Neoadjuvant therapy in pancreatic cancer

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. Surgical resection offers the only hope of cure, though the addition of chemoradiation in the adjuvant setting has been shown to improve survival over surgery alone. Many patients are unable to receive adjuvant therapy due to prolonged postoperative recovery. For this reason, administration of chemoradiation preoperatively (neoadjuvant) has been proposed as an alternative to postoperative treatment. In patients with resectable disease, neoadjuvant therapy results in similar survivals compared to postoperative therapy, with a greater proportion of patients able to complete treatment. For selected patients with borderline or unresectable disease, neoadjuvant therapy offers the potential for tumor downstaging and increasing the likelihood of a margin-negative resection. This article reviews the use of neoadjuvant therapy in the treatment of pancreatic cancer.     

Neoadjuvant therapy followed by prostatectomy for clinically localized prostate cancer

The results of this assessment of the literature indicated that neoadjuvant therapy followed by prostatectomy may improve long-term outcomes for patients with high-risk localized disease. In addition, this approach provides a paradigm for evaluating the activity and mechanism of action of new agents as correlative studies are facilitated by the availability of tumor tissue before and after therapy. The authors determined that a multidisciplinary approach involving oncologists, urologists, and pathologists is critical to the success of this model. Recent and ongoing studies of neoadjuvant therapy followed by prostatectomy were reviewed.     

Adjuvant radiation therapy for pancreatic cancer: a review of the old and the new

Surgery represents the only potential curative treatment option for patients diagnosed with pancreatic adenocarcinoma. Despite aggressive surgical management for patients deemed to be resectable, rates of local recurrence and/or distant metastases remain high, resulting in poor long-term outcomes. In an effort to reduce recurrence rates and improve survival for patients having undergone resection, adjuvant therapies (ATs) including chemotherapy and chemoradiation therapy (CRT) have been explored. While adjuvant chemotherapy has been shown to consistently improve outcomes, the data regarding adjuvant radiation therapy (RT) is mixed. Although the ability of radiation to improve local control has been demonstrated, it has not always led to improved survival outcomes for patients. Early trials are flawed in their utilization of sub-optimal radiation techniques, limiting their generalizability. Recent and ongoing trials incorporate more optimized RT approaches and seek to clarify its role in treatment strategies. At the same time novel radiation techniques such as intensity modulated RT (IMRT) and stereotactic body RT (SBRT) are under active investigation. It is hoped that these efforts will lead to improved disease-related outcomes while reducing toxicity rates.     

直肠癌的新辅助治疗

为了保留肛门、减少复发、延长生存,新辅助化放疗已成为直肠癌治疗的重要组成部分.本文详细论述了直肠癌新辅助治疗的发展和现状.探讨了新辅助放疗、新辅助放化疗与单纯手术及辅助化放疗相比的优劣.     

胰腺癌:新辅助治疗

In spite of the high mortality in pancreatic cancer, significant progress is being made. This review discusses multimodality therapy for patients with pancreatic cancer. Surgical therapy currently offers the only potential monomodal cure for pancreatic adenocarcinoma. However only 10%-20% of patients present with tumors that are amenable to resection, and even after resection of localized cancers, long term survival is rare. The addition of chemoradiation therapy significantly increases median survival. To achieve long-term success in treating this disease it is therefore increasingly important to identify effective neoadjuvant/adjuvant multimodality therapies. Preoperative chemoradiation for potentially resectable pancreatic cancer has the following advantages： （1） neoadjuvant treatment would eliminate the delay of adjuvant treatment due to postoperative complications; （2） neoadjuvant treatment could avoid unnecessary surgery for patients with metastatic disease evident on restaging after neoadjuvant therapy; （3） downstaging after neoadjuvant therapy may increase the likelihood for negative surgical margins; and （4） neoadjuvant treatment could prevent peritoneal tumor cell implantation and dissemination caused during surgery. This review systematically summarizes the current status, controversies, and prospects of neoadjuvant treatment of pancreatic cancer.     

