SBRT results in an overall decrease in cost and improved quality-adjusted life-years in comparison with conventional RT. Interestingly, investigation by Murphy et al. of the cost–effectiveness of IMRT and SBRT Expert Rev. Anticancer Ther. 14(12), (2014)
Expert Review of Anticancer Therapy 2014.14:1461-1475. Downloaded from informahealthcare.com by Emory University on 04/19/15. For personal use only.
SBRT for PCA
in LAPC suggests that gemcitabine-based SBRT is a more cost–effective approach in comparison to IMRT and standard RT [35]. Overall, the primary concern with SBRT is related to toxicities associated with ablative doses of RT. Review of the recent literature has demonstrated minimal acute toxicity associated with SBRT such that it appears to be well tolerated in the short term (TABLE 1). However, the majority of the studies are retrospective with limitations with regard to reporting treatment-related side effects. While modern fractionated (3–5 fractions) SBRT regimens with image guidance and motion management are likely to result in lower rates of chronic toxicity, longer follow-up is necessary. Herein we will comprehensively review the past, present and potential future of SBRT in patients with LAPC. Upfront SBRT in LAPC
Nearly 30% of patients with PCA present with locally advanced disease for which surgical resection is not an option [22]. Unresectable disease is defined as tumor encasement of surrounding veins including the superior mesenteric vein and/or the superior mesenteric vein-portal vein confluence; tumor involvement of the superior mesenteric artery (SMA), aorta or the celiac axis and lymph node involvement and/or distant metastases [1,36–38]. There is extensive literature on outcomes with SBRT in the LAPC setting (TABLE 1). This technique was pioneered at Stanford, where a single-fraction SBRT (25 Gy) regimen without chemotherapy was initially explored [25]. Koong et al. reported a 100% LC rate with 33% grade 1–2 toxicity and a median OS of 11 months [25]. A follow-up Phase II study aimed to assess the efficacy of incorporating a 5-week course of 5-fluorouracil with external beam radiation therapy followed by a SBRT boost of 25 Gy to the primary tumor [39]. Although the 1-year LC rate was excellent at 94%, high rates (up to 69%) of grade 1–2 toxicity were reported. To further evaluate toxicities associated with SBRT, Schellenberg et al. reported on 16 LAPC patients who received concurrent gemcitabine and single-fraction 25 Gy SBRT followed by maintenance gemcitabine [40]. Median OS was 11.4 months with 50% of patients alive at 1 year. LC at 1 year was 100% with much lower rates of acute gastrointestinal toxicity compared with earlier reports (13% grade 2, 6% grade 3 and no acute grade 4 toxicity). Following their initial report, Shellenberg et al. reported on an additional 12 LAPC patients in a Phase II trial with an identical setup as their 2008 study [41]. This 2011 study used the Trilogy planning system instead of the originally used Cyberknife planning system. They found similar results, a median OS was 11.8 months with 50% of patients alive at 1 year [41]. FFLP was 94% at 1 year and no patients suffered from acute grade 3 or greater toxicity [41]. As a result of these studies, understanding the dosimetric constraints to surrounding OARs became an area of interest. Furthermore, these studies supported the notion that SBRT may result in less toxicity while maintaining effective rates of LC. informahealthcare.com
Review
