Million-Strong Study Supports CRC Screening Every 10 Years


Clinicians following guideline recommendations to screen for colorectal cancer once every 10 years can reassure their patients that the time interval is effective and does not put them at increased risk, conclude US investigators.

Researchers evaluated more than 1.2 million Californians aged 50 to 75 years who were enrolled in a health plan. They compared unscreened individuals with those who had a negative colonoscopy result over a 10-year period.

The results showed that the relative risk of developing colorectal cancer in people with a negative result at 10 years was 46% lower than that for unscreened individuals; the relative risk of colorectal cancer death was 88% lower.

The research was published online December 17 in JAMA Internal Medicine.

Lead author Jeffrey K. Lee, MD, Division of Research, Kaiser Permanente Northern California, Oakland, said in a press release: “Our study shows that, following a colonoscopy with normal findings, there is a reduced risk of developing and dying from colorectal cancer for at least 10 years.”

These findings suggest, said Lee, that physicians “can feel confident” about the guideline-recommended 10-year rescreening interval after a negative colonoscopy in which no colorectal cancer or polyps were found.

“There is now solid evidence supporting that recommendation,” he said.

Senior author Douglas A. Corley, MD, PhD, MPH, also of Kaiser Permanente Northern California, added: “This large study is the first with a high enough number of average-risk individuals to evaluate cancer risks after colonoscopy examinations, compared with no screening.”

The study provides “greater certainty regarding the appropriate timing for rescreening after a negative colonoscopy,” he said.

Asked for comment, Robert A. Smith, PhD, vice president of cancer screening, American Cancer Society in Atlanta, Georgia, said that “the new data show that a 10-year interval is pretty effective.”

Approximately 63% of eligible individuals in the United States undergo colorectal cancer screening, Smith told Medscape Medical News. In the majority of cases, screening is opportunistic, with patients referred as a result of another encounter, he explained.

The current study, said Smith, “probably reinforces in people’s minds the importance of screening…. It’s widely accepted that colorectal cancer screening is a good thing.”

On the other hand, some patients either do not undergo colonoscopy or do not prepare for the procedure properly and end up having to cancel.

“A concern is raised that we have uneven quality of colonoscopy in this country,” he said.

“Just because you’ve had a normal examination doesn’t mean that there aren’t some lesions in there that were overlooked but could potentially grow to become malignancies in the interval before your next examination is due,” Smith continued.

Echoing previous suggestions that “a reasonable and safe thing to do is a fecal immunochemical test, say, at 5 years,” Smith argued that “a high-sensitivity stool test would have the opportunity to pick those [malignancies] up.”

Study Details

Although current guidelines recommend that individuals with a negative colonoscopy result be rescreened after 10 years, the California investigators say the evidence supporting this is “modest” and that that recommendation is based on estimates of colonoscopy sensitivity and the time it takes for adenoma to progress.

Clinicians following guideline recommendations to screen for colorectal cancer once every 10 years can reassure their patients that the time interval is effective and does not put them at increased risk, conclude US investigators.

Researchers evaluated more than 1.2 million Californians aged 50 to 75 years who were enrolled in a health plan. They compared unscreened individuals with those who had a negative colonoscopy result over a 10-year period.

The results showed that the relative risk of developing colorectal cancer in people with a negative result at 10 years was 46% lower than that for unscreened individuals; the relative risk of colorectal cancer death was 88% lower.

The research was published online December 17 in JAMA Internal Medicine.

Lead author Jeffrey K. Lee, MD, Division of Research, Kaiser Permanente Northern California, Oakland, said in a press release: “Our study shows that, following a colonoscopy with normal findings, there is a reduced risk of developing and dying from colorectal cancer for at least 10 years.”

These findings suggest, said Lee, that physicians “can feel confident” about the guideline-recommended 10-year rescreening interval after a negative colonoscopy in which no colorectal cancer or polyps were found.

“There is now solid evidence supporting that recommendation,” he said.

Senior author Douglas A. Corley, MD, PhD, MPH, also of Kaiser Permanente Northern California, added: “This large study is the first with a high enough number of average-risk individuals to evaluate cancer risks after colonoscopy examinations, compared with no screening.”

