Timothy D. Wagner

Multimodality approaches for pancreatic cancer

The role of combined‐modality therapy for pancreatic cancer is evolving with the recent development and completion of major, multi‐institutional clinical trials. One of the challenges for the busy clinician is to appreciate the variation in staging, surgical expertise, and application of either definitive chemoradiotherapy or adjuvant chemoradiotherapy for local and/or regionally advanced disease. Our aim is to summarize the current state‐of‐the‐art management and future directions regarding the multimodality approach to pancreatic cancer.

Management of stage II/III rectal cancer

Pelvic and distant recurrences in rectal cancer can be associated with substantial morbidity, and patients with stage II and III disease are at increased risk for both local and distant failure when compared to patients with earlier stage disease. Refinement of surgical techniques have helped to reduce the risk of recurrence, and adjuvant therapies such as radiation to the tumor and regional lymph nodes and 5-fluorouracil-based systemic therapies have helped to further provide local control and may have an impact on overall survival. Numerous studies have been completed internationally in an effort to determine the optimal treatment regimen for this patient population. The importance of pre-therapy staging is of key importance as sequencing of therapy appears to significantly impact outcome. In the United States, patients with stage II/III rectal cancer are recommended to undergo preoperative concurrent pelvic radiation and chemotherapy followed by surgery several weeks later in order to maximize treatment response, which is then followed by approximately 4 months of adjuvant 5-fluorouracil-based systemic therapy. In Europe, there is substantial evidence supporting the use of neoadjuvant radiation therapy, however the role of concurrent chemotherapy remains a question of debate. Regardless of definitive management strategy, close follow-up in the post-treatment setting is important for early tumor detection and for managing treatment-related side-effects.

Cetuximab: Its Use in Combination with Radiation Therapy and Chemotherapy in the Multimodality Treatment of Head and Neck Cancer

Dimerization of epidermal growth factor receptor (EGFR) on the cell membrane of tumor cells has been implicated in triggering a complex signal cascade that leads to increased tumor proliferation and survival. Cetuximab is a human-murine chimeric monoclonal antibody designed to target EGFR and competitively inhibit dimerization by circulating ligands. By this mechanism, it works to prevent this signal cascade thus hindering tumor proliferation. Cetuximab has been shown in a randomized phase III clinical trial to significantly increase overall survival when it is added to radiation therapy in the treatment of locally advanced squamous cell carcinoma of the head and neck. In this manuscript, the mechanism of cetuximab with its associated patents is reviewed, with its role with chemotherapy and radiation in the management of head and neck cancer along with future directions of this targeted cancer therapy.

Long-term outcome of stage I seminoma.

Purpose:To report on long-term outcomes among patients with stage I seminoma treated by orchiectomy with or without adjuvant radiation. Materials and Methods:A retrospective review of medical records of patients treated between 1974 and 2002 was undertaken to identify factors associated with patient outcomes. Results:With a median follow-up of 7.7 years, 80% (4 of 5) of the surveillance group experienced a disease relapse, while only 3% (2 of 70) in the radiation therapy group had disease relapse. This difference in relapse rates was statistically significant, but there was no significant difference in overall survival between the 2 groups. There was a significant relationship between patient age and disease relapse, whereby all of the relapses were seen in patients younger than 36 years at diagnosis (P = 0.03). Of the total 75 patients, 7 (9%) developed second primary tumors. Six of them (6 of 7) were treated with adjuvant radiation, and 1 patient (1 of 7) was on surveillance. Conclusion:In this study, risk of relapse was significantly associated with surveillance and in patients younger than 36 years at diagnosis. These results suggest that surveillance can only be safely adopted for patients who can be followed up closely. We consider adjuvant radiation a very effective choice despite the low risk of associated secondary malignancies.

