Pancreatic cancer is the third leading cause of cancer-related death in the United States. Although surgery remains the only curative treatment, chemotherapy and radiation therapy are frequently used. In the adjuvant setting, radiation is usually delivered with chemotherapy to eradicate residual microscopic or macroscopic disease in the resection bed. Neoadjuvant radiation therapy has become more frequently utilized. This article reviews the historical and modern literature regarding radiation therapy in the neoadjuvant and adjuvant settings, focusing on the evolution of radiation therapy techniques and clinical trials in an attempt to identify patients best suited to receiving radiation therapy.
Key points
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The use of radiation therapy after resection of pancreatic cancer is controversial because of conflicting results in several clinical trials.
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Neoadjuvant radiation therapy for resectable or borderline resectable pancreatic cancer is frequently prescribed in combination with chemotherapy to improve margin-negative resection rates.
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Hypofractionated radiation therapy regimens via stereotactic body radiation therapy or particle therapy have become more commonly used in the neoadjuvant setting.
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The genetic profile of pancreatic cancers may enable physicians to select patients more likely to benefit from local therapies such as radiation.
Introduction
Pancreatic cancer is projected to be the third leading cause of cancer death in the United States in 2016 and is expected to be diagnosed in approximately 53,000 individuals. Although treatment methods have advanced in the last 2 decades, outcomes remain poor, with 5-year survival rates of approximately 8% for patients with ductal carcinoma, the most common form of pancreatic cancer. Most diagnoses of pancreatic cancer cannot be traced to a single identifiable cause; however, smoking tobacco, obesity, and diabetes mellitus are associated with increased risk. Germline mutations in genes such as BRCA1/2, CDKN2A, and PRSS1 have been linked to 5% to 10% of new diagnoses.
Screening for pancreatic cancer may be effective in some high-risk populations, but the lack of an effective method of screening for the general population has contributed to poor outcomes. Early-stage pancreatic cancer is frequently asymptomatic, resulting in most diagnoses occurring at advanced stages of disease. Surgery remains the only definitive cure; however, even in patients with resectable disease, outcomes are far from ideal, with 5-year overall survival (OS) rates of approximately 20%. These dismal survival rates are the result of the high risk of both local and distant disease recurrence after surgery. Despite substantial risk of local progression, the high rate of distant metastases has dominated adjuvant therapy discussions and led many institutions to withhold radiation therapy (RT). A recent autopsy study of patients succumbing to pancreatic cancer provided evidence for the importance of primary tumor control in pancreatic cancer. The study found that 30% of patients died of local progression of primary tumors without evidence of metastatic disease, suggesting the importance of RT to provide local control of primary tumors.
Introduction
Pancreatic cancer is projected to be the third leading cause of cancer death in the United States in 2016 and is expected to be diagnosed in approximately 53,000 individuals. Although treatment methods have advanced in the last 2 decades, outcomes remain poor, with 5-year survival rates of approximately 8% for patients with ductal carcinoma, the most common form of pancreatic cancer. Most diagnoses of pancreatic cancer cannot be traced to a single identifiable cause; however, smoking tobacco, obesity, and diabetes mellitus are associated with increased risk. Germline mutations in genes such as BRCA1/2, CDKN2A, and PRSS1 have been linked to 5% to 10% of new diagnoses.
Screening for pancreatic cancer may be effective in some high-risk populations, but the lack of an effective method of screening for the general population has contributed to poor outcomes. Early-stage pancreatic cancer is frequently asymptomatic, resulting in most diagnoses occurring at advanced stages of disease. Surgery remains the only definitive cure; however, even in patients with resectable disease, outcomes are far from ideal, with 5-year overall survival (OS) rates of approximately 20%. These dismal survival rates are the result of the high risk of both local and distant disease recurrence after surgery. Despite substantial risk of local progression, the high rate of distant metastases has dominated adjuvant therapy discussions and led many institutions to withhold radiation therapy (RT). A recent autopsy study of patients succumbing to pancreatic cancer provided evidence for the importance of primary tumor control in pancreatic cancer. The study found that 30% of patients died of local progression of primary tumors without evidence of metastatic disease, suggesting the importance of RT to provide local control of primary tumors.
