Progress against GI cancer during the American Society of Clinical Oncology's first 50 years.

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JOURNAL OF CLINICAL ONCOLOGY

A S C O 50TH A N N I V E R S A R Y

Progress Against GI Cancer During the American Society of Clinical Oncology’s First 50 Years Robert J. Mayer, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA Alan P. Venook, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA Richard L. Schilsky, American Society of Clinical Oncology, Alexandria, VA

Tumors of the GI tract were frequent causes of cancer-related mortality in 1964 when the American Society of Clinical Oncology (ASCO) was founded and remain so in 2014, 50 years later. GI cancers accounted for 31% of the reported 305,000 cancer-related deaths in the United States in 19671 and 28% of the anticipated 585,720 such deaths in 2014.2 Worldwide, GI cancers led to more than 2.3 million deaths in 2008, far more than deaths resulting from any other group of malignant conditions.3 In 1964, studies related to GI cancer were in their infancy. Newly formed cooperative groups were focused on clinical trials dealing with hematologic malignancies. The chemotherapeutic agent that remains the cornerstone of treatment for GI cancer (fluorouracil [FU]) had recently been synthesized and was being used in early clinical trials at the Mayo Clinic and the University of Wisconsin. The combination of FU and radiation therapy was being explored in the management of locally advanced rectal cancer.4 In 1973, the National Cancer Institute organized the GI Tumor Study Group (GITSG), a multidisciplinary clinical research collaborative from which seminal clinical trials emerged over the subsequent 15 years. Substantial progress in GI oncology has occurred since then, much of which has been specific to individual diseases but also as a result of advances in oncology in general. The creation of the SEER program of the National Cancer Institute and the Nurses’ Health Study and the Health Professionals Follow-Up Study of the Harvard School of Public Health has provided population-based cohorts from which have emerged valuable epidemiologic information, leading to a better understanding of both genetic and environmental risk factors (eg, smoking, obesity, viral carcinogenesis) for cancer. Technological advances such as computed tomography, magnetic resonance imaging, positron emission tomography, fiberoptic endoscopy, endoluminal stents, and the development of immune and molecular biomarkers to refine prognostic and predictive information have all contributed to improved outcomes for patients with GI cancers. Surgical morbidity and outcomes have improved as a result of refinements in technique (such as better-tolerated Whipple resections and the introduction of total mesorectal excisions and minimally invasive resections of the esophagus, stomach, and colorectum), and the introduction of linear accelerators has reduced injury to normal tissues after radiation therapy. The development of effective cytotoxic and targeted drugs in addition to FU and the validation of Journal of Clinical Oncology, Vol 32, No 15 (May 20), 2014: pp 1521-1530

Table 1. Changing 5-Year Survival Expectations in the United States for GI Cancers (1975-1977 v 2003-2009)2 5-Year Survival (%) Cancer Site

1975-1977

2003-2009

Esophagus Gastric Pancreas Hepatobiliary Colon/rectum

5 15 2 3 50

19 29 6 18 66

adjuvant and neoadjuvant treatment strategies have improved clinical outcomes, particularly for patients with colorectal cancer2 (Table 1). Advances in specific GI cancers are presented in subsequent sections of this article. Esophageal Cancer In 1964, the vast majority of esophageal cancers occurring in the United States were squamous cell carcinomas arising in the cervical and thoracic esophagus,5 most frequently in older males with a history of excess alcohol and/or tobacco use.6 Squamous cell carcinomas are still the most frequently observed form of esophageal cancer worldwide, where the disease is the sixth leading cause of cancer-related mortality.3 The incidence of squamous cell esophageal cancer has decreased in the United States during the past 50 years, whereas the incidence of adenocarcinoma of the esophagus has increased sevenfold, such that adenocarcinoma now comprises more than 75% of esophageal tumors.7 These adenocarcinomas, which occur far more often in men than women, arise in the distal esophagus in the presence of chronic gastric reflux,8 often in association with Barrett’s esophagus.9 Chronic gastric reflux, Barrett’s esophagus, and esophageal adenocarcinomas occur more commonly in obese individuals.10 These tumors arise within the dysplastic columnar epithelium of the distal esophagus with aneuploidy and mutations of the p53 gene detectable in the dysplastic epithelium before progression to frank neoplasia.11 Fifty years ago, surgery was the mainstay of treatment for patients with esophageal cancer. Operative procedures were poorly tolerated,12 in part because patients were suboptimal surgical candidates because of malnutrition and the frequent presence of significant comorbid © 2014 by American Society of Clinical Oncology

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Table 2. Important Observations and Advances in Esophageal Cancer Between 1964 and 2014 Observation/Advance Marked increase in adenocarcinomas in the United States Linkage of the development of adenocarcinomas to obesity, chronic gastric reflux, and Barrett’s esophagus Preoperative chemoradiation therapy extends survival PET scans provide more accurate staging and offer rapid early assessment of responsiveness to treatment Abbreviation: PET, positron emission tomography.

