B.W. Chang

Final analysis of a phase II study of modified FOLFIRINOX in locally advanced and metastatic pancreatic cancer.

Background:Modifications of FOLFIRINOX are widely used despite the absence of prospective data validating efficacy in metastatic disease (metastatic pancreatic cancer (MPC)) or locally advanced pancreatic cancer (LAPC). We conducted a multicentre phase II study of modified FOLFIRINOX in advanced pancreatic cancer to assess the impact of dose attenuation in MPC and efficacy in LAPC.Methods:Patients with untreated MPC or LAPC received modified FOLFIRINOX (irinotecan and bolus 5-fluorouracil reduced by 25%). Adverse events (AEs) were compared with full-dose FOLFIRINOX. Response rate (RR), median progression-free survival (PFS) and median overall survival (OS) were determined.Results:In total, 31 and 44 patients with LAPC and MPC were enrolled, respectively. In MPC, efficacy of modified FOLFIRINOX was comparable with FOLFIRINOX with RR 35.1%, OS 10.2 months (95% CI 7.65–14.32) and PFS 6.1 months (95% CI 5.19–8.31). In LAPC, efficacy was notable with RR 17.2%, resection rate 41.9%, PFS 17.8 months (95% CI 11.0–23.9) and OS 26.6 months (95% CI 16.7, NA). Neutropenia (P<0.0001), vomiting (P<0.001) and fatigue (P=0.01) were significantly decreased. [18F]-Fluorodeoxyglucose positron emission tomography imaging response did not correlate with PFS or OS.Conclusions:In this first prospective study of modified FOLFIRINOX in MPC and LAPC, we observed decreased AEs compared with historical control patients. In MPC, the efficacy appears comparable with FOLFIRINOX. In LAPC, PFS and OS were prolonged and support the continued use of FOLFIRINOX in this setting.

Treatment of Locally Advanced Pancreatic Cancer: The Role of Radiation Therapy

Pancreatic cancer remains associated with an extremely poor prognosis. Surgical resection can be curative, but the majority of patients present with locally advanced or metastatic disease. Treatment for patients with locally advanced disease is controversial. Therapeutic options include systemic therapy alone, concurrent chemoradiation, or induction chemotherapy followed by chemoradiation. We review the evidence to date regarding the treatment of locally advanced pancreatic cancer (LAPC), as well as evolving strategies including the emerging role of targeted therapies. We propose that if radiation is used for patients with LAPC, it should be delivered with concurrent chemotherapy and following a period of induction chemotherapy.

The Effect of a Lung Cancer Care Coordination Program on Timeliness of Care

BACKGROUND Timeliness of care improves patient satisfaction and might improve outcomes. The CCCP was established in November 2007 to improve timeliness of care of NSCLC at the Veterans Affairs Connecticut Healthcare System (VACHS). PATIENTS AND METHODS We performed a retrospective cohort analysis of patients diagnosed with NSCLC at VACHS between 2005 and 2010. We compared timeliness of care and stage at diagnosis before and after the implementation of the CCCP. RESULTS Data from 352 patients were analyzed: 163 with initial abnormal imaging between January 1, 2005 and October 31, 2007, and 189 with imaging conducted between November 1, 2007 and December 31, 2010. Variables associated with a longer interval between the initial abnormal image and the initiation of therapy were: (1) earlier stage (mean of 130 days for stages I/II vs. 87 days for stages III/IV; P < .0001); (2) lack of cancer-related symptoms (145 vs. 60 days; P < .0001); (3) presence of more than 1 medical comorbidity (123 vs. 82; P = .0002); and (4) depression (126 vs. 98 days; P = .029). The percent of patients diagnosed at stages I/II increased from 32% to 48% (P = .006) after establishment of the CCCP. In a multivariate model adjusting for stage, histology, reason for imaging, and presence of primary care provider, implementation of the CCCP resulted in a mean reduction of 25 days between first abnormal image and the initiation of treatment (126 to 101 days; P = .015). CONCLUSION A centralized, multidisciplinary, hospital-based CCCP can improve timeliness of NSCLC care, and help ensure that early stage lung cancers are diagnosed and treated.

