While new colorectal cancers in older people have fallen consistently since 1985, rates for people under 50 have risen, particularly for rectal cancer.

Even more concerning, young people with colon cancer were diagnosed at later, less curable stages than those 50 or older. Almost two-thirds had a stage III or IV cancer compared to half of people diagnosed at a later age.

In the Archives of Internal Medicine, Nancy You, MD, of MD Anderson Cancer Center in Houston, and her colleagues ask, “Young-Onset Colorectal Cancer: Is It Time to Pay Attention?”

You and her team analyzed colon and rectal cancer cases in the National Cancer Database diagnosed in the ten years between 1999 and 2007.

About 1 in 10 were diagnosed before the age of 50 — 64,068 of 588,869 in the total database.

After 2001, there was an average annual increase of 2.1 percent in young onset colorectal cancer compared to a decrease of 2.5 percent yearly for those 50 and older. Rectal cancer increased even more rapidly in younger patients at an average annual change of 3.9 percent.

The median age of younger patients was 44, with 3 out of 4 (75.2 percent) diagnosed in their forties.

Cancer that had spread to either regional lymph nodes (stage III) or to distant organs (stage IV) occurred in:

• 63 percent of young colon cancer patients.
• 57.7 percent of young patients with rectal cancer

Compared to colorectal cancer in older patients, young-onset cancer occured more often in

• the rectum or the lower (distal) colon (69% vs 57.7%)
• patients who were uninsured or had Medicaid (16.5 % vs 4.7%)
• patients who lived in the south or western US (56.2% vs 50.3%)

Younger patients were also more likely to have mucinous or signet-ring subtypes and poor differentiation.

Concluding, Dr. You and her team wrote,

These data argue for heightened awareness of these concerning trends in young-onset CRC. Symptomatic young patients should undergo timely sigmoidoscopy at a minimum, if not a full colonoscopy. Identifying high-risk cohorts for targeted screening should be a priority.

What’s Behind the Trend?

Dr. You and her colleagues focused on lack of access to health care and a lack of awareness of both young patients and their doctors of the importance of symptoms of colon and rectal cancer. Commenting on their analysis, they wrote:

In the absence of routine screening, contributing factors to these trends may include

(1) a reluctance on the part of young adults to seek medical care.

(2) the large percentage of young adults without insurance or ready access to care.

(3) an underappreciation of the increasing risk for young-onset CRC, leading clinicians to overlook or dismiss symptoms that are nonspecific but may be consistent with CRC (ie, rectal bleeding, abdominal pain or cramping, change in bowel pattern).

They also commented on screening changes:

Finally, the predilection of young-onset CRCs for the distal colon and rectum identify these as high-yield anatomic regions for endoscopic evaluation in symptomatic patients and as potentially cost-effective targets for screening programs in presymptomatic young adults.

The Annual report to the nation on the status of cancer published in 2010 was concerned that diet, lack of physical exercise, and obesity may be an important factor and one that may reflect in the future for people over 50 as well.

Being overweight and failing to exercise are adverse trends that appear to increase risk for CRC, especially colon cancer. An estimated 33% of US adults are overweight, and another 34% are obese. Increasing CRC incidence among young adults (aged <50 years) may bean early indicator of the adverse impact of these risk factors.

What can young people do to reduce their risk of colorectal cancer?

Given that current analyses show that the benefits of colorectal cancer screening for average risk adults don’t begin to outweigh screening risks until age 50, young people need to:

• Maintain a healthy weight and increase physical activity.
• Reduce red meat and avoid processed meats. Eat more whole grains, fruits, and vegetables.
• Consider their family risk and get screened earlier if they have a family history of colorectal polyps or cancer.
• If they have ulcerative colitis or Crohn’s disease, follow their gastroenterologist’s directions for regular colonoscopies and biopsies.
• Know the symptoms of colon and rectal cancer and get to a doctor right away if they have any of those symptoms.
• Never accept a doctor dismissing or downplaying symptoms without a full evaluation including a colonoscopy, or, if resources are simply not there, a less costly sigmoidoscopy.

SOURCES: You et al., Archives of Internal Medicine, Online First December 12, 2011.

Edwards et al.,Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates., Cancer, February 1, 2010.

It isn’t clear why, but rectal cancer rates in this young group of men and women began increasing in 1984, rising about 3.8 percent a year.

Increases were similar for both sexes and all races.

A research team found 7,661 patients under 40 with colon or rectal cancer, including 1,922 with rectal cancer in the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) cancer registry database between 1973 and 2005.

More than half of the cases, 52 percent, were in patients from 35 to 39, with 28 percent from 30 to 34, and 20 percent under 30.