illness. The probability of 5-year survival in the mid-1970s for American patients with esophageal cancer was approximately 5% (Table 1). In more recent years, surgery has been better tolerated in patients with distal esophageal tumors; the development of minimally invasive surgical techniques has further reduced perioperative morbidity.13 Although treatment outcomes are slightly improved if preoperative radiation therapy or platinum-based chemotherapy is administered, the best survival outcomes are achieved using preoperative chemotherapy combined with radiation therapy14,15 with some reports that focus on squamous cell cancers suggesting no additional benefit when surgery is added if significant shrinkage of tumor has been achieved through the use of chemoradiotherapy.16,17 Sequential positron emission tomography scans seem to be useful in assessing responsiveness to neoadjuvant therapy.18 At present, the estimated likelihood of 5-year survival for American patients is 19%, which still indicates that long-term benefit can be achieved in only a disappointing minority of patients while also demonstrating a fourfold improvement over the 5% likelihood of 5-year survival of 30 years ago2 (Table 1). Major observations and advances in esophageal cancer during the past 50 years are summarized in Table 2. Gastric Cancer The dramatic and poorly explained decrease in the incidence and mortality rates of gastric cancer in the United States that began in 1930 has continued in the past 50 years. Whereas gastric cancer was the cause of 5.7% of cancer-related deaths in the United States in 1967,1 it will result in only 1.9% of the anticipated cancer-related deaths in 2014.2 Nonetheless, gastric cancer remains the second most frequent cause of cancer mortality worldwide.3 The risk for gastric cancer is greater among lower socioeconomic populations.19 Migrants from high- to low-incidence regions maintain their susceptibility to gastric cancer, whereas the risk for their offspring approximates that of the prevailing risk of their new homeland.20 These observations suggest that an environmental exposure, probably beginning early in life, is related to the development of gastric cancer, with dietary carcinogens21 and Helicobacter pylori22 infection being considered contributory factors. During the past 50 years, gastric adenocarcinomas have been subdivided into two types23: an intestinal type characterized by ulcerative lesions in the antrum and lesser curvature preceded by atrophic gastritis and often initiated by H pylori infection; and a diffuse type, which occurs throughout the stomach, often without mucosal ulceration, resulting in a lack of distensibility of the gastric wall (linitis plastica), associated with the loss of expression of E-cadherin and carrying a worse prognosis. Although the incidence of diffuse carcino1522

© 2014 by American Society of Clinical Oncology

mas is similar in most populations, the intestinal type tends to predominate in high-risk geographic regions and is less likely to be found in areas where the frequency of gastric cancer has been declining. A germline mutation in the E-cadherin gene (CDH1) inherited in an autosomal dominant pattern and coding for a cell adhesion protein has been associated with a high incidence of occult diffuse-type gastric cancer in young, asymptomatic carriers.24 During the past two decades, the use of double-contrast radiographic examinations has been replaced by computed tomography scanning and esophagogastroscopy for the evaluation of individuals with epigastric complaints. Although a subtotal gastrectomy remains the operative procedure of choice for patients with distal, intestinaltype carcinomas,25 many patients with diffuse carcinomas now receive preoperative chemotherapy or chemoradiotherapy given that surgical outcomes for these individuals have generally been poor. In highincidence regions of the world such as Asia, large numbers of lymph nodes are routinely removed as part of potentially curative operations for gastric cancer. The value of these so-called D2 and D3 procedures has been assessed in several randomized trials in comparison with resections that remove fewer lymph nodes. These studies have shown that the incremental benefit of the more aggressive surgery is quite modest, possibly because some of the benefit in tumor control achieved by the D2/D3 procedure is offset by increased perioperative morbidity and mortality.26 Several FU-based chemotherapy combinations such as FU/leucovorin/oxaliplatin (FOLFOX), epirubicin/cisplatin/FU (ECF), and docetaxel/cisplatin/FU (TCF) have been studied as potential treatment for patients with advanced gastric cancer. Although response rates vary, the median survival time is generally less than 12 months, with the regimens differing primarily in the severity of adverse effects and cost.27 The addition of trastuzumab to chemotherapy in the 15% of patients with human epidermal growth factor receptor 2/neu overexpressing tumors extends the median survival by 2.7 months.28 Adding bevacizumab to chemotherapy has not prolonged median survival.29 However, preliminary experience using a more recently developed anti–vascular endothelial growth factor receptor monoclonal antibody, ramucirumab, seems promising.30,31 Adjuvant or perioperative chemotherapy has been shown to enhance surgical cure in studies conducted in Asia32,33 and Europe.34 In the United States, perhaps because of the use of somewhat less extensive surgical procedures, the best outcomes have been achieved with chemoradiotherapy after surgery,35 although no added benefit was found when a more intensive chemotherapy regimen (ECF) was compared with FU and leucovorin alone as part of an adjuvant chemoradiotherapy program.36 During the last 30 years, the likelihood of 5-year survival for American patients with gastric adenocarcinoma has increased from 15% to 29%2 (Table 1). Major observations and advances in gastric cancer during the past 50 years are summarized in Table 3. Pancreatic Cancer In 1964, little was known about pancreatic cancer; its cause was unknown, the pancreas could not be adequately imaged, and the disease was almost always far advanced when discovered. On the rare occasions when the diagnosis could be made early, the only treatment was the Whipple procedure, a complex operation associated at that time with high rates of perioperative morbidity and even mortality and which was rarely curative.37 JOURNAL OF CLINICAL ONCOLOGY