Rectal cancer: a truly multidisciplinary challenge

Over 40,000 people will be diagnosed with rectal cancer in the United States in 2014, and colorectal cancer remains the second leading cause of cancer death nationally despite renewed focus on diagnosis and management (1). That being said, the incidence of colorectal cancer has dropped significantly over the last several decades largely attributable to more successful screening programs (2). In addition, cancer-related mortality among those diagnosed with colorectal cancer has also dropped in recent years, which is likely a function of earlier intervention and improved treatment modalities (3). The management of rectal cancer has evolved significantly over the last several decades and through this evolution, patients are now managed with a comprehensive multidisciplinary approach. From routine age-appropriate screening and history-taking through diagnostic work-up, cancer treatment, and survivorship, care of patients with rectal cancer requires a tremendous amount of resources and the expertise of an array of specialties working together to maximize patients’ quality and quantity of life. In this focus issue, our contributors delve into the different aspects of rectal cancer prevention, treatment, and aftercare that are largely responsible for the reduced incidence and mortality associated with this disease. After years of analysis, we now believe that as many as one in five patients diagnosed with colorectal cancer are genetically predisposed to developing invasive disease (4). Recognizing this at-risk population before they develop cancer, educating them, and enrolling them in proper screening protocols should help both in terms of disease prevention and earlier detection of invasive disease. In this issue, cancer genetics pioneer Dr. Lynch and fellow collaborators, Drs. Schlussel, Gagliano, Seto-Donlon, Eggerding, Donlon, and Berenberg have provided two manuscripts which together provide a definitive look at the evolution of colorectal cancer genetics. Part 1 details the background and history of colorectal cancer genetics and how that information has been incorporated into clinical practice (5). In part 2, Dr. Schlussel et al. review the hereditary cancer syndromes and the clinical implications and impact that providers need to be aware of when formulating a management strategy for patients and their families (6). For those patients that are diagnosed with rectal cancer, definitive treatment carries significant morbidity and mortality risks and techniques are continually being refined to reduce these treatment-related risks (7). As knowledge and understanding of rectal cancer continues to grow, identifying and screening at-risk populations in a timely fashion is leading to earlier detection and treatment. With earlier detection come more favorable outcomes and the potential to obviate the need for more traditional radical therapies. Drs. Heafner and Glasgow present a detailed review of the role of local excision in the treatment of early rectal cancers (8). In this review, the authors outline the rationale behind less invasive surgery in rectal cancer, the different techniques utilized, the risks and benefits associated with local excision, and the population that should be considered for this less invasive approach. Despite improvements in screening, prevention, and early detection, a large portion of patients with rectal cancer present with more advanced stages of disease. For patients with locally advanced disease, treatment has long featured combined modality therapy given the propensity of rectal cancer to recur both locally and distantly. Internationally, numerous trials have sought to determine the optimal sequence, duration, and intensity of therapy in an attempt to maximize outcomes while limiting treatment-related toxicities. In the United States, the standard of care in patients with locally advanced disease (at least T3 or node positive) is preoperative 5-flurouracil-based chemotherapy concurrent with external beam irradiation to a dose of approximately 5,000 cGy followed by transabdominal resection 5-12 weeks after completion of neoadjuvant therapy followed by postoperative chemotherapy. This recommended course of therapy is based on the results of the German Rectal Cancer Study which showed improved local control rates and a more favorable morbidity profile with neoadjuvant chemoradiation when compared to adjuvant chemoradiation (9). Building on this and many other trials, there are several studies ongoing, and internationally, there continues to be much debate over the ideal sequencing of treatment. Dr. Fung-Kee-Fung explores the concept of combined modality therapy for locally