胃癌的新辅助治疗

胃癌的预后极差,其死亡率居于所有癌症的第二位。尽管手术切除肿瘤是首选治疗方案,但术后死亡率仍高达60％以上。为了提高治愈性（RO）切除率,降低术后死亡率,延长生存期,提高生活质量,各国医学工作者进行了大量的研究。本文将对近年来胃癌新辅助治疗进展作一综述。     

Neoadjuvant therapy for gastric cancer: current evidence and future directions

Although surgical resection remains the only potentially curative treatment for gastric cancer (GC), poor long-term outcomes with resection alone compel a multimodality approach to this disease. Multimodality strategies vary widely; while adjuvant approaches are typically favored in Asia and the United States (USA), a growing body of evidence supports neoadjuvant and/or perioperative strategies in locally advanced tumors. Neoadjuvant approaches are particularly attractive given the morbidity associated with surgical management of GC and the substantial risk of omission of adjuvant therapy. The specific advantages of chemoradiotherapy (CRT) compared to chemotherapy have not been well defined, particularly in the preoperative setting and trials aimed at determining the optimal elements and sequencing of therapy are underway. Future studies will also define the role of targeted and biologic therapies.     

胰腺癌新辅助治疗和辅助治疗

胰腺癌的新辅助治疗和辅助治疗是目前胰腺癌研究的热点问题。新辅助治疗因为缺乏前瞻性随机对照研究,目前除进行临床研究外,仍不能被推荐为标准治疗方法。根据大宗病例的临床试验研究结果,胰腺癌术后化疗可以降低死亡风险,而放疗的作用仍有待进一步研究。     

Neoadjuvant therapy in resectable pancreatic cancer: A promising curative method to improve prognosis

Currently, 15 randomized controlled trials (RCTs) have been designed to investigate whether neoadjuvant therapy (NAT) benefits patients with resectable pancreatic adenocarcinoma (R-PA) compared to surgery alone. Five of them have acquired results so far; however, corresponding conclusions have not been obtained. We speculated that the reason for this phenomenon could be that some prognostic factors had proven to be adverse through upfront surgery curative patterns, but some of them were not regarded as independent baseline characteristics, which is important to obtaining comparability between the NAT and upfront surgery groups. This fact could cause bias and lead to the difference in the outcomes of RCTs. In this review, we collate data about risk factors (such as tumor size, resection margin, and lymph node status) influencing the prognoses of patients with R-PA from five RCTs and discuss the possible reasons for the varying outcomes.     

Proton therapy for pancreatic cancer

Radiotherapy is commonly offered to patients with pancreatic malignancies although its ultimate utility is compromised since the pancreas is surrounded by exquisitely radiosensitive normal tissues, such as the duodenum, stomach, jejunum, liver, and kidneys. Proton radiotherapy can be used to create dose distributions that conform to tumor targets with significant normal tissue sparing. Because of this, protons appear to represent a superior modality for radiotherapy delivery to patients with unresectable tumors and those receiving postoperative radiotherapy. A particularly exciting opportunity for protons also exists for patients with resectable and marginally resectable disease. In this paper, we review the current literature on proton therapy for pancreatic cancer and discuss scenarios wherein the improvement in the therapeutic index with protons may have the potential to change the management paradigm for this malignancy.     

Neoadjuvant therapy is associated with improved survival in resectable pancreatic adenocarcinoma

BACKGROUND:

Neoadjuvant therapy has been used to improve survival in operable pancreatic cancer. The authors' objective was to compare long‐term outcomes in patients receiving neoadjuvant versus adjuvant therapy for resectable pancreatic adenocarcinoma.

METHODS:

The California Cancer Surveillance Program for Los Angeles County retrospectively identified 458 patients with nonmetastatic pancreatic adenocarcinoma who underwent definitive pancreatic resection and received systemic chemotherapy between 1987 and 2006. The cohort was grouped by timing of systemic therapy—neoadjuvant or adjuvant. Clinicopathologic characteristics and overall survival were compared. Multivariate Cox regression analysis was used to determine the benefit of neoadjuvant therapy, independent of other significant factors.