ASCO 50th Anniversary

Table 3. Important Observations and Advances in Gastric Cancer Between 1964 and 2014 Observation/Advance Incidence and mortality rates in the United States continue to decrease Gastric cancer occurs in two subtypes: Intestinal (ulcerated lesions in antrum after atrophic gastritis) Diffuse (submucosal infiltration causing lack of distensibility) Helicobacter pylori infection is associated with the intestinal subtype A germline mutation in the CDH1 gene, which regulates E-cadherin, is associated with familial gastric cancer The small survival benefit achieved with extended (D2 and D3) surgical resections may be offset by increased perioperative morbidity and mortality Adjuvant chemoradiation therapy prolongs survival

Although pancreatic cancer remains a sinister disease today and represents the fourth most common cause of cancer-related death in the United States, small improvements in outcome are becoming evident. More sophisticated imaging has made the pancreas visible to clinicians, and advances such as endoscopic retrograde cholangiopancreatography38 and transduodenal fine-needle biopsy via an endoscope39 can lead to an earlier diagnosis. Additionally, surgical techniques and postoperative care have improved, with patients being referred to high-volume centers, leading to a marked reduction in postoperative morbidity and mortality.40 Problems such as jaundice, pain, weight loss, anorexia, and hypercoagulability can still be overwhelming early in the course of pancreatic cancer, but aggressive symptom management and the appropriate use of endoluminal stents to relieve biliary tree or gastric outlet obstruction have led to better palliation for most patients. A hallmark of pancreatic cancer is the dense fibrous stroma that often envelops the tumor; this sclerotic process limits the accessibility of tumor tissue, accounting in part for the slow pace of progress in understanding the molecular basis of the disease.41 It is now known that RAS mutations are present in more than 90% of cancers,42 but other key molecular drivers have not yet been identified. The CA19-9 is an accepted serologic marker43 in the disease and is of some clinical use in monitoring the course of the illness. Recently, a transgenic mouse model that spontaneously recapitulates the stroma-laden human disease44 has been introduced and may facilitate the more rapid development of biologic insights regarding the initiation and progression of pancreatic cancer. Epidemiologic studies have linked the development of pancreatic to obesity,45 the recent onset of type II diabetes,46 and cigarette smoking.47 Investigations in families at higher-than-usual-risk for pancreatic cancer have revealed an increased incidence in the setting of Peutz-Jegher syndrome,48 hereditary nonpolyposis colon cancer,49 and mutations in the BRCA1 or, particularly, the BRCA2 genes.50 Sequencing studies have revealed putative pancreatic cancer susceptibility genes,51 but these observations have not yet altered clinical practice or identified individuals in whom intensive screening procedures might be beneficial. Between 1985, when the GITSG established FUchemoradiotherapy as standard adjuvant therapy,52 and 1997, when modest benefits in survival and symptom control led to US Food and Drug Administration approval of gemcitabine,53 the lack of therapeutic progress was disheartening. During the ensuing years, gemcitabine www.jco.org

has been shown to be effective in the adjuvant setting,54 but the role of radiation therapy as part of adjuvant treatment has been questioned.55 It is sobering to note that the median survival time of 20 to 24 months in contemporary adjuvant studies54-57 is no better today than it was in the GITSG report of 1985.52 Given the availability of improved staging techniques, this observation suggests that whatever progress has been made with presently available treatment approaches has been minimal and has not significantly impacted the natural history of the disease. Between 1997 and 2011, despite a host of attempts to combine gemcitabine with other drugs, no significant improvements were made in the treatment of advanced pancreatic cancer.58 Since 2011, the introduction of the FOLFIRINOX (fluorouracil, leucovorin, irinotecan, oxaliplatin) and gemcitabine/NAB-paclitaxel regimens seems to have changed the dynamic. The use of FOLFIRINOX has more than tripled the response rate compared with gemcitabine and has extended the median survival from 5 months to more than 11 months59 while maintaining an acceptable quality of life.60 The administration of the gemcitabine/NAB-paclitaxel doublet has improved the median overall survival achieved with gemcitabine from 5 months to 8.5 months.61 Whether one of these chemotherapy regimens is superior to the other and whether either might prove to be effective in the adjuvant setting are not yet known, but both give hope that the rate of progress over the next 5 years will vastly exceed that of the past 50 years. During the past 30 years, the probability of 5-year survival for American patients with pancreatic cancer has increased slightly from 2% to 6%2(Table 1). Major observations and advances in pancreatic cancer during the past 50 years are summarized in Table 4. Hepatobiliary Cancers In 1964, hepatocellular carcinoma was thought to be primarily a consequence of alcoholic cirrhosis. In large part as a result of the efforts of Beasley et al,62 it is now clear that alcohol accounts for just a small fraction of the global burden of hepatocellular carcinoma with the majority of cases resulting from chronic infection with hepatitis B or hepatitis C virus. Through the prospective surveillance of male governmental employees in Taiwan, the risk for developing hepatocellular carcinoma was shown to be increased by 390-fold in individuals with serologic evidence of hepatitis B infection. The subsequent development of a vaccine against hepatitis B and its administration to

