This article focuses on the management of locally advanced pancreatic cancer, which should be treated as a distinct entity separate from metastatic disease and borderline resectable disease. Although the role, timing, and sequencing of radiation relative to systemic therapy in this disease are controversial, an emerging treatment paradigm involves induction chemotherapy, followed by consolidative chemoradiation in patients who do not progress. In addition, new chemotherapy regimens as well as novel radiosensitizers have shown promise and need to be tested further in the locally advanced setting. Advances in radiotherapy have enabled stereotactic body radiotherapy and should continue to be prospectively evaluated.
Key points
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Locally advanced pancreatic cancer should be treated as a distinct entity separate from metastatic disease.
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The role, timing, and sequencing of radiation relative to systemic therapy for locally advanced pancreatic cancer remain uncertain, even more so with the development of more modern chemotherapy regimens that improves systemic disease control.
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Most clinical trials to date have evaluated initial chemoradiation followed by maintenance chemotherapy; this approach has produced mixed results in terms of whether it confers any survival benefit compared with chemotherapy alone.
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An emerging treatment paradigm for locally advanced pancreatic cancer involves induction chemotherapy, followed by consolidative chemoradiation in patients who do not progress. Dropout rates (ie, patients who do not go on to receive chemoradiation) with this strategy range from 13% to 39%.
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A large randomized phase III trial from Europe (LAP-07) did not indicate a survival benefit of sequential chemotherapy followed by chemoradiation, compared with chemotherapy alone. However, rates of locoregional control were higher for patients who received chemoradiation.
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Newer approaches for radiation, including reduction in target volumes and stereotactic body radiation, are increasingly used and warrant further exploration.
Introduction
Most individuals diagnosed with pancreatic cancer are inoperable at the time of initial presentation, either because of metastatic dissemination of disease or based on the locoregional extent of their primary tumor. Patients in this latter category, who do not have any radiographic evidence of distant metastases, are defined as having locally advanced disease. This article focuses on therapeutic considerations, including current controversies and areas of uncertainty that inform the current approach to patients with this stage of disease. Of note, borderline resectable pancreatic cancer, in which cytoreductive neoadjuvant therapy is used to maximize the chance of R0 resection, is being increasingly viewed as a distinct entity that warrants its own separate discussion from locally advanced disease and is therefore covered elsewhere in the current issue of this journal.
Introduction
Most individuals diagnosed with pancreatic cancer are inoperable at the time of initial presentation, either because of metastatic dissemination of disease or based on the locoregional extent of their primary tumor. Patients in this latter category, who do not have any radiographic evidence of distant metastases, are defined as having locally advanced disease. This article focuses on therapeutic considerations, including current controversies and areas of uncertainty that inform the current approach to patients with this stage of disease. Of note, borderline resectable pancreatic cancer, in which cytoreductive neoadjuvant therapy is used to maximize the chance of R0 resection, is being increasingly viewed as a distinct entity that warrants its own separate discussion from locally advanced disease and is therefore covered elsewhere in the current issue of this journal.
Definition of locally advanced pancreatic cancer: accurate diagnosis and staging
Although nuanced differences exist among expert groups in defining locally advanced pancreatic cancer, the primary basis on which resectability and unresectability is judged is the relationship of the primary pancreatic tumor to adjacent blood vessels. According to criteria outlined by the National Comprehensive Cancer Network (NCCN), this includes (1) encasement of the superior mesenteric artery by greater than 180°; (2) encasement of the celiac axis by greater than 180° (for tumors of the body or tail) or any degree of celiac abutment (for tumors located at the pancreatic head); (3) superior mesenteric vein or portal vein occlusion without possibility of reconstruction; or (4) aortic invasion or encasement. Pancreatic protocol computed tomography (CT) using a multidetector scanner, which entails multiphasic imaging with thin cuts through the pancreas, is the primary diagnostic tool used to adjudicate this. Although endoscopic ultrasound is also frequently used to gain additional information about the tumor and nodal staging of pancreatic cancers, as well as to obtain a tissue diagnosis, it should be considered an adjunct to high-quality CT scanning and not serve as the primary basis for staging and deciding on suitability for surgery. Diagnostic laparoscopy can also be considered in the initial staging workup, because the presence of peritoneal metastases may influence treatment decisions, such as the role for, and relative importance of, locoregional therapy.
