Adjuvant Chemoradiation Trials Involving Gemcitabine(Drug information on gemcitabine)
Unlike in parts of Europe, where the focus of adjuvant therapy has been chemotherapy, adjuvant chemoradiation continues to be utilized in the United States. The Radiation Therapy Oncology Group (RTOG) 9704 study was a randomized trial comparing adjuvant 5-FU–based chemotherapy to gemcitabine-based chemotherapy, with both regimens implementing CRT. Patients with resected pancreatic adenocarcinoma were randomly assigned to receive either continuous infusion 5-FU (250 mg/m2/day) or gemcitabine (1000 mg/m2 weekly) for 3 weeks prior to CRT and for 12 weeks after CRT. CRT in both groups consisted of 50.4 Gy delivered with continuous infusion 5-FU (250 mg/m2/day). Prospective quality assurance of all RT plans was required. This trial was powered to demonstrate a survival benefit for the entire cohort and for the subgroup of patients with pancreatic head lesions. On initial analysis of the pancreatic head subgroup, a non-significant trend toward improved median survival and 3-year OS was seen in the gemcitabine arm: 20.5 months vs 16.9 months, and 31% vs 21%, respectively. However, a higher incidence of ≥ grade 3 hematologic toxicity was also seen in the gemcitabine group, with no significant differences seen in severe nonhematologic toxicities. A recent update of this trial reported median survival and 5-year OS rates in patients with pancreatic head tumors of 20.5 months and 22% in those who received gemcitabine, compared with 17.1 months and 18% in those who received 5-FU. On multivariate analysis, in the subgroup of patients with pancreatic head lesions who received gemcitabine, there was a nonsignificant trend toward improved OS (P = .08).
A secondary aim of RTOG 9704 was to assess the ability of post-resection CA 19-9 levels to predict survival. When CA 19-9 levels were analyzed in a cohort of 385 patients as a dichotomized variable (<180 IU/mL vs ≥ 180 IU/mL, ≤90 IU/mL vs > 90 IU/mL), there was a significant survival difference favoring patients with CA 19-9 levels of less than 180 IU/mL. This corresponded to a 72% reduction in the risk of death. A major strength of the RTOG study was the rigorous, centralized quality control of RT techniques and delivery. A recent analysis demonstrated that patients treated per study guidelines had a significant survival advantage, indicating the importance of centralized review and treatment technique in this disease.
In RTOG 9704, 28% of patients experienced local recurrence as the first site of relapse, which is considerably lower than the rates in previously discussed randomized trials and historical series involving chemotherapy-alone approaches. However, distant failure as first site of relapse remained high at 73%. These high rates of distant failure and the need for more effective systemic therapy, as well as controversy surrounding the role of CRT in resected patients, led to the design of the current, multinational RTOG 0848/EORTC trial discussed below.
The RTOG 0848/EORTC trial randomly assigns patients with resected pancreatic head adenocarcinoma (stratified based on CA 19-9 level and nodal and margin status) to receive treatment with either gemcitabine alone or gemcitabine combined with erlotinib (Tarceva) for five cycles. If no progression is seen on restaging studies following the completion of systemic therapy, patients are further randomized to receive an additional cycle of the previously administered chemotherapy (for a total of six cycles) with or without CRT (50.4 Gy) using modern radiation techniques/central RT quality assurance, with concurrent capecitabine(Drug information on capecitabine) (Xeloda) or 5-FU (Figure). This trial seeks to answer two primary questions: 1) what is the role of the small-molecule epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in the adjuvant therapy of pancreatic cancer? and 2) what is the role of CRT in the era of modern chemotherapy, particularly in patients who do not experience early disease progression? This is the only contemporary randomized clinical trial evaluating the role of CRT in the adjuvant setting.
