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Resectable Pancreatic Cancer
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It is widely known that surgery holds the only hope of cure for patients with pancreatic cancer. With some exceptions, resectable pancreatic cancers are limited to small tumors in the head of the pancreas. These are removed with a Whipple procedure (41), more appropriately described as a pancreaticoduodenectomy. Caution is advised when considering a resection of a tail neoplasm; even when these tumors appear localized, they are associated with a higher likelihood of peritoneal seeding compared to a head lesion. Body lesions are almost never amenable to resection.
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Unfortunately, there are potential drawbacks associated with up-front surgery:
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Surgical morbidity and mortality are inversely correlated to experience with the procedure. Several studies have confirmed significant differences in the risk of major perioperative complications and death between hospitals that perform the operation frequently and those that do not (42,43). Moreover, long-term survival after pancreaticoduodenectomy is improved when performed at a high-volume center (44). This is likely attributable to a combination of decreased operative mortality and superior patient selection.
Positive surgical margins are associated with a very poor prognosis (see Table 21-4). Surgical margins after pancreaticoduodenectomy can be either microscopically positive (R1 resection) or grossly positive (R2). Median survivals with a positive surgical margin usually range between 6 and 12 months, similar to, if not worse than, the survival of patients with locally advanced disease (45,46). Many patients undergo laparotomy without adequate preoperative assessment. Some will be found to have unresectable tumors intraoperatively or be left with a grossly positive surgical margin when it might have been possible to predict this prior to surgery. Patients may therefore have a delay in chemoradiation or systemic therapy while the patient recovers. With the exception of patients who present with gastric outlet obstruction or biliary obstruction not amenable to endoscopic or percutaneous stenting, we discourage surgical intervention without high-quality radiographic evidence of resectability. If the surgeon has failed to perform a complete resection, surgery may even be deleterious and compromise the patient’s survival.
A substantial proportion of patients do not recover sufficiently to receive postoperative adjuvant therapy. Pancreaticoduodenectomy is a major surgical procedure with removal of portions of the stomach, duodenum, pancreas, and bile duct requiring extensive reconstruction of the upper alimentary canal. Pancreatic anastomotic leaks and delayed gastric emptying are common complications. Retrospective analyses and prospective clinical trials of adjuvant therapy demonstrated that a significant percentage of people do not adequately recover to receive postoperative therapy. For example, Johns Hopkins University demonstrated that of 870 patients who underwent resection for pancreatic cancer with curative intent between 1993 and 2005, only 53% received adjuvant therapy (47). Furthermore, analyses of Medicare-eligible patients suggested that among patients 65 years of age or older, fewer than half receive adjuvant therapy (48). It is reasonable to assume that a substantial proportion of elderly patients have sufficient difficulty recovering from surgery and this has an impact on adjuvant therapy.
Surgically resected patients remain at risk for local failure and metastatic disease. Approximately 80% of resected patients will ultimately relapse and die of disease recurrence. The high risk of relapse stems from an inability to prevent locoregional failure and to eradicate microscopic metastatic disease. Factors predisposing to local recurrence have not been fully elucidated, but recent evidence implicated perineural invasion as an important mediating process. Invasion of nerve sheaths may occur as a pervasive superficial infiltration that cannot be appreciated intraoperatively, even by the most experienced surgeons.
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Once patients relapse with distant disease or local failure, no curative strategy is available. Adjuvant therapy, while tending to improve median survival, has not made any significant advances over the past 20 years.
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The Role of Adjuvant Therapy
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Since the mid-1980s, efforts have been directed toward improving outcomes for patients with resected disease by delivering postoperative adjuvant therapy intended to reduce the risk of relapse and improve long-term survival. Early retrospective analyses of resected patients suggested local failure rates as high as 50% to 80%, which prompted many centers to advocate radiotherapy as a component of adjuvant therapy. The first randomized trial, performed by the Gastrointestinal Tumor Study Group (GITSG), demonstrated a significant survival advantage with chemoradiation based on 5-fluorouracil (5-FU) compared with resection alone (21 vs 11 months) (49). The 5-year survival rates were 18% versus 8%, respectively. The European Organization for Research and Treatment of Cancer (EORTC) 40891 trial produced conflicting results 15 years later. In this case, 218 patients receiving 5-FU chemoradiation did not demonstrate a survival advantage over those on observation, although this population was more heterogeneous than that of GITSG because patients with periampullary cancer and those with an R1 resection were included (50).