Table 4. Important Observations and Advances in Pancreatic Cancer Between 1964 and 2014 Observation/Advance The development of a transgenic mouse model that recapitulates the human disease Epidemiologic link to obesity, recent onset of type II diabetes, and chronic cigarette smoking Increased incidence in families with a history of Peutz-Jegher syndrome, hereditary nonpolyposis colon cancer, and BRCA syndromes Introduction of endoscopic retrograde cholangiopancreatography, allowing the placement of stents to nonsurgically relieve tumor-related obstructive jaundice Improved surgical technique leading to decreased operative morbidity and mortality Successful use of gemcitabine as adjuvant therapy and FOLFIRINOX and gemcitabine/NAB-paclitaxel to treat metastatic disease Abbreviation: FOLFIRINOX, fluorouracil, leucovorin, irinotecan, oxaliplatin.



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Taiwanese neonates born to mothers who were hepatitis B carriers essentially eradicated hepatocellular carcinoma in a generation of Taiwanese citizens,63 confirming the causative relationship between hepatocellular carcinoma and hepatitis B. The present inability to develop a vaccine against hepatitis C has resulted in continued high rates of hepatocellular carcinoma infection in endemic areas such as Africa but also in the United States and Europe.64 The development of orthotopic liver transplantation during the past 50 years has provided a dramatic and potentially curative form of therapy for some patients with hepatocellular carcinoma. The process of organ allocation for such patients remains controversial, but experience gathered during the 1990s in selected patients has confirmed the feasibility and long-term benefit of liver transplantation in patients with hepatocellular carcinoma.65 The original eligibility criteria for transplantation—three or fewer hepatic nodules and the absence of major blood vessel involvement and extrahepatic tumor spread— have subsequently been liberalized66 to the extent that approximately 17% of all liver transplantation procedures performed in the United States are now carried out on patients with hepatocellular carcinoma.67 For patients with hepatocellular carcinoma not suitable for liver transplantation, standard cytotoxic chemotherapy has produced disappointing results. Therapeutic efforts have focused on a unique feature of such hepatic tumors: their hypervascularity. The use of transhepatic arterial chemoembolization has proven to be effective in providing transient local tumor control and even an apparent slight prolongation in survival.68 However, hepatocellular carcinoma ultimately represents a systemic rather than a local disease; the poor hepatic reserve of patients with hepatocellular carcinoma and their frequent comorbid conditions have hampered the development of effective systemic treatment. Sorafenib, a tyrosine kinase inhibitor thought to target the RAF gene, was the first drug approved for the treatment of hepatocellular carcinoma on the basis of studies conducted in Asia69 and the United States and Europe.70 These pivotal trial results only emerged after it was decided to limit entry to patients with adequate liver function, thereby minimizing the impact of an impaired liver on the outcome of the study and offering a more meaningful setting to better examine the efficacy of the study drug.71 Biliary tract cancers (ie, cholangiocarcinoma, gall bladder cancer, and ampullary cancer) have also proven to be difficult to study and to treat. Although once considered uncommon, the introduction of cytokeratin immunohistochemical staining and the availability of circulating tumor markers such as CA19-9 have indicated that they occur more commonly than previously recognized. The observation in 2010 that the combination of gemcitabine and cisplatin was superior to gemcitabine alone72 has led to this regimen becoming the standard treatment against which new combinations are being compared. The probability of 5-year survival for American patients with hepatobiliary cancer has increased from 3% to 18% during the past 30 years2 (Table 1). Major observations and advances in hepatobiliary cancers during the past 50 years are summarized in Table 5. Pancreatic Neuroendocrine and Intestinal Carcinoid Tumors In contrast to the outlook for the majority of GI cancers, the prognosis for patients with GI neuroendocrine cancers has signifi1524