SBRT delivered in more than one fraction was first investigated by a group in Denmark, in which patients with LAPC underwent SBRT to 45 Gy delivered in three fractions [24]. Of the 22 patients, only 5% were alive after 1 year and rates of toxicity were unacceptable (TABLE 1). These poor outcomes were likely a result of inaccurate positioning due to the lack of effective motion management techniques and lack of dose constraints for OARs. A group from Beth Israel Deaconess reported on 36 LAPC patients using a similar regimen of 8–12 Gy 3 fractions along with post-SBRT gemcitabine [26]. The 1-year LC rate was 78% with a median OS of 14.3 months. Low rates of toxicity were also reported, with 33% experiencing grade 1–2 toxicity and only 8% experiencing grade 3 toxicity. A follow-up report from the same group incorporated neoadjuvant gemcitabine with the same SBRT fractionation scheme [29]. They observed a 1-year LC rate of 85% in 39 patients with LAPC, with a higher median OS of 20 months. A total of 56% of patients had grade 1 fatigue and approximately 23% of patients suffered from grade 2 nausea. Overall, 9% experienced late grade 3 toxicities such as gastrointestinal bleeding or bowel obstruction. An Italian study evaluated neoadjuvant gemcitabine followed by SBRT (10 Gy 3) among 23 patients with LAPC [27]. A lower 1-year LC rate of 50% and median OS of 10.6 months was reported, along with no grade 2 or greater acute or late gastrointestinal toxicity [27]. Of note, the heterogeneous definition of LC and local tumor control among these studies is inconsistent and, therefore, hinders direct comparative analyses. Additionally, groups from Georgetown, Moffitt Cancer Center and Johns Hopkins Hospital (JHH) have evaluated multifraction regimens. Gurka et al. evaluated 10 LAPC patients who received 25 Gy in five fractions along with pre- and postSBRT gemcitabine [42]. The patients had a 1-year LC rate of 40%, median OS of 12.2 months and 0% rate of acute grade 3 toxicity [42]. Chuong et al. investigated the effect of gemcitabine-based or FOLFIRINOX-based chemotherapy prior to the delivery of SBRT in LAPC and BRPC [28]. The LAPC patients (n = 16) had a median OS of 15 months and none of their patients suffered from acute grade 3 or greater toxicity [28]. However, no LAPC patients in this study experienced tumor regression that allowed them to undergo surgery. As mentioned previously, a recently completed multiinstitutional prospective Phase II study, involving JHH, Memorial Sloan Kettering Cancer Center and Stanford University, evaluated the toxicity and outcomes associated with SBRT (33 Gy in five fractions) in patients with LAPC (TABLE 1) [33]. Pancreatic fiducial markers, motion management techniques and strict dose constraints were required. All plans were centrally reviewed prior to treatment. Median OS was 13.9 months and rates of gastritis, enteritis, ulcer and fistula were minimal with 2 and 11% grade ‡2 acute and late toxicity reported, respectively. Prospective QoL questionnaires demonstrated no decrease in QOL following SBRT and a significant improvement in pain scores. A retrospective series of 74 patients with LAPC received gemcitabine or FOLFIRINOX-based 1463
1464
15 (LA)
16 (LA)
22 (LA)
16 (LA)
36 (LA)
39 (LA)
23 (LA)
71 (LA, LR, RPM, MD)
10 LA
73 (BR, LA)
49 (LA)
Koong et al. (2004)
Koong et al. (2005)
Hoyer et al. (2005)
Schellenberg et al. (2008)
Mahadevan et al. (2010)
Mahadevan et al. (2011)
Polistina et al. (2010)
Rwigema et al. (2011)
Gurka et al. (2013)
Chuong et al. (2013)
Herman et al. (2014)
BED3 (Gy)/ BED10 (Gy) 90.0/ 37.5 233.3/ 87.5 270.0/ 112.5 233.3/87.5
88.0–180.0/ 43.2–79.2 88.0–180.0/ 43.2–79.2 130.0/60.0
432.0/ 163.2
66.7/ 37.5
66.7–216.7/ 37.5–100.0 102.9/ 53.6
SBRT dose/ fraction 15–25 Gy 1 25 Gy 1 (boost) 15 Gy 3 25 Gy 1
8–12 Gy 3 8–12 Gy 3
10 Gy 3
24 Gy 1
5 Gy 5
5–10 Gy 5 6.6 Gy 5
83% FFLP at 1 year
81%
40%
71.7% at 6 months
82% 6 months 50% at 1 year
85%
78%
100%
57%
94%
100%
1-year Local control†
13.9
16.4 BR 15 LA
12.2
10.3
10.6
20
14.3
11.4
5.4
8.3
11
Median survival (months)
2% Acute Grade ‡2 11% Late Grade ‡2
5% Late Grade 3
0% Grade 3
39.5% Grade 1–2 4.2% Grade 3
20% Grade 1 0% Grade 2
41% Grade 1–2 0% Acute Grade 3 9% Late Grade 3
33% Grade 1–2 8% Grade 3
19% Acute 47% Late
79% Grade 2 4.5% Grade 4
69% Grade 1–2 12.5% Grade 3
33% Grade 1–2 0% Grade 3
Toxicity
GEM followed by SBRT
3 cycles of GTX
1 cycle GEM prior to SBRT, 6 cycles GEM total
90% received chemotherapy (various regimens)
6 weeks of induction GEM
2 cycles induction GEM
Post-SBRT GEM
1 cycle of induction GEM + post-SBRT GEM
5-FU with EBRT prior to boost
None
Chemotherapy
[HERMAN JM SUBMITTED]
ET AL.,
[28]
[41]
[20]
[27]
[29]
[26]
[39]
[24]
[38]
[25]
Ref.
