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Correspondence to: Michele Molinari, MD, MSc, Senior Scientist, Surgeon, Associate Professor, Department of Surgery, University of Pittsburgh Medical Center, 3459 Fifth Avenue, N758, Pittsburgh, PA 15213, United States. ude.cmpu@miranilom
Telephone: +1-412-6475734 Fax: +1-412-6475736
The use of neoadjuvant therapies has played a major role for borderline resectable and locally advanced pancreatic cancers (PCs). For this group of patients, preoperative chemotherapy or chemoradiation has increased the likelihood of surgery with negative resection margins and overall survival. On the other hand, for patients with resectable PC, the main rationale for neoadjuvant therapy is that the overall survival with current strategies is unsatisfactory. There is a consensus that we need new treatments to improve the overall survival and quality of life of patients with PC. However, without strong scientific evidence supporting the theoretical advantages of neoadjuvant therapies, these potential benefits might turn out not to be worth the risk of tumors progression while waiting for surgery. The focus of this paper is to provide the readers an overview of the most recent evidence on this subject.
Core tip: The use of neoadjuvant therapy for patients with resectable pancreatic cancer (PC) has been used by an increasing number of cancer centers around the world. The main rationale of using neoadjuvant therapies in resectable PC is the hope that patients’ likelihood of long-term overall survival will benefit from the chemo or chemoradiation therapy administered when their overall conditions allow them to tolerate the treatment. At this time, there is no phase III trial to support the use of neoadjuvant therapies in resectable PC. Without strong scientific evidence supporting the theoretical advantages of neoadjuvant therapies, these potential benefits might turn out not to be worth the risk of tumors progression while waiting for surgery.
The most common form of pancreatic cancers (PCs) originates from the ductal cells of the exocrine gland[1,2]. In the United States, it represents the fourth leading cause of cancer-related deaths with 44000 new cases per year[2,3]. The prognosis of patients with PC remains poor with only 5%-10% of patients alive after five years. Their outcome is significantly improved if they undergo surgery; however, even in this case, 5-year survival is only 25%-40%[1,4]. PC is a difficult tumor to cure as it behaves as a systemic disease even in its early stages. Although surgery remains the only potential cure, it is still inadequate for most of the patients who will develop recurrent disease within five years. The use of multimodality therapy (surgery, chemotherapy and radiation therapy) provides the best chance for long-term survival, but the ideal sequence and duration of these treatments remain unknown due to the lack of scientific evidence.
Despite these limitations, there is a consensus that, because of the poor outcomes observed with old treatment modalities, new strategies are necessary. Among them, the use of neoadjuvant chemotherapy has gained traction and, in recent years, an increasing number of oncologists and surgeons are recommending it[7,8].
For borderline resectable and locally advanced PC, there is evidence that neoadjuvant therapy increases the probability of negative resection margins and the number of patients who can undergo surgery[8,9]. On the other hand, for resectable PC, neoadjuvant chemotherapy or chemoradiation remains debatable because of the conflicting data on its effectiveness, and because there is no phase III trial to support their use[10-12]. The focus of this publication is to provide an overview of the most recent evidence on this topic, appraise the potential benefits and disadvantages of neoadjuvant vs surgery first approach, and finally, to review the ongoing phase III trials that might address some of the questions that are still unanswered.
Surgery remains the only potential cure for patients with PC. Determining if the disease is resectable or not at the time of diagnosis is crucial, but often subjective to the interpretation of preoperative imaging tests. Resectability is usually determined using a combination of imaging tests and laparoscopic assessment of the peritoneal cavity to rule out small hepatic or peritoneal metastases that might be missed even with high-quality contrast enhanced computerized tomography (CT scans) or magnetic resonance imaging (MRI) studies[2,13]. There are several definitions of tumor resectability that are summarized in Table Table11[13-16]. All criteria currently used to identify patients with resectable disease are based on the degree of contact between the tumor and blood vessels adjacent to the pancreas in the absence of distant disease.