Table 5. Important Observations and Advances in Hepatocellular Carcinoma Between 1964 and 2014 Observation/Advance Chronic infection with hepatitis B or hepatitis C virus is the most common causative factor and the incidence of hepatocellular carcinoma can be markedly reduced by vaccination against hepatitis B Curative potential of orthotopic liver transplantation in highly selected patients Palliative benefit of transhepatic chemoembolization Sorafenib prolongs survival in patients with preserved liver function

cantly improved during the past 50 years. The discovery of somatostatin in 197373 led to a series of advances that have transformed the pancreatic neuroendocrine tumors (PNET) and intestinal carcinoid tumors into manageable, chronic diseases. Because both of these entities can have clinical syndromes that result from hormone excess, they have often been considered to be a single pathologic entity. The introduction of octreotide (an octapeptide analog of somatostatin with a longer half-life than the native molecule that is capable of blocking hormone release)74 has been shown to diminish the associated symptoms experienced by patients with both carcinoid tumors (eg, overwhelming diarrhea) and PNETs (eg, abnormal glucose metabolism from the hormonal effects of insulin or glucagon). The widespread use of abdominal imaging along with the ability to biopsy lesions deep within the abdomen may account for the apparent increasing frequency of these diagnoses. It is now clear that most PNETs do not secrete hormones and that the cellular proliferative index may be the best predictor of prognosis. Advances such as somatostatin and its sustained-release formulations allow many of these patients to live longer with a better quality of life.75 Patients with carcinoid disease may live for decades with a chronic condition, whereas patients with PNETs typically succumb to cancer progression after approximately 5 to 8 years. During the last several years, the ability to target metabolic and angiogenesis pathways with oral tyrosine kinase inhibitors76 and with everolimus77 has provided new treatment options and stimulated new research approaches for these rare diseases. Colorectal Cancer At the birth of ASCO in 1964, little was known about the causes of colorectal cancer; treatment was largely limited to surgical resection of the primary tumor, and FU was used with marginal effectiveness in treating patients with metastatic disease. Since then, substantial progress has been made in the early detection, prevention, and treatment of colorectal cancer leading to significant reductions in the incidence and mortality in the United States and most resource-rich countries.2 Observational studies have linked the consumption of red meat,78 obesity,79 and lack of physical activity80 to an increased risk of colon cancer; the regular use of aspirin seems to reduce that risk.81,82 Aspirin use83 and vigorous physical activity84 also seem to decrease the risk of recurrence and death among patients already diagnosed with colon cancer. Familial colon cancer syndromes such as familial adenomatous polyposis and hereditary nonpolyposis colon cancer have been well characterized both clinically and genetically, and the introduction of genetic counseling services for high-risk families has enabled comprehensive risk assessment and early intervention to reduce JOURNAL OF CLINICAL ONCOLOGY



the risk of colorectal cancer in affected individuals.85 Sporadic colonic adenomas are now generally accepted to be premalignant lesions with the risk of malignancy related to polyp size, villous morphology, and sessile appearance.86 Thus, screening the general population for colorectal polyps and cancer, previously with fecal occult blood testing and more recently by direct visualization through sigmoidoscopy or colonoscopy, has become established and has been proven to reduce cancer incidence and mortality.87-89 Unfortunately, the proportion of the eligible population who actually undergo screening remains suboptimal, largely as a result of misunderstandings regarding individual risk, poor access to care, and concerns about the discomfort of the bowel preparation before endoscopy. In recent years, new technologies, such as computed tomographic colonography, have emerged as effective screening strategies, at least for larger polyps, and may be more acceptable to the public than endoscopic procedures; however, the widespread use of computed tomographic colonography will likely be limited by the continued need for bowel preparation, cost, and the availability of radiologists with the necessary expertise to interpret the images.90 Fecal DNA testing for mutations in shed epithelial cells offers the promise of a screening test that is far more specific than testing for fecal occult blood, but this test will not eliminate the need for direct visualization of the colon to identify and remove the source of the abnormal cells.91 Among the most important advances of the last 50 years has been the delineation of the molecular pathways leading to colorectal cancer, described initially by Vogelstein et al92 and Markowitz et al93 and subsequently refined by the Cancer Genome Atlas Network.94 The microsatellite instability pathway, related to mutation or hypermethylation of DNA mismatch repair genes, and the chromosome instability pathway, associated with tumor suppressor gene deletion or oncogene mutation, are now known to lead to aberrations in specific molecular pathways such as WNT, MAPK, PI3K, TGFB, and p53 that contribute to the formation of the majority of colorectal tumors. These new insights will no doubt lead to more effective early detection, prevention, and treatment strategies in coming years.93 The prognosis for newly diagnosed patients with colorectal cancer is primarily related to tumor stage as determined by the TNM classification.95 Other pathologic (eg, tumor perforation, obstruction, perineural and/or vascular invasion, lymphocytic infiltration, number of involved nodes, and total number of nodes in the resected specimen96,97), clinical (eg, elevated preoperative carcinoembryonic antigen level98), and molecular characteristics that may impact prognosis have also been recognized. Among the latter, high microsatellite instability in colon cancer resulting from mutation in certain DNA mismatch repair genes has consistently been associated with more favorable outcomes99 and may predict lack of responsiveness to FU chemotherapy as well.100 BRAF mutations are emerging as an independent adverse prognostic feature,101,102 and several gene expression profiling tests have been introduced that seem useful in refining the prognosis (albeit not presently the management) of patients with stage II disease.103-105 The primary treatment of colon cancer is surgical resection, and several prospective randomized clinical trials have now shown that laparoscopic colectomy produces similar outcomes with reduced morbidity compared with open colectomy.106 Since a series of randomized clinical trials conducted in the 1980s and 1990s clearly established the value of 6 months of postoperative adjuvant chemotherapy for patients with stage III colon cancer, the major subsequent advance www.jco.org