† 1-year local control rate unless otherwise specified. EBRT: External beam radiation therapy 5-FU: 5-Fluorouracil; BR: Borderline resectable; FFLP: Freedom from local progression; GEM: Gemcitabine; GTX: Gemcitabine, taxotere, and xeloda.LA: Locally advanced; LR: Locally recurrent; MD: Metastatic disease; RPM: Resected-positive margin; SBRT: Stereotactic body radiation therapy.
Number
Study (year)
Table 1. Recently completed clinical studies evaluating stereotactic body radiation therapy in pancreatic cancer.
Expert Review of Anticancer Therapy 2014.14:1461-1475. Downloaded from informahealthcare.com by Emory University on 04/19/15. For personal use only.
Review Moningi, Marciscano, Rosati et al.
Expert Rev. Anticancer Ther. 14(12), (2014)
SBRT for PCA
chemotherapy followed by 25–33 Gy SBRT in five fractions. The median OS was 18.4 months and 15 (20%) patients underwent successful surgical resection following SBRT [MONINGI ET AL. THE ROLE
OF
STEREOTACTIC BODY RADIATION THERAPY
FOR
PANCREATIC CANCER: A SINGLE-
INSTITUTION EXPERIENCE, (2014), SUBMITTED].
Six (31%) of these patients had a pathological complete response at the time of surgery, the R0 resection rate was 84% and 74% were node negative.
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Neoadjuvant SBRT in BRPC
Neoadjuvant CRT has been shown to increase the rate of margin- and node-negative resections and improve survival for those patients who are able to undergo curative surgical resection. Furthermore, delivery of CRT prior to resection is suggested to allow for histopathological assessment of tumor response to therapy [43], safer surgical resection and improved toleration of therapy [14,44–46] and decreased incidence of pancreatic anastomotic leak due to pancreatic fibrosis [47,48]. Following a pancreaticoduodenectomy (PD or Whipple procedure), patients can experience complications such as delayed gastric emptying and increased lengths of hospital stay [47,48]. These complications can delay or prevent the delivery of adjuvant therapy and result in poor survival. Therefore, when possible, CRT may be preferred in the neoadjuvant setting [1,14,43,45,46]. Unfortunately, most patients experience recurrence within the first 2 years after surgical resection. [49]. It is thought that these high rates of recurrences following resection are due to the existence of micrometastatic disease at the time of resection [1,49]. Therefore, neoadjuvant CRT and chemotherapy may be considered beneficial as micrometastases may be controlled or even eradicated prior to resection [1]. Furthermore, surgical resection alters the anatomy of the tumor bed, which in turn alters blood flow and oxygenation [43]. As a result, the efficacy of adjuvant CRT may be compromised [1,43]. The literature exploring the outcomes of SBRT in the BRPC setting is more limited. The group from Moffitt Cancer Center recently published a report on 30 patients with BRPC receiving neoadjuvant SBRT and concurrent gemcitabine/Taxotere/Xeloda chemotherapy [43]. Twenty-one (70%) patients underwent resection following SBRT, with a 95% marginnegative and a 76% node-negative resection rate at resection [43]. Two (7%) patients had a pathological partial response and 1 (3%) patient had a near complete response. Median OS was 20 months and 1-year progression-free survival was 61%. No high-grade (>2) acute toxicity or late toxicity was reported [43]. Following this initial report, Chuong et al. reported another retrospective analysis of both LAPC and BRPC patients receiving upfront chemotherapy and SBRT (TABLE 1) [28]. Out of the 73 patients in their cohort, 57 patients (78%) were initially diagnosed with BRPC. Thirty-two (44%) patients underwent surgical resection following SBRT, with rates of margin and node-negative resections of 96.9% and 65.6%, respectively. Six of these patients required a vein resection and repair. Additionally, pathological response after definitive SBRT for LAPC patients has been explored. Rajagopalan et al. at the University of Pittsburgh Cancer Institute recently published their informahealthcare.com
Review
Table 2. Pancreas stereotactic body radiation therapy target dose prescription and organs at risk dosimetric constraints. Target
Constraints
Prescription dose
PTV
V33 > 95%
660 cGy 5
PTV80 (adjuvant)
V42.9
Stereotactic body radiation therapy in pancreatic cancer: the new frontier Expert Review of Anticancer Therapy 2014.14:1461-1475. Downloaded from informahealthcare.com by Emory University on 04/19/15. For personal use only.