Staging
Initial work-up and staging in pancreatic cancer centers on the ability to distinguish between those tumors that are likely to be resectable with clear margins (R0) and those that are likely to result in a positive margin (R1 or R2) after surgery alone. To that end, nonmetastatic pancreatic cancers are categorized into 3 groups: resectable pancreatic cancer (RPC; likely to be resected with R0 margins), borderline RPC (BRPC; likely to result in R1 margins), and locally advanced pancreatic cancer (LAPC; likely to result in R2 margins). American Joint Committee on Cancer staging can be used for prognostic information, and primary tumor (T) staging roughly corresponds with tumor resectability: RPC (T1 and T2), BRPC (T3), and LAPC (T4).
One of the challenges in initial diagnosis and staging of pancreatic cancer is detection of the true extent of disease. Computed tomography (CT) pancreas protocols include a high-resolution abdominal CT scan that captures images during 2 phases (portal venous and pancreatic) after administration of intravenous contrast and have become the standard test for local and distant tumor staging. However, nearly one-third of patients with locally advanced disease identified by CT are found to have occult metastases by staging laparoscopy. Although 18 F-fluorodeoxyglucose PET/CT imaging has shown a sensitivity of 87% for detection of metastatic disease in patients with pancreatic cancer, National Comprehensive Cancer Network (NCCN) pancreatic cancer guidelines recommend that PET imaging be used only in high-risk patients to detect extrapancreatic metastases but not in place of high-quality, contrast-enhanced CT. MRI can be used in patients with severe allergies to iodinated contrast or when findings on pancreas protocol CT are unclear. Endoscopic ultrasonography is not recommended for routine staging but can be used to guide fine-needle aspiration biopsy of a pancreatic mass.
Three organizations have produced definitions of resectability for pancreatic cancer to standardize and improve patient selection for surgery: (1) MD Anderson Cancer Center (MDACC) ; (2) a consortium of gastrointestinal (GI) surgery organizations, including the Americas Hepato-Pancreato-Biliary Association, the Society of Surgical Oncology, and the Society for the Surgery of the Alimentary Tract ; and (3) the Intergroup, which is a consortium of 3 cooperative clinical trial groups, namely the Alliance for Clinical Trials in Oncology, Southwest Oncology Group (SWOG), and Eastern Cooperative Oncology Group (ECOG). The most restrictive definition of BRPC tumors was that published by the Intergroup, in which the circumferential degree of contact between tumor and blood vessels is quantified rather than using a definition with more subjective terms such as impingement and abutment. The Intergroup definition of pancreatic tumor resectability has been endorsed by the NCCN and can be found in Table 1 .
| Resectable | Borderline Resectable | Locally Advanced | |
|---|---|---|---|
| SMV/PV | Interface between tumor and vessel measuring <180° of circumference of vessel wall | Interface between tumor and vessel measuring ≥180° of circumference of vessel wall, and/or reconstructable a occlusion | Not reconstructable |
| SMA/hepatic | No contact | Interface between tumor and vessel measuring <180° of circumference of vessel wall | Interface between tumor and vessel measuring ≥180° of circumference of vessel wall |
| CHA | No contact | Reconstructable, a short-segment interface between tumor and vessel of any degree | Not reconstructable, or long-segment interface between tumor and vessel |
| Celiac trunk | No contact | Interface between tumor and vessel measuring <180° of circumference of vessel wall | Interface between tumor and vessel measuring ≥180° of circumference of vessel wall |
a Normal vein or artery proximal and distal to site of suggested tumor-vessel involvement suitable for vascular reconstruction.
Adjuvant radiation therapy for pancreatic cancer
Although adjuvant chemotherapy clearly improves survival after surgery for pancreatic cancer, the role of RT has been contested for many years. This controversy stems from historical randomized trials showing a lack of consensus on benefits compared with adjuvant chemotherapy or surgery alone.
The Gastrointestinal Tumor Study Group 9173 trial was the first to evaluate adjuvant chemoradiation (CRT) in a randomized fashion. A total of 43 patients with resected pancreatic cancer and negative margins were randomized to observation or CRT. RT was delivered to a dose of 40 Gy in 2-Gy fractions in split-course fashion (a 2-week break was planned after 20 Gy). Concurrent and maintenance 5-fluorouracil (5-FU) were given. Despite the trial closing early because of poor accrual, a significant survival benefit was found favoring the CRT arm. Thirty additional patients were later treated on a nonrandomized CRT arm, and their survival was similar to that of subjects in the randomized CRT arm.
