We have made great progress in the past decade. We have gone from a 6-month median overall survival with best supportive care to close to 30 months for incurable colorectal cancer.
—Richard M. Goldberg, MD
The 2013 Gastrointestinal Cancers Symposium marked the 10th anniversary of the meeting. Richard M. Goldberg, MD, the Klotz Family Chair in Cancer Research, Professor of Medicine, and James Cancer Hospital Physician-in-Chief at The Ohio State University, looked back over the decade to highlight the important advances made—many reported just last year—in preventing, diagnosing, and treating cancers of the colon and rectum.
“We have made great progress in the past decade, much of it reported at this meeting,” Dr. Goldberg said. “We have seen mortality reduced by 10%, and the curves are headed downward still. We have gone from a 6-month median overall survival with best supportive care to close to 30 months for incurable colorectal cancer (Fig. 1), which is a consequence of having more tools in our toolkit for the various permutations of this disease. That’s the real measure of what our efforts are doing,” he commented.
“We are seeing the potential for universal Lynch syndrome screening. We are unraveling the mysteries of the genome, and this will impact our clinical practices. We have strategies for preventing colon cancer and its recurrence that patients can engage in. We have new screening tools, new surgical tools, new radiation tools, and additional drugs in our armamentarium,” he said. “The cup is more than half full.”
“When the Symposium began in 2003, Henry Lynch had been pounding the podium for years, trying to convince the world that familial colon cancer existed. Today, we are aware of this,” Dr. Goldberg said. Some 2% to 3% of patients with colorectal cancer have Lynch syndrome, and not only can they be identified, but so can affected family members (averaging three per proband). Interventions can “prevent them from suffering the ravages of their inherited predisposition,” he said.
A strong case is being made for universal screening of colorectal cancer, based on data that restricting screening to cases fitting the Amsterdam criteria misses one-quarter of affected persons. Universal screening should result in the diagnosis of more than 15,000 individuals nationally. “This is evidence that molecular genetics is making a difference in the clinic,” he said.
Molecular Characterization of Tumors
The Cancer Genome Atlas Network recently published a comprehensive molecular characterization of colon and rectal cancer.1 The key findings were that 16% of tumors are hypermutated, but only 75% are microsatellite instability–high, indicating “we need to understand more about the hypermutated subset,” he said.
Also revealed were similar patterns of genomic alterations for colon and rectal cancers. In particular, some two dozen genes are significantly mutated, “many of which would have been predicted but some of which were unexpected,” he said. These can be exploited for therapeutic gain; druggable opportunities already exist for some (ERBB2 and IGF2).
The identification and validation of gene-expression subtypes is now underway by many research groups. “In some ways, this is the Rosetta Stone we hope will allow us to translate clinical and genetic information into real advances for our patients,” Dr. Goldberg said.
Prevention Is Possible
The potential for preventing primary or recurrent colorectal cancer is becoming more real. The observation that risk factors for developing cancer overlap with those associated with outcomes means “the biology that is driving the occurrence of colorectal cancer is apparently driving the progression or lack of it,” he suggested.
Observational studies in patients with stage I–III disease have yielded information that is clinically useful. Factors known to reduce the risk of recurrence include physical activity (> 10 MET-hours/wk), avoidance of a Western diet, avoidance of obesity (body mass index > 35 kg/m2), intake of aspirin or COX2 inhibitors, and high vitamin D levels. An intriguing new observation is that high glycemic load (ie, sugar intake) may raise the risk of recurrence or death by more than 200%.2 Recurrence has not been associated, however, with weight change (gain or loss), smoking status or history, and multivitamin intake.
Also intriguing are recent findings that the protective effect of aspirin may vary according to PIK3CA mutation status. (Inhibition of COX2 by aspirin appears to down-regulate PI3 kinase signaling activity.) Among patients with mutated PIK3CA tumors, regular use of aspirin after diagnosis was associated with an 82% reduction in cancer-related mortality and a 46% reduction in all-cause mortality, but had no effect in those with wild-type PIK3CA.3 This suggests the PIK3CA mutation may serve as a predictive molecular biomarker for adjuvant aspirin therapy, Dr. Goldberg said, adding that he now makes specific recommendations to patients about “diet and exercise, and the possibility of taking aspirin.”
Colorectal Cancer Screening
The benefit of colonoscopy and polypectomy in reducing colorectal cancer deaths was established in 2012 in the National Polyp Study of 2,602 patients with adenomas removed between 1980 and 1990.4 By comparing deaths observed with those expected, a 53% reduction in mortality was achieved with polypectomy.
In addition, CT colonography emerged as a new screening modality. In experienced hands, CT colonography has a sensitivity of about 96%,5 though clinician experience is critical for a good test. Not yet FDA-approved, fecal DNA is under evaluation as a widely accessible screening test requiring no cathartic preparation, dietary restriction, or visit to the physician’s office. Fecal DNA has shown 85% specificity for colorectal cancer and a 65% specificity for adenomas > 1 cm.6
Surgical and Radiation Advances
The laparoscopic approach to colectomy proved comparable and in some ways superior to open surgery in a 2004 study of 872 patients.7 Recurrence rates, overall survival, and complications were similar between the arms, but the laparoscopic arm had faster recovery, shorter hospital stay, and less use of narcotics. The study showed that laparoscopically assisted colectomy “is just as good a cancer operation as open colectomy,” he said.
The next surgical advance is robotics, although it is entering mainstream use without a proven track record. “The studies we are seeing are often retrospective comparisons. It is a technique many hospitals employ as a marketing tool, and we don’t know its relative efficacy, whether it’s a better operation,” Dr. Goldberg maintained.