Until recently, the most accepted treatment paradigm for resectable PC was surgery followed by postoperative systemic chemotherapy or chemoradiation. In recent years, the use of systemic pre-operative chemotherapy alone or in combination with radiation therapy has been offered to an increasing number of patients with the main intent of reducing the size of the tumor, increase the likelihood of negative resection margins, and test the effects of cytotoxic medications in vivo. Most patients who are treated with neoadjuvant chemotherapy or chemoradiation receive oral or intravenous medications for the duration of three to six months before undergoing surgery.
Neoadjuvant therapy has several theoretical benefits but also drawbacks (Table (Table2).2). It is usually well tolerated, does not increase the perioperative morbidity, reduces the interval between diagnosis and the initiation of systemic treatment and has the potential benefit of facilitating radical resections by lessening the size of the tumors before surgery. Despite these advantages, postponing surgery for neoadjuvant treatment might give enough time for the tumor to progress and become unresectable[17,18].
Table Table33 summarizes details of the latest phase I and II trials reporting the outcomes of patients treated with neoadjuvant chemotherapy or chemoradiation for radiologically resectable PC. In all these studies, tumor response was evaluated differently as some investigators reported radiographic or clinical response before surgical exploration and others the histopathological response observed in the surgical specimen.
Gillen et al published the first systematic meta-analysis on the effects of preoperative therapy in PC. The authors reviewed 515 studies, but only 111 trials were included with a total of 4394 patients. Among these studies, 15 were a phase I, 13 were a phase I/II, 28 were phase II, 14 were cohort studies, and 41 were case series. Most the studies were prospective (No. 78). Chemotherapy was used as neoadjuvant therapy in 107 (96%) and radiotherapy in 104 (94%) with doses ranging from 24 to 63 Gy. In 13 trials, patients received intraoperative radiation therapy with doses between 10 and 30 Gy.
Six studies stated that the RECIST criteria were used to assess the preoperative radiological response to neoadjuvant therapy. The criteria used to evaluate tumor response were clearly stated in 44 studies, while in 61 studies the criteria used were not adequately reported. Pooled results of patients with resectable cancers at the time of diagnosis showed a complete response in 3.6%, partial response in 30.6%, progression in 20.9% and stable disease in 42.1%. Resections were performed in 73.6% (95%CI: 65.9%-80.6%) of patients. Perioperative morbidity occurred in 26.7% (95%CI: 20.7%-33.3%) and mortality in 3.9% (95%CI: 2.2%-6.0%) which were comparable to the outcomes of patients undergoing surgery first. Negative resection margins (R0) were observed in 82.1% of patients (95%CI: 73.1%-89.6%) with a median survival of 23.3 mo (range 12-54). Analysis of trials with monotherapy vs poly-chemotherapy revealed higher rates of complete or partial response when multiple chemotherapy agents were used. Higher response rates, however, did not translate into higher resection rates.
One year later, Assifi et al, published a second systematic review and meta-analysis of only phase II neoadjuvant therapy trials. Out of 397 studies published from 1993 to 2010, 14 trials were included with a total of 536 patients. All studies were prospective, with 12 out of 14 (86%) being a single arm. Patients who had resectable tumors were 402 (75% of the sample). Gemcitabine was used in 8 trials, while the remaining 6 used 5-FU. Radiotherapy was given in 12 of 14 studies (85%) with doses ranging between 30 and 50.4 Gy. In patients with resectable disease at diagnosis, complete radiological response was observed in 0.8% (95%CI: 0.0%-2.6%), partial response in 9.5% (95%CI: 2.9%-19.4%), stable disease in 73.9% (95%CI: 63.2%-83.3%) and progression in 17.0% (95%CI: 11.9%-22.7%). After neoadjuvant therapy, the resection rate was 65.8% (95%CI: 55.4%-75.6%) and negative resection margins were observed in 85.1% (95%CI: 76.8%-91.9%). Median survival was 23.0 mo (range 11.7-34.0). The most significant finding of these two meta-analyses was that even if safe, neoadjuvant therapy did not seem to add any substantial survival advantage.