Conflicting conclusions were reported from several subsequent European randomized trials. In a randomized trial from the European Organization for Research and Treatment of Cancer (EORTC), patients were assigned to either surgery alone or surgery and adjuvant CRT. The final analysis reported no statistically significant differences in survival between the study arms; however, it is important to recognize that almost 50% of the study population had more favorable periampullary tumors, 20% of patients randomized to receive CRT did not receive adjuvant therapy, and nearly 50% of patients did not receive chemotherapy per protocol. Moreover, had statistical analyses used a 1-sided and not 2-sided log rank test, the higher survival in the CRT arm would have reached statistical significance ( P = .049).
The largest prospective study to evaluate adjuvant therapy for patients with pancreatic cancer is the European Study for Pancreatic Cancer (ESPAC-1) trial, which randomized 254 patients to observation versus chemotherapy or observation versus CRT. A 2 × 2 factorial randomization between observation, chemotherapy, CRT, and CRT with maintenance chemotherapy included 285 additional patients. Chemotherapy alone was associated with improved survival, but CRT was associated with worse survival than no CRT (10% and 20%, respectively; P = .05). These findings have been questioned, with investigators noting that physicians were allowed to choose the randomization; centralized review of RT was lacking, as were standardized RT dose and fields; background adjuvant therapy, consisting of chemotherapy or chemoradiotherapy before the patient entered the trial, was used in 42% of enrolled patients; and a longer interval to treatment initiation was seen in the CRT arm. Despite the many flaws of the EORTC and ESPAC-1 trials, their results were used as justification for a shift away from adjuvant RT toward the use of adjuvant chemotherapy alone at many institutions, especially in Europe.
In contrast with historical trials that used antiquated radiation techniques and suboptimal split-course dosing, recent studies have suggested that modern treatment planning and higher doses of RT may increase the benefit of adjuvant CRT. In a retrospective analysis from the Mayo Clinic and Johns Hopkins University (two very-high-volume centers with experienced pancreatic multidisciplinary teams), results from 1386 patients with resected pancreatic cancer who received adjuvant CRT to 50.4 Gy were compared with surgery alone. Patients who underwent adjuvant CRT had improved survival on propensity score analysis ( P <.001). Higher median survival favoring receipt of CRT was found on matched-pair analysis (21.9 vs 14.3 months; P <.001). High-quality RT was also shown to be critical in the Radiation Therapy Oncology Group (RTOG) 9704 trial, which randomized resected patients to CRT sandwiched between either gemcitabine or 5-FU. This randomized trial was the first to require central quality assurance review of radiation fields and showed that treatment per protocol was significantly associated with improved survival.
The results of the ongoing RTOG 0848 randomized trial are eagerly awaited for clarification of the role of adjuvant CRT. This trial is currently randomizing patients to adjuvant gemcitabine with or without adjuvant CRT. The trial design originally included an initial randomization to gemcitabine with or without erlotinib, but erlotinib has been removed based on recently reported results of a trial for LAPC in which no survival difference was found with the addition of erlotinib.
Neoadjuvant therapy rationale: resectable pancreatic cancer
Although surgical resection continues to be required for treatment of pancreatic cancer with curative intent, the rate of micrometastatic disease dissemination at the time of diagnosis remains high. As a result of surgical complications, detection of metastatic disease, and declining performance status, only two-thirds of patients receive adjuvant therapy with curative intent after resection. In an effort to maximize treatment and minimize surgical morbidity, multiple groups have performed prospective trials of neoadjuvant CRT for RPC and BRPC.
Neoadjuvant therapy is now widely used in the treatment of GI malignancies. In addition to decreasing the use of surgery in patients unlikely to benefit, neoadjuvant therapy has several potential benefits. Postsurgical disruption of vasculature results in hypoxia in the tumor bed, decreasing both the effectiveness of radiation and delivery of chemotherapeutics. Neoadjuvant therapy can also increase the rate of R0 resections, which is known to be an important prognostic factor for survival. Interpreting the relevant data is challenging, because most of the completed clinical trials for neoadjuvant therapy were small studies designed to assess safety and feasibility and because wide heterogeneity characterizes the RPC and BRPC populations. In addition, because distant metastatic disease continues to drive outcomes, advances showing the superiority of systemic therapy with gemcitabine and later FOLFIRINOX (5FU, leucovorin, irinotecan, oxaliplatin) in metastatic pancreatic cancer led to reevaluation of radiation safety and efficacy. Prospective clinical trials investigating adjuvant RT for pancreatic cancer are shown in Table 2 .