The study provides “greater certainty regarding the appropriate timing for rescreening after a negative colonoscopy,” he said.

Asked for comment, Robert A. Smith, PhD, vice president of cancer screening, American Cancer Society in Atlanta, Georgia, said that “the new data show that a 10-year interval is pretty effective.”

Approximately 63% of eligible individuals in the United States undergo colorectal cancer screening, Smith told Medscape Medical News. In the majority of cases, screening is opportunistic, with patients referred as a result of another encounter, he explained.

The current study, said Smith, “probably reinforces in people’s minds the importance of screening…. It’s widely accepted that colorectal cancer screening is a good thing.”

On the other hand, some patients either do not undergo colonoscopy or do not prepare for the procedure properly and end up having to cancel.

“A concern is raised that we have uneven quality of colonoscopy in this country,” he said.

“Just because you’ve had a normal examination doesn’t mean that there aren’t some lesions in there that were overlooked but could potentially grow to become malignancies in the interval before your next examination is due,” Smith continued.

Echoing previous suggestions that “a reasonable and safe thing to do is a fecal immunochemical test, say, at 5 years,” Smith argued that “a high-sensitivity stool test would have the opportunity to pick those [malignancies] up.”

Study Details

Although current guidelines recommend that individuals with a negative colonoscopy result be rescreened after 10 years, the California investigators say the evidence supporting this is “modest” and that that recommendation is based on estimates of colonoscopy sensitivity and the time it takes for adenoma to progress.

Anti-EGFR Therapy in Right-Sided Metastatic Colorectal Cancer: Right or Wrong?


Colorectal cancer (CRC) is the second leading cause of cancer-related death in the United States after lung cancer, and American Cancer Society sources estimate that more than 50,000 Americans will die of CRC this year alone.1 In addition to chemotherapy, biologic agents are an important component of the arsenal against metastatic CRC (mCRC). Use of cetuximab and panitumumab, which are monoclonal antibodies targeting the epidermal growth factor receptor (EGFR), has evolved substantially over the past 2 decades.2 Immunohistochemical evidence of EGFR-positivity in tumors was initially thought to be an appropriate therapeutic biomarker, but this EGFR expression was not predictive of response to cetuximab,2 and the response rate for patients with EGFR-positive chemorefractory mCRC treated with cetuximab was only 8%.3 Further work demonstrated that cetuximab treatment outcomes were worse for patients with tumor mutations in KRAS exon 2 than for their wild-type counterparts.4 However, KRAS exon 2 mutations are only part of the picture; thus, patients with mutations in KRAS exons 3–4 and NRAS exons 2–4 also do not benefit from anti-EGFR therapy.5,6 Patients with BRAF V600E mutations likewise do not benefit from EGFR inhibitors unless combined with irinotecan and BRAF-targeted therapies.

More recently, tumor sidedness has emerged as another predictive biomarker for response to cetuximab and panitumumab in the RAS and BRAF wild-type population. Patients with mCRC and right-sided primary tumors (cecum, ascending and proximal transverse colon) have inferior overall survival compared with patients with mCRC and left-sided primaries (distal transverse, descending, and sigmoid colon and rectum).7 Moreover, patients with right-sided primaries do not benefit from cetuximab in the first-line setting, whereas patients with left-sided primaries clearly benefit.8

In the CALGB/SWOG 80405 study of first-line chemotherapy plus cetuximab versus chemotherapy plus bevacizumab in patients with KRAS exon 2 wild-type mCRC, the longest overall survival was seen in the study arm that included patients with left-sided tumors treated with cetuximab (36.0 months), followed by the left-sided tumors treated with bevacizumab arm (31.4 months), followed by the right-sided tumors treated with bevacizumab arm (24.2 months), and finally the right-sided tumors treated with cetuximab arm (16.7 months).8 Although cetuximab led to worse outcomes in patients with right-sided tumors regardless of KRAS status, it can be suggested that patients with RAS and BRAF wild-type left-sided primary tumors should receive anti-EGFR therapy in the first line. Perhaps the treatment sequence is important in this latter case, and EGFR therapy upfront improves response to future lines of therapy.