Expert Rev. Anticancer Ther. 14(12), 1461–1475 (2014)
Shalini Moningi1, Ariel E Marciscano1, Lauren M Rosati1, Sook Kien Ng1, Roland Teboh Forbang1, Juan Jackson1, Daniel T Chang2, Albert C Koong2 and Joseph M Herman*1 1
Department of Radiation Oncology and Molecular Radiation Sciences, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, 401 N. Broadway, Weinberg Suite 1440, Baltimore, MD 21231, USA 2 Department of Radiation Oncology, Stanford University, Stanford, CA, USA *Author for correspondence: Tel.: +1 410 955 6980 Fax: +1 410 502 1419 [email protected]
informahealthcare.com
Pancreatic cancer (PCA) remains a disease with a poor prognosis. The majority of PCA patients are unable to undergo surgical resection, which is the only potentially curative option at this time. A combination of chemotherapy and chemoradiation (CRT) are standard options for patients with locally advanced, unresectable disease, however, local control and patient outcomes remains poor. Stereotactic body radiation therapy (SBRT) is an emerging treatment option for PCA. SBRT delivers potentially ablative doses to the pancreatic tumor plus a small margin over a short period of time. Early studies with single-fraction SBRT demonstrated excellent tumor control with high rates of toxicity. The implementation of SBRT (3–5 doses) has demonstrated promising outcomes with favorable tumor control and toxicity rates. Herein we discuss the evolving role of SBRT in PCA treatment. KEYWORDS: locally advanced • pancreatic cancer • radiation oncology • radiation therapy • stereotactic body radiation therapy
Pancreatic cancer (PCA) is one of the most lethal cancers in the USA, contributing to more than 37,500 deaths in 2013 [1]. In developed countries, it is the fourth leading cause of cancer death in both men and women [2]. Despite aggressive combined modality treatment, 5-year survival remains poor at less than 5% [1,3]. PCA can manifest as aggressive local and/or systemic disease; therefore, local and systemic therapies should be considered. However, the optimal role and sequencing of these therapies in the management of PCA remains unclear. In 2009, a study by Iacobuzio-Donahue et al. reported that up to 30% of patients with PCA died from isolated local progression of disease [4]. This study importantly highlighted that although the majority of patients with PCA end up with metastatic disease, a significant proportion of patients (~30%) die as a result of isolated local tumor progression. This finding supports the role of local radiation therapy (RT) in select patients. Along with efforts to advance local therapy, there has also been progress with regard to systemic therapy. Recent studies have demonstrated that aggressive regimens such as FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and
10.1586/14737140.2014.952286
oxaliplatin; FFX) or gemcitabine and nabpaclitaxel improve survival when compared with gemcitabine alone [5,6]. As advances in systemic therapy continue to improve patient outcomes, the occurrence of morbidity and mortality from local progression of disease will likely increase. History of RT & the evolution of stereotactic body radiation therapy
Chemoradiation (CRT) has played a role in the management of patients with PCA for the past four decades, particularly among patients with borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC). In LAPC, the role of standard CRT remains unclear due to conflicting results from previous clinical trials. Although three trials, the Gastrointestinal Tumor Study Group 9283, the Eastern Cooperative Oncology Group 4201 and the Groupe Coope´rateur Multidisciplinaire en Oncologie trials, confirmed an increase in overall survival (OS) with CRT compared with chemotherapy alone, there was also a substantial increase in toxicity in the CRT arms of the first two studies [7,8]. In contrast, patients undergoing CRT in the Fe´de´ration Francophone de Cance´rologie Digestive and Socie´te´ Francophone de Radiothe´rapie Oncologique study
2014 Informa UK Ltd
ISSN 1473-7140
1461
Expert Review of Anticancer Therapy 2014.14:1461-1475. Downloaded from informahealthcare.com by Emory University on 04/19/15. For personal use only.
