J Gastrointest Canc DOI 10.1007/s12029-015-9734-z

ORIGINAL RESEARCH

A Meta-analysis of Randomized Clinical Trials of Chemoradiation Therapy in Locally Advanced Pancreatic Cancer Chenwi Ambe 1 & William Fulp 2 & Gregory Springett 1 & Sarah Hoffe 3 & Amit Mahipal 1

# Springer Science+Business Media New York 2015

Abstract Objectives Pancreatic cancer is the fourth most common cause of cancer deaths in the USA. Despite the fact that the radiotherapy in addition to chemotherapy (CT) is frequently employed, the role of chemoradiation therapy (CRT) in the treatment of locally advanced pancreatic cancer (LAPC) remains controversial. We conducted a systemic review and meta-analysis to evaluate the effect of radiation treatment in addition to CT in patients with LAPC. Methods Only randomized controlled trials that compared CRT to CT and reported time to event summary were included in this study. The primary end point was overall survival expressed as hazard ratio (HR). Due to significant heterogeneity, random-effects model statistics were used. Results Five eligible studies were included with a total of 593 patients (CT, N=298; CRT, N=295). Two studies demonstrated statistically significant difference in OS in favor of CRT and the rest of the studies did not demonstrate any significant differences. Meta-analysis demonstrated that there was a nonsignificant trend toward a survival benefit in the CRT arm; HR Electronic supplementary material The online version of this article (doi:10.1007/s12029-015-9734-z) contains supplementary material, which is available to authorized users. * Amit Mahipal [email protected] 1

Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive FOB-2, Tampa, FL 33612, USA

2

Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

3

Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

0.913 (95 % CI 0.595–1.400, p=0.675). No significant differences in overall results were seen with sensitivity analysis. Conclusions The addition of radiation therapy to CT in the treatment of LAPC is associated with a non-significant trend toward survival advantage. Larger randomized controlled trials using modern CT regimens and radiation techniques are needed to further clarify the role of radiation in this setting. Keywords Pancreatic neoplasms . Radiotherapy . Chemotherapy . Meta-analysis

Introduction Pancreatic cancer is the fourth most common cancer worldwide. In the USA, 46,420 patients will be diagnosed and 39, 590 patients will die of the disease in 2014 [20]. Surgical resection with negative margins, when feasible, followed by adjuvant chemotherapy with or without radiation, remains the best treatment option for these patients. Unfortunately, less than 20 % of patients present with surgically resectable disease [17, 25]. The remainder of the patients is unresectable at diagnosis, due to either locally advanced disease (40–50 %) or metastatic disease [27]. Locally advanced pancreatic cancer (LAPC) is defined by involvement of essential surrounding structures, which make surgical extirpation with negative margins impossible or subject to prohibitively high surgical risks. For example, for pancreatic head tumors, according to NCCN guidelines, these are tumors with no evidence of metastatic disease and that have greater than 180° encasement of the superior mesenteric artery, any celiac axis abutment, unreconstructible superior mesenteric vein or portal vein occlusion, aortic or inferior vena cava invasion or encasement, and lymphatic disease beyond the field of resection [1].

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Patients with locally advanced disease have a better prognosis compared to patients with metastatic disease, with a median survival of 6–10 months versus 3–6 months, respectively [20]. This would suggest that these patients should be treated more aggressively than patients with metastatic disease. However, the ideal treatment regimen for these patients is not well defined. Chemotherapy (CT) is the cornerstone of the management of patients with locally advanced disease. A Cochrane review by Yeo et al. showed that chemotherapy improved quality of life and survival compared to the best supportive care. There was a 36 % reduction in the risk of death, with an HR of 0.64; 95 CI 0.42–0.98 [27]. Radiation therapy is frequently administered in conjunction with chemotherapy in patients with LAPC. However, the role of chemoradiation therapy in patients with locally advanced disease remains controversial [8, 12, 13, 16, 18, 19]. A previous meta- analysis comparing chemotherapy to chemoradiotherapy (CRT) did not show any difference in overall survival between the two arms (HR 0.79, 95 % CI 0.32–1.95) [21]. However, this report only used data from two of the four studies identified. Moreover, since the publication of this study, there have been two new trials published. The first one was a randomized controlled trial (Eastern Cooperative Oncology Group (ECOG) E4201), which compared gemcitabine alone versus gemcitabine plus radiotherapy in patients with LAPC. This study demonstrated an increase in survival with the addition of radiation therapy to the chemotherapy regimen [18]. The second study (LAP-07) was a phase III trial of chemoradiotherapy and chemotherapy after 4 months of gemcitabine with or without erlotinib. In contrast to the ECOG study, this study demonstrated that induction CRT did not improve survival compared to induction CT alone [19]. The inconsistent results of the published studies to date have failed to bring clarity to this question. The goal of this study was to do a comprehensive search for published and unpublished data in all randomized control trials comparing chemotherapy alone to combined modality therapy of chemotherapy and radiation therapy for the treatment of LAPC. Data from these studies were then used to perform a meta-analysis to evaluate if the addition of radiation leads to an improvement in overall survival.