These findings raise some inevitable questions: can we ever use anti-EGFR drugs in the treatment of patients with right-sided mCRC, particularly in those with RAS and BRAF wild-type tumors, as a later line of therapy, and what other biomarkers can we use to inform this decision? In this issue of JNCCN, Kratz et al attempt to answer this question by looking at tumor bulk using 3.5 cm as a cutoff. In a small retrospective analysis in the late-line setting, these authors show that anti-EGFR therapies work best in nonbulky (small) tumors, especially when the tumors are on the left side. Most importantly, nonbulky right-sided mCRCs respond to anti-EGFR therapy, but only with the addition of chemotherapy.

Small sample numbers make drawing definitive conclusions difficult, but these results suggest that anti-EGFR monotherapy should be avoided in patients with nonbulky right-sided mCRC and that anti-EGFR therapy, whether alone or in combination, should be avoided altogether in patients with bulky right-sided mCRC. The authors reasonably propose that as tumor bulk increases, the anti-EGFR monoclonal antibodies are less likely to reach their target on the tumor cell surface. Tumor bulk should theoretically not present a similar issue for bevacizumab, which binds to soluble vascular endothelial growth factor A (VEGF-A) in the extracellular space, not on the tumor cell surface.

Putting bulk aside, what is the biological explanation for tumor sidedness affecting response to anti-EGFR therapies in patients with RAS and BRAF wild-type mCRCs? The right- and left-colon arise from different embryologic structures (midgut and hindgut, respectively) and have different blood supplies (superior and inferior mesenteric arteries, respectively). Tumor mutational profiles vary throughout the colon, with higher rates of BRAF– and PIK3CA-mutated and microsatellite unstable tumors on the right side and higher rates of TP53– and APC-mutated and HER2-amplified tumors on the left side and in the rectum. Importantly, mutational profiles continuously change throughout the colon, and there is not a dichotomous split between right and left. Indeed, recent work suggests that tumor profiles vary across specific regions in the right colon, left colon, and rectum, further complicating matters.9

What causes such genomic diversity in CRC? Part of the answer lies in the colonic microbiome, which varies among individuals, age groups, and locations within the colon and rectum. Certain culprit bacteria such as Fusobacterium nucleatum, Bacteriodes fragilis, and Streptococcus gallolyticus have known roles in CRC carcinogenesis.10 More research is necessary to elucidate whether certain carcinogenic bacteria give rise to CRC with more or less sensitivity to anti-EGFR drugs. Bacteria may be the missing link accounting for the different tumor biology of the right colon that leads to resistance to anti-EGFR therapy.

For now, the right colon is probably the wrong place to consider using single-agent cetuximab or panitumumab. The impulse to use these agents when all other available therapies have been exhausted should be countered by the concern that EGFR blockade in this setting may actually result in worse patient outcomes. Right-sided mCRC tumors that are RAS and BRAF wild-type and nonbulky may respond to combination chemotherapy with anti-EGFR antibodies, but not to anti-EGFR therapy alone. Future efforts need to address the mechanisms of resistance to anti-EGFR therapy in right-sided RAS, BRAF, and PIK3CA wild-type mCRC.

Are Certain Bacteria Associated With Development of Colorectal Cancer?


The gut microbiome may play an important role in the development of colorectal cancer, according to a study published in the Journal of Gastrointestinal Oncology. Study author Jessica D. Dahmus, MD, of the Thomas Jefferson University Hospital, and colleagues sought to analyze the potential carcinogenic associations of five strains of sulfidogenic bacteria based on prior published research.

Sulfidogenic bacteria was focused on due to its production of hydrogen sulfide, which has been shown to cause DNA damage. This can result in genomic instability, notably found in more than 80% of sporadic colorectal cancers. The authors suggested that hydrogen sulfide affects mitochondrial function in intestinal epithelial cells, resulting in hyperproliferation in the Ras/MAPK pathway. Colorectal cancer is one of many malignancies for which this pathway is a known mechanism of carcinogenesis.

