Management of borderline resectable pancreatic cancer

Pancreatic cancer is the fourth most common cause of cancer death in the United States. Surgery remains the only curative option; however only 20% of the patients have resectable disease at the time of initial presentation. The definition of borderline resectable pancreatic cancer is not uniform but generally denotes to regional vessel involvement that makes it unlikely to have negative surgical margins. The accurate staging of pancreatic cancer requires triple phase computed tomography or magnetic resonance imaging of the pancreas. Management of patients with borderline resectable pancreatic cancer remains unclear. The data for treatment of these patients is primarily derived from retrospective single institution experience. The prospective trials have been plagued by small numbers and poor accrual. Neoadjuvant therapy is recommended and typically consists of chemotherapy and radiation therapy. The chemotherapeutic regimens continue to evolve along with type and dose of radiation therapy. Gemcitabine or 5-fluorouracil based chemotherapeutic combinations are administered. The type and dose of radiation vary among different institutions. With neoadjuvant treatment, approximately 50% of the patients are able to undergo surgical resections with negative margins obtained in greater than 80% of the patients. Newer trials are attempting to standardize the definition of borderline resectable pancreatic cancer and treatment regimens. In this review, we outline the definition, imaging requirements and management of patients with borderline resectable pancreatic cancer.     

Therapy of locally advanced pancreatic adenocarcinoma: unresectable and borderline patients

Systemic chemotherapy for advanced pancreatic cancer is commonly used in practice; however, the optimal strategy for both neoadjuvant and adjuvant therapy in this disease remains controversial. A particular challenge remains in patients who are considered to be locally advanced and either unresectable or borderline resectable. Offering optimal neoadjuvant therapy to this group of patients may give them the opportunity to have a curative surgical approach. This article will discuss the potential role of neoadjuvant therapy in borderline, potentially resectable pancreatic cancer. It will also discuss areas of interest in potential targets as the biology of pancreatic adenocarcinoma is further explored.     

Therapy of locally advanced pancreatic adenocarcinoma: unresectable and borderline patients

Systemic chemotherapy for advanced pancreatic cancer is commonly used in practice; however, the optimal strategy for both neoadjuvant and adjuvant therapy in this disease remains controversial. A particular challenge remains in patients who are considered to be locally advanced and either unresectable or borderline resectable. Offering optimal neoadjuvant therapy to this group of patients may give them the opportunity to have a curative surgical approach. This article will discuss the potential role of neoadjuvant therapy in borderline, potentially resectable pancreatic cancer. It will also discuss areas of interest in potential targets as the biology of pancreatic adenocarcinoma is further explored.     

The yield of staging laparoscopy for resectable and borderline resectable pancreatic cancer in the PREOPANC randomized controlled trial

BackgroundThe necessity of the staging laparoscopy in patients with pancreatic cancer is still debated. The objective of this study was to assess the yield of staging laparoscopy for detecting occult metastases in patients with resectable or borderline resectable pancreatic cancer.MethodThis was a post-hoc analysis of the randomized controlled PREOPANC trial in which patients with resectable or borderline resectable pancreatic cancer were randomized between preoperative chemoradiotherapy or immediate surgery. Patients assigned to preoperative treatment underwent a staging laparoscopy prior to preoperative treatment according to protocol, to avoid unnecessary chemoradiotherapy in patients with occult metastatic disease.ResultsOf the 246 included patients, 7 did not undergo surgery. A staging laparoscopy was performed in 133 patients (55.6%) and explorative laparotomy in 106 patients (44.4%). At staging laparoscopy, occult metastases were detected in 13 patients (9.8%); 12 liver metastases and 1 peritoneal metastasis. At direct explorative laparotomy, occult metastases were found in 9 patients (8.5%); 6 with liver metastases, 1 with peritoneal metastases, and 2 with metastases at multiple sites. One patient had peritoneal metastases at exploration after a negative staging laparoscopy. Patients with occult metastases were more likely to receive palliative chemotherapy if found with staging laparoscopy compared to laparotomy (76.9% vs. 30.0%, p = 0.040).ConclusionsStaging laparoscopy detected occult metastases in about 10% of patients with resectable or borderline resectable pancreatic cancer. These patients were more likely to receive palliative systemic chemotherapy compared to patients in whom occult metastases were detected with laparotomy. A staging laparoscopy is recommended before planned resection.     

