Suzanne Russo

ACR Appropriateness Criteria®: Local Excision in Early-Stage Rectal Cancer

Low anterior resection or abdominoperineal resection is considered standard treatment for early rectal cancer. These procedures, however, carry a risk of morbidity and mortality that may not be warranted for early distal lesions, which may be treated with local excision. Emerging data has investigated the efficacy of local excision in patients with early stage rectal cancers. An expert panel designated by the American College of Radiology has reviewed supporting data, from a few prospective multi-institutional trials and a number of single-institution, retrospective reviews. The consensus recognizes the importance of accurate staging to identify patients who may be candidates for a local excision approach. Optimal candidates for local excision alone include small, low-lying T1 tumors, without adverse pathologic features. A number of procedures may be safely used including transanal, posterior trans-sphincteric, posterior proctotomy, transanal excision, or transanal microsurgery. It is important to note that none of these include lymph node evaluation, and depending on the risk of lymph node metastases, adjuvant radiation with or without chemotherapy may be warranted. Patients with positive margins or T3 lesions are at high risk of local recurrence and should be offered immediate APR or LAR. However, patients with high-risk T1 tumors, T2 tumors, or those who are not amenable to more radical surgery may benefit from adjuvant treatment. Data have also reported excellent local control rates for neoadjuvant radiation +/- chemotherapy followed by local excision in higher risk patients, but it is not yet clear if this approach reduces recurrence rates over surgery alone.

Stereotactic body radiotherapy for pancreatic cancer: recent progress and future directions.

ABSTRACT Despite advances in surgical, medical, and radiation therapy for pancreatic cancer, the prognosis remains poor. At this time, the only chance for long-term survival is surgical resection. More challenging is the optimal management of unresectable locally advanced pancreatic cancer, which has historically been treated with concurrent chemoradiation or chemotherapy alone. However, the survival and local control benefit of conventional radiotherapy in addition to chemotherapy was unclear. More recently, stereotactic body radiotherapy (SBRT) is emerging as a viable approach to maximizing local tumor control with a tolerable side effect profile. SBRT achieves sharp dose fall-off facilitating safe delivery of highly focused radiation to the tumor over 1-5 days. Although the optimal regimen of pancreas SBRT has not yet been established, its short treatment course limits the delay of additional. Future directions involve prospective study of pancreas SBRT and exploration of biomarkers and imaging technology in order to adopt a personalized management paradigm.

The role of neoadjuvant therapy in pancreatic cancer: a review

Controversy remains regarding neoadjuvant approaches in the treatment of pancreatic cancer. Neoadjuvant therapy has several potential advantages over adjuvant therapy including earlier delivery of systemic treatment, in vivo assessment of response, increased resectability rate in borderline resectable patients and increased margin-negative resection rate. At present, there are no randomized data favoring neoadjuvant over adjuvant therapy and multiple neoadjuvant approaches are under investigation. Combination chemotherapy regimens including 5-fluorouracil, irinotecan and oxaliplatin, gemcitabine with or without abraxane, or docetaxel and capecitabine have been used in the neoadjuvant setting. Radiation and chemoradiation have also been incorporated into neoadjuvant strategies, and delivery of alternative fractionation regimens is being explored. This review provides an overview of neoadjuvant therapies for pancreatic cancer.

Neoadjuvant therapy for pancreatic cancer: an ongoing debate

http://tag.sagepub.com 429 2016 Gastrointestinal Cancers Symposium summary of plenary session, 21–23 January 2016, San Francisco, CA, USA The 2016 Gastrointestinal Cancers Symposium pancreatic cancer session focused on current controversies in the management of pancreatic cancer and novel treatment approaches that hold promise for the future. The session began with a thought-provoking debate of the pros and cons of neoadjuvant therapy for resectable pancreatic cancer. Robert Wolff MD from MD Anderson Cancer Center emphasized that pancreatic cancer is both a locally invasive disease and a systemic disease, and reviewed adjuvant therapy data that demonstrate little to no improvement in outcome over the last 25 years. He pointed out that results from adjuvant trials only apply to the 50–60% of surgical patients who are not found to have occult metastatic disease [Herman et al. 2008; Parmar et al. 2014], undergo R0-1 resections and are medically fit to undergo postoperative treatment. The locally invasive nature of resectable pancreatic cancer was emphasized using surgical data demonstrating R1 resection rates ranging from 17% to 42% [Richter et al. 2003; Takai et al. 2003; Winter et al. 2006; Oettle et al. 2007; Regine et al. 2008; Neoptolemos et al. 2010] associated with inferior median survival rates compared with R0 resections [Richter et al. 2003; Fatima et al. 2010; Neoptolemos et al. 2010]. He also reviewed autopsy data showing 75–85% local and over 80% distant recurrence rates in patients who underwent curative resection [Hishinuma et al. 2006; Iacobuzio-Donahue et al. 2009]. He emphasized that delay in systemic treatment results in rapid radiology progression of initially occult metastatic disease [Glant et al. 2009] and showed data revealing that 16% of patients thought to have resectable disease develop radiographic metastatic disease at the end of neoadjuvant therapy [Evans et al. 1992; Hoffman et al. 1998; Pisters et al. 1998; White et al. 2001; Pisters et al. 2002]. He argued that neoadjuvant therapy provides early treatment of micrometastatic disease, avoids surgery in patients with rapidly progressive disease and provides an opportunity to observe patient tolerance to therapy. Dr Wolff reviewed data from MD Anderson using the neoadjuvant approach resulted in 66% of patients completing all prescribed therapy resulting in a lower R1 resection rate (8%) and improved median survival rates (31–34 months for resected patients). [Evans et al. 2008; Varadhachary et al. 2008]. He proposed that the neoadjuvant approach provides a platform for clinical investigation that will allow more patients to receive new systemic therapies which may result in improvements in outcome.

