Neoadjuvant therapy is an attractive approach with the promise of clinical benefit for patients with surgically resectable pancreatic cancer. However, clinical trial results in support of this approach remain unconvincing.
Oncology (Williston Park). 32(1):39, 42-44.
Pablo Sala Elarre, MD
Kenneth H. Yu, MD
Neoadjuvant therapy is an attractive approach with the promise of clinical benefit for patients with surgically resectable pancreatic cancer. However, clinical trial results in support of this approach remain unconvincing. It is our position that neoadjuvant therapy should not be used routinely outside of a clinical trial. Surgical resection remains a critical component of curing patients who present with early-stage pancreatic cancer. Due to the absence of specific symptoms and the aggressive tumor biology of pancreatic cancer, only 15% of patients present with early-stage disease that allows for surgical resection.[1,2] Furthermore, the vast majority of patients undergoing surgical resection will experience disease recurrence, and the 5-year survival rate post resection ranges from 7% to 25%.[3,4] Recent studies have focused on multimodality approaches to improve survival outcomes, integrating chemotherapy and radiation therapy (RT) in the adjuvant and neoadjuvant settings.
Adjuvant chemotherapy remains a standard of care, and was first definitively shown to improve outcomes in the CONKO-001 study. Patients treated with adjuvant gemcitabine in addition to surgery experienced superior 5-year survival rates (20.7% vs 10.4% with surgery alone) and overall survival (22.8 months vs 20.2 months). More recent studies have looked at combination chemotherapy, and results of the ESPAC-4 study further support the benefit of this approach. Patients receiving adjuvant chemotherapy with a combination of gemcitabine and capecitabine experienced superior 5-year survival rates (28.8% vs 16.3%) and overall survival (28 months vs 25.5 months) compared with patients who were treated with adjuvant gemcitabine alone. At Memorial Sloan Kettering Cancer Center, adjuvant combination treatment with gemcitabine and capecitabine after surgical resection is now considered a standard approach for the treatment of surgically resectable pancreatic cancer. One adjuvant study that recently completed accrual is APACT, which is evaluating the effectiveness of a combination of gemcitabine and nab-paclitaxel. We eagerly await the results of APACT and are hopeful that this regimen will further improve outcomes for our early-stage patients.
The use of adjuvant chemoradiotherapy for patients with resected pancreatic cancer is controversial, with published studies in the literature suggesting either modest benefit[7,8] or possible detriment. Therefore, the role of RT in the adjuvant setting remains undefined. We are hopeful that the ongoing Radiation Therapy Oncology Group 0848 study (ClinicalTrials.gov identifier: NCT01013649) will settle the question once and for all. This randomized study will determine whether adjuvant gemcitabine/combination cytotoxic chemotherapy, administered either as single modality or followed by concurrent fluoropyrimidine and RT, delivers superior survival outcomes.
The role of RT in the neoadjuvant setting is equally unclear. Several phase II studies have been completed, with mixed results. Overall, there are no convincing data to support a role for RT in the neoadjuvant setting. In the absence of conclusive data, current guidelines from the American Society of Clinical Oncology suggest the use of chemoradiation following 4 to 6 months of adjuvant chemotherapy in cases of R1 resection and/or node-positive disease. We are hopeful that new radiation techniques, such as intensity-modulated RT and stereotactic body RT, will improve efficacy without added toxicity,[11,12] and that ongoing studies, such as the Alliance A021501 study (ClinicalTrials.gov identifier: NCT02839343) of neoadjuvant folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) with or without hypofractionated RT, will provide a more definitive answer to the question of whether RT has added benefit in the neoadjuvant treatment of resectable pancreatic cancer.
Based on the encouraging results of the aforementioned recent studies of adjuvant chemotherapy in patients with resected pancreatic cancer, and the development of more effective-albeit more toxic-combination chemotherapy regimens such as FOLFIRINOX and gemcitabine with nab-paclitaxel, there has been great interest in the investigation of neoadjuvant chemotherapy approaches. For the time being, however, neoadjuvant chemotherapy should be administered to patients with early-stage resectable pancreatic cancer only as part of a clinical trial, and should not be used as part of standard clinical practice. In the era of evidence-based medicine, the strongest argument for this position is that we do not have results from any large randomized studies to support the superior efficacy of neoadjuvant chemotherapy compared with adjuvant chemotherapy. The available data are limited to results of small phase II studies and retrospective analyses.