Multidetector computer tomography in the pancreatic adenocarcinoma assessment: an update

Ductal adenocarcinoma of the pancreas is one of the most aggressive forms of cancer, with only a minority of cases being resectable at the moment of their diagnosis. The accurate detection and characterization of pancreatic carcinoma is very important for patient management. Multidetector-row computed tomography (MDCT) has become the cross-sectional modality of choice in the diagnosis, staging, treatment planning, and follow-up of patients with pancreatic tumors. However, approximately 11% of ductal adenocarcinomas still remain undetected at MDCT because of the lack of attenuation gradient between the lesion and the adjacent pancreatic parenchyma. In this systematic literature review we investigate the current evolution of the CT technique, limitations, and perspectives in the evaluation of pancreatic carcinoma.     

多层螺旋CT诊断胰腺癌的进展

胰腺癌是恶性程度很高的癌症之一,目前诊断出胰腺癌的患者大多都错过了最佳手术时机。胰腺癌的早期且准确诊断对于患者的治疗和预后十分关键。多层螺旋CT（multidetector-row computed tomography,MDCT）已成为胰腺癌诊断、肿瘤分期、治疗计划制定和治疗后随访的重要检查方式。然而,大约11%的胰腺导管腺癌在多层螺旋CT图像中由于病变和邻近胰腺实质之间密度差异仍出现漏诊情况。本文总结当前的多层螺旋CT在胰腺癌诊断方面的进展、限制及其它影像学检查方式的临床应用。     

Quelle place pour la radiothérapie dans la prise en charge des cancers du pancréas localisés ?

At diagnosis, about 15% of patients with pancreatic cancer present with a resectable tumour, 50% have a metastatic tumour, and 25% a locally advanced tumor (non-metastatic but unresectable due to vascular invasion) or borderline resectable. Despite the technical progress made in the field of radiation therapy and the improvement of the efficacy of chemotherapy, the prognosis of these patients remains very poor. Recently, the role of radiation therapy in the management of pancreatic cancer has been much debated. This review aims to evaluate the role of radiation therapy for these patients.     

Neoadjuvant therapy for localized pancreatic cancer: guiding principles

The management of localized pancreatic cancer (PC) remains controversial. Historically, patients with localized disease have been treated with surgery followed by adjuvant therapy (surgery-first approach) under the assumption that surgical resection is necessary, even if not sufficient for cure. However, a surgery-first approach is associated with a median overall survival of only 22-24 months, suggesting that a large proportion of patients with localized PC have clinically occult metastatic disease. As a result, adjuvant therapy has been recommended for all patients with localized PC, but in actuality, it is often not received due to the high rates of perioperative complications associated with pancreatic resections. Recognizing that surgery may be necessary but usually not sufficient for cure, there has been growing interest in neoadjuvant treatment sequencing, which benefits patients with both localized and metastatic PC by ensuring the delivery of oncologic therapies which are commensurate with the stage of disease. For patients who have clinically occult metastatic disease, neoadjuvant therapy allows for the early delivery of systemic therapy and avoids the morbidity and mortality of a surgical resection which would provide no oncologic benefit. For patients with truly localized disease, neoadjuvant therapy ensures the delivery of all components of the multimodality treatment. This review details the rationale for a neoadjuvant approach to localized PC and provides specific recommendations for both pretreatment staging and treatment sequencing for patients with resectable and borderline resectable (BLR) disease.     