Advances have also been impressive with regard to the surgical resection of liver metastases. A recent meta-analysis showed that 5-year survival after resection was 40% and median overall survival was 3.6 years.8 Chemotherapy can make some unresectable lesions resectable, though there remains a risk for chemotherapy-induced hepatic injury. Stereotactic radiotherapy for liver metastases is also promising, especially for problematically located lesions. “We are at an early stage in evaluating this modality, but many retrospective series are showing some value,” he said, citing local control rates exceeding 90% at 1 year.
For rectal cancer, the standard of care shifted from postoperative to preoperative chemoradiotherapy. A recent 40-month update of a landmark study indicated a halving of local recurrence rates—from 12% to 6%—with less anastomotic stenosis or need for abdominal perineal resection.9
A new era of chemotherapy for colorectal cancer began a decade ago, when the addition of oxaliplatin, and then bevacizumab (Avastin), improved outcomes when added to irinotecan, fluorouracil, and leucovorin (IFL). Findings from these landmark studies, both published in 2004,10,11 changed the standard of practice across the world, he said.
The controversy over the benefit of oxaliplatin in patients with stage II disease still simmers, he said, but large randomized trials—MOSAIC12 and the NSABP C-07 trial13—changed the standard of care for stage III patients. Confirmatory studies have shown a clear separation of disease-free survival curves in stage III patients and a trend toward overall survival benefit with oxaliplatin, but no differences among stage II patients. Therefore, oxaliplatin should not be the standard of care for patients with routine-risk stage II disease, Dr. Goldberg said.
Additional Novel Agents
A few years later, cetuximab (Erbitux) and panitumumab (Vectibix) proved capable of improving outcomes as well, at least in a subset of patients.14–16 These patients were soon identified when “the oncology world cried out for a biomarker to determine who was in that subset,” he said. “In many ways, the identification of KRAS as this marker was a seminal finding because it unlocked the door for using biomarkers to predict treatment benefits.”
The pharmacologic advances that began in the late 1990s have continued with the rapid approval of two drugs in 2012, regorafenib (Stivarga) and ziv-aflibercept (Zaltrap). “These agents are also translating into better outcomes,” Dr. Goldberg said.
Ziv-aflibercept showed a benefit in the second-line setting, coupled with FOLFIRI (leucovorin, fluorouracil, irinotecan), improving overall survival by 1.5 months (HR = 0.817; P = .0032) and progression-free survival by more than 2 months (HR = 0.758; P < .0001).17 Regorafenib, tested as a late-line treatment vs best supportive care, was similarly effective in the CORRECT trial, which showed a 1.4-month overall survival benefit (HR = 0.77; P = .0052).18
“The progression-free survival curves for regorafenib, cetuximab, and panitumumab mirror each other,” he said. “We have a genetic predictor for the last two, but we have not identified one for regorafenib. Work must continue on this, to determine how to select which patients to treat with a pricey drug that has some potential side effects.” ■
Disclosure: Dr. Goldberg has received research support from and has been an unpaid consultant for Bayer and Sanofi. He has also served on data monitoring boards for Pfizer and Lilly.
1. Cancer Genome Atlas Network: Comprehensive molecular characterization of human colon and rectal cancer. Nature 487:330-337, 2012.
2. Meyerhardt JA, Sato K, Niedzwiecki D, et al: Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Natl Cancer Inst 104:1702-1711, 2012.
3. Liao X, Lochhead P, Nishihara R, et al: Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367:1596-1606, 2012.
4. Zauber A, Winower SJ, O’Brien MJ, et al: Colonoscopic polypectomy and long-term prevention of colorectal-cancer deaths. N Engl J Med 366:687-696, 2012.
5. Pickhardt PJ, Hassan C, Halligan S, et al: Colorectal cancer: CT colonography and colonoscopy for detection—systematic review and meta-analysis. Radiology 259:393-405, 2011.
6. Ahlquist DA, Zou H, Domanico M, et al: Next-generation stool DNA test accurately detects colorectal cancer and large adenomas. Gastroenterology 142:248-256, 2012.
7. Clinical Outcomes of Surgical Therapy Study Group: A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 350:2050-2059, 2004.
8. Kanas GP, Taylor A, Primrose JN, et al: Survival after liver resection in metastatic colorectal cancer: Review and meta-analysis of prognostic factors. Clin Epidemiol 4:283-301, 2012.
9. Sauer R, Liersch T, Merkel S, et al: Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/AOR/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol 30:1926-1933, 2012.
10. Goldberg RM, Sargent DJ, Morton RF, et al: A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 22:23-30, 2004.
11. Hurwitz H, Fehrenbacher L, Novotny W, et al: Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350:2335-2342, 2004.
12. André T, Boni C, Mounedji-Boudiaf L, et al: Oxaliplatin, fluorouracil and leucovorin as adjuvant treatment for colon cancer. N Engl J Med 350:2343-2351, 2004.
13. Yothers G, O’Connell MJ, Alegra CJ, et al: Oxaliplatin as adjuvant therapy for colon cancer: Updated results of NSABP C-07, including survival and subset analyses. J Clin Oncol 29:1768-1774, 2011.
14. Jonker DJ, O’Callaghan CJ, Karapetis C, et al: Cetuximab for the treatment of colorectal cancer. N Engl J Med 357:2040-2048, 2007.
15. Van Cutsem E, Peeters M, Salvatore Siena S, et al: Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy refractory metastatic colorectal cancer. J Clin Oncol 25:1658-1664, 2007.
16. Amado RG, Wolf M, Peeters M, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 26:1626-1634, 2008.
17. Van Cutsem E, Tabernero J, Lakomy R, et al: Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 30:3499-3506, 2012.
18. Grothey A, Van Cutsem E, Sobrero A, et al: Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): An international multicenter, randomized, placebo-controlled, phase 3 trial. Lancet 381:303-212, 2013.