| Study, Report Year | N | Treatment Arms | R1 Resection Rate (%) | Any Grade ≥3 Toxicity (%) | Median Survival (mo) |
|---|---|---|---|---|---|
| GITSG, 1985 | 22 | Observation | — | 0 | 10.9 |
| 21 | 5-FU + 40 Gy split-course RT | — | 14 | 20.0 | |
| EORTC, 1999 | 54 | Observation | — | 0 | 12.6 |
| 60 | 5-FU + 40 Gy split-course RT | — | 2 | 17.1 | |
| Van Laethem et al, 2003 | 22 | Gem then gem + 40 Gy split-course RT | 0 | 36 (heme) 32 (nonheme) | 15.0 |
| Wilkowski et al, 2004 | 30 | Gem + cis + 45-Gy RT then gem + cis | 100 | — | 22.8 |
| Allen et al, 2004 | 32 | Gem + 24–42-Gy RT then gem | 25 (R1) 6 (R2) | — | 16.5 |
| ESPAC-1, 2004 | 69 | Observation | — | — | 16.9 |
| 75 | 5-FU | — | — | 21.6 | |
| 73 | 5-FU + 20-Gy RT | — | — | 13.9 | |
| 72 | 5-FU then 5-FU + 20-Gy RT | — | — | 19.9 | |
| Demols et al, 2005 | 30 | Gem then gem + 45-Gy RT | 0 | 33 (grade 3) 10 (grade 4) | 19.0 |
| Blackstock et al, 2006 | 46 | Gem + 50.4-Gy RT then gem | 0 | — | 18.3 |
| Brade et al, 2007 | 32 | Gem then gem + 35–52.5-Gy RT | 25.0 | 48% during CRT | 18.4 |
| RTOG 9704, 2008 | 230 | 5-FU then 5-FU + 50.4-Gy RT | 33.0 | 9 | 16.9 |
| 221 | Gem then 5-FU + 50.4-Gy RT | 35.0 | 58 | 20.5 | |
| Linehan et al, 2008 | 53 | 5-FU + cis + IFNα + 50.4-Gy RT then gem | 33.0 | 68 | 25 |
| EORTC 40013/FFCD 9203/GERCOR, 2010 | 45 | Gem | 2.0 | 0 (grade 4) | 24.4 |
| 45 | Gem + 50.4-Gy RT | 4.0 | 4.7 (grade 4) | 24.3 | |
| Morganti et al, 2010 | 12 | Cape + 50–55-Gy RT over 5 wk | — | 0 | — |
| Katz et al, 2011 | 28 | IFNα-2b + 5-FU/cis + 50.4-Gy RT then 5-FU | 14.0 | 89 | 42.3 |
| ACOSOG Z05031, 2011 | 89 | IFNα-2b + 5-FU/cis + 50.4-Gy RT then 5-FU | 25.0 | 95 | 25.4 |
| CapR1, 2012 | 53 | 5-FU/cis + IFNα-2b + 50.4-Gy RT | 45.0 | 85 | 26.5 |
| 57 | 5-FU | 34.0 | 16 | 28.5 | |
| Herman et al, 2013 | 48 | Erlotinib + cape + 50.4-Gy RT | 16.7 | 33 (CRT) 43 (post-CRT) | 24.4 |
| Cho et al, 2015 | 29 | Gem and docetaxel then cape + 50.4-Gy RT | — | 15 a | 17 |
a Included additional 21 patients with ampullary or biliary cancers.
Neoadjuvant therapy: resectable pancreatic cancer
Initial efforts to treat RPC with neoadjuvant therapy focused on safety and efficacy. Multiple trials at MDACC were performed on small patient numbers with infusional 5-FU and conventional fractionation (50.4 Gy in 28 fractions) as well as hypofractionation (30 Gy in 10 fractions) and paclitaxel-based CRT. During the same period, ECOG completed a phase II trial of conventionally fractionated radiation with continuous infusional 5-FU and mitomycin. Of 53 patients enrolled, 41 (77%) underwent exploratory surgery, with only 24 (45%) ultimately undergoing resection. Median OS rates for all patients and the 24 who underwent resection were 9.7 and 15 months, respectively. The predominant pattern of failure in these patients remained distant disease dissemination.