A novel modified dynamic conformal arc technique for treatment of peripheral lung tumors using stereotactic body radiation therapy

PURPOSE To describe and compare a novel, modified dynamic conformal arc (MDCA) technique for lung stereotactic body radiation therapy with the standard noncoplanar beam (NCB) technique based on stereotactic body radiation therapy (SBRT) coverage, dose conformality, normal tissue constraints, and treatment time. MATERIALS AND METHODS Twenty consecutive medically inoperable patients with early stage, peripheral, non-small cell lung cancer treated with SBRT using an NCB technique were re-planned with a novel MDCA technique. Treatment plans were compared based on Radiation Therapy Oncology Group (RTOG) 0236 criteria for planning treatment volume (PTV) coverage and normal tissue dose constraints, as well as high- and moderate-dose conformality. Treatment times necessary to deliver the NCB plans were compared with the times of a separate group of 12 consecutive patients treated with the MDCA technique at our institution. RESULTS The MDCA technique resulted in improved coverage of the cranial and caudal regions of the PTV and generated plans that were significantly more conformal by all high-dose criteria proposed by the RTOG protocol. In terms of moderate-dose criteria, MDCA plans had a significantly lower maximum dose (2 cm from the PTV), whereas the ratio of the 50% dose volume to the volume of the PTV was equivalent between the 2 techniques. All normal tissue dose constraints proposed in the RTOG 0236 protocol were met by each plan, although the median lung V20 and mean lung dose were slightly higher in the MDCA plans, whereas the chest wall dose was slightly lower. A 42% reduction in treatment time was observed when patients treated with the NCB technique were compared with a separate cohort of 12 patients treated with the MDCA technique (P < .0001). CONCLUSIONS The new MDCA technique described in this study resulted in enhanced PTV coverage, improved high- and moderate-dose conformality, simplified treatment planning, and reduced treatment time compared with results using the standard NCB technique.

Motion management in gastrointestinal cancers.

The presence of tumor and organ motions complicates the planning and delivery of radiotherapy for gastrointestinal cancers. Without proper accounting of the movements, target volume could be under-dosed and the nearby normal critical organs could be over-dosed. This situation is further exacerbated by the close proximity of abdominal tumors to many normal organs at risk (OARs). A number of strategies have been developed to deal with tumor and organ motions in radiotherapy. This article presents a review of the techniques used in the evaluation, quantification, and management of tumor and organ motions for radiotherapy of gastrointestinal cancers.

Locally Advanced Pancreatic Adenocarcinoma: Where Are We and Where Are We Going?

Although many cancers have seen a decline in rates due to screening techniques, the lack of viable screening for pancreatic cancer yields a large number of patients presenting with locally advanced and metastatic disease. Interesting new data regarding the management of locally advanced pancreatic cancer was presented at the 2010 ASCO Gastrointestinal Cancers Symposium, January 22-24, Orlando, FL, USA. Crane et al. presented phase II data exploring induction chemotherapy followed by chemoradiotherapy with multiple agents including cetuximab, gemcitabine, oxaliplatin and capecitabine (Abstract #132). Phase II data was also presented examining the role of S-1, an oral fluoropyrimidine, in the locally advanced setting (Abstract #196). In the wake of several studies exploring the role of platinum compounds in combination with gemcitabine; Raftery et al. explored the combination of oxaliplatin and gemcitabine with concomitant radiotherapy (Abstract #220). As surgical resection still represents the only clear pathway towards cure, data was presented exploring the factors associated with patients who are converted from unresectable to resectable in the locally advanced setting (Abstract #218). The authors summarize and discuss the data from the meeting.

Is There a Role of Radiotherapy in the Management of Pancreatic Neuroendocrine Tumors (PNET)

Pancreatic neuroendocrine tumors (PNET) represent a heterogeneous group of tumors with varying tumor biology and prognosis. Advanced PNETs remain a difficult therapeutic challenge because of their high malignant potential and their resistance to conventional chemotherapy although there have been recent developments with promising results with the use of novel agents for the treatment of this disease. Combined modality chemoradiation is not widely used in the management of locally advanced pancreatic endocrine tumors. We discuss Abstract #335 from 2012 ASCO GI Cancers Symposium and share our experience to discuss efficacy and toxicity of concurrent capecitabine or infusional 5-fluorouracil and radiotherapy in patients with resected, locally advanced and metastatic PNET. Prospective studies to investigate the role of radiation and chemoradiation are warranted.

Updates in Locally Advanced Pancreatic Cancer

Pancreatic cancer is the 4 th leading cancer cause mortality in both men and women. Pancreatic cancer is usually diagnosed in the advanced setting, and only 10-15% of patients present with operable disease. About 25% are locally advanced and unresectable and the rest are metastatic. Studies presented at the 2010 American Society of Clinical Oncology (ASCO) Annual Meeting highlighted both current treatment options and promising novel therapeutic agents and approaches. Image: Design of the ongoing UK SCALOP phase II study.