Treatment of locally advanced pancreatic cancer
There remains much uncertainty regarding the optimal therapeutic approach for patients with locally advanced disease, including the respective roles, importance, and sequencing of chemotherapy and radiation, as well as many specifics regarding how best to deliver each of these modalities. Although such patients have often been grouped together with those with metastatic disease in chemotherapy clinical trials, it is becoming increasingly clear that differences in biology and natural history warrant separate therapeutic approaches and studies for these patient subsets.
Chemoradiation: Is There a Role?
One of the primary questions in locally advanced pancreatic cancer is the role that radiation plays and the importance of locoregional control. A postmortem study from Johns Hopkins indicated that up to 30% of patients with pancreatic cancer died of “locally destructive” rather than extensive metastatic disease, highlighting the potential importance of achieving locoregional control in this malignancy.
There are conflicting data regarding the role of combined-modality therapy for locally advanced pancreatic cancer. In terms of concurrent administration of chemotherapy with radiation, an early study conducted by the Gastrointestinal Tumor Study Group (GITSG) demonstrated the superiority of chemotherapy (bolus 5-fluorouracil [5-FU]) administered together with radiation when compared with radiation alone in patients with locally advanced disease, with improved median survival, and with 1-year survival rates. Although this informs the current practice standard of administering radiosensitizing doses of chemotherapy concurrently with radiation, it is worth noting that a much later published study conducted by the Eastern Cooperative Group (ECOG) failed to demonstrate any survival improvement when mitomycin C (MMC) and 5-FU were administered concurrently with radiation compared with radiation alone.
The Question of Timing: Induction Chemoradiation
Most studies evaluating a treatment paradigm that includes chemoradiation for locally advanced disease have used it as part of initial therapy ( Table 1 ). Several of these have used a randomized design to analyze whether sequential chemoradiation, followed by chemotherapy, is superior to chemotherapy alone (ie, what benefit is conferred by the addition of induction chemoradiation in this disease context). Notably, these trials have produced markedly discordant results: 2 trials demonstrated a survival advantage, 1 trial showed no difference, and 1 trial actually indicated a detrimental effect of using induction chemoradiation in this patient population. These disparate findings may be potentially explained by several factors that could have affected clinical outcomes: different radiation doses and treatment plans, radiosensitizing agents, and stand-alone chemotherapy regimens. For example, in the one modern phase III study to demonstrate a shorter median survival with combined-modality therapy, conducted by the Federation Francophone de Cancerologie Digestive (FFCD) and the Societe Francophone de Radiotherapie Oncologique (SFRO), induction chemoradiation consisted of 6000 cGy of radiation over 30 fractions with 2 concurrent cycles of cisplatin (20 mg/m 2 /d on days 1 through 5 during weeks 1 and 5) and continuous infusion 5-FU (300 mg/m 2 /d, days 1 through 5 for 6 weeks). Not surprisingly, patients receiving this chemoradiation regimen incurred more frequent grade 3 to 4 toxicities when compared with those receiving chemotherapy alone, both during the corresponding induction periods and during the maintenance chemotherapy phase with gemcitabine, leading to early treatment interruption and shorter duration and lower cumulative dose of subsequent chemotherapy. Such factors may have contributed to the poorer outcomes, highlighting the importance of radiation treatment planning and selection of radiosensitizing agents, as is discussed later.