Subsequent trials transitioned to gemcitabine-based chemotherapy after demonstration of improved survival in locally advanced and metastatic disease. Talamonti and colleagues reported in 2006 on a small multi-institutional phase II trial of neoadjuvant full-dose gemcitabine chemotherapy with concurrent hypofractionated radiation (36 Gy over 15 daily fractions). Seventeen of the 20 patients enrolled underwent resection with a median OS of 26 months and 2-year OS of 61%. One grade 3 GI toxicity was reported with neoadjuvant therapy, and an R0 resection was reported in 94% of resected patients. Although small enrollment numbers limited the scope of the findings, this study showed the feasibility of neoadjuvant treatment with gemcitabine.
Evans and colleagues reported on a phase I/II trial of 86 patients with RPC head/uncinate process adenocarcinoma treated with concurrent low-dose gemcitabine and radiation (30 Gy in 10 fractions). Median OS was almost 23 months for all patients and 34 months for the 74% of patients who underwent surgery. Five-year OS rates for resection and no resection were 36% and 0%, respectively. R1 resection rates were decreased from 20% in their institutional report on patients treated without neoadjuvant therapy to 11% with concurrent low-dose gemcitabine and radiation. Published concurrently, a phase II study by the same group incorporated cisplatin with gemcitabine before gemcitabine-based CRT. That study reported a similar survival benefit for the 66% of patients who underwent surgery (31 months) compared with those who did not (10.5 months). Local failure was reported in 25% of patients undergoing resection, with only 2 patients showing isolated local recurrence. Distant disease continued to predominate, with 42% developing distant disease and 31% showing peritoneal dissemination. The investigators also noted that outcomes with dual-agent therapy were not improved compared with gemcitabine-only CRT, suggesting that alternative approaches were required.
In an effort to shorten the duration of RT, Hong and colleagues used proton therapy (PT) for phase I dose escalation from 30 Gy in 10 fractions to 5 Gy in 5 sequential fractions with concurrent capecitabine. They had previously performed dosimetric analyses showing decreased radiation exposure to surrounding organs with PT compared with intensity-modulated RT (IMRT). Initial results showed acceptable toxicity at all treatment levels. A subsequent phase II study of 25 Gy given in 5 fractions reported that 37 of 48 patients (77%) underwent surgery. A median OS of 17.2 months was observed for all patients, which extended to 27 months for those completing resection. Thirty-one of 37 patients (84%) received postoperative gemcitabine chemotherapy; however, distant recurrence continued to dominate, with 35 of 48 patients (73%) failing distantly and only 8 of 48 patients (17%) failing locally.
Neoadjuvant therapy: borderline resectable pancreatic cancer
The likelihood of R0 resection decreases in patients with evidence of tumor involvement of the peripancreatic vasculature. It is thought that R1 resections result in survival similar to that in patients with unresected LAPC and with increased morbidity, so that neoadjuvant CRT may play a greater role in BRPC. An initial study by Mehta and colleagues characterized BRPC as having portal vein, superior mesenteric vein, or superior mesenteric artery involvement. In that study, 15 patients completed CRT with infusional 5-FU and standard fractionated radiation (50.4–56 Gy) with a 60% resection rate and a median OS of 30 months for those who underwent resection. Since publication of that study in 2001, several prospective studies have evaluated the role of neoadjuvant therapy in patients with BRPC. However, because of the varying definitions used for BRPC, as well as multiple studies that combined BRPC and RPC, a large degree of heterogeneity characterized initial reports on neoadjuvant treatment outcomes.
Van Buren and colleagues published a phase II trial including 59 patients with BRPC and RPC treated with full-dose gemcitabine and bevacizumab, a vascular endothelial growth factor inhibitor, followed by hypofractionated radiation (30 Gy in 10 fractions) and concurrent bevacizumab. Similar to prior reports, 73% of patients underwent resection with a median OS of 16.8 months for all patients and 19.7 months for those undergoing resection. R0 resection was attained in 88% and local control was 75%, both of which were similar to prior studies with only RPC. A study using similar chemotherapy and radiation schema with a median survival of 46 months was presented in 2012.