Looking through the medical literature,the study authors couldn’t find an explanation for why rectal cancer was going up while colon cancer wasn’t.  Screening or lifestyle issues couldn’t be identified as a possible reason.

Both rectal and colon cancer are rare in people under 40 with slightly over 1 case of colon cancer for every 100,000 people in the United States and less than 0.5 cases of rectal cancer.  This compares to 34.5 new colon cancer cases per 100,000 people and 13.4 new rectal cancer cases in the overall US population of all  ages.

Because the overall incidence of rectal cancer in this age group is so low, the authors do not recommend changes in screening guidelines.  However, they do urge that symptoms of rectal cancer, including rectal bleeding, be followed up.

Dr. Jeffrey Meyer, lead author of the study, recommends,

We suggest that in young people presenting with rectal bleeding or other common signs of rectal cancer, endoscopic evaluation should be considered in order to rule out a malignancy. This is in contrast to what is frequently done, which is to attribute these findings to hemorrhoids. More frequent endoscopic evaluation may be able to decrease the documented delay in diagnosis among young people.

Concluding, Dr. Meyer and his team wrote,

The incidence of rectal and rectosigmoid cancer appears to be increasing in patients aged less than 40 years. Patients presenting with rectal bleeding or other alarming signs or symptoms should be evaluated with this finding in mind.

SOURCE: Meyer et al., Cancer, Early View, August 23, 2010.

Rectal cancer patients without insurance or covered by Medicaid are almost twice as likely to die within five years as those privately insured.

Not only are they diagnosed at a later stage, but fewer receive recommended treatments at every stage.

More than half of the difference between patients with private insurance and those without was due to differences in how early they were diagnosed and whether or not they got standard treatment.

Researchers looked at information from the National Cancer Data Base, a national hospital-based cancer registry, to study insurance and other factors related to survival among 19,154 rectal cancer patients aged 18 to 64 years old.

They analyzed the impact of  insurance, age, sex, race and ethnicity, neighborhood education and income levels, cancer treatment facility type, stage, pathology features, and treatment on survival at five years.

Rectal cancer patients were diagnosed between 1998 and 2002, and their progress was followed until 2007.

Results

• Uninsured patients were diagnosed at Stage I (17.6 percent) less often than those with private insurance (31 percent).
• Uninsured were diagnosed at late Stage IV (22.5 percent) more often than privately insured (13.8 percent).
• Uninsured were twice as likely not to have a high school diploma (38.9% versus 19.9%) and be poor (44.8 percent vs. 24.1%).
• Patients with private insurance were more likely to be treated in comprehensive community cancer centers, while patients with no insurance were more likely to be treated in teaching/research hospitals.

Differences in standard treatment

• Stage I:  95.1 percent of private patients had surgery with or without chemo/radiation  compared to  83.4 percent of uninsured.
• Stage II:  91.4 percent of privately insured had recommended surgery with or without chemo/radiation while 79.4 percent of uninsured did.   7.7 percent of private patients had chemo/radiation but no surgery compared to 19.2 percent of uninsured.
• Stage III:  4.7 percent of private patients had chemo/radiation without surgery while twice as many (9.6 percent) of uninsured patients received this substandard treatment.
• Stage IV:  More than 3 times as many uninsured patients (14.8 percent) had no treatment at all compared to 4.4 percent of those with insurance.  Again, uninsured patients got less surgery (42.2 percent) than those with insurance coverage (60 percent).

Writing in an early online edition of Cancer, Anthony S. Robbins, MD, PhD and his team in the Department of Surveillance and Health Policy Research at the American Cancer Society said,

Our main finding that most of the excess mortality seen among Medicaid-insured and uninsured patients was explained by 2 modifiable factors (stage and treatment) suggests that improving insurance coverage and reducing cost-related barriers to primary care, CRC screening, and high-quality treatment would have a major impact on CRC survival disparities.

SOURCE: Robbins et al., Insurance status and survival disparities among nonelderly rectal cancer patients in the National Cancer Data Base, Cancer, Early View, June 2010.

Before it can become routine practice, the gene panel will need to be checked in another group of patients and clinical trials will need to be conducted to see if patients who have pathological complete responses and no surgery do as well as those who do have surgery.

After presurgical chemoradiation treatments, about 1 in 5 rectal cancer patients will have all signs of cancer disappear in pathology tests after surgery.  But surgeons don’t know which patients those are until they operate and remove the rectal tumor and its attached tissue and lymph nodes.

M.D. Anderson researchers assessed gene expression in tumor tissue from 46 patients with locally advanced rectal cancer.  They found that the expression of 87 genes was more common in those patients who had no cancer cells remaining in rectal tissue removed during surgery.