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Large randomized adjuvant trials were conducted by the European Study Group for Pancreatic Cancer (ESPAC). In the ESPAC-1 trial, 289 patients were randomized to observation, chemotherapy, chemoradiation, or chemoradiation followed by chemotherapy (51). Interestingly, chemoradiation was found to have a deleterious effect on survival (median survival 15.9 vs 17.9 months, respectively, P = .05). On the other hand, chemotherapy appeared beneficial over observation, with a median survival of 20.1 months versus 15.5 months (P = .009). As a result of these studies, the role of radiation in adjuvant therapy became controversial. Radiation has been abandoned in the adjuvant setting in many European centers.
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After gemcitabine showed superiority to 5-FU in advanced disease, a number of randomized trials tested its role in the adjuvant setting. The Radiation Therapy Oncology Group (RTOG) 9704 trial compared gemcitabine with 5-FU given before and after 5-FU–based chemoradiation. Gemcitabine demonstrated a modest, but not significant, improvement in survival over 5-FU (20.5 months compared to 16.9 months, P = .09) (52).
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The benefit of adjuvant gemcitabine was further confirmed with the long-term data from the CONKO 001 trial. Investigators showed a significant improvement in disease-free survival and overall survival with the use of gemcitabine postoperatively (13 and 22.8 months, respectively) compared to surgery alone (6.9 and 20.2 months) (53). ESPAC-3 further compared postoperative gemcitabine to 5-FU (54). No statistical difference in survival was noted after a median follow-up of 34 months, although gemcitabine appeared to be better tolerated.
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Picozzi and colleagues reported their findings of a phase II study involving adjuvant interferon alpha-2b (IFN-α2b), cisplatin, and continuous infusion 5-FU given concurrently with external beam radiation (55). In this study, 89 patients with R0 or R1 resections received IFN-α2b on days 1, 3, and 5 each week for 5½ weeks, cisplatin weekly for 6 weeks, and infusional 5-FU for 38 days with radiation dosed to 50.4 Gy. Overall survival at 18 months was 69% with a median disease-free survival of 14.1 months and overall survival of 25.4 months. Of the patients, 95% experienced grade 3 or greater toxicity. Additional combination trials, however, did not show an improvement in survival compared to 5-FU monotherapy (56). Table 21-5 summarizes the adjuvant trials.
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Preoperative Therapy for Potentially Resectable Disease
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Sadly, there has been no significant progress in adjuvant therapy since the GITSG study was first reported in 1985. More recent studies have been fairly consistent with the GITSG findings: Median survival for resected patients treated with postoperative therapy hovers around 20 months and remains at 12 months for patients undergoing surgery alone. Of the patients who undergo potentially curative surgery, up to 50% do not recuperate enough to begin postoperative chemoradiation or require prolonged recovery to consider treatment. Moreover, rapid disease progression with early systemic relapse is not uncommon after surgery. Therefore, neoadjuvant therapy followed by surgery offers some theoretical advantages over immediate surgery.
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Patients who present with potentially resectable disease are generally physiologically fit and make attractive candidates for neoadjuvant therapy. Preoperative therapy allows delivery of chemotherapy or chemoradiation to a relatively well-perfused tumor bed and provides early treatment to microscopic metastases. Positive surgical margins are commonly reported after up-front resection; this is associated with poor prognosis, suggesting that surgery alone provides inadequate local control. Preoperative therapy may provide for sufficient tumor destruction, particularly at the periphery, to increase the chances of a margin-negative resection. Preoperative therapy also allows for observation of the tumor’s underlying biology, and those with aggressive disease are spared a major surgical procedure.
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Five preoperative trials have been completed at MDACC (Table 21-6) (57,58,59,60,61). These trials, performed in sequence, have had nearly identical inclusion criteria, with standardized radiographic criteria for resectability, surgical technique, and assessment of resection margins. Our data demonstrated that preoperative therapy is associated with a relatively low local failure rate compared to adjuvant therapy and, over time, modest improvements in overall survival, especially with the use of gemcitabine over 5-FU or paclitaxel-based chemoradiation.