| Study | N | Induction Chemoradiation | Maintenance Chemotherapy After RT? | Median Survival | (For Randomized Trials): | ||||
|---|---|---|---|---|---|---|---|---|---|
| Radiation (Dose/Schedule) | Concurrent Chemotherapy | n | Comparator Arm (RT Alone or Chemo Alone) | Median Survival | Statistically Significant? | ||||
| Randomized trials vs radiation alone | |||||||||
| GITSG 9273 | 169 | 4000 or 6000 cGy (split course) | Bolus 5-FU | Bolus 5-FU | 40 wk | 25 | RT | 23 wk | Yes, in favor of chemoRT ( P <.01) |
| ECOG 8282 | 55 | 5940 cGy | MMC/5-FU | No | 8.4 mo | 49 | RT | 7.1 mo | No |
| Randomized trials vs chemotherapy alone | |||||||||
| ECOG (1985) | 47 | 4000 cGy | Bolus 5-FU | Bolus 5-FU | 8.3 mo | 44 | Bolus 5-FU | 8.2 mo | No |
| GITSG 9283 | 54 | 5400 cGy | Bolus 5-FU | Streptozocin, MMC, 5-FU | 42 wk | Streptozocin, MMC, 5-FU | 32 wk | Yes, in favor of induction chemoRT ( P <.02) | |
| FFCD/SFRO | 59 | 6000 cGy | Cisplatin/5-FU | Gemcitabine | 8.6 mo | 60 | Gemcitabine | 13.0 mo | Yes, in favor of chemo alone ( P = .03) |
| ECOG 4201 | 34 | 5040 cGy | Gemcitabine | Gemcitabine | 11.1 mo | 37 | Gemcitabine | 9.2 mo | Yes, in favor of induction chemoRT ( P = .034) |
| Nonrandomized trials | |||||||||
| RTOG 9812 | 122 | 5040 cGy | Paclitaxel | No | 11.3 mo | N/A | |||
| RTOG PA 0020 | 154 | 5040 cGy | Paclitaxel/gemcitabine | R115777 (farnesyl transferase inhibitor) | 11.7 mo | ||||
| RTOG PA-0411 | 94 | 5040 cGy | Capecitabine/bevacizumab | Capecitabine/bevacizumab | 11.9 mo | ||||
| CALGB 80003 | 81 | 5040 cGy | Gemcitabine/infusional 5-FU | Gemcitabine | 12.2 mo | ||||
Delayed Chemoradiation Following Induction Chemotherapy
An emerging and promising treatment paradigm for locally advanced pancreatic cancer consists of delaying chemoradiation until after patients have completed a period of induction chemotherapy. This strategy would address 2 important issues: (1) the need to optimally address systemic disease first, which is usually the most significant factor affecting longevity in most patients; and (2) limiting the use of radiation to that subgroup of patients whose tumors are well-controlled with this initial period of systemic therapy and do not develop metastatic disease. This approach would spare a subset of individuals the potential toxicities associated with radiation.
Support for this strategy came from the Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR), which performed a retrospective analysis on 181 patients with locally advanced pancreatic cancer who had participated in several separate phase II or phase III trials and received initial chemotherapy with a gemcitabine-based combination regimen for 3 months or more. For those patients who showed good disease control (70.7%, n = 128), the treating investigator was then permitted to decide whether to continue with the same chemotherapy or proceed onto consolidative chemoradiation. Seventy-two (56%) patients received consolidative radiation (5500 cGy with concurrent infusional 5-FU), whereas the remaining 56 (44%) patients continued with chemotherapy alone. Patients receiving chemoradiation had longer rates of overall survival (OS) and progression-free survival (PFS) (median OS 15.0 vs 11.7 months, P = .0009; median PFS 10.8 vs 7.4 months, P = .005).
Krishnan and colleagues similarly performed a retrospective analysis of 323 patients with locally advanced pancreatic cancer treated at M.D. Anderson Cancer Center, 76 of whom received gemcitabine-based induction chemotherapy (for a median duration of 2.5 months) before chemoradiation. These patients, when compared with those who had received chemoradiation as part of their initial treatment, were found to have significantly longer OS and PFS rates (median OS, 11.9 vs 8.5 months, P <.001; median PFS, 6.4 vs 4.2 months, P <.001, respectively).