Borderline resectable pancreatic cancer: conceptual evolution and current approach to image-based classification

BackgroundDiagnostic imaging plays a critical role in the initial diagnosis and therapeutic monitoring of pancreatic adenocarcinoma. Over the past decade, the concept of ‘borderline resectable’ pancreatic cancer has emerged to describe a distinct subset of patients existing along the spectrum from resectable to locally advanced disease for whom a microscopically margin-positive (R1) resection is considered relatively more likely, primarily due to the relationship of the primary tumor with surrounding vasculature.Materials and methodsThis review traces the conceptual evolution of borderline resectability from a radiological perspective, including the debates over the key imaging criteria that define the thresholds between resectable, borderline resectable, and locally advanced or metastatic disease. This review also addresses the data supporting neoadjuvant therapy in this population and discusses current imaging practices before and during treatment.ResultsA growing body of evidence suggests that the borderline resectable group of patients may particularly benefit from neoadjuvant therapy to increase the likelihood of an ultimately margin-negative (R0) resection. Unfortunately, anatomic and imaging criteria to define borderline resectability are not yet universally agreed upon, with several classification systems proposed in the literature and considerable variance in institution-by-institution practice. As a result of this lack of consensus, as well as overall small patient numbers and lack of established clinical trials dedicated to borderline resectable patients, accurate evidence-based diagnostic categorization and treatment selection for this subset of patients remains a significant challenge.ConclusionsClinicians and radiologists alike should be cognizant of evolving imaging criteria for borderline resectability given their profound implications for treatment strategy, follow-up recommendations, and prognosis.     

局限期胰腺癌放化疗的临床试验研究进展

根据术前肿瘤与相邻血管的关系胰腺癌分为可手术切除、临界可切除和不可手术切除病变。就诊时大部分患者已为局部晚期或出现远处转移,只有20%患者有手术机会,放化疗对于胰腺癌至关重要。本文回顾近年来的相关文献,着重介绍局限期胰腺癌新辅助放化疗、立体定向放疗及放化疗联合免疫治疗的临床试验研究进展。     

Treatment outcome of lung cancer patients as optimized by preoperative whole-body positron emission tomography fluorodeoxyglucose imaging

Positron emission tomography (PET) fluorodeoxyglucose (FDG) imaging may be more accurate than computed tomography (CT) scanning for staging of lung cancer disease. In the present study, we evaluate whether whole-body PET-FDG imaging can accurately stratify lung cancer patients by stage and thus predict patient outcome. Forty-one consecutive patients underwent whole-body PET and CT scanning for preoperative staging, which was then confirmed by mediastinoscopy, thoracotomy, and/or other tests revealing distant metastases. The effect of PET on patient management was determined. PET was significantly more accurate than CT for staging of lung cancer (97.6% vs. 70.7%). One-year follow-up for survival rate and treatment response was also compared in different patient groups. PET accurately identified patients with resectable disease (Group A). Group B patients, with medically inoperable disease, and Group C patients, with unresectable advanced disease, had 100% and 53% incidence of adverse events (defined as recurrence, evidence of new disease, or death), respectively. Group A patients with resectable disease who underwent surgery showed the best patient outcome, with only 7% incidence of adverse events. In conclusion, whole-body PET can be useful in identifying a group of lung cancer patients with resectable disease most likely to benefit from surgical resection. Further studies are needed to explore whether PET can predict patient outcome of various lung cancer patients receiving different treatment regimens.     

Imaging of pancreatic cancer: An overview

Pancreatic cancer (PaCa) is the fourth leading cause of cancer-related death in the United States. The median size of pancreatic adenocarcinoma at the time of diagnosis is about 31 mm and has not changed significantly in last three decades despite major advances in imaging technology that can help diagnose increasingly smaller tumors. This is largely because patients are asymptomatic till late in course of pancreatic cancer or have nonspecific symptoms. Increased awareness of pancreatic cancer amongst the clinicians and knowledge of the available imaging modalities and their optimal use in evaluation of patients suspected to have pancreatic cancer can potentially help in diagnosing more early stage tumors. Another major challenge in the management of patients with pancreatic cancer involves reliable determination of resectability. Only about 10% of pancreatic adenocarcinomas are resectable at the time of diagnosis and would potentially benefit from a R0 surgical resection. The final determination of resectability cannot be made until late during surgical resection. Failure to identify unresectable tumor pre-operatively can result in considerable morbidity and mortality due to an unnecessary surgery. In this review, we review the relative advantages and shortcomings of imaging modalities available for evaluation of patients with suspected pancreatic cancer and for preoperative determination of resectability.     