Due to the heterogeneity of these studies, no conclusion can be drawn regarding the overall impact on survival and what are the most effective chemotherapy agents or the best combination of chemotherapy agents for resectable PC.
More recently, D’Angelo et al completed another systematic review of randomized controlled trials on adjuvant and neoadjuvant therapies for resectable PC. Fifteen studies were included covering a period of 30 years (1985 to 2015). Their analysis suggested that despite all the best efforts, the question whether neoadjuvant therapy provides a better overall survival than adjuvant therapy remains unanswered.
VanHouten et al used a decision analysis model to assess what is the best treatment strategy for resectable PC. A survival advantage of 7 mo was found in patients who underwent neoadjuvant therapy in comparison to surgery first (27.2 mo vs 19.9 mo).
Another Markov decision analysis by de Geus et al supported the use of neoadjuvant chemotherapy that provided longer overall survival (32 mo vs 27 mo) and quality-adjusted life expectancy (25 mo vs 21 mo) in comparison to surgery followed by adjuvant chemotherapy. Sensitivity analysis of the model showed that if the probability of surgical resection after neoadjuvant therapy was lower than 57%, upfront surgery was the best treatment option.
Another group led by Sharma et al compared the efficacy of neoadjuvant-based chemotherapy with adjuvant treatment with an intention-to-treat analysis using a two-arms Markov model. In the neoadjuvant group, patients were treated with an average of 3 mo of neoadjuvant therapy followed by surgery. After surgery, patients who received preoperative chemotherapy did not receive any adjuvant treatment. On the other hand, patients who underwent surgery first, underwent chemotherapy after they recovered from their operations. In this model, the median overall survival was longer for the neoadjuvant cohort (22 mo) in comparison to the adjuvant group (20 mo), and the cumulative quality-adjusted survival for patients who underwent the neoadjuvant strategy was 19.8 mo compared to 18.4 mo for patients who had adjuvant therapy. One-way sensitivity analysis showed that surgery first provided higher quality-adjusted survival rates if more than 44% of patients treated with neoadjuvant therapy experienced progression of their disease and failed to undergo surgical resection.
All these models provided evidence that neoadjuvant therapies have better overall survival and quality of life in comparison to surgery first, although the differences were clinically quite small.
For borderline or locally advanced PC, the use of neoadjuvant therapy makes sense, and it is desirable for both patients and physicians. For patients’ perspective, neoadjuvant treatments might decrease the tumor burden and give them the chance of becoming resectable. Similarly, for the surgeons’ perspective, any reduction of the tumor size is welcomed as it facilitates the technical aspect of the resection around critical vascular structures such as the superior mesenteric-portal vein junction or superior mesenteric artery.
However, this is not the case for resectable PC. Neoadjuvant therapy does not facilitate surgery, as the tumor is resectable at the time of diagnosis. Preoperative therapy might increase the rate of negative margins; however, this needs to be proven in randomized controlled trials, as the current evidence is not sufficient. Furthermore, for patients’ perspective, there is a considerable risk of missing out the only opportunity of being cured with surgery as the tumor might progress to become unresectable while neoadjuvant therapies are delivered.
Because the current evidence is inadequate, there are no unequivocal criteria able to assist health-care providers to select the strategy with the best long-term survival for resectable PC. Physicians are left to decide whether to use neoadjuvant therapy and whether to use of one or multiple pre-operative chemotherapeutic agents or chemoradiation is worth the risk of toxicities and the possibility of disease progression. In theory, neoadjuvant treatments would be unanimously recommended for patients at high risk of positive resection margins, as their surgery would not be curative. The selection of these patients is not easy. To overcome this concerns, Bao et al developed a predictive module to maximize the probability of identifying patients with true resectable tumors by using commonly available preoperative imaging modalities. With this model, the authors could classify patients with low-risk and high-risk for noncurative resections and concluded that until better evidence is available, patients who are unlikely to have R0 margins should be treated with neoadjuvant therapy.