In addition to the randomized studies above, several large, single-institution series have suggested a benefit for adjuvant CRT. A review of the Mayo Clinic experience reported the outcomes of 472 patients who underwent R0 resection between 1975 and 2005. Despite more adverse prognostic features in patients receiving CRT (higher histological grade and greater lymph node involvement), median survival, 2-year OS, and 5-year OS were significantly improved in the CRT cohort compared with patients who received no adjuvant therapy: 25.2 months vs 19.2 months, 50% vs 39%, and 28% vs 17%, respectively. A similar series from Johns Hopkins compared 908 patients who underwent pancreaticoduodenectomy between 1993 and 2005 and received surgery alone or CRT. Patients receiving CRT experienced a significant improvement in median survival, 2-year OS, and 5-year OS: 21.2 months vs 14.4 months, 43.9% vs 31.9%, and 20.1% vs 15.4%, respectively. Despite the inherent biases of non-randomized, retrospective trials, these data, along with data on the patterns of failure in the above randomized studies, suggest that there are patient subgroups that stand to benefit from the addition of CRT to surgical resection.
In other gastrointestinal malignancies (ie, rectum, esophagus), the use of neoadjuvant CRT has become standard practice. Given the potential for significant delays in the delivery of adjuvant therapy in up to one third of patients following surgical resection and the modest survival gains associated with adjuvant therapy, delivery of neoadjuvant therapy offers a potentially attractive alternative. Potential advantages of preoperative therapy include an undisrupted tumor vasculature, which allows for improved delivery of chemotherapy and radiosensitizing oxygenation. Downstaging may occur, potentially allowing the resection of more advanced lesions and sterilization of the operative region, which may reduce the risk of spread during surgical manipulation. Preoperative treatment also avoids delay in adjuvant therapy delivery due to postoperative recovery, and importantly, avoids potentially morbid radical resection in patients with rapidly progressive disease. Finally, neoadjuvant CRT has also been associated with a reduction in the incidence of pancreatic leak, as well as leak-associated morbidity and mortality.
Unlike with adjuvant therapy, no phase III randomized trials of neoadjuvant CRT have been performed, and the vast majority of data come from phase II and retrospective studies (Table 2). The evolution of CRT in the neoadjuvant setting appears to parallel advances made with adjuvant therapy, with its transition to gemcitabine-containing regimens. In 2008, two published phase II studies from MD Anderson Cancer Center evaluated the use of gemcitabine as part of a neoadjuvant regimen. One trial enrolled 86 patients with radiographically resectable adenocarcinoma of the pancreatic head/uncinate. Patients received weekly gemcitabine (400 mg/m2) with 30 Gy RT over 2 weeks. After restaging 4 to 6 weeks post-CRT, 73 patients (85%) underwent surgery, with 64 (74%) undergoing successful resection. Median survival in resected vs unresected patients was 34 months vs 7 months, with corresponding 5-year OS rates of 36% and 0%, respectively. In patients undergoing pancreaticoduodenectomy, only 11% experienced local failure, with distant failure accounting for the majority of the mortality.
Given the high incidence of distant disease development, a simultaneously conducted phase II trial incorporated cisplatin(Drug information on cisplatin) (CDDP) and gemcitabine prior to initiation of CRT with gemcitabine. Induction chemotherapy consisted of CDDP (30 mg/m2) and gemcitabine (750 mg/m2) every 2 weeks for four cycles followed by four weekly infusions of gemcitabine (400 mg/m2) together with 30 Gy RT. Sixty-two patients (78%) underwent surgery, and 52 (66%) had successful resection. The median survival for patients undergoing surgery was 31 months, compared with 10.5 months in the unresected patients.
A recent review of the Surveillance, Epidemiology, and End Results (SEER) database also supports the use of neoadjuvant treatment. This analysis included 3,885 patients treated for resectable pancreatic cancer: 70 patients (2%) received neoadjuvant RT, 1,478 (38%) received adjuvant RT, and 2,337 (60%) were treated with surgery alone. Given that the SEER database does not provide information on administration of CT, this variable could not be assessed. Median OS was 23 months in patients receiving neoadjuvant RT, 17 months in those who received adjuvant RT, and 12 months in the surgery-alone cohort.