Radiology of pancreatic neoplasms: An update

Diagnostic imaging is an important tool to evaluate pancreatic neoplasms. We describe the imaging features of pancreatic malignancies and their benign mimics. Accurate detection and staging are essential for ensuring appropriate selection of patients who will benefit from surgery and for preventing unnecessary surgeries in patients with unresectable disease. Ultrasound, multidetector computed tomography with multiplanar reconstruction and magnetic resonance imaging can help to do a correct diagnosis. Radiologists should be aware of the wide variety of anatomic variants and pathologic conditions that may mimic pancreatic neoplasms. The knowledge of the most important characteristic key findings may facilitate the right diagnosis.     

What is the optimal treatment of localized pancreatic adenocarcinoma?

The term localized disease as it applies to pancreatic adenocarcinoma encompasses distinct entities associated with varied prognoses and therapeutic recommendations. These include three disease categories: (1) disease that is localized and resectable, (2) localized disease that is borderline resectable, and (3) unequivocally unresectable pancreatic adenocarcinoma, all representing a continuum. The incorporation of systemic chemotherapy into the management of pancreatic adenocarcinoma at all stages has become standard of care, and the basis for this is discussed with reference to the major clinical trial landmarks. The role of radiation therapy (in association with concomitant chemotherapy) in the management of localized pancreatic adenocarcinoma, however, has become less clear and represents an area of management confusion in this disease. Going forward, with the expectation of new and improved systemic agents, locoregional tumor control and, hence, chemoradiotherapy are anticipated to have a greater role and impact.     

Neoadjuvant Therapy for Potentially Resectable Pancreatic Cancer: An Emerging Paradigm?

Although neoadjuvant chemoradiotherapy has been tested for more than two decades and can be safely delivered to patients with non-metastatic pancreatic cancer, no randomised trials have been reported until now. Here we provide an overview of the first randomised trial in patients with potentially resectable cancer and of the latest developments in neoadjuvant therapy for this group of patients. It is necessary to continue to perform clinical trials in this field to accurately identify the effect on survival and quality of life in patients with potentially resectable, borderline resectable and unresectable pancreatic cancer. Aspects of imaging for restaging and clinical prognostic factors are also discussed given they will be useful instruments for future trials.     

Localized adenocarcinoma of the pancreas: the rationale for preoperative chemoradiation

Pancreatic adenocarcinoma is the fifth leading cause of cancer-related death in the U.S. In spite of advancements in surgical treatment, nearly 80% of patients thought to have localized pancreatic cancer die of recurrent or metastatic disease when treated with surgery alone. Therefore, efforts to alter the patterns of recurrence and improve survival for patients with pancreatic cancer currently focus on the delivery of systemic therapy and irradiation before or after surgery. Postoperative adjuvant therapy appears to improve median survival. However, more than one-fourth of patients do not complete planned adjuvant therapy due to surgical complications or a delay in postoperative recovery of performance status. Utilizing a preoperative (neoadjuvant) approach, overall treatment time is reduced, a greater proportion of patients receive all components of therapy, and patients with rapidly progressive disease are spared the side effects of surgery as metastatic disease may be found at restaging following chemoradiation (prior to surgery). This paper examines the factors pertinent to clinical trial design for resectable pancreatic cancer, and carefully reviews the existing data supporting adjuvant and neoadjuvant therapy for potentially resectable disease.     

Pancreatic cancer: current concepts in imaging for diagnosis and staging

Because of its late clinical presentation, pancreatic cancer remains the fourth most common cause of cancer death. Surgery is the only option for cure, and advancements in surgical technique and neoadjuvant therapy have the potential to increase the number of patients who could undergo surgery for potential cure. Accurate diagnosis and staging of pancreatic ductal carcinoma are therefore of great importance. This paper reviews the state of the art for such diagnostic modalities as computed tomography, magnetic resonance imaging, endoscopic ultrasound, positron emission tomography, and laparoscopic surgery and laparoscopic ultrasound for diagnosis and staging of pancreatic cancer. Currently, accurate diagnosis and staging probably require the use of a combination of techniques, including multiphase helical or multidetector computed tomography and/or dynamically enhanced magnetic resonance imaging with endoscopic ultrasound with fine-needle aspiration. The role of positron emission tomography still needs to be determined. The role of laparoscopic surgery and laparoscopic ultrasound may be limited in those institutions with state-of-the-art imaging techniques.     