has been the addition of oxaliplatin to FU/leucovorin (ie, FOLFOX).107 Irinotecan was shown to be ineffective when added to FU/ leucovorin in the adjuvant setting.108,109 Surprisingly, neither bevacizumab110 nor cetuximab,111 when added to chemotherapy, has been shown to be useful in the adjuvant setting either, although both drugs are effective in the treatment of patients with metastatic disease. The primary treatment of rectal cancer has evolved considerably in the last 50 years, in large part as a result of information generated from prospective randomized clinical trials conducted primarily outside the United States. Optimal local control and reduced perioperative and long-term morbidity can be achieved with a total mesorectal excision of the rectum after combined chemotherapy (infusional FU or capecitabine) and pelvic radiation and the subsequent administration of adjuvant systemic treatment.112,113 A definitive randomized comparison of administering chemoradiotherapy before or after surgery has demonstrated no significant difference in survival between these two approaches after 11 years of follow-up, but a reduced risk of local recurrence and late complications favors the preoperative treatment.114 In the surgical management of both colon and rectal cancer, outcome is related to clinical volume and the experience of the surgical team with the best outcomes achieved in the high-volume centers.115 The treatment of patients with metastatic colorectal cancer has changed substantially in the last 50 years; although most patients with metastatic disease remain incurable, the median survival has now been prolonged from 6 to 9 months to longer than 2 years. The introduction in the 1970s of the carcinoembryonic antigen as a serum marker, useful in monitoring the course of the disease, facilitated the early detection of disease recurrence after completion of initial treatment. Indeed, a 2006 ASCO clinical practice guideline recommended the measurement of the carcinoembryonic antigen every 3 months for at least 3 years after the completion of initial treatment for patients who are candidates for additional antitumor treatment.116 Up to 25% of patients with a limited number of metastatic sites confined to a single organ (typically liver) may be curable through surgical resection. Other ablative techniques such as radiofrequency ablation, cryoablation, and localized external-beam radiotherapy have shown promise as well, although a 2009 ASCO clinical evidence review called for additional research on radiofrequency ablation before its widespread adoption.117 For the majority of patients with more widely metastatic disease, systemic chemotherapy remains the treatment of choice. Treatment programs in the 1980s focused on optimizing the delivery of FU and enhancing its activity with the addition of leucovorin, a reduced folate that enhances the binding of FU to its target enzyme, thymidylate synthase.118 New cytotoxic drugs for the treatment of colorectal cancer began to be introduced during the late 1990s with the development of irinotecan119 and oxaliplatin,120 both of which improved survival for patients with metastatic colorectal cancer when added to FU and leucovorin, optimally administered in an infusional schedule. These regimens (FOLFIRI and FOLFOX respectively) have been shown in clinical trials to produce similar outcomes, although they differ substantially in their toxicity profiles.121 Capecitabine, an oral prodrug of FU, was also introduced, and in a series of randomized trials in both the metastatic and adjuvant settings, was shown to produce similar outcomes to FU-based chemotherapy.122,123 The next major advance came with the addition of bevacizumab, an anti–vascular endothelial growth factor receptor monoclonal antibody, to cytotoxic chemotherapy as part of the bolus © 2014 by American Society of Clinical Oncology