Materials and Methods Search Criteria Randomized controlled trials published in the English literature were identified by searching PUBMED, MEDLINE, OLD MEDLINE, ISI Web of Science, Cancer Lit, EMBASE, and the entire contents of databases from 1980 to 2013. Conference proceedings and trial registries were also searched. The references of all selected studies and prior meta-analyses were searched for other potential studies.

Selection Criteria Inclusion criteria: (1) patients with a diagnosis of locally advanced exocrine pancreatic cancer, (2) prospective randomized controlled trials; both blinded and non-blinded studies were included, and (3) treatment with chemotherapy or combined chemotherapy and radiation therapy. Exclusion criteria: (1) trials that were not randomized, (2) patients with metastatic disease or patients who had undergone surgery, (3) trials, which had two separate cancer types and did not report the pancreatic data separately, (4) no available data on survival, and (5) treatment with radiation therapy alone. Using the above criteria, the abstracts of all articles were reviewed. Studies were initially chosen based on their abstract. Selected studies were then reviewed, and if they met all of the inclusion criteria, they were included. End Point The end point of the study was overall survival (OS) defined as time from randomization to death and expressed as the hazard ratios (HRs) and confidence intervals (CIs). Data Extraction Data extraction was performed by two of the authors. Any disparities were resolved by consensus agreement after further discussion. Statistical Analysis Using previously published methods, we calculated the time to event (OS) for each study summarized by the log HR and its variance. We relied on the techniques published by Tierney et al. to estimate HRs for the studies that did not primarily report this information utilizing the survival curves [22]. Statistical analysis was performed using Stata, StataCorp 2013, Stata Statistical Software: Release 13, College Station, TX, USA: StataCorp LP. The degree of combinability of the studies was assessed by estimating the inconsistency (I2) statistic. Due to significant heterogeneity, random-effects model statistics were used. Sensitivity analysis was conducted by comparing the five random-effects models, each obtained by excluding a single study. P value of ≤0.05 was considered significant.

Results We identified a total of six studies that met the inclusion criteria [8, 12, 13, 16, 18, 19]. Five studies with 593 patients were included for the meta-analysis; 298 patients were

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randomized to the chemotherapy arm and 295 patients were randomized to the combined modality arm. The sixth study by Hazel et al. was excluded as this study either did not mention HRs for survival or did not provide survival curves needed for the meta-analysis. The sample size for the five studies varied from 45 to 263 patients with LAP-07 being the largest study. The treatment modalities used in various studies included in this meta-analysis are listed in Table 1. Capecitabine or 5fluorouracil was the most common chemotherapy administered concomitantly with radiation therapy as a radiosensitizer. The schedule and the dose of chemotherapy varied by the trial. In the study by Loehrer et al., gemcitabine was administered concurrently with radiation therapy [18]. For the chemotherapy only group, 5-fluorouracil was utilized in earlier trials and gemcitabine was administered in later trials. This reflects the change in management of patients with unresectable pancreatic cancer. In the trial by Chauffert et al., patients in the chemotherapy group received gemcitabine, while 5-fluorouracil and

