John L. Marshall, MD

The expert from the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers discusses the implications of precision medicine for cancer care, and the need to make that care more accessible for the global community at large.

A previously healthy 36-year-old man initially presented to his primary care physician with occasional bloody stools and dull right upper quadrant pain. Blood was sometimes mixed into his stools but was more often seen on the toilet paper after wiping.

In this review, we address specific issues pertaining to AYA patients with colorectal cancer, including evaluation for hereditary colorectal cancer syndromes, clinicopathologic and biologic features unique to AYA patients with colorectal cancer, treatment outcomes, and survivorship.

Recent improvements in our understanding of the biology of colorectal cancer have led to the identification of several important prognostic and predictive markers of disease-associated risk and treatment response for the individual patient.

Here we discuss the evolution of standard therapy for rectal cancer patients and the use of preoperative CRT for the treatment of locally advanced disease. Treatment schemes that have attempted to broaden the horizons of standard therapy include the use of induction chemotherapy and “watch-and-wait” approaches.

Here, we review the studies that have explored different treatment regimens, therapeutic sequencing, and biologic inclusions for the treatment of these patients, with neoadjuvant intent. We also describe how we have established our own treatment paradigm for the management of potentially curable metastatic colorectal cancer.

In all other settings, giving chemotherapy just to make us feel better emotionally in exchange for potential harm to the patient is not the right strategy. We need to find better treatments for this new clinical indication.

We have yet to establish a standard practice for maintenance therapy in metastatic colorectal cancer. Of course, ideally we could find a biomarker of benefit for patients who should be managed this way, but thus far we have had no such luck.

In this Stump the Professor video, two fellows test Dr. Marshall's diagnostic skills with a unique case study involving an 80-year-old patient who presents with abdominal pain, bilateral edema, weight loss, and dark, tarry stools.

During the past decade, targeted therapeutics have changed the landscape of cancer therapy with bold brush strokes, but the resulting images are still unclear. As we enter into the second decade of targeted therapy, our increased understanding of tumor biology together with cancer genomic sequencing tools will clearly show the way forward. It is imperative that we use these fine brushes, not only to improve precision, but in the end to realize the art of medicine.

In my practice as an oncologist specializing in gastrointestinal tract cancers, a recent week was fairly typical. I saw 50 patients, ranging in age from 32 to 87, equally divided between men and women. Though a couple of them have inherited a gene that may have caused their GI cancers, I have no explanation for why most developed their disease. It is as if they were simply struck by lightning.

In the treatment of colon cancer today, the decision-making involved in the treatment of stage II disease is probably the most challenging aspect. The major question is whether or not these patients should receive postoperative adjuvant chemotherapy. Approximately 75% of stage II colon cancer is cured by surgery alone. For the remaining 25% of cases, there is great debate over whether adjuvant chemotherapy is sufficiently effective in enough patients to warrant the exposure to potentially toxic treatments. In the important QUASAR clinical trial, stage II patients were randomized to either fluorouracil (5-FU)-based therapy or observation. The results demonstrated an approximate 3% improvement in outcome for the 5-FU–treated patients. This leads to the assumption that treating all stage II patients with adjuvant chemotherapy is gross overtreatment, when essentially 97% of these patients will not benefit. Clearly the only way to approach this decision is through risk determination. In this article, I will describe the current state of defining high- and low-risk disease, which is mainly through histopathologic characteristics, as well as discuss emerging approaches such as molecular markers and genomic profiling

Preliminary results from two trials presented at the 44th Annual Meeting of ASCO in Chicago have consolidated the role of K-ras as a biomarker of nonresponse to cetuximab and panitumumab in metastatic colorectal cancer (mCRC). The phase III CRYSTAL and OPUS trials presented unplanned subgroup analyses of the correlation of K-ras status with response to therapy with first-line FOLFIRI or FOLFOX, respectively, with or without cetuximab in patients with mCRC. Both studies demonstrated a clear benefit with the addition of cetuximab in K-ras WT patients.