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FU, leucovorin, irinotecan regimen known as IFL. The registrationdirected clinical trial comparing IFL plus placebo with IFL plus bevacizumab resulted in an improvement in median overall survival from 15.6 to 20.3 months and led to the initial US Food and Drug Administration approval of this first-in-class antiangiogenic treatment.124 Subsequent studies supported its use in combination with both irinotecan- and oxaliplatin-based regimens, and the drug is now widely used as part of first-line chemotherapy treatment for metastatic colorectal cancer.125 Anti– epidermal growth factor receptor (EGFR) monoclonal antibodies also have an established role in the treatment of colorectal cancer.126 First developed and approved as a single-agent treatment for patients with EGFR-expressing metastatic colorectal cancer after progression on standard treatments, cetuximab and panitumumab use is now limited to the treatment of patients with KRAS wild-type tumors (approximately 60% of colorectal cancers).127 The analysis of multiple clinical trial data sets has demonstrated that these drugs are not effective in colorectal tumors that harbor mutations in KRAS and NRAS genes (and likely the BRAF gene) and may even result in inferior outcomes when administered to patients whose tumors have such mutations.128,129 Thus, testing for the presence of mutations in the KRAS gene, and potentially other RAS family genes as well, is now standard practice when deciding whether to prescribe an anti-EGFR antibody for the treatment of patients with metastatic colorectal cancer, either as a single agent or in combination with chemotherapy.130 Although bevacizumab and anti-EGFR antibodies are each effective when combined with chemotherapy in the treatment of metastatic colorectal cancer, several clinical trials have shown that combining thesetargetedagentsproducesinferioroutcomescomparedwithchemotherapy plus bevacizumab alone.131,132 Ongoing studies that directly compare bevacizumab with cetuximab used with chemotherapy as initial treatment for patients with metastatic disease will determine the superior approach; an initial report of a recently completed randomized study suggests that cetuximab may be superior to bevacizumab when added to FOLFIRI in the treatment of patients with metastatic KRAS wild-type colon cancer.133 Two other targeted agents have recently been approved for treatment of advanced colorectal cancer, ziv-aflibercept134 and regorafenib,135 although their modest benefit and high cost has stimulated debate regarding their clinical value in this group of patients. Since 1975, the probability for 5-year survival for American patients with colorectal cancer has increased from 50% to 66%2 (Table 1). Major observations and advances in colorectal cancer during the past 50 years are summarized in Table 6. Anal Cancer In 1964, anal cancer was thought to be an uncommon malignancy, arising most frequently in women with a history of condylomata acuminata (otherwise known as venereal warts).136 Standard treatment at that time was an abdominal-perineal resection, necessitating a permanent colostomy. Despite such an extensive procedure, recurrences developed in more than 25% of patients.137 Much progress has been made against anal cancer during the past 50 years. It is now known that anal cancer is caused by human papillomavirus (HPV) infection transmitted through sexual activity.138 The risk for anal cancer is increased among homosexual males, presumably related to anal intercourse.139 Anal cancer risk is increased in both men and women with AIDS,140 perhaps because their immuno1526


Table 6. Important Observations and Advances in Colorectal Cancer Between 1964 and 2014 Observation/Advance Elucidation of the molecular evolution of colorectal cancer from normal mucosa to polyp to tumor Several familial colon cancer syndromes described and their genetic underpinnings identified Sporadic adenomatous polyps recognized as premalignant lesions Recognition of the impact of diet, obesity, physical activity, and aspirin use on colon cancer risk Effective screening strategies introduced to decrease incidence and mortality Adjuvant chemotherapy for colon cancer and chemoradiotherapy for rectal cancer prolongs survival and has become the standard of care, particularly for stage III disease Laparoscopic colectomy and total mesorectal excision lead to reduced morbidity and improved outcomes for patients with colon and rectal cancer, respectively New cytotoxic and targeted therapy have led to the improved survival of patients with metastatic colorectal cancer

suppressed state predisposes them to HPV infections. Preliminary data suggest that vaccination against HPV may reduce the likelihood of developing anal cancer.141 In 1974, a colorectal surgeon named Norman Nigro published the initial results of his experience treating patients with anal cancer with several weeks of radiation therapy, infusional FU, and mitomycin.142 This treatment program, which became known as the Nigro regimen, resulted in pathologic complete response in more than 80% of patients whose primary cancers were less than 3 cm in size; with less than 10% of these patients experiencing tumor recurrences, the so-called Nigro regimen has led to cure in approximately 70% of patients without surgery and without the need for a colostomy.143 Randomized trials conducted during the past 20 years have confirmed the advantage of adding chemotherapy (ie, FU/mitomycin) to radiation,144,145 the value of including mitomycin in the chemotherapy regimen,146 and the superiority of FU/mitomycin compared with FU/cisplatin.147 In 2014, 6,260 (86.8%) of the 7,210 individuals anticipated to develop anal cancer are projected to be cured of their disease.2 Major observations and advances in anal cancer during the past 50 years are summarized in Table 7. Summary GI cancers are among the most common tumors and represent the leading cause of cancer-related death worldwide.3 Most of the

Table 7. Important Observations and Advances in Anal Cancer Between 1964 and 2014 Observation/Advance Anal cancer is a sexually transmitted condition associated with HPV infection Increased risk in patients with AIDS The risk for developing anal cancer may be reduced through vaccination for HPV The high colostomy-free cure rate associated with radiation/FU/mitomycin treatment originally described nearly 50 years ago remains the standard of care Abbreviations: FU, fluorouracil; HPV, human papillomavirus.