cisplatin combination was administered concurrent with radiation therapy during the induction phase of the treatment [8]. Baseline characteristics including demographics, location of tumor, and performance status of the patients enrolled in various studies are mentioned in Table 2. The median age for patients in these trials was between 60 and 70 years. The chemotherapy and chemoradiation therapy groups were similar in the majority of clinical trials. In the trial by Chauffert et al., patients in the chemoradiotherapy group had better performance status (PS) with an ECOG PS of 0 or 1 in 91 % of the patients as compared to 77 % in the chemotherapy alone group (p=0.027). All the trials except the LAP-07 study included in the metaanalysis included the delivery of radiation at the beginning of treatment. The LAP-07 trial had the unique design to select patients who potentially might benefit the most from the addition of radiation to chemotherapy. Patients in this trial received 4 cycles of chemotherapy. Patients who did not have

Table 1 Regimens used in the randomized controlled trials comparing chemoradiation therapy to chemotherapy in patients with locally advanced pancreatic cancer Author (year of publication)

Study size and distribution

Chemotherapy/Chemoradiotherapy used and dose

Hazel et al. [13]

Chemotherapy (n=15) Combined modality (n=15)

Klaassen et al. [16]

Chemotherapy (n=44) Combined modality (N=47)

GISTG [12]

Chemotherapy (n=21)

5-FU 500 mg/m2 weekly and methyl CCNU 100 mg/m2 every 6 weeks 5-FU 500 mg/m2 weekly, radiotherapy 46 Gy over 4.5 weeks, and then CCNU added to 5-FU 5-FU 600 mg/m2 weekly 40 Gy over 4 weeks plus 5-FU 600 mg/m2 on the first 3 days of therapy and then 5-FU 600 mg/m2 starting day of completion of radiation 5-FU 600 mg/m2 on days 1, 8, 29, and 36; streptozocin 1 g/m2 every 8 weeks; and mitomycin 10 mg/m2 8 weeks Rad 5400 rad (1.8 Gy×5 days every week for 6 weeks and 5-FU 350 mg/m2 iv daily on first 3 days and last 3 days of radiotherapy. SMF: begin on day 64 (after combine modality) 5-FU 600 mg/m2 on days 1,8, 29, and 36; streptozocin 1 g/m2 every 8 weeks; and mitomycin 5 mg/m2 first dose (day 64) then 10 mg/m2 day 120 and every 8 weeks Gem 1000 mg/m2 weekly for 7 weeks and then 1000 mg/m2 3 weeks every 4 weeks 60 Gy over 6 weeks, 5 days per week concomitant 5-FU 300 mg/m2/day days 1–5 each week during radiation and cisplatin 20 mg/m2 day from days 1–5 only during weeks 1 and 5 Gem 1000 mg/m2 weekly for 6 weeks 1 week off then 1000 mg/m2 weekly for 3 weeks 50.4 Gy in 28 fractions over 5.5 weeks with Gem 600 mg/m2 beginning the first day of radiation and then weekly while getting radiation, followed by Gem 1000 mg/m2 weekly 3 weeks on and 1 week off × 5 cycles Gem 1000 mg/m2 weekly for 7 weeks and then 1000 mg/m2 3 weeks every 4 weeks with or without erlotinib 150 mg/day for a total of 6 months Gem 1000 mg/m2 weekly for 7 weeks and then 1000 mg/m2 3 weeks every 4 weeks with or without erlotinib 150 mg/day for a total of 4 months followed by concomitant radiation 54 Gy and capecitabine 1600 mg/ m2/day for 2 months

Combined modality (N=22)

Chauffert et al. [8]

Chemotherapy (N=60) Combined modality (N=59)

Loehrer et al. [18]

Chemo (n=37) Combined modality (n=34)

LAP-07 (2013)

Chemotherapy (n=136)

Combined modality (N=133)

Gem gemcitabine, 5-FU 5-fluorouracil

J Gastrointest Canc Table 2 Baseline characteristics of the patients enrolled in the clinical trial included in the metaanalyses

Clinical trials

Klaassen et al. [16] GISTG [12] Chauffert et al. [8] Loehrer et al. [18] LAP-07 (2013)

CRT CT CRT CT CRT CT CRT CT CRT CT

Median age, years

Sex, M (%)

Head (%)

Body/Tail (%)

PS 0/1 (%)