Review
Moningi, Marciscano, Rosati et al.
reported inferior OS when compared with chemotherapy alone [9]. In an attempt to settle the controversy regarding the role of standard CRT for LAPC patients, the Phase III Groupe Coope´rateur Multidisciplinaire en Oncologie LAP 07 study sought to evaluate the role of capecitabine-based CRT following induction chemotherapy with gemcitabine or gemcitabine/ erlotinib [10]. The preliminary results from this study suggest no significant improvement in OS with the addition of CRT compared with gemcitabine-based chemotherapy alone. In fact, patients receiving chemotherapy alone had a slightly higher median OS (16.5 months) compared with patients receiving CRT (15.3 months). It is important to stress that only 60% of patients made it to randomization due to progression and/or toxicity. For BRPC patients, CRT has shown benefit in the neoadjuvant setting. Those BRPC patients who undergo surgery have been shown to have high rates of R0 (margin-negative) resection and OS [11–15]. A review of the literature shows that resection rates in patients with BRPC have ranged from 30 to 66%, with rates of R0 resection reaching up to 98% [11–15]. Standard CRT alone has led to moderate improvements in median OS (10–16 months) among all BRPC patients; however, the greatest survival benefit is appreciated among patients who successfully undergo surgical resection following CRT (17–40 months) [11–15]. Also evaluated in the adjuvant setting, standard CRT has demonstrated a survival benefit in PCA patients when administered after resection [16–18]. However, two studies conducted by the European Organization for Research and Treatment of Cancer and the European Study Group for Pancreatic Cancer have questioned the benefit of adjuvant CRT; furthermore, the efficacy of standard CRT appears to be most beneficial in resected patients with close or positive margins [19–21]. However, with improved chemotherapy, local radiation therapy may become more important. Nevertheless, the current treatment options available for patients with PCA are suboptimal and outcomes remain poor. Standard-dose CRT results in suboptimal local control (LC, ~50–60%) and a poor median OS. Therefore, the role of standard-dose CRT has been called into question [22]. Thus, an emphasis has been placed on dose escalation to the primary tumor while limiting dose to adjacent bowel using modern techniques including intensity-modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT). Ben-Josef et al. evaluated the role of dose-escalated IMRT among patients with LAPC treated and full-dose gemcitabine to 50–60 Gy [23]. In this study, IMRT had low rates of treatment-related toxicity and achieved a favorable median OS of 14.8 months. However, freedom from local progression (FFLP) at 2 years was 59% [23]. SBRT is an alternative modality capable of delivering higher doses of radiation to the pancreatic tumor while sparing adjacent normal tissues. To date, the majority of SBRT reports have focused on patients with LAPC. Initial reports from the 1462
Stanford group explored a single-fraction SBRT (25 Gy) regimen for LAPC patients. They demonstrated excellent LC rates, but subsequent studies from the same group and Hoyer et al. showed increased rates of late gastrointestinal toxicity [24,25]. In addition, median OS was approximately 10 months, suggesting that treatment-related toxicity from SBRT may have prevented subsequent chemotherapy. Early SBRT studies likely had higher toxicity rates due to lack of fractionation, inadequate motion management (e.g., lack of fiducial placement) and/or lack of specific dose constraints for organs at risk (OARs). In the hopes of addressing these inadequacies, investigators have shifted to delivering SBRT in 2–5 fractions [26–28]. Small, retrospective reports have suggested that these SBRT regimens for unresectable LAPC result in comparable rates of LC to those of single-fraction SBRT, but with a lower incidence of high-grade toxicities [20,28,29]. Given the promising preliminary data, the role of SBRT in PCA patients is undergoing further exploration. Rationale for SBRT in PCA
In comparison to standard RT techniques, SBRT delivers highly conformal RT to smaller target volumes, which permits dose escalation and sparing of normal tissues. These dosimetric advantages have led to improvements in LC and in acute treatment-related toxicity, which may ultimately translate to improved survival outcomes for PCA patients. Although the literature on SBRT to pancreas has reported on outcomes with heterogeneous dose and fractionation schedules, it is hypothesized that the biologically effective dose delivered with SBRT is higher than conventional fractionation schedules. However, the applicability of the linear-quadratic model to hypofractionated regimens delivering ablative doses remains controversial [30–32]. A short course of SBRT (3–5 days) allows for earlier initiation or resumption of systemic therapy in addition to minimizing the delay to surgery. An Italian group reported good short-term pain control and quality of life (QoL) among patients with LAPC who received gemcitabine-based CRT with SBRT (10 Gy 3) [27]. Furthermore, a multi-institutional Phase II study reported stable QoL scores at 4 months and a significant improvement in pancreatic pain was observed 4–6 weeks post-SBRT (6.6 Gy 5) [33]. Given the significant number of PCA patients with poor performance status, further research regarding QoL outcomes and pain control in patients treated with SBRT is very much needed. Although the data are limited, SBRT also appears to be an appealing modality from a health economics perspective. If SBRT is proven to be a clinically safe and effective approach when compared with other modern RT techniques, it has the potential for cost savings for both payers and providers [33–35]. This is presumably due to the fact that despite the associated increase in technology demands, the noninvasive approach and shorter treatment duration with SBRT results in an overall decrease in cost and improved quality-adjusted life-years in comparison with conventional RT. Interestingly, investigation by Murphy et al. of the cost–effectiveness of IMRT and SBRT Expert Rev. Anticancer Ther. 14(12), (2014)
Expert Review of Anticancer Therapy 2014.14:1461-1475. Downloaded from informahealthcare.com by Emory University on 04/19/15. For personal use only.