Although intriguing, the retrospective nature of both these analyses prevents any definitive conclusions about the benefit of delayed chemoradiation compared with either no chemoradiation or induction chemoradiation. Data are now available from several prospectively designed phase II studies, and most recently, a large randomized phase III study, that have analyzed this sequential approach of induction chemotherapy followed by chemoradiation ( Table 2 ). These studies have highlighted several important findings: (1) approximately 13% to 39% of patients receiving induction chemotherapy will not be candidates for subsequent chemoradiation, most commonly due to disease progression; and (2) patients who successfully undergo sequential chemotherapy followed by chemoradiation typically have survival outcomes greater than 1 year.
| Author | N | Induction Chemotherapy Regimen (Duration) | Patients NOT Receiving ChemoRT (%) a | Chemoradiation Regimen | Additional Chemo After ChemoRT Complete? | Median Survival (mo) |
|---|---|---|---|---|---|---|
| Ko et al, 2007 | 25 | Gemcitabine, cisplatin (6 mo) | 32 | 50.4 Gy + capecitabine | No | 13.5 |
| Moureau-Zabotto et al, 2008 | 59 | Gemcitabine, oxaliplatin (2 mo) | 15 | 55 Gy + 5-FU + oxaliplatin | No | 12.2 |
| Crane et al, 2011 | 69 | Gemcitabine, oxaliplatin, cetuximab (2 mo) | 13 | 50.4 Gy + capecitabine + cetuximab | Cetuximab × 1 mo | 19.2 |
| Ch’ang et al, 2011 | 50 | Gemcitabine, 5-FU, oxaliplatin (3 mo) | 40 | 50.4 Gy + gemcitabine | Gemcitabine, 5-FU, oxaliplatin until progression | |
| Kim et al, 2012 | 37 | Gemcitabine, cisplatin (9 wk) | 19 | 55.8 Gy + capecitabine | Gemcitabine × 3 cycles | 16.8 |
| Mukherjee (SCALOP) et al, 2013 | 114 | Gemcitabine, capecitabine (12 wk) | 35 | 50.4 Gy + (gemcitabine or capecitabine) | No | 14.5 |
| Hammel (LAP-07) et al, 2013 | 442 (133) b | Gemcitabine ± erlotinib (4 mo) | 39 | 54 Gy + capecitabine | Erlotinib (for patients on gemcitabine/erlotinib arm) | 15.3 |
a Due to disease progression, toxicity, or doctor/patient choice.
b 442 represents all patients enrolled in study; 133 includes only patients demonstrating nonprogressive disease after induction chemotherapy who were randomized to receive chemoradiation. Survival result reflects only this limited subset.
More recently, this strategy of delayed chemoradiation was attempted to be addressed more definitively via a phase III European study conducted by GERCOR (LAP-07). In this trial, patients with locally advanced pancreatic cancer were initially randomized to receive gemcitabine with or without the epidermal growth factor receptor inhibitor erlotinib for 4 months. Patients who did not progress during this initial treatment were then included in the second randomization step, which involved either continuation of systemic therapy for 2 more months (patients receiving erlotinib could be maintained on this agent indefinitely) versus chemoradiation (54 Gy in 30 fractions, with concurrent capecitabine at 800 mg/m 2 twice a day). Results of this 442-patient study were initially presented by Hammel and colleagues at the 2013 annual American Society of Clinical Oncology meeting. Of 442 patients enrolled to this study, 269 reached the second randomization step, representing a 39% dropout rate following induction chemotherapy (primarily due to progressive disease). Updated efficacy results in 2014 indicated that patients assigned to receive chemoradiation experienced no improvement in survival compared with those continuing with chemotherapy alone (median OS, 15.2 vs 16.5 months, respectively; log-rank P = .829), although there was a trend toward improved PFS in the chemoradiation-treated patients (median PFS 9.9 vs 8.4 months, log-rank P = .055). Not surprisingly, patterns of disease progression differed between the 2 arms: patients receiving chemoradiation did have a lower rate of subsequent local progression as well as a longer treatment-free interval before having to resume therapy at a later time. As the systemic therapy used in LAP-07 (gemcitabine ± erlotinib) is no longer commonly given, it is unclear whether the results of this trial will still be applicable, and whether newer and more effective modern chemotherapy regimens administered in the induction setting will attenuate or magnify any potential benefits associated with radiation in this patient population.