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In the work of Evans et al, a total of 86 patients received gemcitabine followed by chemoradiation, and 74% of them were able to undergo pancreaticoduodenectomy (57). The median survival was 34 months compared to 7 months for those who did not receive resection. The pattern of failure favored distant metastases; thus, a second trial was designed to increase the amount of systemic therapy. This trial enrolled 90 patients to receive gemcitabine with cisplatin followed by chemoradiation, and 66% underwent resection. The addition of cisplatin did not improve survival beyond gemcitabine alone (31 vs 34 months). While these studies were not designed to be compared to adjuvant trials, the median survival in both preoperative studies was notably better than that seen in the adjuvant data we have to date. In the gemcitabine-based chemoradiation trial, complete pathologic responses were observed in two surgical specimens. While preoperative chemoradiation has not been established as a standard approach, by using preoperative therapy, negative surgical margins are more frequently reported. While these are probably not sufficient to ensure cure, they are likely to be necessary for extended survival (Fig. 21-3).
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MDACC Approach to Adjuvant Therapy
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At MDACC, adjuvant therapy is delivered with the following principles:
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Patients must demonstrate adequate recovery from surgery to be considered for further treatment. This includes ample oral caloric intake and no significant impairment of the alimentary tract (delayed gastric emptying, dumping syndrome, uncontrolled pancreatic exocrine insufficiency). Adequate wound healing and absence of infection are also required. Patients should have a PS of 0 to 1.
Patients must have adequate hepatic and renal function with sufficient hematologic parameters to undergo cytotoxic therapy.
Restaging CT scans are obtained just prior to initiation of adjuvant therapy generally performed 6 to 10 weeks postoperatively. A serum CA19-9 level twice the upper limit of normal precludes patients from enrollment on adjuvant therapy on in-house protocols. Recent retrospective analysis suggested that 5% to 10% of patients who undergo surgery at MDACC will have early radiographic or serologic evidence of relapsing disease prior to initiation of adjuvant therapy. When this occurs, any further therapy is not considered adjuvant.
Chemotherapy plus or minus chemoradiation remains the foundation of adjuvant therapy.
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At MDACC, patients are encouraged to enroll in postoperative trials of adjuvant therapy. To extrapolate from the experience in locally advanced unresectable disease, patients benefiting from chemoradiation are those who have experienced stable disease with induction chemotherapy. Therefore, our approach at this time includes induction chemotherapy with gemcitabine or a gemcitabine-based doublet for 3 months followed by restaging scans. If no radiographic or serologic evidence of relapse is present at that time, chemoradiation with 5-FU or capecitabine is advised. Radiation is administered in a dose of 50.4 Gy in 28 fractions.
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Once postoperative therapy has been completed, patients are followed with restaging CT scans, chest x-ray, physical examination, and standard laboratory tests, including CA19-9 every 6 months for the first 5 years and annually thereafter. A rising CA19-9 after adjuvant therapy does not trigger further systemic therapy until clear evidence of relapse based on physical examination or radiographic studies. Scanning by PET is considered in this situation.
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MDACC Approach to Preoperative Therapy
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Patients with clinical and radiographic evidence of potentially resectable disease are generally advised to receive protocol-based preoperative therapy, which typically involves chemoradiation. Chemoradiation regimens have varied, and our most encouraging results have been achieved with our gemcitabine-based regimen. After chemoradiation is completed, patients are allowed to recover over 4 to 5 weeks prior to restaging studies. For patients with no clinical or radiographic evidence of metastatic disease and no contraindications to surgery, laparotomy proceeds. At the time of exploration, when no visible evidence of distant disease is encountered, pancreaticoduodenectomy is performed. Postoperatively, further chemotherapy or radiation may be delivered based on the final pathology and the consensus of the multidisciplinary group. Patients are then followed expectantly with periodic restaging studies as outlined previously. Patients who relapse with adequate PS are offered further systemic therapy on or off protocol.