SBRT for PCA
in LAPC suggests that gemcitabine-based SBRT is a more cost–effective approach in comparison to IMRT and standard RT [35]. Overall, the primary concern with SBRT is related to toxicities associated with ablative doses of RT. Review of the recent literature has demonstrated minimal acute toxicity associated with SBRT such that it appears to be well tolerated in the short term (TABLE 1). However, the majority of the studies are retrospective with limitations with regard to reporting treatment-related side effects. While modern fractionated (3–5 fractions) SBRT regimens with image guidance and motion management are likely to result in lower rates of chronic toxicity, longer follow-up is necessary. Herein we will comprehensively review the past, present and potential future of SBRT in patients with LAPC. Upfront SBRT in LAPC
Nearly 30% of patients with PCA present with locally advanced disease for which surgical resection is not an option [22]. Unresectable disease is defined as tumor encasement of surrounding veins including the superior mesenteric vein and/or the superior mesenteric vein-portal vein confluence; tumor involvement of the superior mesenteric artery (SMA), aorta or the celiac axis and lymph node involvement and/or distant metastases [1,36–38]. There is extensive literature on outcomes with SBRT in the LAPC setting (TABLE 1). This technique was pioneered at Stanford, where a single-fraction SBRT (25 Gy) regimen without chemotherapy was initially explored [25]. Koong et al. reported a 100% LC rate with 33% grade 1–2 toxicity and a median OS of 11 months [25]. A follow-up Phase II study aimed to assess the efficacy of incorporating a 5-week course of 5-fluorouracil with external beam radiation therapy followed by a SBRT boost of 25 Gy to the primary tumor [39]. Although the 1-year LC rate was excellent at 94%, high rates (up to 69%) of grade 1–2 toxicity were reported. To further evaluate toxicities associated with SBRT, Schellenberg et al. reported on 16 LAPC patients who received concurrent gemcitabine and single-fraction 25 Gy SBRT followed by maintenance gemcitabine [40]. Median OS was 11.4 months with 50% of patients alive at 1 year. LC at 1 year was 100% with much lower rates of acute gastrointestinal toxicity compared with earlier reports (13% grade 2, 6% grade 3 and no acute grade 4 toxicity). Following their initial report, Shellenberg et al. reported on an additional 12 LAPC patients in a Phase II trial with an identical setup as their 2008 study [41]. This 2011 study used the Trilogy planning system instead of the originally used Cyberknife planning system. They found similar results, a median OS was 11.8 months with 50% of patients alive at 1 year [41]. FFLP was 94% at 1 year and no patients suffered from acute grade 3 or greater toxicity [41]. As a result of these studies, understanding the dosimetric constraints to surrounding OARs became an area of interest. Furthermore, these studies supported the notion that SBRT may result in less toxicity while maintaining effective rates of LC. informahealthcare.com
Review
SBRT delivered in more than one fraction was first investigated by a group in Denmark, in which patients with LAPC underwent SBRT to 45 Gy delivered in three fractions [24]. Of the 22 patients, only 5% were alive after 1 year and rates of toxicity were unacceptable (TABLE 1). These poor outcomes were likely a result of inaccurate positioning due to the lack of effective motion management techniques and lack of dose constraints for OARs. A group from Beth Israel Deaconess reported on 36 LAPC patients using a similar regimen of 8–12 Gy 3 fractions along with post-SBRT gemcitabine [26]. The 1-year LC rate was 78% with a median OS of 14.3 months. Low rates of toxicity were also reported, with 33% experiencing grade 1–2 toxicity and only 8% experiencing grade 3 toxicity. A follow-up report from the same group