Researchers analyzed Streptococcus bovis, Fusobacterium nucleatum, Helicobacter pylori, Bacteroides fragilis, and Clostridium septicum. S. bovis seems to be associated with higher rates of both adenomas and carcinomas. Patients with colorectal cancer have been shown to have high concentrations of F. nucleatum and less microbial diversity than control groups. H. pylori infections appear to be associated with a 1.4-fold risk increase for colorectal cancer, although the authors mentioned that data may be controversial due to publication bias from the original research. The subtype Enterotoxigenic Bacteroides fragilis produces a toxin that has been shown to affect the development of colorectal cancer. Finally, C. septicum has not been associated with the initial appearance of colorectal cancer, but it does appear to have a mutually beneficial relationship with malignancies in progress.

“Future research may focus on whether the detection of certain bacterial concentrations within stool or biopsied polyps could serve as adjuncts to current screening modalities to help identify higher risk patients,” the authors concluded.

Study Confirms Lifesaving Value of Colonoscopy


A large study has confirmed what many public health experts have long believed: Colonoscopy saves lives.

The study looked at roughly 25,000 patients in the Veterans Affairs (VA) health system, where colonoscopy is widely used. The VA views it as the main screening test for patients aged 50 and older who have average odds for developing colon or rectal cancer.

Of that group, close to 20,000 patients were cancer-free between 2002 and 2008. About 5,000 were diagnosed with colorectal cancer during that time and died of the disease by 2010.

Those who died were significantly less likely to have had a colonoscopy, the study found.

A comparison of screening histories over about two decades found that “colonoscopy was associated with a 61 percent reduction in colorectal cancer mortality,” said study author Dr. Charles Kahi.

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Kahi is gastroenterology section chief with the Roudebush VA Medical Center in Indianapolis.

The U.S. Centers for Disease Control and Prevention recommends everyone between the ages of 50 and 75 get screened for colon cancer. Those at high risk — including those with a family history of the disease — should be tested even earlier, the CDC advises.

Screening can take several forms, including stool tests; a lower colon exam called flexible sigmoidoscopy; and even a “virtual” colonoscopy that relies on X-rays to scan the entire colon.

But many public health advocates favor a full colon exam, or colonoscopy. For the test, a patient is typically sedated and a doctor inserts a flexible, lighted tube to examine the entire colon. If found, growths called polyps can be removed during the procedure.

Between 11.5 million and 14 million Americans have a colonoscopy each year, according to the study team.

The new study focused on patients aged 50 and older who were treated at VA facilities between 1997 and 2010.

The investigators found that a colonoscopy reduced the risk of death from right-sided colorectal cancer by 46 percent and left-sided cancer by 72 percent, equaling a combined drop of 61 percent.

“These findings are important at several levels,” Kahi said.

For one, the study shows that the quality of care within the VA system — the nation’s largest — “is at least as good as other health care settings,” despite recent concerns, he suggested.

But more broadly, Kahi noted, the finding removes any doubt as to whether a colonoscopy can effectively reduce cancer deaths.

The answer, he said, “is an unequivocal ‘yes.'”

Both points were seconded by Dr. Andrew Chan, an associate professor of medicine at Harvard Medical School who reviewed the findings.

“I am not surprised,” Chan said. “The results confirm an already substantial body of data supporting that colonoscopy is associated with a substantial reduction in risk of colorectal cancer.”

The results provide reassurance that colonoscopy is an effective screening tool for patients in the massive VA health care system, he explained.

Chan added that doctors need to make colorectal cancer screening a routine part of their patients’ preventive care.

“And it is clear that we need to improve the performance of colonoscopy in the prevention of cancers that arise in the right side of the colon,” he concluded.

“This will likely require a focus on ensuring that patients undergo an optimal bowel preparation for the procedure and the physician performing the procedure does a high-quality exam with a focus on careful inspection of the entire colon,” Chan said.

Kahi and his colleagues published their findings online March 13 in the Annals of Internal Medicine.

New biomarkers for colorectal cancer


https://speciality.medicaldialogues.in/new-biomarkers-for-colorectal-cancer/

Systemic Versus Local Therapies for Colorectal Cancer Pulmonary Metastasis: What to Choose and When?