After determination of safety in a phase I trial, a multi-institutional phase II clinical trial evaluated 68 patients with RPC, BRPC, or LAPC who were treated with full-dose gemcitabine and oxaliplatin with concurrent fractionated radiation (30 Gy in 15 fractions). Surgical resection was completed in 63% of the entire study population and 62% of patients with BRPC. Patients with BRPC had a median OS of 25.4 months. R0 resection was obtained in 84% of patients, for whom median OS was 34.6 months. Although the trial failed to show an improvement in 2-year disease-free survival (26.1%) compared with the historical control of 35% from the Charité Onkologie 001 (CONKO 001) study of patients with RPC receiving adjuvant gemcitabine, the patients had more advanced tumors given the large proportion of BRPC.
Given the high rate of distant metastatic disease in BRPC, several groups have added induction systemic therapy before CRT as a method to increase systemic doses of chemotherapy. Pipas and colleagues reported on a single-institutional phase II study of patients with RPC, BRPC, and LAPC with cetuximab, an epidermal growth factor receptor antibody, followed by concurrent gemcitabine and radiation. The median OS for resected patients was 24.3 months and for R0 resection was 92%, similar to prior trials. A study by Landry and colleagues attempted to randomize patients between gemcitabine-based CRT and induction gemcitabine and cisplatin followed by 5-FU–based CRT. Only 21 patients (10 CRT and 11 induction chemotherapy followed by CRT) were enrolled, and the trial closed early as a result of poor accrual. The study was also challenging to interpret because of enrollment of both patients with LAPC and patients with BRPC.
Trials discussed thus far have used standard radiation fractionation schedules. More contemporary studies have also explored the use of hypofractionated regimens using stereotactic body RT (SBRT), particularly in the setting of BRPC. Shaib and colleagues performed a single-institution phase I dose-escalation trial to determine the safety and efficacy of 3-fraction SBRT delivered after FOLFIRINOX. SBRT doses ranged from 30 Gy with a 2-Gy-per-fraction boost to the posterior margin of the tumor up to 36 Gy with a 3-Gy-per-fraction boost. In the 12 treated patients, no grade 3 or 4 toxicities were noted over a median follow-up of 18 months. Seven of the 12 patients treated with SBRT underwent resection, with one patient having in situ disease at the margin. Median OS was 11 months, although interpretation is challenging in a small cohort with poor prognostic factors, including nodal disease and increased levels of carbohydrate antigen 19-9.
Several planned or ongoing studies are evaluating SBRT for BRPC. Researchers at the University of Maryland School of Medicine are conducting a phase II trial of FOLFIRINOX followed by a 5-fraction SBRT regimen in BRPC (NCT01992705). Based on their recently published phase II trial of induction gemcitabine followed by SBRT in LAPC, the Alliance for Clinical Trials in Oncology is performing a multi-institutional randomized phase II trial of FOLFIRINOX with or without SBRT or hypofractionated image-guided RT for BRPC. Prospective clinical trials of neoadjuvant CRT for RPC and BRPC are listed in Table 3 .
| Study, Report Year | N | Resectability | Total RT Dose (Gy) | RT Dose per Fraction (Gy) | CRT Regimen | Any Grade ≥3 Toxicity (%) | Resection Rate (%) | R0 Resection Rate (%) | Median OS (mo) |