incorporated neoadjuvant gemcitabine with the same SBRT fractionation scheme [29]. They observed a 1-year LC rate of 85% in 39 patients with LAPC, with a higher median OS of 20 months. A total of 56% of patients had grade 1 fatigue and approximately 23% of patients suffered from grade 2 nausea. Overall, 9% experienced late grade 3 toxicities such as gastrointestinal bleeding or bowel obstruction. An Italian study evaluated neoadjuvant gemcitabine followed by SBRT (10 Gy 3) among 23 patients with LAPC [27]. A lower 1-year LC rate of 50% and median OS of 10.6 months was reported, along with no grade 2 or greater acute or late gastrointestinal toxicity [27]. Of note, the heterogeneous definition of LC and local tumor control among these studies is inconsistent and, therefore, hinders direct comparative analyses. Additionally, groups from Georgetown, Moffitt Cancer Center and Johns Hopkins Hospital (JHH) have evaluated multifraction regimens. Gurka et al. evaluated 10 LAPC patients who received 25 Gy in five fractions along with pre- and postSBRT gemcitabine [42]. The patients had a 1-year LC rate of 40%, median OS of 12.2 months and 0% rate of acute grade 3 toxicity [42]. Chuong et al. investigated the effect of gemcitabine-based or FOLFIRINOX-based chemotherapy prior to the delivery of SBRT in LAPC and BRPC [28]. The LAPC patients (n = 16) had a median OS of 15 months and none of their patients suffered from acute grade 3 or greater toxicity [28]. However, no LAPC patients in this study experienced tumor regression that allowed them to undergo surgery. As mentioned previously, a recently completed multiinstitutional prospective Phase II study, involving JHH, Memorial Sloan Kettering Cancer Center and Stanford University, evaluated the toxicity and outcomes associated with SBRT (33 Gy in five fractions) in patients with LAPC (TABLE 1) [33]. Pancreatic fiducial markers, motion management techniques and strict dose constraints were required. All plans were centrally reviewed prior to treatment. Median OS was 13.9 months and rates of gastritis, enteritis, ulcer and fistula were minimal with 2 and 11% grade ‡2 acute and late toxicity reported, respectively. Prospective QoL questionnaires demonstrated no decrease in QOL following SBRT and a significant improvement in pain scores. A retrospective series of 74 patients with LAPC received gemcitabine or FOLFIRINOX-based 1463
1464
15 (LA)
16 (LA)
22 (LA)
16 (LA)
36 (LA)
39 (LA)
23 (LA)
71 (LA, LR, RPM, MD)
10 LA
73 (BR, LA)
49 (LA)
Koong et al. (2004)
Koong et al. (2005)
Hoyer et al. (2005)
Schellenberg et al. (2008)
Mahadevan et al. (2010)
Mahadevan et al. (2011)
Polistina et al. (2010)
Rwigema et al. (2011)
Gurka et al. (2013)
Chuong et al. (2013)
Herman et al. (2014)
BED3 (Gy)/ BED10 (Gy) 90.0/ 37.5 233.3/ 87.5 270.0/ 112.5 233.3/87.5
88.0–180.0/ 43.2–79.2 88.0–180.0/ 43.2–79.2 130.0/60.0
432.0/ 163.2
66.7/ 37.5
66.7–216.7/ 37.5–100.0 102.9/ 53.6
SBRT dose/ fraction 15–25 Gy 1 25 Gy 1 (boost) 15 Gy 3 25 Gy 1
8–12 Gy 3 8–12 Gy 3
10 Gy 3
24 Gy 1
5 Gy 5
5–10 Gy 5 6.6 Gy 5
83% FFLP at 1 year
81%
40%
71.7% at 6 months
82% 6 months 50% at 1 year
85%
78%
100%
57%
94%
100%
1-year Local control†
13.9
16.4 BR 15 LA
12.2
10.3
10.6
20
14.3
11.4
5.4
8.3
11
Median survival (months)
2% Acute Grade ‡2 11% Late Grade ‡2
5% Late Grade 3
0% Grade 3
39.5% Grade 1–2 4.2% Grade 3
20% Grade 1 0% Grade 2
41% Grade 1–2 0% Acute Grade 3 9% Late Grade 3
33% Grade 1–2 8% Grade 3
19% Acute 47% Late
79% Grade 2 4.5% Grade 4
69% Grade 1–2 12.5% Grade 3
33% Grade 1–2 0% Grade 3
Toxicity
GEM followed by SBRT
3 cycles of GTX
1 cycle GEM prior to SBRT, 6 cycles GEM total
90% received chemotherapy (various regimens)
6 weeks of induction GEM
2 cycles induction GEM
Post-SBRT GEM
1 cycle of induction GEM + post-SBRT GEM
5-FU with EBRT prior to boost
None
Chemotherapy
[HERMAN JM SUBMITTED]
ET AL.,
[28]
[41]
[20]
[27]
[29]
[26]
[39]
[24]
[38]
[25]
Ref.