NR (>60, 31 %) NR (>60, 25 %) 61 60 60 62 66 69 63 63

47 70 64 62 52 58 56 49 52 51

NR

NR

86 86 78 67 59 68 71 65

14 14 22 33 26 13 28 34

74 84 91 86 91 77 100 100 92 92

CRT chemoradiation therapy, CT chemotherapy, NR not reported

progression on chemotherapy were then randomized to receive combined chemotherapy and radiation therapy or chemotherapy alone. One study demonstrated statistically significant improvement in survival with addition of radiation therapy. One study favored chemoradiation therapy but did not achieve statistical significance due to a relatively small number of patients. No differences in the two arms were reported in the two studies. Chauffert et al. reported significantly better survival in the chemotherapy arm [8]. This could be secondary to use of gemcitabine in the chemotherapy arm only and 5fluorouracil and cisplatin combination in the chemoradiation group. Random-effects model was used for meta-analyses, as there was significant heterogeneity between the studies (I2, p value=0.001). Our meta-analysis demonstrated that there was a non-significant trend toward survival benefit with the addition of radiation to chemotherapy with an HR of 0.913 (95 % CI 0.595–1.400, p=0.675) (Fig. 1). Sensitivity analyses were performed to explore the effect of particular study design or other factors on the aggregate results. After reanalyzing the above studies by removing one Fig. 1 Meta-analysis of the clinical trials comparing chemotherapy to chemoradiation therapy. CT chemotherapy, CRT chemoradiation therapy

study at a time from the meta-analysis, the results were found to be consistent. No significant differences in the results of our meta-analysis were observed (Fig. 2). Funnel plot did not suggest any evidence of publication bias (Fig. 3). As expected, grade 3–4 toxicities were consistently higher in patients in the combined modality arm (Table 3). The data on long-term toxicities are lacking in these studies. Loehrer et al. reported similar incidence of grade 3 and 4 toxicities (79 vs. 77 %, p value=1.0), but the severity of toxicities was much higher in the CRT arm compared to CT alone (grade 4 and 5 toxicities, 41 vs. 9 %). Due to different methods of reporting toxicities, especially in the earlier trials, comparison across trials is not feasible.

Discussion This paper, to our knowledge, represents the most comprehensive meta-analysis of chemotherapy alone versus chemoradiotherapy for the treatment of LAPC. A previous study only used data from two studies [21]. In the previous meta-analysis,

J Gastrointest Canc Fig. 2 Sensitivity analysis. The results of meta-analysis are provided by removing one study at a time

the study by Chauffert et al. was not included as the updated results were not available to calculate HR. One of the strengths of our meta-analyses is inclusion of only randomized controlled trials, so that the treatment is similar among the two arms except for radiation therapy. There are several limitations to our study as is the case with any meta-analysis. The trials included in this study were conducted at different times over three decades. This undoubtedly resulted in heterogeneity with regard to the study subjects as well as study treatment. It was not until recently that standardized definitions of LAPC were established by various organizations. Further, the definition of resectability of primary tumor is not uniform across various institutions. Recent improvements in diagnostic imaging have resulted in more accurate clinical staging of pancreatic cancer resulting in reclassification of the staging of pancreatic cancer. Apart from the most recent trial (LAP-07), other trials included in this meta-analysis are small or were prematurely closed secondary to lack of funding or accrual. Radiation techniques have improved to the point that they could result in more focused radiation therapy to the tumor tissue with less toxicities. In addition, consensus guidelines have been developed to guide the desired dose and treatment

volume in the setting of LAPC [14]. Although not yet available in the LAPC setting, we can extrapolate from the results published by Abrams et al. that indicated that failure to adhere to protocol quality assurance guidelines was associated with decreased survival [2]. Thus, it is possible that there could also be an effect on the meta-analysis results given the variations in radiation dose, target volume, and technique in the studies included. The chemotherapy type and dosage administered concurrently with radiation therapy were also different in these trials. The standard of chemotherapy has also changed in the last few years in the treatment of LAPC. Gemcitabine was the mainstay of the treatment for unresectable pancreatic cancer for many years after it was demonstrated to be superior to 5-FU [4–7]. Recently, two other different regimens gemcitabine/ nab-paclitaxel combination and FOLFIRINOX (5-FU,