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It is important to emphasize that we do not deliver preoperative therapy as a means of staging the primary tumor downward. The medical literature has scattered reports of neoadjuvant therapy being used to successfully stage down patients with locally advanced disease to the point of resectability (62). Caution is advised in interpreting these results because we believe it is possible to stage down patients with borderline or marginally resectable tumors (tumors that abut but do not encase the celiac artery or SMA). These tumors represent a discrete subset; their management, while similar, is more tailored. Figure 21-4 displays an algorithmic approach for resectable pancreatic cancer.
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MDACC Approach to Patients With Borderline Resectable Pancreatic Cancer
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As high-quality, dynamic-phase, helical CT scanning has developed, an appreciation for the existence of a distinct subset of tumors best described as borderline resectable or marginally resectable has emerged. In this situation, some authorities believe that up-front surgery is more likely to lead to an R1 or R2 rather than an R0 resection. This entity is defined as ≤180 tumor abutment of the SMA or celiac axis, short segment abutment or encasement of the common hepatic artery that is amenable to segmental resection and reconstruction, or short segment occlusion of the SMV, PV, or SMV-PV confluence with a normal SMV below and PV above the tumor to allow for reconstruction (63). Up to 40% of patients with borderline resectable disease have been seen at MDACC, and these patients have a median survival of more than 40 months.
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At MDACC, patients with marginally resectable tumors are typically treated with gemcitabine-based chemotherapy for an indefinite period of time, with restaging studies every 2 months. Treatment is continued to maximum benefit, as defined by a nadir in the CA19-9 level or best radiographic response. Thereafter, chemoradiation is delivered, and subsequent restaging studies are performed about 4 to 6 weeks after treatment is complete. Surgery will proceed if there has been some evidence of tumor response, and if no interval development of metastatic disease is apparent, an attempt at surgery will proceed. It remains unclear whether the staging of such tumors downward to technical resectability is of biological significance; therefore, at least 6 months generally elapse at MDACC prior to the contemplation of surgery.
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Management of Patients With Locally Advanced Disease
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Patients are defined as having locally advanced pancreatic cancer when there is radiographic evidence of SMA or celiac artery encasement, occlusion of the SMV-PV confluence, or significant involvement of the common hepatic artery originating from the celiac trunk. There should be no clinical or radiographic evidence of metastatic disease. Currently, roughly half of all patients present with locally advanced disease. As with resectable pancreatic cancer, an understanding of certain principles will aid in decision making.
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Locally advanced pancreatic cancer typically progresses over the course of some months. Local tumor progression with worsening pain, new or recurrent biliary obstruction, and gastric outlet obstruction represent difficult management problems. Development of metastatic disease is usually associated with worsening functional status and, unless preceded by a long progression-free interval, is rarely responsive to further therapy.
Assessment of response to therapy can be challenging. These tumors may be composed of small nests of adenocarcinoma surrounded by large areas of desmoplasia (Fig. 21-5). Even when cytotoxic therapy is effective, the desmoplastic component of the residual mass may not regress, and the overall tumor mass may appear unchanged. Furthermore, distinguishing the primary tumor mass from surrounding inflammatory changes can complicate the reliable measurement of tumors.
All surgical interventions should be considered carefully and be based on PS and life expectancy. Palliative nonsurgical procedures may produce results similar to those of aggressive surgery.
One of the primary reasons for considering chemoradiation for patients with locally advanced disease is palliation of pain. However, the clinical benefit associated with chemoradiation has not been rigorously studied. Minsky et al reported significant variations in the estimation of pain relief, with 31% to 77% of patients having improvement in pain after receiving chemoradiation for unresectable disease (64).
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Data Regarding Chemoradiation Based on 5-Fluoruracil
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Support for chemoradiation originates from studies performed by the GITSG. In the original study, patients with locally advanced pancreatic cancer were randomly assigned to receive 40 Gy of radiation plus 5-FU, 60 Gy plus 5-FU, or 60 Gy alone. The median survival was 10 months in each of the chemoradiation groups and 6 months for patients who received 60 Gy without 5-FU (65). Of note, these patients had undergone laparotomy and were surgically staged. Only those patients with disease confined to the pancreas and peripancreatic organs, regional lymph nodes, or regional peritoneum were eligible for the study. While this made for a more uniform study population, it also introduced significant selection bias: Enrollment was limited to rapidly recovering patients. In subsequent GITSG studies, neither doxorubicin used as a radiation sensitizer nor multidrug chemotherapy with streptozocin, mitomycin, and 5-FU (SMF) alone or continued after chemoradiation was found to be superior to 5-FU–based chemoradiation (66). Additional chemotherapy after 5-FU–based chemoradiation increased toxicity without apparent therapeutic benefit.