Despite the potential advantages and encouraging results using a neoadjuvant CRT approach, no randomized trial results exist comparing neoadjuvant to adjuvant therapy, and its role continues to be investigated. A multicenter randomized phase II study evaluating neoadjuvant therapy in pancreatic carcinoma is currently recruiting. This multinational study is comparing outcomes of patients with resectable disease treated with neoadjuvant gemcitabine-based CRT followed by surgery to outcomes in patients undergoing upfront surgery. Resection is followed by adjuvant gemcitabine-based chemotherapy in both arms.
Emerging Radiotherapy Technologies
Intensity-modulated radiotherapy (IMRT) is a technique that breaks up a typical radiation treatment field into smaller "beamlets." It is implemented either as dynamic IMRT (collimating leaves move in and out of the radiation beam path during treatment) or as "step and shoot" IMRT (leaves change field shape while the machine is off). The cumulative effect is that the prescription dose conforms around delineated target volumes, significantly reducing doses to adjacent normal tissues. This technology has increasingly been used in a number of gastrointestinal malignancies, including pancreatic cancer. Early clinical data support both the feasibility of this technique and its potential for reducing acute gastrointestinal toxicity.[29-31] An analysis from the University of Maryland evaluated 46 patients treated with IMRT and concurrent 5-FU–based chemotherapy. Acute toxicities in these patients were compared with those in a control group enrolled in RTOG 9704 who received conventional 3D treatment. There was a statistically significant reduction in acute grade 3-4 GI toxicity in the patients who received radiotherapy via IMRT compared with those who received 3D conformal radiotherapy. IMRT can also result in a significant reduction of dose to normal structures, including the liver, kidneys, stomach, and small bowel. This may allow alternate novel systemic agents to be administered with radiotherapy.
Another radiation technique being investigated in the treatment of pancreatic cancers is stereotactic body radiotherapy (SBRT). SBRT involves the delivery of high dose-per-fraction radiation treatments over a small number of fractions (generally 1 to 5 treatments), utilizing techniques that permit very highly conformal dose delivery of external beam radiotherapy. The postulated advantage of SBRT is that it can potentially improve local control through the delivery of ablative doses of radiation, while minimizing associated side effects. Few institutions have published experience utilizing this technique, and the data are largely in the setting of locally advanced disease.[32,33] Stanford University has implemented an institutional protocol for the treatment of locally advanced pancreatic cancer utilizing 25 Gy single fraction with systemic therapy. This single, high dose of radiation has been estimated to result in delivery of a higher biologically equivalent dose compared with more standard, protracted course radiation therapy, although there is also a potential for increased risk of injury to normal tissue. A recent report from these investigators described 77 patients treated with SBRT and found that freedom from local progression was 91% at 6 months and 84% at 12 months. No patients experienced grade 3 acute toxicity and 9% had ≥ grade 3 late toxicity. Ultimately the role of IMRT and SBRT in treatment of pancreatic cancer remains to be further defined.
Older trials evaluating outcomes of CRT, CT, and surgery alone in patients with resected pancreatic cancer are fraught with flaws. Despite this, adjuvant CT alone has evolved and remains the standard of care in the adjuvant treatment of resectable pancreatic cancer throughout much of Europe. In the United States, the role of CRT continues to be redefined in the era of modern chemotherapeutics. The currently active RTOG 0848/EORTC study will help not only to further clarify the role of CRT, but also to assess the utility of small-molecule EGFR therapy in the treatment of this disease. The use of neoadjuvant CRT in patients with resectable disease offers potential advantages as well as promising local control and survival results based on institutional data, although randomized trials are lacking.
Despite advances in many aspects of oncologic evaluation and management, including preoperative evaluation (endoscopic ultrasound, computed tomography), surgical techniques, perioperative care, systemic therapy, and radiotherapy, the 5-year OS rate for patients with resectable pancreatic cancer remains approximately 20%. Further advances in systemic therapies, study of the optimal sequencing of therapies, earlier detection of disease, and development of new and novel therapeutic options are urgently needed in the treatment of this formidable disease.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.