|---|---|---|---|---|---|---|---|---|---|
| 3DCRT/IMRT | |||||||||
| Evans et al, 1992 | 28 | RPC | 50.4 | 1.8 | 5-FU + RT | — | 61 | 82 | — |
| Yeung et al, 1993 | 26 | RPC/BRPC LAPC | 50.4 | 1.8 | 5-FU + MMC + RT | — | 46 | — | 10.0 |
| Pisters et al, 1998 | 35 | RPC | 30 | 3.0 | 5-FU + RT + IORT 10–15 Gy | 9 | 57 | 90 | 25 e |
| ECOG, 1998 | 53 | RPC/BRPC | 50.4 | 1.8 | 5-FU + MMC + RT | — | 45 | 33 a | 9.7 |
| Mehta et al, 2001 | 15 | BRPC | 50.4–56 | 1.8–2.0 | 5-FU + RT | 0 | 60 | 100 | 30 e |
| Pisters et al, 2002 | 35 | RPC | 30 | 3.0 | Paclitaxel + RT ± IORT | 46 | 57 | 68 | 12 |
| Joensuu et al, 2004 | 28 | BRPC | 50.4 | 1.8 | Gem + RT | 6 | 75 | — | 25.0 |
| Pipas et al, 2005 | 24 | RPC (17%) BRPC (29%) LAPC (54%) | 50.4 | 1.8 | Gem + docetaxel then gem + RT | — | 71 | 76 | 14.0 |
| SFRO-FFCD 97–04, 2006 | 41 | RPC/BRPC | 50 | 2.0 | 5-FU + cis + RT | 66 | 63 | 80 | 9.4 |
| Talamonti et al, 2006 | 20 | RPC/BRPC | 36 | 2.4 | Gem then gem + RT | 10 | 85 | 94 | 26 e |
| Desai et al, 2007 | 44 | RPC/BRPC (27%) LAPC (66%) Met (7%) | 27.0 | 1.8 | Gem + oxali + RT | — | 58 c | 100 | 12.5 d |
| Macchia et al, 2007 | 28 | RPC/BRPC (32%) LAPC (68%) | 39.6 | 1.8 | 5-FU + RT then surgery + IORT 10 Gy then 5-FU + doxo + MMC | 10.7 during CRT | 78 in RPC/BRPC 11 in LAPC | 89 | 11.3 |
| Evans et al, 2008 | 86 | RPC/BRPC | 30.0 | 3.0 | Gem + RT | — | 74 | 89 | 22.7 |
| Varadhachary et al, 2008 | 79 | RPC/BRPC | 30.0 | 3.0 | Gem + cis then gem + RT | — | 66 | 96 | 17.4 |
| Small et al, 2008 | 39 | RPC (41%) BRPC (23%) LAPC (36%) | 36.0 | 2.4 | Gem + RT | 25.6 (nonheme related to treatment) | 44 | — | — |
| Landry et al, 2010 | 10 | BRPC | 50.4 | 1.8 | Gem + RT | 36 (grade 4) | 30 | 33 | 19.4 |
| 11 | BRPC | 50.4 | Gem/cis then 5-FU + RT | 18 (grade 4) | 18 | 50 | 13.4 | ||
| Turrini et al, 2010 | 34 | RPC | 45 | 1.8 | Docetaxel + RT | 6 | 50 | 100 | 15.5 |
| Small et al, 2011 | 32 | RPC/BRPC/LAPC | 36 | 2.4 | Gem + bev | 79 | 18.8 b | — | 11.8 |
| Leone et al, 2013 | 39 | BRPC (38%) LAPC (62%) | 50.4 | 1.8 | Gem + oxali then gem + RT | — | 60 in BRPC 8 in LAPC | 82 | 16.7 |
| Pipas et al, 2012 | 33 | RPC (12%) BRPC (70%) LAPC (18%) | 54 | 1.92 | Gem + cetuximab + RT | — | 78 in BRPC 50 in LAPC | 92 | 17.3 |
| Satoi et al, 2012 | 34 | BRPC/LAPC | 50.4 | 1.8 | S-1 + RT | — | 88 | 93 | — |
| Shroff et al, 2012 | 11 | RPC/BRPC | 50.4 | 1.8 | Gem + bev + RT | — | 82 | 100 | 30.1 |
| Van Buren et al, 2013 | 59 | BRPC/RPC | 30 | 3.0 | Gem + bev then RT + bev | — | 73 | 88 | 16.8 |
| Kim et al, 2013 | 39 | RPC (34%) BRPC (57%) LAPC (9%) | 30 | 2.0 | Gem + oxali + RT | 37 (heme grade 3) 18 (heme grade 4) 46 (nonheme grade 3) 1 (nonheme grade 4) | 63 | 84 | 18.2 |
| Jensen et al, 2014 | 23 | BRPC/LAPC | 50.4 | 1.8 | 5-FU + cis + IFNα | 82.6 | 30.4 | 85.7 | 11.5 |
| Wo et al, 2014 | 10 | RPC | 25–30 | 3–5 | Cetuximab + RT | 70 (grade 3) 10 (grade 4) | 80 | — | — |
| Esnaola et al, 2014 | 13 | BRPC/LAPC | 54 | 1.8 | Gem + oxali + cetuximab then cape + RT | 29.7 during chemo; 9.5 during CRT | 69.2 | 100 | 24.1 |
| SBRT | |||||||||
| Shaib et al, 2016 | 13 | BRPC | 36–45 | 12–15 | mFOLFIRINOX then SBRT | 0 | 62 | 100 | 11 |
| PT | |||||||||
| Hong et al, 2014 | 50 | RPC | 25 Gy RBE | 5 Gy RBE | Cape + RT | — | 77 | 84 | 17 |
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