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In contrast to the results from the GITSG, an ECOG study suggested no benefit of chemoradiation over 5-FU alone (67). The ECOG study randomly assigned patients with locally advanced or incompletely resected pancreatic adenocarcinoma to receive chemoradiation (40 Gy and 600 mg/m2/d 5-FU for 3 days) or 5-FU alone (600 mg/m2/week). As in the GITSG studies, all patients were surgically staged and entered in the study within 6 weeks of surgery. The median survival was 8.3 months in the group that received chemoradiation and 8.2 months in the group that received 5-FU alone.
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More recent trials of chemoradiation for locally advanced pancreatic cancer have investigated continuous infusion 5-FU in combination with EBRT (external beam radiation). The ECOG performed a phase I study to determine the maximal tolerated dose (MTD) of prolonged infusional 5-FU when combined with EBRT to 59.4 Gy. The MTD of 5-FU was 250 mg/m2/d, with GI toxicity the dose-limiting factor (68). A subsequent study conducted in Japan demonstrated the feasibility of utilizing low-dose continuous infusion 5-FU (200 mg/m2/d) over 5.5 weeks combined with a single course of EBRT to 50.4 Gy. This was followed by weekly 5-FU treatments until disease progression. The median survival of treated patients was 10 months, similar to that of patients treated with bolus 5-FU and EBRT in the GITSG trials (69). Thus, while infusional 5-FU may provide greater radiosensitivity than bolus 5-FU, no clear survival advantage has been established. In general, for selected patients, treatment programs consisting of EBRT and chemotherapy may result in median survivals of approximately 10 to 12 months and a 2-year survival rate of 20%. Long-term survivors are rare.
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Concurrent Chemoradiation Versus Systemic Chemotherapy
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Chemoradiotherapy was compared with chemotherapy in a randomized trial by the French Fédération Francophone de Cancérologie Digestive (FFCD) group. In this study, chemoradiotherapy was administered in a dose of 60 Gy concurrently with cisplatin and 5-FU (continuous infusion at 300 mg/m2/d). The chemotherapy arm consisted of gemcitabine (1,000 mg/m2/week). Surprisingly, the overall survival was shorter in the chemoradiotherapy arm (70). Higher grade 3 to 4 toxicity rates were observed in the chemoradiotherapy arm compared with the chemotherapy arm (66% vs 40%, respectively), which may partially account for the worse survival.
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In 2008, ECOG 4201 compared chemoradiotherapy and chemotherapy alone in a phase III trial. Patients with locally unresectable disease were randomly assigned between chemoradiotherapy with concurrent gemcitabine followed by gemcitabine and gemcitabine alone. In the chemoradiotherapy arm, the total radiotherapy dose was 50.4 Gy with concurrent gemcitabine (600 mg/m2/week). The inclusion of 316 patients was planned, but the study closed after the inclusion of 74 patients because of low accrual. Median overall survival was slightly better in the chemoradiotherapy arm (11 vs 9.2 months, P = .044) (71). These results should be considered cautiously because of the limited number of patients included. A literature-based meta-analysis concluded that overall survival was not significantly different after chemoradiotherapy or chemotherapy (72).