Locally Advanced Unresectable Pancreatic Cancer

Twenty-five percent of patients with pancreatic cancer present with locally advanced disease that is unresectable, and the treatment strategy for these patients is controversial, with options including chemotherapy alone, concurrent chemoradiation, or induction chemotherapy followed by chemoradiation. Abstracts presented at the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting (#4001, #4126, and #4024) addressed local control, quality of life, and prognostic factors associated with current regimens of induction chemotherapy and subsequent chemoradiation.

The art and science of radiation therapy for gastrointestinal cancers.

The use of radiotherapy to treat gastrointestinal cancers has evolved in a gradual, step-wise fashion over the past six decades. By nature, gastrointestinal cancers are often diagnosed at a locally advanced stage. This fact, combined with the inherent sensitivity of most parts of the luminal gastrointestinal tract to high-dose radiation, has meant that radiation is often best used as part of a multimodality regimen, instead of as a sole curative modality. At times progress may have seemed modest and incremental, but when we look back, it is indeed remarkable how far we have come and how much our treatments have improved. We now have technology that allows us to extend life, cure disease while preserving critical organs, and ablate previously untouchable tumors. The era of modern gastrointestinal radiation therapy arguably began in the 1960’s, when investigators first combined fractionated radiotherapy with concomitant 5-fluoruracil (5-FU). This approach was ultimately carried forth into large cooperative group trials in rectal, pancreatic, gastric and other cancers, and showed benefit both in the adjuvant setting and as a definitive therapy (1-4). In the following two decades, investigators at Wayne State University discovered that chemoradiation with a combination of 5-FU and mitomycin C could be used as a non-surgical, organ-sparing option in the treatment of anal cancer (5), while RTOG 85-01 established that a subset of esophageal cancers could be cured by radiation combined with 5-FU and cisplatinum, again without the need for radical surgery (6). In the 1990’s, an elegant series of prospective studies at the University of Michigan brought important breakthroughs in the understanding of hepatic radiation tolerance (7). In conjunction with improvements in computers and linear accelerator technology, these efforts bore further fruit in the 2000’s, as prospective studies showcased the power and safety of stereotactic body radiotherapy (SBRT) for liver tumors (8,9). Most recently, we now have definitive evidence that preoperative chemoradiation improves survival in esophageal cancers over surgery alone (10). This list, by no means exclusive, highlights some of the major landmarks and turning points on our quest to overcome some of the most difficult-to-treat human cancers. This issue reviews some areas of recent progress, new knowledge, and controversy in the field of gastrointestinal radiation oncology. In the first article, Dr. Lloyd and I explore the nuances that may allow us to enhance the therapeutic ratio of esophageal chemoradiation, now well established as a standard of care (11). Dr. Regine and colleagues then offer a masterful and balanced look at the very controversial area of adjuvant chemoradiation for pancreatic cancer (12). The liver has traditionally been an organ that radiation oncologists have been hesitant to treat. The next two articles explore emerging therapies with great potential for local control of hepatic tumors. Dr. Kennedy, one of the preeminent authorities on hepatic radioembolization, offers a fascinating review of this very promising modality (13). Dr. Scorsetti looks at progress in liver SBRT, where remarkable advances in biological understanding and technology allow us to deliver treatment with previously unthinkable power and precision (14). In the next section, Dr. Jabbour’s team shares their expertise in the very technically demanding subject of radiation for anal cancers, where recent innovations with intensity modulated radiation therapy (IMRT) have led to significant therapeutic gains (15). Similarly, Dr. Sun Myint and Dr. Kovacs demonstrate that techniques with a long history of use in rectal and anal cancer such as contact therapy and interstitial brachytherapy have been recently improved by technological developments. In expert hands, these techniques can be used to deliver to highly effective and personalized treatments with minimal morbidity (16,17). With regard to the application of new radiation therapy techniques, gastrointestinal cancers offer some unique challenges and difficulties. Dr. Chen addresses the problem of organ motion, an issue that constantly threatens to degrade the radiation oncologist’s therapeutic advantage, particularly in the abdomen (18). Dr. Lo leads a team of experts in an outstanding review of the tolerance of the gastrointestinal organs to the high-dose-per-fraction radiation that will be an increasingly important part of our anti-cancer arsenal (19). There is actually a lot going on just below the surface in gastrointestinal radiation oncology. Doors have swung partly or fully closed on some indications, in that radiotherapy is no longer considered a primary part of treatment, or there are other options. Yet there are also new areas with incredible potential that we are just beginning to appreciate. Some of these techniques require new skills and many have steep learning curves. However, this should not dissuade us, nor should the ongoing need to perform the sometimes complex prospective trials needed to prove their value as we continue our search for the best possible treatments for our patients.