† 1-year local control rate unless otherwise specified. EBRT: External beam radiation therapy 5-FU: 5-Fluorouracil; BR: Borderline resectable; FFLP: Freedom from local progression; GEM: Gemcitabine; GTX: Gemcitabine, taxotere, and xeloda.LA: Locally advanced; LR: Locally recurrent; MD: Metastatic disease; RPM: Resected-positive margin; SBRT: Stereotactic body radiation therapy.
Number
Study (year)
Table 1. Recently completed clinical studies evaluating stereotactic body radiation therapy in pancreatic cancer.
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Review Moningi, Marciscano, Rosati et al.
Expert Rev. Anticancer Ther. 14(12), (2014)
SBRT for PCA
chemotherapy followed by 25–33 Gy SBRT in five fractions. The median OS was 18.4 months and 15 (20%) patients underwent successful surgical resection following SBRT [MONINGI ET AL. THE ROLE
OF
STEREOTACTIC BODY RADIATION THERAPY
FOR
PANCREATIC CANCER: A SINGLE-
INSTITUTION EXPERIENCE, (2014), SUBMITTED].
Six (31%) of these patients had a pathological complete response at the time of surgery, the R0 resection rate was 84% and 74% were node negative.
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Neoadjuvant SBRT in BRPC
Neoadjuvant CRT has been shown to increase the rate of margin- and node-negative resections and improve survival for those patients who are able to undergo curative surgical resection. Furthermore, delivery of CRT prior to resection is suggested to allow for histopathological assessment of tumor response to therapy [43], safer surgical resection and improved toleration of therapy [14,44–46] and decreased incidence of pancreatic anastomotic leak due to pancreatic fibrosis [47,48]. Following a pancreaticoduodenectomy (PD or Whipple procedure), patients can experience complications such as delayed gastric emptying and increased lengths of hospital stay [47,48]. These complications can delay or prevent the delivery of adjuvant therapy and result in poor survival. Therefore, when possible, CRT may be preferred in the neoadjuvant setting [1,14,43,45,46]. Unfortunately, most patients experience recurrence within the first 2 years after surgical resection. [49]. It is thought that these high rates of recurrences following resection are due to the existence of micrometastatic disease at the time of resection [1,49]. Therefore, neoadjuvant CRT and chemotherapy may be considered beneficial as micrometastases may be controlled or even eradicated prior to resection [1]. Furthermore, surgical resection alters the anatomy of the tumor bed, which in turn alters blood flow and oxygenation [43]. As a result, the efficacy of adjuvant CRT may be compromised [1,43]. The literature exploring the outcomes of SBRT in the BRPC setting is more limited. The group from Moffitt Cancer Center recently published a report on 30 patients with BRPC receiving neoadjuvant SBRT and concurrent gemcitabine/Taxotere/Xeloda chemotherapy [43]. Twenty-one (70%) patients underwent resection following SBRT, with a 95% marginnegative and a 76% node-negative resection rate at resection [43]. Two (7%) patients had a pathological partial response and 1 (3%) patient had a near complete response. Median OS was 20 months and 1-year progression-free survival was 61%. No high-grade (>2) acute toxicity or late toxicity was reported [43]. Following this initial report, Chuong et al. reported another retrospective analysis of both LAPC and BRPC patients receiving upfront chemotherapy and SBRT (TABLE 1) [28]. Out of the 73 patients in their cohort, 57 patients (78%) were initially diagnosed with BRPC. Thirty-two (44%) patients underwent surgical resection following SBRT, with rates of margin and node-negative resections of 96.9% and 65.6%, respectively. Six of these patients required a vein resection and repair. Additionally, pathological response after definitive SBRT for LAPC patients has been explored. Rajagopalan et al. at the University of Pittsburgh Cancer Institute recently published their informahealthcare.com
Review
Table 2. Pancreas stereotactic body radiation therapy target dose prescription and organs at risk dosimetric constraints. Target
Constraints
Prescription dose
PTV
V33 > 95%
660 cGy 5
PTV80 (adjuvant)
V42.9