I will never forget the moment when I first found out about my wife's breast cancer. She had noticed an abnormal thickening in her breast and even though we were spending most of our attention focused on an adenoma on the opposite side, the surgeon felt that a biopsy would be prudent. It was a Monday morning, and I was at my desk. Because of my position within our institution, I happened to be on the distribution list of my wife's pathology report. However, before I got to that point in the mail, my close colleague came to my office to notify me of her diagnosis of invasive breast cancer.

The majority of patients who undergo resection for gastric cancer experience relapse and ultimately die of their disease. Therefore, considerable attention has been paid to neoadjuvant and adjuvant strategies to improve surgical outcomes. Two different approaches have been tested in major clinical trials conducted in the past several years: Postoperative chemoradiotherapy was assessed in a US Southwest Oncology Group/Intergroup study (SWOG 9008/INT 0116), and perioperative chemotherapy was studied in a UK Medical Research Council (MRC) randomized trial (the MRC Adjuvant Gastric Infusional Chemotherapy [MAGIC] trial). These trials demonstrated statistically significant survival benefits in patients with resectable gastric cancer. This review will consider these trials and their implications for clinical practice.

Over the past decade, new cytotoxic and biologic therapies beyond the old standard-of-care, biomodulated fluorouracil (5-FU), have become available for the treatment of metastatic colorectal cancer (mCRC). The introductions of irinotecan (Camptosar), oxaliplatin (Eloxatin), and bevacizumab (Avastin) have prolonged survival, but the optimal use of these new therapies remains to be determined. Issues remain regarding management of toxicities, treatment of elderly patients or those with poor performance status, and the duration of treatment with front-line therapy. This article reviews recent and ongoing studies of newer therapies in an effort to determine the best use of these drugs in the treatment of mCRC. Current data support the front-line use of bevacizumab added to either 5-FU/leucovorin alone or 5-FU/leucovorin in combination with oxaliplatin (FOLFOX/bevacizumab) or irinotecan (FOLFIRI/bevacizumab). If oxaliplatin is used in first-line therapy, oxaliplatin should be discontinued before the development of severe neurotoxicity and be reintroduced or replaced with irinotecan on disease progression. Definitive conclusions on the sequence and duration of front-line therapy and the most effective strategy to ameliorate toxicity await results of ongoing prospective clinical trials.

The three papers contained in this supplement to ONCOLOGY were designed to serve as practical "keep on the shelf" references for the current management of metastatic colon cancer and screening and management of patients at high risk of colon cancer.

In medicine today, we all promise to offer the best medical care available to each of our patients, and I would argue that most of us believe we are delivering on this promise. But how do we know that we are living up to that promise? Outside of board exams and CME requirements, there is virtually no internal scoring of our performance. The legal community has been happy to judge us, and they created a legal term—standard of care—against which we are all to be compared. The original intent of this term was to define a minimum level of care, a lowest common denominator. If we at least offered the standard of care, we were delivering acceptable care. We would not be committing malpractice. This is nothing to brag about, but at least we were not dangerous.

In the past several years, the impact of the new biologic therapies oncolorectal cancer has been dramatic. The focus of this article is to summarizesome of the key advances of incorporating biologically targetedtherapies into the routine management of patients with colorectal cancer.We will review important data presented at the 2005 American Society ofClinical Oncology annual meeting and discuss the incorporation of thesedata into the most optimal management of our patients, including howbest to manage side effects and keep quality of life as high as possible.

Continuing advances in immunology and molecular biology duringthe past several decades have provided optimism that immunomodulatorystrategies may be clinically useful in patients with cancer.Key advances have included: (1) recognition of the critical role of theantigen-presenting cell and greatly improved understanding of antigenprocessing and presentation, including the molecular interactionsbetween HLA molecules and antigenic epitopes on the antigen-processingcell and the receptors on T cells, and (2) the roles ofcostimulatory molecules such as B7.1, ICAM-1, and LFA-3 in the inductionand maintenance of an immune response. In addition, newtechniques have allowed us to identify immunogenic antigenic determinants,alter their binding affinities, and evaluate the overall successof the intervention through both in vivo and in vitro assays.Carcinoembryonic antigen (CEA) is overexpressed in a large numberof gastrointestinal, lung, and breast cancers. Clinical trials have establishedtreatment protocols using viral vectors to immunize patients toCEA without producing deleterious autoimmune phenomena. By combiningvarious vectors to include MUC-1 and/or CEA plus costimulatorymolecules in a prime-and-boost regimen, we are beginning to see signsthat this intervention can not only produce changes in immune functionbut also potentially improve clinical outcomes. Phase III studies totest these hypotheses are under way.