Systemic therapy in locally advanced pancreatic cancer
Selection of Chemotherapy Administered Independently of Radiation
Two regimens have emerged as front-line standards of care for the treatment of metastatic pancreatic cancer: FOLFIRINOX (a biweekly regimen consisting of 5-FU administered over 48 hours plus leucovorin, irinotecan, and oxaliplatin); and the combination of gemcitabine and nab-paclitaxel. Both of these regimens demonstrated significantly prolonged survival times compared with gemcitabine monotherapy in randomized phase III trials (FOLFIRINOX vs gemcitabine, median OS 11.1 vs 6.8 months; hazard ratio [HR] 0.57, P <.001; gemcitabine/nab-paclitaxel vs gemcitabine, median OS 8.5 vs 6.7 months; HR 0.72, P <.001), as well as improvements in other clinically relevant endpoints including PFS and objective response rate. However, it is important to recognize that both of these trials enrolled patients exclusively with metastatic disease, and hence, use of either of these regimens in the locally advanced setting requires some extrapolation as the experience to date in this context has been limited to small single-institution series. Of note, NCCN guidelines do not make a distinction in choice of chemotherapy between patients with metastatic versus locally advanced disease. In a recently opened national cooperative group trial (RTOG 1201), all patients will receive induction chemotherapy with the combination of gemcitabine and nab-paclitaxel, followed by a randomization to 1 of 3 arms: continued chemotherapy, standard-fractionation radiation, or higher-dose intensity-modulated radiation ( ClinicalTrials.gov NCT01921751 ).
Selection of Radiosensitizing Agents
Historically, most studies for locally advanced pancreatic cancer have delivered fluoropyrimidine- or gemcitabine-based therapies concurrent with radiation. Older trials used bolus 5-FU, but administration of fluoropyrimidine therapy continuously throughout the course of radiation (either as infusional 5-FU or as the oral prodrug capecitabine), rather than in bolus fashion, may provide superior radiosensitization and represents the currently accepted standard of care. Although gemcitabine is a more potent radiosensitizer, rates of severe toxicity may be higher with gemcitabine-based chemoradiation, as suggested from a retrospective analysis by Crane and colleagues of patients with locally advanced disease treated at M.D. Anderson. However, other data have shown that full doses of gemcitabine, if delivered with limited volume and highly conformal radiotherapy, can be well-tolerated and efficacious. A comparison of fluoropyrimidine-based versus gemcitabine-based chemoradiation was performed in the context of a randomized phase II study (the SCALOP trial), in which 74 patients with locally advanced disease were randomized, after a 12-week course of induction chemotherapy with gemcitabine/capecitabine, to receive radiation (5040 cGy over 28 fractions) with either concurrent capecitabine (830 mg/m 2 twice a day Monday through Friday) or gemcitabine (300 mg/m 2 weekly). Median OS was significantly superior in the former group (15.2 vs 13.4 months; adjusted HR 0.39, P = .012), suggesting that a capecitabine-based regimen may be the preferred choice in the context of consolidative chemoradiation.
Other radiosensitizing agents that have been explored for locally advanced pancreatic cancer include new oral fluoropyrimidine derivatives (S-1 ), taxanes, epidermal growth factor receptor inhibitors (erlotinib, cetuximab ), anti-angiogenic therapy (bevacizumab ), and protease inhibitors (nelfinavir ); however, at present, these should only be administered in the context of a clinical trial. One interesting recent study intending to enhance the effects of radiation involved localized injection of TNFerade, a replication-deficient adenoviral vector expressing the transgene tumor necrosis factor-α, regulated by the radiation-inducible promoter Egr-1. However, final results of a 187-patient randomized phase III trial demonstrated that the addition of TNFerade to 5-FU-based chemoradiation did not prolong survival compared with standard of care therapy (median OS 10.0 vs 10.0 months; HR 0.90, P = .26).
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