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At the 2013 annual American Society of Clinical Oncology (ASCO) conference, Hammel and colleagues presented the final results of the phase III international LAP 07 study (73). The objective was to determine whether consolidative chemoradiotherapy affected overall survival in patients with inoperable locally advanced pancreatic cancer when tumors were controlled after 4 months of induction gemcitabine-based chemotherapy. Patients were randomly assigned to gemcitabine (1,000 mg/m2/week × 3) or gemcitabine plus erlotinib (100 mg/d) for 4 months. Participants with controlled disease were subsequently randomly assigned to further chemotherapy or chemoradiation (54 Gy [5 × 1.8 Gy/d] and capecitabine 1,600 mg/m2/d). Of the 442 patients initially randomly assigned, 269 patients (61%) entered the second-round randomization phase. A planned interim analysis was conducted after a median follow-up of 36 months and 221 deaths. Median overall survival in the chemotherapy arm was 16.4 months compared with 15.2 months for the chemoradiation group (hazard ratio [HR] 1.03, 95% CI, 0.79-1.34, P = .8295). It appeared neither radiation nor erlotinib improved survival in this population (73). However, administration of radiation did delay the institution of second-line chemotherapy for progressive disease, which had an impact on quality of life.
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Integration of Novel Agents Into Concurrent Chemoradiation Strategies
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Given the limited benefit noted with 5-FU–based chemoradiation, there has been an effort to incorporate alternative agents into concurrent therapies, including gemcitabine, paclitaxel, capecitabine, and targeted agents, including bevacizumab, cetuximab, and erlotinib. Because of its role in metastatic disease, gemcitabine with EBRT has been extensively investigated for patients with localized cancer. Currently, there is no compelling evidence to suggest improved survival using gemcitabine-based chemoradiation over 5-FU for patients with locally advanced disease. Li et al conducted a small randomized trial that directly compared 5-FU–based chemoradiation with gemcitabine-based chemoradiation. Median survival for the 18 patients randomized to receive gemcitabine with EBRT was 14.5 months, compared with 6.7 months in 16 patients treated with 5-FU. This trial should be interpreted with caution, given the small sample size and poor outcome of patients treated with 5-FU and EBRT (74). Another prospective study compared FU with cisplatin-gemcitabine–based chemoradiation and did not demonstrate any difference in overall survival (75).
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At present, there is no standard approach, dose, or schedule for gemcitabine combined with radiation. Based on completed phase I and II studies, we have defined the MTD of gemcitabine, associated toxicity, and the size of radiation port (76). 5-Fluorouracil or capecitabine-based chemoradiation is now standard at MDACC for locally advanced pancreatic cancer.
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At MDACC, investigations of novel agents used after chemoradiation have been conducted. In RTOG 0411, patients with locally advanced pancreatic cancer were treated with capecitabine, bevacizumab, and radiation followed by maintenance with capecitabine and bevacizumab. The overall median survival reported was 11 months, which is similar to previous RTOG trials that did not include bevacizumab (77).
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Systemic chemotherapy alone may improve both pain control and PS and avoids the GI toxicity associated with chemoradiation. For those patients with stable or responding disease after 4 to 6 months of treatment, chemoradiation is often delivered to maximize locoregional tumor control. Chemoradiation is applied only to the patients most likely to benefit as defined by the absence of disease progression during systemic therapy. This strategy was validated by the Groupe Cooperateur Multidisciplinaire en Oncologie (GERCOR) group, who performed a retrospective analysis of patients with locally advanced cancer who received chemoradiation. Investigators noted that 30% of patients developed metastatic disease after induction chemotherapy and were not candidates for radiation. The remaining 70% received continued chemotherapy or consolidative chemoradiation. The overall survival in the two groups was 12 and 15 months (P = .0009) and the progression-free survival was 7 and 11 months, respectively. These data support the strategy of consolidative chemoradiation following induction chemotherapy in patients with locally advanced disease (78). Retrospective data from MDACC also strongly suggested that patients who have received induction chemotherapy have a better outcome than those receiving primary chemoradiation (79).
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MDACC Approach to Locally Advanced Pancreatic Cancer
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For patients who have poor PS, supportive care is encouraged, and radiation is contraindicated. In the subgroup of patients with significant pain related to the primary tumor, aggressive use of narcotics is initiated. For patients with poor tolerance of narcotics or inadequate pain control with their administration, celiac or splanchnic nerve block is recommended. Once pain control has improved, therapeutic options are discussed. In our institution, consolidative chemoradiation continues to be used in select cases after an informative discussion with the patient regarding the issues mentioned. When so chosen, at least 3 to 4 months of induction chemotherapy with a gemcitabine-based regimen followed by capecitabine or 5-FU and radiation is the favored approach. Figure 21-6 shows the MDACC protocol for treatment of patients with locally advanced disease.