advanced rectal cancer from a historical perspective, showing how we have arrived at the current standards and postulating on where we are heading in the future (10). Local control following treatment is a major priority in rectal cancer both because of the historically high prevalence of local failure and due to the impact and morbidity associated with recurrent disease in the pelvis. Thus, many clinical trials for rectal cancer have focused on local control as a primary or secondary endpoint and based on the success of these studies, current treatment regimens yield long-term local control rates in excess of 90% (11). While local control rates in rectal cancer are now excellent, studies are finding that distant failure remains a persistent issue. There are a number of reasons to explain why, one being that after aggressive neoadjuvant chemoradiation and surgery, many patients never get their full course of adjuvant systemic therapy. In this issue, Drs. Boland and Fakih present the emerging role of neoadjuvant chemotherapy and how this change in therapy sequencing may further improve outcomes, particularly in terms of reducing rates of distant metastatic disease (12). With improving systemic therapy approaches, refined surgical techniques, and emerging radiation technologies, patients with all stages of rectal cancer are experiencing better treatment outcomes than they had historically, even those with advanced stages of disease (3). Advances in systemic therapy have made long-term disease control a reality for patients with a small metastatic burden, opening the door for aggressive local therapy for the treatment of limited metastatic disease. The majority of studies investigating local treatment of metastatic colorectal cancer have focused on disease metastatic to the liver. The liver is the most common site for colorectal metastases and spread to the liver is responsible for the majority of colorectal cancer-related deaths (13,14). In their manuscript, Drs. Clark and Smith lead a comprehensive discussion on liver-directed therapies in metastatic colorectal cancer (15). They take a step-wise approach to this complex treatment algorithm, focusing on the when, why and how of each treatment strategy along with the potential alternatives depending on the specific scenario. Rectal cancer is a challenging disease, and as outlined above and throughout this issue, the treatments themselves can be quite complex. Over the course of treatment, there is a significant physical and emotional toll on patients and their loved ones. And with improving outcomes, more and more patients are becoming long term survivors of this disease. And while these improving outcomes are cause for excitement, there is often disease- and treatment-related morbidity which complicates their recovery and impacts on their post-treatment quality of life. From the perceived stigma of dealing with a permanent ostomy to chronic sexual dysfunction, patients face an array of life-altering morbidity in the post-treatment setting and these issues many times go undetected by providers and thus are left untreated. In this focus issue, Drs. Averyt and Nishimoto have developed two unique manuscripts designed to help providers understand what patients are going through after treatment and to provide them with tools to help break down the barriers that are often faced in colorectal cancer survivorship. The first manuscript focuses specifically on addressing the sexual dysfunction that patients face following diagnosis and treatment (16). This topic is often largely ignored by providers and patients are many times reluctant to address this subject on their own in their routine follow-up. The authors present very effective tools to aid clinicians in opening a dialogue with patients early on in their treatment course and throughout their therapy and the end result is getting these patients the help and therapy that they need and ultimately improving their quality of life. The second manuscript takes the reader into the mind of the patient, giving insight into the top 10 questions that patients may be thinking but not asking (17). This manuscript serves as a valuable reference for providers to utilize, helping them build a strong and trusting relationship with their patients. As outlined, rectal cancer represents a comprehensive multidisciplinary challenge for many different providers who must work in concert to maximize the patient care experience. The goals of this focus issue of the Journal of Gastrointestinal Oncology are to educate our readership about many of the issues that are faced when treating rectal cancer and to provide the necessary tools needed to enhance their care of these unique patients.