RESULTS:

Of the 458 patients, 39 (8.5%) received neoadjuvant therapy, and 419 (91.5%) received adjuvant therapy. There was a significantly lower rate of lymph node positivity in the neoadjuvant group (45% vs 65%; P = .011) despite a higher rate of extrapancreatic tumor extension. On Kaplan‐Meier analysis, the neoadjuvant group had significantly better overall survival compared with the adjuvant group (median survival, 34 vs 19 months; P = .003). Overall survival was also improved in the neoadjuvant therapy patients with extrapancreatic disease (median survival, 31 vs 19 months; P = .018). On multivariate Cox regression analysis, neoadjuvant therapy was an independent predictor of improved survival (hazard ratio, 0.57; 95% confidence interval, 0.37‐0.89; P = .013).

CONCLUSIONS:

This is the first population‐based study to compare neoadjuvant versus adjuvant treatment strategies in resectable pancreatic cancer. Neoadjuvant therapy is associated with a lower rate of lymph node positivity and improved overall survival and should be considered an acceptable alternative to the surgery‐first paradigm in operable pancreatic cancer. Cancer 2011. © 2010 American Cancer Society     

Neoadjuvant therapy preceding prostatectomy for prostate cancer: rationale and current trials

Neoadjuvant therapy improves outcomes for a number of malignancies and provides intermediate pathologic outcomes, which correlate with long-term outcomes. Neoadjuvant androgen-deprivation therapy, alone or with docetaxel chemotherapy, preceding prostatectomy for localized prostate cancer is feasible and demonstrates pathologic activity, but evidence for improved long-term outcomes is lacking. Data in support of the further exploration of neoadjuvant therapy for localized prostate cancer preceding prostatectomy are reviewed. Ongoing randomized trials are elucidating the impact of neoadjuvant androgen deprivation combined with docetaxel chemotherapy on pathologic and long-term outcomes. The correlation of pathologic and biologic outcomes with long-term outcomes in this setting is unknown. The neoadjuvant therapy approach followed by prostatectomy is feasible with a wide array of agents and provides a paradigm for evaluating the activity, and mechanism of action and resistance to new treatments. This promising modality may aid the rapid development of novel therapeutic agents. A multidisciplinary approach involving oncologists, urologists and pathologists is critical to the success of this model.     

Pathology reporting of margin status in locally advanced pancreatic cancer: challenges and uncertainties

Chemo(radio)therapy is becoming the new standard for patients with locally advanced pancreatic cancer. In case of tumor regression on imaging, surgical resection can be undertaken, albeit often with the need for extended procedures. Reevaluation of the current routine pathology procedures is required to establish the appropriate histopathological approach of the resulting specimens. This review focusses on margin status, which is universally considered a core data item of the pathology report, of relevance to both the management of the individual patient and the evaluation of the result of surgery in this particular patient group. As explained in this review, due to the cytoreductive effect of neoadjuvant therapy, the conventional definition of a tumor-free margin (“R0”) based on 1 mm clearance is not adequate. Furthermore, the complexity of many of the specimens following extended or multivisceral en bloc surgical resection make margin assessment challenging. These large specimens require extensive sampling, which is not always easily implemented in daily practice. At present, there is marked divergence in pathology practice, and consequently, neither the true R0-rate nor the exact prognostic effect of the margin status have been definitively established for resected locally advanced pancreatic cancer. A concerted effort towards uniform and optimal margin assessment is unfortunately still lacking.     