progress against these cancers over the last 50 years has resulted from either earlier detection of premalignant lesions or to improved treatment linked to a better understanding of the molecular drivers of malignancy. However, much remains unknown about the fundamental biology of gastric, pancreatic, and biliary tract cancers, and although many of the molecular pathways of colon and rectal cancer have now been elucidated, few effective targeted agents have yet been introduced into clinical practice for these diseases. Although the relatively easy access of the GI tract to endoscopic surveillance and imaging should enable widespread screening of high-risk populations for premalignant and early-stage lesions, much remains to be done to widely disseminate screening programs in many communities. A recent colon cancer screening pilot program in the state of Delaware demonstrated that highly committed efforts can increase screening rates, reduce incidence rates, eliminate racial disparities in outcomes, and reduce cost.148 Vaccination against viral causes of GI cancer such as hepatitis B and C and HPV as well as the eradication of H pylori, if widely applied in high-risk regions, have the potential to eliminate or substantially decrease the incidence of these diseases where they are endemic but will require concerted public health efforts in many countries to achieve these goals. As is the case with most cancers, it is the interplay of basic science research, robust clinical trials, and dissemination of known effective treatments to all communities that will enable continued progress against GI cancers during ASCO’s next 50 years. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) and/or an author’s immediate family member(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Alan P. Venook, Bristol-Myers Squibb (U), Genentech/Roche (U) Stock Ownership: None Honoraria: None Research Funding: Alan P. Venook, GlaxoSmithKline, Genentech, Genomic Health Expert Testimony: None Patents, Royalties, and Licenses: None Other Remuneration: None AUTHOR CONTRIBUTIONS

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145. UKCCCR Anal Cancer Trial Working Party: Epidermoid anal cancer: Results from the UKCCCR randomised trial of radiotherapy alone versus radiotherapy, 5-fluorouracil, and mitomycin. Lancet 348:1049-1054, 1996 146. Flam M, John M, Pajak TF, et al: Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: Results of a phase III randomized intergroup study. J Clin Oncol 14:2527-2539, 1996 147. Gunderson LL, Winter KA, Ajani JA, et al: Long-term update of US GI Intergroup RTOG 98-11 phase III trial for anal carcinoma: Survival, relapse, and colostomy failure with concurrent chemoradiation involving fluorouracil/mitomycin versus fluorouracil/cisplatin. J Clin Oncol 30:4344-4351, 2012 148. Grubbs SS, Polite BN, Carney J Jr, et al: Eliminating racial disparities in colorectal cancer in the real world: It took a village. J Clin Oncol 31:1928-1930, 2013

DOI: 10.1200/JCO.2014.55.4121; published online ahead of print at www.jco.org on April 21, 2014

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ASCO Celebrates 50 Years of Advancing Progress Against Cancer This historic year, as ASCO proudly commemorates its 50th anniversary and decades of evolutionary growth, the Society also celebrates the significant progress that has been made against cancer throughout history. ASCO’s anniversary website, CancerProgress.Net, chronicles these achievements and more. We invite you to visit the upgraded Cancer Progress Timeline to explore advances in 18 different cancers and several types of care, peruse stories about ASCO’s evolution and progress in the field, check out the site’s new social media features, and vote on the most significant milestones in the field. You can also follow ASCO on ASCO Connection, Twitter, and Facebook to join in on the conversation about progress.

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Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer from the American Society of Clinical Oncology.

Clinical Cancer Advances 2016: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology.

Autoimmune hepatitis: 50 Years of (slow) progress.

The First 50 Years of Molecular Pharmacology.

American Society of Clinical Oncology And European League Against Rheumatism.

The American Society of Nephrology at 50: A Personal Perspective.

50 Years of progress in the systemic therapy of non-small cell lung cancer.

American Society of Clinical Oncology.

American society of clinical oncology.

Burn bacteriology during the last 50 years.

American orthopedic surgery: the first 200 years.

First meeting of the American Orthopaedic Society for Sports Medicine.

Progress in the treatment of ovarian cancer-lessons from homologous recombination deficiency-the first 10 years.

The war against tobacco: 50 years and counting.

Looking back, moving forward: 1988-2013. The first 25 years of the American Society of Emergency Radiology.

American Society of Nephrology clinical pathological conference.

The 2014 Surgeon General's report: "The health consequences of smoking--50 years of progress": a paradigm shift in cancer care.

eMERGEing progress in genomics-the first seven years.

Hereditary colorectal cancer syndromes: American Society of Clinical Oncology clinical practice guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology clinical practice guidelines.

The first American medical school: the formative years.

Prostate cancer survivorship care guideline: American Society of Clinical Oncology Clinical Practice Guideline endorsement.

Metastatic Pancreatic Cancer: American Society of Clinical Oncology Clinical Practice Guideline.

American Society of Clinical Oncology clinical expert statement on cancer survivorship care planning.

The American Cancer Society and comprehensive cancer centers.