Abstract

Background

Lung is the second most common site of colorectal cancer metastasis. Treatment is based mainly on systemic therapy which has largely evolved lately, but outcome remains relatively poor. The place of locoregional therapies as curative strategies is still debated.

Method

A systematic literature review was performed by the authors for systemic therapy, surgery, radiofrequency ablation (RFA), and stereotactic body radiation therapy (SBRT). The highest level of evidence for each strategy was presented. Major findings were addressed in a summarized and clinically relevant manner.

Results

All reported studies were descriptive non comparative reports except for one retrospective study comparing surgery to SBRT. The highest level of evidence for each therapeutic strategy are presented as follows: three large meta-analyses for surgery as well as seven and three prospective trials for RFA and SBRT, respectively.

Discussion

Surgery has the highest level of evidence for cure followed by RFA and SBRT. However, careful patient selection and complete resection of all metastasis are the main principles behind the efficacy of local therapies in the curative setting. Despite encouraging results, randomized trials are still needed.

Aspirin As Secondary Prevention in Patients With Colorectal Cancer: An Unselected Population-Based Study


Abstract

Purpose Regular use of aspirin (acetylsalicylic acid) is associated with reduced incidence and mortality of colorectal cancer (CRC). However, aspirin as primary prevention is debated because of the risk of hemorrhagic adverse effects. Aspirin as secondary prevention may be more justified from a risk-benefit perspective. We have examined the association between aspirin use after the diagnosis of CRC with CRC-specific survival (CSS) and overall survival (OS).

Materials and Methods An observational, population-based, retrospective cohort study was conducted by linking patients diagnosed with CRC from 2004 through 2011 (Cancer Registry of Norway) with data on their aspirin use (The Norwegian Prescription Database). These registries cover more than 99% of the Norwegian population and include all patients in an unselected and consecutive manner. Exposure to aspirin was defined as receipt of aspirin prescriptions for more than 6 months after the diagnosis of CRC. Multivariable Cox-proportional hazard analyses were used to model survival. The main outcome measures of the study were CSS and OS.

Results A total of 23,162 patients diagnosed with CRC were included, 6,102 of whom were exposed to aspirin after the diagnosis of CRC (26.3%). The median follow-up time was 3.0 years. A total of 2,071 deaths (32.9%, all causes) occurred among aspirin-exposed patients, of which 1,158 (19.0%) were CRC specific. Among unexposed patients (n = 17,060), there were 7,218 deaths (42.3%), of which 5,375 (31.5%) were CRC specific. In multivariable analysis, aspirin exposure after the diagnosis of CRC was independently associated with improved CSS (hazard ratio [HR], 0.85; 95% CI, 0.79 to 0.92) and OS (HR, 0.95; 95% CI, 0.90 to 1.01).

Conclusion Aspirin use after the diagnosis of CRC is independently associated with improved CSS and OS.

HER2 Therapy in Advanced Colorectal Cancer: ‘Extraordinary’


A small group of patients with treatment-refractory, HER2-positive metastatic colorectal cancer achieved a remarkable response with a common targeted therapy regimen used to treat HER2-positive breast cancer with no need of a chemotherapy backbone.

Patients were treated with a combination of trastuzumab (Herceptin, Genentech/Roche) and lapatinib (Tykerb, GlaxoSmithKline).

The new data come from a proof-of-concept study published online April 20 in the Lancet Oncology.

“In this heavily pretreated population, these outcome data are extraordinary, and they show the relevance of HER2 as a target in the treatment of colorectal cancer,” Hans-Joachim Schmoll, MD, PhD, Martin Luther University of Halle-Wittenberg, Germany, writes in anaccompanying editorial.

These results represent a breakthrough, even though they apply only to a small subgroup of patients.Dr Hans-Joachim Schmoll

“These results represent a breakthrough, even though they apply only to a small subgroup of patients,” he adds.

Small Study, Impressive Results

The study, known as HERCULES, was conducted by Andrea Sartore-Bianchi, MD, Niguarda Cancer Center, Grande Ospedale, Milano, Italy, and colleagues at four Italian academic cancer centers.