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Management of Metastatic Disease
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Compared with patients having other common malignancies, such as cancer of the colon or breast, patients with advanced pancreatic cancer are often much more debilitated. Palliation remains the primary goal of therapy. Management of metastatic disease should be guided by the following principles:
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The disease course may be quite dynamic, and the clinical status of a patient can change quickly. Patients therefore require frequent reassessment, whether or not they are undergoing cytotoxic therapy.
Pancreatic cancer is quite resistant to systemic therapy, and responses to therapy are rarely observed in patients with poor PS or high tumor burden.
Peritoneal disease is usually not responsive to chemotherapy and carries a particularly poor prognosis. Metastatic disease predominantly located in the liver or lung is more likely to be responsive to systemic therapy. When the disease is metastatic to the lung only, its course may be somewhat more indolent.
Improvement in the treatment for pancreatic cancer is desperately needed, and patients with good PS should be encouraged to participate in clinical trials.
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Systemic Therapy for Metastatic Disease—Lessons From the Past
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Early published data frequently reported response rates to chemotherapy exceeding 20%. However, with the advent of high-quality CT and MRI, substantially lower response rates have been reported. Importantly, cooperative group studies dating to the 1980s have not clearly demonstrated meaningful survival advantage for patients treated with single-agent chemotherapy compared with 5-FU combinations or even best supportive care. Thus, for many years, no standard drug or drug regimen had emerged as an accepted frontline therapy for metastatic pancreatic cancer.
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Gemcitabine for Metastatic Pancreatic Cancer
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Chemotherapy for pancreatic cancer changed with the advent of gemcitabine, which was developed in the 1990s. In an early multicenter trial of gemcitabine in 44 patients, 5 objective responses (11%) were documented (80). In another study, gemcitabine again led to few objective responses (2 of 32 patients), but symptomatic improvement was also reported (81). Based on these observations, two subsequent trials of gemcitabine for advanced pancreatic cancer were completed. In the randomized trial that led to gemcitabine’s approval in the United States, weekly gemcitabine was compared to bolus weekly 5-FU in previously untreated patients (82). Patients treated with gemcitabine achieved a higher response rate (5.4% vs 0%) and a statistically significant improvement in median survival compared to those treated with 5-FU (5.65 vs 4.41 months, P = .0025). The 1-year survival rate for gemcitabine-treated patients was 18%, compared to 2% for those treated with 5-FU. Importantly, more clinically meaningful effects on disease-related symptoms were recorded with gemcitabine. This trial enrolled a heterogeneous patient population, with patients having either locally advanced, unresectable disease or metastatic disease. About 70% of the treated patients had metastatic pancreatic cancer, and this is the basis for its use as frontline therapy in patients with disseminated disease.
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Gemcitabine is a prodrug that is phosphorylated to its active metabolites gemcitabine diphosphate and triphosphate. Gemcitabine diphosphate inhibits ribonucleotide reductase, thereby depleting intracellular pools of the triphosphate nucleotides. Gemcitabine triphosphate can incorporate into an elongating chain of DNA and lead to premature chain termination and cell death. Gemcitabine triphosphate may also inhibit normal DNA repair mechanisms. This may explain its potent radiosensitizing properties and synergy with other DNA-damaging cytotoxic agents.
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Once phosphorylated intracellular concentrations are highest when the drug is given at a fixed-dose rate (FDR) of 10 mg/m2/min. A randomized phase II trial in metastatic pancreatic cancer demonstrated that gemcitabine given at 2,300 mg/m2 over 30 min compared to 1,500 mg/m2 delivered over 150 min (10 mg/m2/min) led to a higher objective response rate (16.2 vs 2.7%) and a trend toward improved survival (6.1 vs 4.7 months) (83). Therefore, when used off protocol, it is administered at an FDR.