Recent advances in understandingthe cellular mechanismsthat determine tumor developmentand progression havespawned a plethora of the so-called“smart therapies”-targeting variousaspects of aberrant cell signaling.Some of the most promising of theseinclude agents targeting tumor angiogenesis,among them the vascularendothelial growth factor (VEGF)-specific humanized monoclonal antibodybevacizumab (Avastin), whichis the most advanced antiangiogenicagent in clinical development. Theinitial promise of this agent is nowsupported by proof-of-concept clinicaldata and is discussed in the comprehensivereview by Olszewski andcolleagues. But the question remains:How does bevacizumab achieve thisclinical benefit?

The manuscript written by Drs.Hoff, Ellis, and Abbruzzese isan outstanding overview of thedevelopment, mechanism of action,and key clinical data for bevacizumab(Avastin) and cetuximab (Erbitux).Over the past several years,the landscape for treating patients withcolorectal cancer has changed dramaticallywith the inclusion of irinotecan(Camptosar), oxaliplatin (Eloxatin),and capecitabine (Xeloda). Then, beforewe can even catch our breath,along come cetuximab and bevacizumab.The next several years will befocused on testing these agents in avariety of clinical trial settings to optimizetheir use for patients with colorectalcancers. Three issues come tomind after reviewing the Hoff et almanuscript: (1) semantics, (2) awkwardUS Food and Drug Administration(FDA) indications, and (3) money.

Irinotecan (CPT-11, Camptosar) is one of the new generation ofchemotherapeutic agents that has activity in advanced colorectal cancer.It has antitumor efficacy as a single agent, and also has beencombined with fluorouracil (5-FU) and leucovorin (IFL) to treat thesepatients. Randomized studies have confirmed the superiority of IFL to5-FU and leucovorin alone with regard to patient survival, time toprogression, and tumor response rate. The optimal schedule for combiningthese agents remains uncertain, but in the United States, theschedule of IFL weekly for 4 consecutive weeks repeated every 6 weeks,according to the schedule reported by Saltz et al, has been widely used,although with some toxicity (especially myelosuppression and diarrhea).In an attempt to improve the tolerability of IFL, some haveadvocated modifying the schedule of IFL to weekly for 2 weeks, withrepeated cycles every 21 days. Twenty-three patients with advancedcolorectal cancer have been treated on this schedule at a single institution.Therapy was well tolerated, with 35% of patients experiencinggrade 3/4 neutropenia, two of whom had episodes of febrile neutropenia,and 9% with grade 3/4 diarrhea. The median relative dose intensityof irinotecan administered in the first 18 patients treated with thisregimen was 94%. These data support the hypothesis that modifying theschedule of administration of IFL improves the tolerability and abilityto deliver the regimen, but must be confirmed by randomized prospectivestudies, which may also attempt to evaluate the role of bolus 5-FUin the treatment of advanced colorectal cancer.

Both irinotecan (CPT-11, Camptosar) and epirubicin (Ellence) are significant chemotherapeutic agents that are used in the management of many different cancers. Each agent works through the inhibition of topoisomerases, and inhibition of topoisomerases I and II may possibly result in significant clinical synergy. This phase I clinical study represents an investigation of the first combination of irinotecan and epirubicin in patients with advanced cancer.

Capecitabine (Xeloda) is the first orally available fluoropyrimidine approved for use in patients with cancer. It was initially approved for use in metastatic breast cancer, but significant data also support its use in the management