From August 2012 to May 2015, investigators screened 914 patients with KRAS exon 2 (codons 12 & 13) wild-type metastatic colorectal cancer and identified 5% of patients who had HER2-positive tumors. Two patients died before being enrolled; 27 patients were eligible for the trial.

“Most patients had extensive metastatic disease and distal colon tumours,” Dr Sartore-Bianchi notes.

Almost 75% of the group had received at least four prior treatment regimens and had spent a median total time of 20 months on previous treatments.

Notably, all patients had also previously been treated with epithelial growth factor receptor–targeted antibodies, but none of 15 patients who were evaluable achieved an objective response to either cetuximab (Erbitux, ImClone Systems Incorporated) or panitumumab (Vectibix, Amgen Inc), she said.

Patients then received the HER2-targeted therapy combination. Trastuzumab, an anti-HER2 antibody, was given intravenously at a loading dose of 4 mg/kg, followed by 2 mg/kg once a week. Lapatinib, a tyrosine kinase inhibitor, was given by mouth at a dose of 1000 mg/day in 21-day treatment cycles, so patients received one dose of trastuzumab each week and one dose of lapatinib each day.

At a median follow-up of 94 weeks, one of the 27 patients (4%) had achieved a complete response, seven patients (26%) had achieved a partial response, and disease stabilized in another 12 patients (44%).

Eight patients, or 30% of the group overall, achieved an overall objective response, determined in accordance with RECIST 1.1 criteria, Dr Sartore-Bianchi points out.

Among the 12 patients in whom disease stabilized, duration of response lasted 16 weeks or longer in eight patients.

Overall, 59% of the group achieved either a complete response, a partial response, or stable disease lasting longer than 16 weeks. Responses were also durable, lasting a median of 38 weeks.

Furthermore, “of the 25 patients assessed for radiological response, 21 (84%) had tumour shrinkage,” Dr Sartore-Bianchi notes.

Median progression-free survival was 21 weeks, and median overall survival, calculated post hoc, was 46 weeks.

Quite remarkably, 12 patients, or 45% of all patients receiving the proof-of-concept regimen, were alive at 1 year.

Adverse Events

More than three quarters of the group developed diarrhea, and almost half developed a rash or fatigue in response to treatment.

One third reported paronychia, but there were no treatment-related grade 4 or 5 toxicities, and no patient developed treatment-related cardiotoxicity.

None of the patients were obliged to stop treatment because of adverse events, and there were no instances of withdrawal from treatment, although the dose of lapatinib was reduced in three patients because of side effects.

As Dr Sartore-Bianchi notes, results from the HERACLES study are “particularly meaningful” when they are compared with other third-line therapies. For example, the multikinase inhibitor regorafenib (Stivarga, Bayer HealthCare Pharmaceuticals) has shown objective responses in only 1% to 4% of patients, and the trifluridine-tipiracil combination TAS-102 has shown objective responses in only 2% of patients in this setting.

“Our results show that HER2 amplification is a clinically relevant genetic alteration in metastatic colorectal cancer,” Dr Sartore-Bianchi concludes.

Established diagnostic tools can now be used to screen colorectal cancer patients for the presence of HER2, and results can be acted upon if tumors prove to be HER2 positive.

Clinical Implications

Asked to comment further on the clinical implications of the HERACLES study, Dr Schmoll said that for any patient with colorectal cancer who has already received several lines of treatment, “there is no chance for regression of the metastases ― not even a minimal chance, since there are no drugs available that have at least some activity for patients like these,” he said.

In light of this, the remission rate reported by the Italian team is extremely high and in fact has never before been achieved in patients with this type of treatment-refractory tumor, he added.

“Clearly, this relates only to a small minority of patients,” Dr Schmoll cautioned.

“But this is characteristic of the new molecular targeted treatments ― there are several different molecular subgroups of colorectal cancer, with different specific treatments — and now there is a new subgroup,” he said.

“This trial was done in patients who were refractory to all available treatment options, and to see such a high efficacy in patients who would be expected to die very soon means that this new regimen must and will be evaluated as a first-line treatment. In fact, clinical trials to evaluate the new regimen in this setting are starting.”

The HER2 genetic alteration occurs in 3% to 5% of patients with KRAS codon 12/13 wild-type metastatic cancer.