Table 3 analysis

Hematological toxicity

Non-hematological toxicity

CRT, N (%)

CT

CRT

CT

Klaassen et al. [16] GISTG [12] Chauffert et al. [8]

8 (17) 14 (64)

1 (2) 3 (14)

NR 3 (14)a

NR 3 (14)a

Induction phase Maintenance phase Loehrer et al. [18] LAP-07 (2013)c

17 (31) 29 (71) 27 (79)b 4 (3)

15 (27) 12 (27) 27 (77)b 12 (8)

24 (44) 12 (29) 27 (79)b 14 (10)

10 (18) 11 (24) 27 (77)b 7 (5)

a

Includes worst-grade nausea, vomiting, diarrhea, and renal toxicities

b

Includes both hematological and non-hematological toxicities

c

Fig. 3 Bias plot demonstrating distribution of hazard ratio across studies

Adverse events reported in clinical trials included in the meta-

Adverse event data for the LAP-07 study were extracted from the slides presented at the 2013 annual American Society of Clinical Oncology meeting

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irinotecan, and oxaliplatin) have been shown to improve survival compared to gemcitabine alone in patients with metastatic pancreatic cancer [10, 26]. These regimens are frequently incorporated for the treatment of LAPC. Interestingly, a small retrospective study by Faris et al. reported on the use of FOLFIRINOX followed by CRT in patients with LAPC at a single institution. In this series, 23 % (5/22) of the patients were able to undergo an R0 resection after this regimen. Unfortunately, three of these five patients had distant recurrence within 5 months of surgery [11]. Our results suggest a survival benefit of chemoradiation over chemotherapy alone in patients with LAPC but did not reach statistical significance. A specific regimen of chemoradiation cannot be recommended as different types and schedules were utilized in these trials. Clearly, more studies are needed to clarify the role of radiation therapy in this patient population. Unfortunately, it is unlikely that such a study will be performed, especially in the USA, for several reasons. Historically, these trials have been very slow to accrue and have been unable to reach completion. The funding for these trials is usually limited. Moreover, at the majority of academic centers, radiation therapy is administered as part of the standard of care for patients with LAPC despite the paucity of the data. Recently, some patients who in the past may have been classified as locally advanced are now being reclassified as Bborderline resectable^ due to improvements in surgical techniques and perioperative care. At most centers, these patients are now being enrolled in studies of neoadjuvant chemotherapy with or without radiation. While not studying a patient population with locally advanced disease per se, these studies may shed some light on the role of radiation in the primary or neoadjuvant treatment of patients with pancreatic cancer. With advanced radiation capabilities that now include the ability to use endoscopically placed radio-opaque fiducial markers to guide focal high-dose ablative stereotactic body radiation therapy (SBRT) [9, 24], the question now becomes whether these new modalities can increase the therapeutic ratio over conventionally fractionated treatments. If indeed they can, then we will need to optimize patient selection, perhaps by incorporating estimates of the individual patient’s local versus systemic disease risk by virtue of DPC4 gene status [3]. Indeed, the rapid autopsy data from Johns Hopkins suggest that there are two divergent patterns of failure unrelated to initial stage, treatment, or histopathological features [15]. Moreover, radiation sensitivity analyses, such as the one pioneered by Torres Roca et al., may be predictive of identifying which patients have resistant tumors that could be spared unnecessary radiation [23]. The paucity of studies that address the issue of the role of radiation therapy in LAPC clearly shows the need for randomized controlled studies to answer this question. Our results suggest a trend toward improved survival with combination modality but were not statistically significant. Ideally, newer

trials would use modern chemotherapy regimens like FOLFIRINOX or gemcitabine/nab-paclitaxel as the chemotherapy backbone. 5-FU or capecitabine could be used as the radiosensitizing chemotherapy. Patients with rapidly progressing disease should be excluded as they are unlikely to benefit from radiation therapy. One approach, as employed in the LAP-07 trial and practiced in our institution as well, is to administer induction chemotherapy and only deliver radiation therapy if patients have stable disease or better response. Until such trials are performed, the role of radiation therapy in LAPC will remain unclear.

Conflicts of Interests None Funding Source None

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