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Gemcitabine Combinations: Cytotoxic Agents
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In an effort to build on gemcitabine for advanced cancer, one approach has been to combine gemcitabine with other cytotoxic drugs. In addition, regimens using two to four other drugs with gemcitabine are reported in the literature. These include combinations of gemcitabine, capecitabine, and docetaxel (GTX) and gemcitabine, 5-FU, leucovorin, irinotecan, and cisplatin (G-FLIP). Randomized trials of gemcitabine versus gemcitabine-based doublets of cytotoxic therapy have shown no statistically significant survival advantage (Table 21-7). However, gemcitabine combined with a platinum does appear to have some benefit in patients with good PS (84).
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Recent Trials Evaluating Combination Therapy
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Cancer and Leukemia Group B (CALGB) 89904 was a four-arm phase II study comparing FDR gemcitabine with the gemcitabine doublets cisplatin, docetaxel, and irinotecan. Six-month survival, the primary end point, did not differ significantly between the four arms (range 53%-57%) (85). Overall survival was also similar across groups. A phase III trial combining gemcitabine and cisplatin had a non–statistically significant improvement in progression-free and median survival over single-agent gemcitabine (median survival 7.5 vs 6.0 months, P = .15) (86). Similarly, a phase III trial evaluating the combination of gemcitabine and irinotecan versus gemcitabine alone failed to demonstrate a survival advantage over gemcitabine (87).
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Previously, the GERCOR/GISCAD (Italian Group for the Study of Digestive Tract Cancer) phase III trial with FDR gemcitabine and oxaliplatin demonstrated a statistically significant higher response rate and progression-free survival in patients with locally advanced and metastatic disease; however, overall survival did not reach statistical significance (9.0 vs 7.1 months, P = .13) (88). ECOG 6201 enrolled 832 patients in three arms: gemcitabine in a 30-minute infusion, FDR gemcitabine, and FDR gemcitabine with oxaliplatin. Overall survival was not statistically different between the three groups: 4.9, 6.2, and 5.7 months, respectively (89).
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It was not until September 2013 when the Food and Drug Administration (FDA) first approved a gemcitabine-based combination chemotherapy regimen with nab-paclitaxel. This was based on a follow-up phase III study published in the New England Journal of Medicine that showed an overall survival advantage of gemcitabine plus nab-paclitaxel over gemcitabine alone (8.5 months vs 6.7 months, HR for death, 0.72; 95% CI, 0.62 to 0.83; P < .001). The 1-year survival rates were 35% versus 22%, respectively. The response rate according to independent review was 23% versus 7% in the two groups (P < .001). The combination arm did have increased neutropenia, fatigue, and neuropathy (90).
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Capecitabine, the orally bioavailable fluorinated pyrimidine, when combined with gemcitabine, demonstrated a modest clinical benefit over gemcitabine alone and appeared to improve median overall survival in patients with good PS (91). In a phase III trial, Cunningham and colleagues randomized patients to receive gemcitabine versus gemcitabine plus capecitabine (gemcitabine 1,000 mg/m2 IV weekly × 3 every 4 weeks; capecitabine 1,660 mg/m2/d by mouth for 3 weeks and 1 week’s rest) (92). The addition of capecitabine to gemcitabine significantly improved overall response rate and progression-free survival (P = .03 and .004, respectively) and trended toward an improved overall survival (P = .08).
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Based on preclinical data showing effectiveness of combination chemotherapy in solid tumors, investigators tested a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine. There was random assignment of 342 patients with an ECOG PS of 0 or 1 to receive FOLFIRINOX (oxaliplatin, 85 mg/m2 body surface area; irinotecan, 180 mg/m2; leucovorin, 400 mg/m2; and fluorouracil, 400 mg/m2 given as a bolus followed by 2,400 mg/m2 given as a 46-hour continuous infusion every 2 weeks) or gemcitabine at a dose of 1,000 mg/m2 weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. The primary end point was overall survival. The median overall survival was 11.1 months in the FOLFIRINOX group as compared to 6.8 months in the gemcitabine group (HR for death, 0.57; 95% CI, 0.45 to 0.73; P < .001). The objective response rate was also improved in the FOLFIRINOX group, 31.6% versus 9.4% (P < .001). More adverse events were noted in the FOLFIRINOX group. At 6 months, 31% versus 66% of patients in the FOLFIRINOX versus gemcitabine group had a definitive degradation of the quality of life (HR, 0.47; 95% CI, 0.30 to 0.70; P < .001) (93).