Currently standard treatment for locally advanced rectal cancer is chemotherapy and radiation followed by surgery to remove part of the rectum.  If the gene profile could identify patients who would have complete responses and clinical trials showed that not doing surgery was as effective as surgery in those patients, some patients with rectal cancer could be spared the risks, pain, and potential long-term effects of surgery.

Isabelle Bedrosian, MD, FACS, assistant professor of surgery at the University of Texas M.D. Anderson Cancer Center, explained,

We typically say that patients need chemotherapy, radiation therapy, and surgery to get the best outcomes. The upfront chemotherapy and radiation therapy helps shrink tumors down so they can be more easily removed surgically and decreases the chance that the tumor will come back in the pelvis.

Dr. Bedrosian continued,

Findings from this study suggest that we may have a new tool to say to a patient whose tumor has a specific DNA profile and who has had a complete clinical response to chemotherapy and radiation therapy that he may not need radical surgery.

Plans are underway to validate the gene panel in another group of patients.  If successful, clinical trials can be planned to compare recurrences and survival between groups of patients, whose tumors fit the gene profile, who do and do not have surgery.

Dr. Bedrosian’s study was reported at the American College of Surgeons Clinical Congress last week in Chicago.

What This Means for Patients

Discovering the genes that appear to predict pathological complete response is only the first step.  The genes will need to be independently verified in another group of patients.  Then randomized clinical trials will be necessary to see if outcomes like cancer returning in or near the rectum or cancer-free survival are the same whether or not patients have surgery.

So the gene testing is not yet ready for use in today’s patients.

Even if surgeons had to change their approach during the operation and convert from laparoscopic to open surgery, outcomes were not affected.

A surgical team in France compared two similar groups of patients with rectal cancer that had not spread beyond the rectum.  238 had laparoscopic surgery, 233 a more traditional open operation.

They found that there was no difference in deaths immediately after surgery, surgical complications, or quality of surgery.  After five years:

• 3.9 percent of patients in laparoscopic group had cancer return locally versus 5.5 percent of open operations, but this was not a significant difference.
• Cancer-free survival was also not different, with 82 percent of laparoscopic and 79 percent of open patients alive without recurrences.
• Overall survival (death from any cause) was lower among patients who had open surgery (72 percent were alive) compared to 83 percent in the laparoscopic group.  This difference was almost entirely found in stage III patients.

During 36 laparoscopic operations (15 percent), surgeons had to change tactics and perform an open surgery, but this had no negative impact on death after surgery, local recurrence, or survival.

Study results were limited because patients were not randomized.  All surgery was done by a team of colorectal surgeons in a single hospital center using standardized approaches to surgery.  Surgeons removed all signs of cancer in more than 90 percent of both laparoscopic and open operations.

Christophe Laurent, MD, PhD, and his team at the University of Bordeaux in France concluded,

The efficacy of laparoscopic surgery in a team specialized in rectal excision for cancer (open and laparoscopic surgery) is suggested with similar long-term local control and cancer-free survival than open surgery. Moreover, conversion had no negative impact on survival.

SOURCE: Laurent et al., Annals of Surgery, Volume 250, Issue 1, July 2009.

The complete study can be found on Medscape Today. (registration is required to view it.)

What This Means for Patients

The study reinforces the message that patients with rectal cancer should be treated by specialists in colon and rectal surgery.  In addition, patients should ask their surgeons about their experience in laparoscopic surgery for rectal cancer.

To find a colorectal surgeon, go to the American Society of Colon and Rectal Surgeons website where you can search members both within the United States and internationally.

Based on a German study published a couple of years ago, chemoradiation became the standard therapy for patients with resectable rectal cancer. The rate of sphincter-sparing surgeries and lower toxicities were the reason to prefer chemoradiation prior to surgery instead of adjuvant treatment after surgery.

Over the last couple of years many studies aimed to improve the efficacy of neoadjuvant chemoradiation therapies by intensifying the chemotherapy.  Standard therapy is 5-FU or Xeloda® (capecitabine). By adding oxaliplatin it was hoped that  the success rate of chemoradiation could be increased.

Success of neoadjuvant radiation is measured by a complete pathological response rate (complete disappearance of cancer cells). With 5-FU or Xeloda that can be reached in about 10-15% of the cases. Smaller studies have suggested that the addition of oxaliplatin could double the rate.

However the studies presented at ASCO a couple of weeks ago (ACCORD) did not show any significant difference when oxaliplatin was added. However there was interestingly a lower risk of developing metastases in the patients who received the additional oxaliplatin therapy. These findings may question the ongoing R-04 study which compares 5-FU to 5-FU plus oxaliplatin in combination with radiation therapy.

In the Southwest Oncology Group (SWOG) we have choosen another way. In the study just opened, we started with Xeloda, oxaliplatin and Erbitux (kras wild type), then we continue with the chemo and add radiation to have a both powerful systemic effect and a local effect.