D’Angelo et al pointed out that the current literature is biased because the likelihood that radiologically resectable PCs is indeed unresectable at the time of surgery is only about 40%. Therefore, the only way to find out if there is any benefit from neoadjuvant therapy is to complete an intention to treat randomized controlled trial where one arm entails surgery followed by adjuvant therapy (current standard of care) and the second arm involves neoadjuvant therapy followed by surgery followed by adjuvant therapy (experimental group).
Recent chemotherapy regimens, such as FOLFI RINOX [folinic acid (leucovorin)/5-FU/Irinotecan/Oxaliplatin], have already demonstrated promising results in a small group of patients with borderline resectable tumors[26,27]. Given these findings, several ongoing prospective studies are examining the role of FOLFIRINOX in a neoadjuvant setting for resectable disease (Table (Table4).4). Other studies include NEOPAC, NEONAX, NCT01660711, and NCT02172976. NEOPAC (Adjuvant vs Neoadjuvant Plus Adjuvant Chemotherapy in Resectable Pancreatic Cancer) will compare neoadjuvant gemcitabine and oxaliplatin plus adjuvant gemcitabine vs adjuvant gemcitabine alone. NEONAX, (Neoadjuvant Plus Adjuvant or Only Adjuvant Nab-Paclitaxel Plus Gemcitabine for Resectable Pancreatic Cancer) will assess the effects of neoadjuvant plus adjuvant Nab-Paclitaxel plus gemcitabine vs adjuvant only Nab-Paclitaxel plus gemcitabine. Other ongoing trials are a single-arm nonrandomized trial evaluating preoperative and postoperative FOLFIRINOX in patients with resectable disease (NCT01660711) and the multicenter German randomized trial investigating adjuvant gemcitabine compared with neoadjuvant and adjuvant FOLFIRINOX (NCT02172976).
Based on the current literature, there is still insufficient evidence to fully support the use of neoadjuvant therapy for all patients with radiologically resectable PC. Randomized controlled trials are urgently needed to address many of the questions that are still unanswered. Until then, clinicians need to weigh the pros and cons of the two treatment strategies and guide their patients. Ideally, patients should be educated on the advantages, and detrimental effects associated with each of the two possible therapies and their preferences should be elicited. Since each patient is unique, proposing neoadjuvant therapy with one-size-fits-all approach should be discouraged, and patients should become active participants and share with their physicians the responsibility of selecting the treatment strategy that fits best with their goals and values.
The authors would like to acknowledge: Stefanie Condon-Oldreive founder and director of Craig’s Cause Pancreatic Cancer Society (www.craigscause.ca) for the research scholarship that supported Dr. Sheikh Hasibur Raman while working on this project. The authors thank Melissa Connell for her administrative support and technical and language editing that helped improving the quality of the manuscript and the quality of the audio file.
Conflict-of-interest statement: The authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.
Manuscript source: Unsolicited manuscript
Specialty type: Oncology
Country of origin: United States
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Peer-review started: June 27, 2017
First decision: August 7, 2017
Article in press: September 15, 2017
P- Reviewer: Kim SM, Munoz M, Nakai Y, Sun XT S- Editor: Ji FF L- Editor: A E- Editor: Lu YJ
Sheikh Hasibur Rahman, Department of Surgery, Dalhousie University, Halifax B3H 2Y9, Nova Scotia, Canada.
Robin Urquhart, Department of Surgery, Dalhousie University, Halifax B3H 2Y9, Nova Scotia, Canada.
Michele Molinari, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, United States. Email: ude.cmpu@miranilom.