胰腺癌的诊断和临床分期

全球范围内，胰腺癌的发病率和罹患率逐年升高，中国也不例外。胰腺癌常见危险因素包括糖尿病、慢性胰腺炎、吸烟、胰腺癌家族史和酗酒等。胰腺癌缺乏特异的临床表现和敏感的早期诊断指标，其诊断和随访常用的血清标志物是CA19—9。目前胰腺癌术前的诊断和分期主要依赖于影像学表现，螺旋CT增强扫描是最常用的影像手段。超声造影、超声内镜、PET／CT等新出现的影像诊断方法进一步提高了诊断的敏感性和特异性。对胰腺癌可切除的患者，不推荐常规作术前穿刺活检；但对拟直接作放化疗的患者，建议穿刺活检取得病理。术前腹腔镜检查可检出腹膜播散的患者，应避免不必要的手术。对Ⅰ、Ⅱ期的胰腺癌患者，应争取达到R0切除，以提高生存率。     

Neoadjuvant Treatment for Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited effective therapeutic options and exceedingly high mortality rates. Currently, cure can only be achieved through resection, however the vast majority of patients present with advanced disease for which upfront surgery is not an option. In an effort to improve surgical candidacy, neoadjuvant chemotherapy, with or without radiation therapy, is often used in an effort to downstage borderline resectable and locally advanced tumors, and some argue for its use even in patients with resectable tumors. Underlying this thinking is the recognition that pancreatic cancer is simultaneously both a locally invasive and systemic disease, even in patients without evidence of metastasis on imaging. Current evidence to date is largely retrospective, but suggests that neoadjuvant therapy can increase R0 (pathologically negative margin) resection rates and improve overall survival. The standard approach to neoadjuvant treatment involves choosing between the two most active combination regimens for metastatic disease, namely modified FOLFIRNOX and gemcitabine/nab-paclitaxel. Nonrandomized data indicate that these regimens can yield resection rates up to 68% and 36%, in borderline resectable and locally advanced PDAC, respectively. Furthermore, randomized data in patients with resectable PDAC treated with gemcitabine-based neoadjuvant therapy suggests that despite an approximate 10% drop in resection rates, there is a significant improvement in median overall survival. Herein, we will discuss the rationale for neoadjuvant therapy, current and former treatment regimens, common issues faced by clinicians when using these combinations, and several ongoing clinical trials.     

Optimizing the management of locally advanced pancreatic cancer with a focus on induction chemotherapy: Expert opinion based on a review of current evidence

Surgical resection of pancreatic cancer offers a chance of cure, but currently only 15–20% of patients are diagnosed with resectable disease, while 30–40% are diagnosed with non-metastatic, unresectable locally advanced pancreatic cancer (LAPC). Treatment for LAPC usually involves systemic chemotherapy, with the aim of controlling disease progression, reducing symptoms and maintaining quality of life. In a small proportion of patients with LAPC, primary chemotherapy may successfully convert unresectable tumours to resectable tumours. In this setting, primary chemotherapy is termed ‘induction therapy’ rather than ‘neoadjuvant’. There is currently a lack of data from randomized studies to thoroughly evaluate the benefits of induction chemotherapy in LAPC, but Phase II and retrospective data have shown improved survival and high R0 resection rates. New chemotherapy regimens such as nab–paclitaxel + gemcitabine and FOLFIRINOX have demonstrated improvement in overall survival for metastatic disease and shown promise as neoadjuvant treatment in patients with resectable and borderline resectable disease. Prospective trials are underway to evaluate these regimens further as induction therapy in LAPC and preliminary data indicate a beneficial effect of FOLFIRINOX in this setting. Further research into optimal induction schedules is needed, as well as guidance on the patients who are most suitable for induction therapy. In this expert opinion article, a panel of surgeons, medical oncologists and gastrointestinal oncologists review the available evidence on management strategies for LAPC and provide their recommendations for patient care, with a particular focus on the use of induction chemotherapy.