Big Difference in Colorectal Cancer on Right vs Left Side


There is a big difference in colorectal cancer when it occurs on the right side compared with the left side, according to a new analysis of data from a large, federally funded trial. There is also a suggestion that the position of the primary tumor could influence treatment choice.

Survival was significantly longer for patients with primary tumors that originated on the left side of the colon (in the descending colon, sigmoid colon, and rectum) than for patients with primary tumors that originated on the right side of the colon (in the cecum and ascending colon).

The median overall survival (OS) was 19.4 months for patients with right-sided tumors vs 33.3 months for patients with left-sided tumors.

“While previous studies had suggested that tumor location may impact clinical colorectal cancer outcomes, the effect we observed in this analysis appears to be far greater than we expected,” said lead study author Alan Venook, MD, professor of medicine at the University of California, San Francisco.
“These findings will likely change the way we approach colorectal cancer treatment and research, even as we seek to more deeply understand the biology,” he said in a statement.

Dr Venook will present the new data at the forthcoming American Society of Clinical Oncology (ASCO) 2016 Annual Meeting. He was discussing the findings at a premeeting presscast.

New Analysis of Data

The new findings derive from a further analysis of data from the CALGB/SWOG 80405 (Alliance) study, conducted in 1137 patients with metastatic colorectal cancer. The trial compared first-line treatment with two different chemotherapy regimens ― oxaliplatin, 5-fluorouracil, and leucovorin (FOLFOX), and irinotecan, 5-fluorouracil, and leucovorin (FOLFIRI) ― and two targeted agents, bevacizumab (Avastin, Genentech, Inc) and cetuximab (Erbitux, ImClone Systems Incorporated).
The main results from this trial, presented at ASCO 2014, showed no difference in either progression-free survival (PFS) or overall survival (OS) between any of the treatment arms, leading to the conclusion that either chemotherapy regimen and either targeted agent could be used as first-line therapy.

A follow-up to this, showing how a consideration of costs changes the conclusion, was reported at ASCO 2015.

This new analysis looks at patient outcomes with respect to where the original cancer was found.

Dr Venook reported that 293 patients had right-sided primary tumors, and 732 patients had left-sided primary tumors. An additional 66 patients had transverse tumors; these patients were excluded from the analysis, inasmuch as it made no difference to the results whether they were included among either the patients with right-sided tumors or those with left-sided tumors, Dr Venook explained. An additional 46 patients had tumors that were designated as uncertain; these patients were also excluded.

All the patients in this analysis had tumors without a mutated KRAS gene, which is a known biomarker of response to certain colorectal cancer therapies, including cetuximab (in fact, cetuximab is approved only for use in such patients).

The primary analysis showed that patients with colorectal cancer that originated on left side had better outcomes and longer survival than patients with cancer that originated on the right, regardless of the treatment they received.

However, a further exploratory analysis found differences that were related to treatment.

During the presscast, Dr Venook highlighted the finding that among patients who received cetuximab, those with left-sided tumors had a median OS of 36 months vs 16.7 months for patients with right-sided tumors.

 The magnitude of this difference was “surprising to us,” he said. He noted that this 16-month survival of patients with right-sided tumors who received cetuximab is “quite different” from what was seen in all the other subgroups. “It is clearly an outlier.”

The exploratory analysis also showed that among patients who received bevacizumab, overall survival for those with left-sided tumors was 31.4 months vs 24.2 months for those with right-sided tumors.

“It appears that patients with right-sided colorectal cancer, broadly speaking, do not get benefit from cetuximab,” Dr Venook said. He suggested that this finding will change clinical practice. “This could very well represent a shift,” he said. Other factors need to be taken into consideration, but for now, these data argue strongly against using cetuximab and other EGFR antibodies in patients with colorectal cancer originating on the right side, he said.

 He noted that further work is underway. Detailed, ongoing analysis is being conducted on 44,000 tumor samples taken from patients enrolled in this trial, and he hopes that this work will show that “sidedness” is a surrogate for biological markers. He said that for the time being, “The side can help us make decisions in the context of all the other information we gather.”