The theoretical benefits of delivering combination chemotherapy in the neoadjuvant setting are attractive. Pancreatic cancer is widely accepted as a systemic disease. Therefore, aggressive chemotherapy given early could potentially eradicate micrometastases. Furthermore, due to surgical complications, many patients cannot tolerate adjuvant chemotherapy. However, these potential advantages must be weighed against equally important disadvantages. For example, not all tumors will respond to chemotherapy, allowing some resectable tumors treated with neoadjuvant chemotherapy to become unresectable due to local progression or metastasis. Regimens such as FOLFIRINOX and combination treatment with gemcitabine plus nab-paclitaxel can cause toxicities such as nausea, vomiting, diarrhea, and infection. Patients who experience severe treatment toxicity may have resection of their cancer delayed, or they may become poor surgical candidates. In a phase II study performed at Memorial Sloan Kettering Cancer Center, using neoadjuvant gemcitabine with oxaliplatin, 8 of 35 patients (23%) were not resected due to disease progression and 3 of 38 patients (8%) were not resected due to toxicities or clinical deterioration. Finally, these regimens can cause neuropathy and paresthesia, which in turn can have a negative long-term impact on patients’ quality of life. Results of small phase II studies performed over the past decade (recently reviewed by Sohal) are inconclusive. Resection rates varied widely among these studies, ranging from 38% to 89%, and overall survival ranged from 9.9 months to 27.2 months. None of these studies report results using the newest, most active combination chemotherapy regimens (FOLFIRINOX or the combination of gemcitabine with nab-paclitaxel).
A recently published analysis of outcomes of early-stage pancreatic cancer from the National Cancer Database (2006–2013) compared upfront resection and adjuvant treatment against neoadjuvant therapy followed by surgery. Although a modest survival benefit was shown in the neoadjuvant treatment group, this analysis should be viewed as hypothesis-generating only, since there was significant variation in the types of treatment regimens used and the results are limited by the retrospective and uncontrolled nature of the included studies. A second study, a meta-analysis looking at a broader range of studies from 1966 through 2009, concluded that resection rates and survival outcomes did not differ between patients who received neoadjuvant chemotherapy and patients who were treated with upfront resection followed by adjuvant chemotherapy.
As previously discussed, patients may be better able to complete a full course of neoadjuvant chemotherapy compared with adjuvant chemotherapy, due to worse tolerance of systemic therapy in the postoperative setting. As an example, in the ESPAC-4 study, only 54% of patients in the combination chemotherapy group and 65% of patients in the mono-chemotherapy group completed their course of adjuvant therapy. However, while other studies show that multimodality neoadjuvant programs do not increase high-grade postoperative complications, it remains to be seen whether these findings hold up when more toxic combination chemotherapeutic regimens are used.
Only two phase III trials have been published that compare neoadjuvant multimodality therapy with upfront surgery in resectable pancreatic cancer.[19,20] Both studies were underpowered due to difficulty with patient recruitment, with no possibility to draw any meaningful practice-changing conclusions. A number of important clinical trials addressing the issue of neoadjuvant and perioperative chemotherapy are underway. Two studies in particular are designed to answer the specific question of neoadjuvant vs adjuvant treatment with modern combination chemotherapy. NEPAFOX (ClinicalTrials.gov identifier: NCT02172976) is a randomized phase II/III study of adjuvant gemcitabine vs perioperative FOLFIRINOX chemotherapy in patients with resectable or borderline resectable disease. NEONAX (ClinicalTrials.gov identifier: NCT02047513) is a randomized phase II study of adjuvant plus neoadjuvant vs only adjuvant therapy with gemcitabine plus nab-paclitaxel in resectable pancreatic cancer. We eagerly await the results of these studies, and are hopeful that they will provide clear guidance regarding which chemotherapy regimen to give which patient, and when.