A prospective trial of stereotactic body radiation therapy for unresectable pancreatic cancer testing ablative doses

BackgroundWe explored the safety and efficacy of ablative doses of stereotactic body radiation therapy (SBRT) for unresectable pancreatic cancer.MethodsThis phase I/II trial included patients with unresectable pancreatic cancer previously treated with any number of cycles of induction chemotherapy. Patients were enrolled according to a 3+3 dose escalation design at 10, 12.5, and 15 Gy ×3, with subsequent patients at the maximally tolerated dose (MTD). Treatment was delivered to gross tumor delineated with MRI fusion using image-guidance to fiducial markers. Dose-limiting toxicity (DLT) was defined as grade 3+ toxicity within 30 days. Secondary endpoints included late gastrointestinal (GI) toxicity, freedom from local failure (FFLF), and survival.ResultsFifteen patients received a median 10 cycles of chemotherapy. There were no DLTs, and the MTD was 15 Gy ×3. Thirty-day toxicity included grade 2 nausea (46%) and grade 2 diarrhea (7%). Median survival after SBRT was 12.8 months (23 months after diagnosis) and median relapse-free survival was 7 months. At 1-year, FFLF was 80%. Four patients had grade 3+ GI bleeding after 30 days (median 6 months). Grade 3+ GI bleeding was associated with tumor volume (P=0.01), heterogeneity of dose within the planning target volume (PTV) (V120, P=0.03), and duodenal dose (V26–30 Gy, P<0.2).ConclusionsThis aggressive SBRT regimen demonstrated limited 30-day morbidity, a moderate degree of local control, and a moderate risk for late GI bleeding. Further work is necessary to define the most appropriate hypofractionated radiation therapy (RT) regimen in the ablative dose range.     

Research progress on microRNAs as molecular markers in pancreatic cancer: a narrative review

Background and ObjectiveThe incidence and mortality of pancreatic cancer (PC) have increased in recent years. The current status of PC diagnosis and treatment remains grim in clinical practice because the commonly used early screening tools are not sufficient. Improving the early detection of PC and strengthening standardized comprehensive treatment remain the focus of PC research. Many studies have shown that micro RNAs (miRNAs) play an important role in the occurrence, development, and treatment of PC. It is expected that miRNAs will become new molecular markers of PC.MethodsWe extracted and compiled useful information from the PubMed database that met our criteria for analyzing PC diagnosis, treatment, and prognosis.Key Content and FindingsIn this narrative review, we summarize the mechanism of some miRNAs in the occurrence and development of PC and review them as potential markers for the diagnosis, treatment, and prognosis of PC. The function of miRNAs in PC has great potential in studying the pathogenesis of PC. The discovery of many important oncogenic miRNAs and their downstream targets will bring new ideas and research paths for the diagnosis and targeted therapy of PC.ConclusionsMiRNAs are expected to provide novel ideas and research directions for the diagnosis and targeted treatment of PC. However, more patient data and clinical trials are needed before miRNAs can become novel molecular markers for PC.     

Surgery for oligometastasis of pancreatic cancer

The incidence of pancreatic adenocarcinoma (PDAC) has steadily increased over the past several decades. The majority of PDAC patients will present with distant metastases, limiting surgical management in this population. Hepatectomy and pulmonary metastasectomy (PM) has been well established for colorectal cancer patients with isolated, resectable hepatic or pulmonary metastatic disease. Recent advancements in effective systemic therapy for PDAC have led to the selection of certain patients where metastectomy may be potentially indicated. However, the indication for resection of oligometastases in PDAC is not well defined. This review will discuss the current literature on the surgical management of metastatic disease for PDAC with a specific focus on surgical resection for isolated hepatic and pulmonary metastases.     

直肠癌新辅助放化疗

根治性手术结合术后放、化疗一度被作为国际公认的Ⅱ及Ⅲ期直肠癌的标准疗法。近年,新辅助放化疗逐渐得到广泛的关注。大量研究表明,与术后放化疗相比,新辅助放化疗结合根治性手术的多模式联合治疗在降低直肠癌的局部复发率、延长生存时间等方面均显示出更好的效果,特别是在提高保肛率方面具有突出的优势。目前认为,新辅助放化疗适用于局部进展期(T3~4)或有系膜内淋巴结转移的低位直肠癌患者(Ⅱ~Ⅲ期)。随着先进的诊断技术、更优化的放疗模式,以及更多有效的药物及新配伍方案的引入,对直肠癌患者采取个体化的术前新辅助治疗,将使直肠癌的治疗效果得到进一步提高。