A coauthor of the abstract was a little more cautious. “These are preliminary data and need confirmation,” commented Richard Schilsky, MD, ASCO chief medical officer and former chief of the Section of Hematology-Oncology at the University of Chicago.

The new data suggest that left-sided and right-sided colorectal cancers are both biologically and anatomically different, he commented. “There have been some data trickling through that these differences may exists, but this was quite a large trial and is more definitive evidence to suggest that these are real differences that we should be paying attention to,” he told Medscape Medical News.

“The bottom-line conclusion is that in the future, clinical trials for colon cancer should stratify patients by ‘sidedness,’ so we can better understand this issue,” Dr Schilsky commented.

“We’re not ready yet to make treatment decisions on real-world practice based on this information, but it’s pretty provocative…given that the overall results show that the choice of targeted therapy doesn’t really matter. This new info suggests that it does matter, depending on sidedeness,” he added.

Another expert also urged caution in acting upon the findings. Julien Taieb, MD, head of the gastroenterology and gastrointestinal oncology department of the Georges Pompidou European Hospital, Paris, pointed out that the new findings come from a post hoc analysis of subgroups of patients, which does not theoretically allow definitive conclusion. “From a scientific point of view, we now have to meet the standards for evidence-based medicine with a randomized controlled trial on that topic,” he said.

“I think that these are very interesting findings on a huge clinical trial, but in my opinion, these results are not sufficient to change our practice,” Dr Taieb told Medscape Medical News.

In addition, although talk of sidedness is interesting, it is not accurate enough in the current era of genetic and genomic medicine, he commented, adding: “We are now trying to move to international consensual molecular classifications to better define and treat the different types of colon cancer.” He noted that it is already known that the two anatomic sites have different concentrations of some biological markers that may be involved in anti-EGFR resistance, including BRAF and RAS mutations.

“However, sidedness remains an easy factor to identify, either by colonoscopy or on a CT scan, and it is something that is ‘doable’ in every country in the world, where sophisticated genomic/genetic analyses may not be possible,” he said.

He noted that the original trial found no difference between cetuximab and bevacizumab, whereas two smaller studies had found a significant difference, with improved OS on anti-EGFRs compared with bevacizumab in patients with wild-type disease who had undergone full RAS testing (which was not available for the whole population of the present trial).

Aspirin As Secondary Prevention in Patients With Colorectal Cancer: An Unselected Population-Based Study


Purpose Regular use of aspirin (acetylsalicylic acid) is associated with reduced incidence and mortality of colorectal cancer (CRC). However, aspirin as primary prevention is debated because of the risk of hemorrhagic adverse effects. Aspirin as secondary prevention may be more justified from a risk-benefit perspective. We have examined the association between aspirin use after the diagnosis of CRC with CRC-specific survival (CSS) and overall survival (OS).

Materials and Methods An observational, population-based, retrospective cohort study was conducted by linking patients diagnosed with CRC from 2004 through 2011 (Cancer Registry of Norway) with data on their aspirin use (The Norwegian Prescription Database). These registries cover more than 99% of the Norwegian population and include all patients in an unselected and consecutive manner. Exposure to aspirin was defined as receipt of aspirin prescriptions for more than 6 months after the diagnosis of CRC. Multivariable Cox-proportional hazard analyses were used to model survival. The main outcome measures of the study were CSS and OS.

Results A total of 23,162 patients diagnosed with CRC were included, 6,102 of whom were exposed to aspirin after the diagnosis of CRC (26.3%). The median follow-up time was 3.0 years. A total of 2,071 deaths (32.9%, all causes) occurred among aspirin-exposed patients, of which 1,158 (19.0%) were CRC specific. Among unexposed patients (n = 17,060), there were 7,218 deaths (42.3%), of which 5,375 (31.5%) were CRC specific. In multivariable analysis, aspirin exposure after the diagnosis of CRC was independently associated with improved CSS (hazard ratio [HR], 0.85; 95% CI, 0.79 to 0.92) and OS (HR, 0.95; 95% CI, 0.90 to 1.01).

Conclusion Aspirin use after the diagnosis of CRC is independently associated with improved CSS and OS.