In conclusion, the preponderance of data continues to support adjuvant chemotherapy as the standard of care for patients with resectable pancreatic cancer. The development of active combination chemotherapy regimens has created the opportunity to improve the prognosis of these patients. While neoadjuvant chemotherapy holds great promise, this approach cannot be recommended outside of the clinical trial setting. It is hoped that, in the coming years, the results of ongoing clinical trials will clarify the best approach to the management of resectable pancreatic cancer.
Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Al-Hawary MM, Francis IR, Chari ST, et al. Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the Society of Abdominal Radiology and the American Pancreatic Association. Radiology. 2014;270:248-60.
2. Kamarajah SK, Burns WR, Frankel TL, et al. Validation of the American Joint Committee on Cancer (AJCC) 8th edition staging system for patients with pancreatic adenocarcinoma: a Surveillance, Epidemiology, and End Results (SEER) analysis. Ann Surg Oncol. 2017;24:2023-30.
3. Nitecki SS, Sarr MG, Colby TV, van Heerden JA. Long-term survival after resection for ductal adenocarcinoma of the pancreas: is it really improving? Ann Surg. 1995;221:59-66.
4. Trede M, Schwall G, Saeger HD. Survival after pancreatoduodenectomy: 118 consecutive resections without an operative mortality. Ann Surg. 1990;211:447-58.
5. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: the CONKO-001 randomized trial. JAMA. 2013;310:1473-81.
6. Neoptolemos JP, Palmer DH, Ghaneh P, et al. Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. Lancet. 2017;389:1011-24.
7. Klinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC Gastrointestinal Tract Cancer Cooperative Group. Ann Surg. 1999;230:776-82.
8. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized controlled trial. JAMA. 2008;299:1019-26.
9. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350:1200-10.
10. Khorana AA, Mangu PB, Berlin J, et al. Potentially curable pancreatic cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2016;34:2541-56.
11. Herman JM, Chang DT, Goodman KA, et al. Phase 2 multi-institutional trial evaluating gemcitabine and stereotactic body radiotherapy for patients with locally advanced unresectable pancreatic adenocarcinoma. Cancer. 2015;121:1128-37.
12. Park JJ, Hajj C, Reyngold M, et al. Stereotactic body radiation vs. intensity-modulated radiation for unresectable pancreatic cancer. Acta Oncol. 2017;56:1746-53.
13. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364: 1817-25.
14. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med. 2013;369:1691-703.
15. O’Reilly EM, Perelshteyn A, Jarnagin WR, et al. A single-arm, nonrandomized phase II trial of neoadjuvant gemcitabine and oxaliplatin in patients with resectable pancreas adenocarcinoma. Ann Surg. 2014;260:142-8.
16. Sohal DPS. Adjuvant and neoadjuvant therapy for resectable pancreatic adenocarcinoma. Chin Clin Oncol. 2017;6:26.
17. Mokdad AA, Minter RM, Zhu H, et al. Neoadjuvant therapy followed by resection versus upfront resection for resectable pancreatic cancer: a propensity score matched analysis. J Clin Oncol. 2016 Sep 12. [Epub ahead of print]
18. Gillen S, Schuster T, Meyer Zum BÃ¼schenfelde C, et al. Preoperative/neoadjuvant therapy in pancreatic cancer: a systematic review and meta-analysis of response and resection percentages. PLoS Med. 2010;7:e1000267.
19. Golcher H, Brunner TB, Witzigmann H, et al. Neoadjuvant chemoradiation therapy with gemcitabine/cisplatin and surgery versus immediate surgery in resectable pancreatic cancer: results of the first prospective randomized phase II trial. Strahlenther Onkol. 2015;191:7-16.
20. Casadei R, Di Marco M, Ricci C, et al. Neoadjuvant chemoradiotherapy and surgery versus surgery alone in resectable pancreatic cancer: a single-center prospective, randomized, controlled trial which failed to achieve accrual targets. J Gastrointest Surg. 2015;19:1802-12.