Perioperative chemotherapy versus postoperative chemoradiotherapy in patients with resectable gastric/gastroesophageal junction adenocarcinomas: A survival analysis of 5058 patients: PECT Versus POCRT

Both perioperative chemotherapy (PECT) and postoperative chemoradiotherapy (POCRT) have a significant survival advantage over surgery alone for the treatment of patients with gastric cancer. However, to the best of our knowledge, these regimens have not been compared in a randomized clinical trial. The purpose of the current observational study was to compare overall survival among patients receiving PECT versus POCRT for the treatment of gastric/gastroesophageal junction (GEJ) adenocarcinomas.

Roles of p53, NF-κB and the androgen receptor in controlling NGAL expression in prostate cancer cell lines

Neutrophil gelatinase-associated lipocalin (NGAL a.k.a lipocalin 2, lnc2) is a secreted protein which can form a complex with matrix metalloproteinase-9 (MMP9). This MMP9/NGAL complex has been associated with metastasis. MMP9 and NGAL are detected in the urine of patients afflicted with many different types of cancer, including prostate cancer. The effects of p53, NF-κB and the androgen receptor (AR) on the expression of NGAL was examined in four prostate cancer cell lines. Prostate cancer cell lines that are AR negative and expressed either mutant or no p53 (DU145 and PC3) displayed higher levels of NGAL expression compared to the prostate cancer cell lines (LNCaP and 22Rv-1) which are AR positive and express wild type (WT) p53. Introduction of WT-p53 into the PC3 prostate cancer cell line, resulted in reduction of the levels of NGAL expression. Conversely, introduction of dominant negative (DN) p53 or a retroviral construct expressing NF-κB into LNCaP cells increased NGAL expression. NGAL expression had functional effects on the ability of the cells to form colonies in soft agar. Whereas suppression of WT-53 in LNCaP cells increased NGAL expression, the introduction of WT-p53 suppressed NGAL transcription activity in PC3 prostate cells which normally express high level of NGAL. NF-κB and p53 were determined to regulate NGAL expression by positive and negative mechanisms, respectively. Our data indicate that prostate cancer growth, progression and sensitivity to chemotherapeutic drugs are regulated in part by NGAL and may involve complex interactions between NGAL, MMP9, NF-κB and p53.

ACR Appropriateness Criteria® Local Excision in Early Stage Rectal Cancer.

Low anterior resection or abdominoperineal resection are considered standard treatments for early rectal cancer but may be associated with morbidity in selected patients who are candidates for early distal lesions amenable to local excision (LE). The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. The panel recognizes the importance of accurate staging to identify patients who may be candidates for a LE approach. Patients who may be candidates for LE alone include those with small, low-lying T1 tumors, without adverse pathologic features. Several surgical approaches can be utilized for LE however none include lymph node evaluation. Adjuvant radiation±chemotherapy may be warranted depending on the risk of nodal metastases. Patients with high-risk T1 tumors, T2 tumors not amenable to radical surgery may also benefit from adjuvant treatment; however, patients with positive margins or T3 lesions should be offered abdominoperineal resection or low anterior resection. Neoadjuvant radiation±chemotherapy followed by LE in higher risk patients results in excellent local control, but it is not clear if this approach reduces recurrence rates over surgery alone.

Resectable and Borderline Resectable Pancreatic Cancer

The standard treatment for resectable pancreatic cancer continues to evolve, and controversy remains regarding the role of radiation. Surgery followed by adjuvant treatments results in disappointing outcomes. Neoadjuvant therapy has several potential advantages over adjuvant therapy including earlier delivery of systemic treatment, in vivo assessment of response, increased resectability rate in borderline resectable patients, and increased margin-negative resection rate. Radiation and chemoradiation have been incorporated into neoadjuvant and adjuvant strategies, especially with the development of newer technologies and improved radiotherapy techniques capable of safely delivering intensified therapy with alternative fractionation regimens. This chapter provides a guide for treatment planning for radiation-containing treatment strategies incorporating radiation for resectable and borderline resectable pancreatic cancer.

Dosimetry and Physics Quality Assurance

Careful attention to detail for radiation treatment planning and quality assurance is paramount to achieve best results from treatment. Reproducible patient setup, thin-sliced quality imaging during simulation preferably utilizing 4D CT or fluoroscopy for motion evaluation, motion management and image-guidance during treatment delivery, adherence to standardized treatment volume definitions, and attention to published dose-volume limits are all important components in radiation treatment planning and delivery. Prospective peer-review and quality assurance also have been shown to improve radiation therapy for patients. This chapter outlines key considerations for quality assurance programs for 3D CRT, IMRT/VMAT, SBRT, and Proton Therapy.

Current topics in the multimodality treatment of locally advanced rectal cancer

The multimodality approach to the treatment of locally advanced rectal cancer has evolved to include neoadjuvant radiotherapy with or without concurrent chemotherapy, total mesorectal excision and adjuvant fluoropyrimidine-based chemotherapy. Though this broad strategy has yielded improvements in local control compared with historical data, overall survival remains largely unchanged. Current investigations focus on improving patient selection through new imaging modalities, improving surgical techniques, incorporating more aggressive systemic treatment regimens and the selective use of radiation. Here, we review emerging data regarding newer staging techniques, neoadjuvant chemotherapy, optimal timing of surgery, selective use of radiation and nonoperative approaches to the management of locally advanced rectal cancers.