Pure Tubular Breast Carcinoma: A 34 year Study of Outcomes

To the Editor: Tubular carcinoma of the breast is a rare, well-differentiated variant of invasive ductal carcinoma which is thought to carry an excellent prognosis (1–3). The purpose of this study is to review the Roswell Park Cancer Institute experience with tubular breast cancers. Between September of 1971 and January 2004, 8,832 patients were treated for both invasive and noninvasive breast cancer, and 44 (0.5%) were coded as tubular carcinoma or invasive ductal carcinoma with tubular features. Tumors were considered tubular only if the pathology report specifically identified the histology as tubular carcinoma, and did not include a description of other histologic types. This process identified 27 of the 44 cases as tubular cancers, while 17 were considered of mixed tubular or other histology. Staging was according to the American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 6th edition (4). Patient follow-up time was calculated using the potential follow-up method (5). The Kaplan–Meier method was used to derive survival probabilities (6). The mean patient age was 59.3 years and all patients were Caucasian. Seventy-eight percent (21 ⁄ 27) of patients had stage I disease, while 19% (5 ⁄ 27) had stage IIA disease, and 4% (1 ⁄ 27) was stage IIIA. Forty-one percent (11 ⁄ 27) of patients had a first-degree relative with breast or ovarian cancer. The initial detection of a breast tumor was made by mammogram in 52% (14 ⁄ 27) of cases, while a mass was palpated by the patient or a physician in 37% (10 ⁄ 27) of cases. Tumor characteristics are summarized in Table 1. The mean tumor diameter was 1.09 cm (range, 0.2–4.2 cm). The majority of patients, who had lymph nodes assessed by either axillary node dissection or a sentinel node biopsy, had no positive lymph nodes on presentation (84%), while 11% (2 ⁄ 19) had 1–3 positive nodes and 5% (1 ⁄ 19) had four positive axillary node metastases. Ductal carcinoma in situ was reported in 59% (16 ⁄ 27) of patients. All patients who had hormone receptor status assessed (16 ⁄ 16) were estrogen receptor (ER) positive, while the majority of patients (10 ⁄ 14) were also progesterone receptor positive. The upper outer quadrant was the site of occurrence in 67% (18 ⁄ 27) of patients and with 89% (24 ⁄ 27) of patients having unifocal disease and 11% (3 ⁄ 27) of patients having multifocal distribution. Seventy-four percent (20 ⁄ 27) of patients were treated with breast-conserving surgery, while 22% (6 ⁄ 27) underwent modified radical mastectomy (MRM), and one patient received no additional surgery after biopsy. In the post-operative setting, one third of patients (9 ⁄ 27) received no adjuvant treatment. Over half (15 ⁄ 27) of patients received post-operative radiation (XRT), 14 of which had undergone a previous breast conserving surgery, and one of which had a previous MRM. Thirty percent of patients (8 ⁄ 27) had XRT alone in the adjuvant setting, while 19% (5 ⁄ 27) receive a combination of XRT and hormonal therapy (HT), and 7% (2 ⁄ 27) received XRT and HT in combination with systemic chemotherapy. Eleven percent (3 ⁄ 27) of patients received HT alone in the adjuvant setting. With a median follow-up period was 5.3 years (range; <1–24 years), none of the patients had evidence of either local or systemic recurrence, and no patients had died of breast cancer. Seventy-eight percent (21 ⁄ 27) of patients were alive at the time of last follow-up and 22% (6 ⁄ 27) had died of other causes not related to breast cancer. Of patients with at least five-years of follow-up, overall survival at 5-years was 89% (16 ⁄ 18) while for those with at least 10-year follow-up, overall survival is 70% (7 ⁄ 10). Twenty-two percent of patients (6 ⁄ 27) were diagnosed with a second cancer, two of which developed infiltrating ductal carcinoma. Of those who developed a second malignancy, the only patient who received XRT, was a patient who developed infiltrating ductal carcinoma in the contralateral breast 7 years after completing XRT. Address correspondence and reprint requests to: Gary Y. Yang, MD, Department of Radiation Medicine, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, or e-mail: Gary.yang@roswellpark.org.

Stereotactic body radiation therapy in primary hepatocellular carcinoma: current status and future directions

Stereotactic body radiation therapy (SBRT) is a form of radiation therapy that has been used in the treatment of primary hepatocellular carcinoma (HCC) over the past decade. To evaluate the clinical efficacy of SBRT in primary HCC, a literature search was conducted to identify original research articles published from January 2000 through January 2018 in PubMed on SBRT in HCC. All relevant studies published from 2004 to 2018 were included. Prospective studies demonstrated 2-year local control (LC) rates ranging from 64-95% and overall survival (OS) rates ranging from 34% (2-year) to 65% (3-year). Retrospective studies demonstrated 2-year LC rates of 44-90% and 2-year OS rates of 24-67%. Reported toxicities in primary HCC patients vary but SBRT appears to be relatively well tolerated. Studies comparing SBRT to radiofrequency ablation (RFA) are few, but they suggest SBRT may be more effective than RFA in specific primary HCC populations. Additionally, SBRT appears to increase the efficacy of both transarterial chemoembolization (TACE) and sorafenib in selected primary HCC populations.