• The STAR trial from Italy found that adding oxaliplatin to chemoradiotherapy before rectal surgery did nothing to improve the rate of complete responses found at surgery.  There was also no decrease in the number of patients who needed a permanent colostomy.  Serious diarrhea was significantly worse in the oxaliplatin arm. However, unexpectedly, more distant metastases were found at the time of surgery among patients who didn’t get oxaliplatin (16 patients with spread to lungs, liver, or peritoneal surfaces vs only 2 who got oxaliplatin prior to surgery.)  Survival data is not yet available.
• In France, researchers in the ACCORD trial combined both an increase in radiation to 50Gy and the addition of oxaliplatin to standard treatment of 45Gy and capecitabine in an attempt to improve pathological complete response rates for chemoradiotherapy before rectal cancer surgery.  However, there was no significant impact on tumor response at surgery and no decrease in colostomies.  Serious diarrhea was significant worse (3 percent with no oxaliplatin, 13 percent in the increased radiation with oxaliplatin.)  They did show that Xeloda® (capecitabine) can be substituted for infusional 5-FU in chemoradiotherapy regimens.
• A large trial of anal cancer in the United Kingdom tried to improve both complete response to chemoradiation and disease-free and overall survival by using cisplatin instead of standard mitomycin-C during radiotherapy and by randomly giving two doses of cisplatin and 5-FU after radiation treatment ended.  Response to chemoradiation was excellent with 95 percent of patients having a complete response with either mitomycin-C or cisplatin.  Furthermore, maintenance chemotherapy didn’t change relapse-free survival at three years, with 75 percent of patients without recurrences whether or not they had the extra chemo.  The research team concluded that mitomycin-C remains standard treatment for anal cancer.

Doctors in Ireland developed a simple, three point, tumor regression grade or TRG, to measure the amount of change during chemoradiotherapy before surgery to remove rectal cancer.  After five years, all patients with the best tumor regression grade — complete or near complete response to chemoradiation — were alive and disease-free.

In a series of 126 patients with locally advanced rectal cancer (T3/T4 or spread into nearby lymph nodes), five year disease-free survival after chemoradiotherapy followed by surgery was 72 percent.  Seven percent of patients had cancer recur locally in or near the rectum.

After pathologists examined the surgical specimen, a standard score was used grade response to chemoradiation: complete or near-complete response (TRG1), partial response (TRG2), or no response (TRG3).

Patients with near or complete response (TRG1) had 100 percent disease-free survival at five years.  For those with partial (TRG2) response, five year DFS was 71 percent. No response (TRG3) led to a 66 percent disease-free survival.  Six in ten patients had some response to the presurgical chemoradiotherapy.

D. Beddy and colleagues concluded,

Tumor regression grade measured on a 3-point system predicts outcome after chemoradiotherapy and surgery for locally advanced rectal cancer.

SOURCE: Beddy et al., Annals of Surgical Oncology, Volume 15, Number 12, December 2008.

Within the Surveillance,Epidemiology, and End Results (SEER) registry using data from January1, 1994, through December 31,2003, researchers studied nearly 11,000 people with rectal cancer — 3,760 who were treated with radiotherapy and 7,200 who had stage I cancer and received only surgery.

They found

• For patients who responded to presurgical radiotherapy, 94 percent were alive without cancer five years later compared to 78 percent of those who didn’t respond with tumor shrinkage.
• Overall survival at five years was 82 percent in responders, 60 percent in those with no tumor downstaging.
• For stage I patients with surgery only, disease-free survival at 5 years was 97 percent, overall survival 79 percent.

Eric T. Castaldo, MD, MPH and his colleagues at Vanderbilt University Medical Center in Nashville concluded,

Patients with rectal adenocarcinoma downstaged after neoadjuvant radiotherapy have improved survival compared with nonresponders. While disease-free survival is excellent for responders to neoadjuvant radiotherapy, it did not equal the disease-free survival of patients with stage I disease undergoing resection alone.

SOURCE: Castaldo et al., Archives of Surgery, Volume 144, Number 2, February 2009.

Can adding Avastin® (bevacizumab) to FOLFOX therapy after surgery and presurgical chemoradiotherapy reduce recurrence and improve survival for patients with rectal cancer?

A clinical trial to answer this question is underway and is looking for participants.  Led by a team of researchers from several clinical trials cooperative groups, the E5204 study randomly assigns patients who have already completed a course of chemoradiotherapy and had their rectal cancer removed surgically to either FOLFOX or FOLFOX plus Avastin.

While surgery is the primary treatment for people with rectal cancer, cancer can return, both in or near the rectum (local recurrence) or at distant sites (metastases) in the body.  Giving radiation enhanced with chemotherapy before or after surgery can reduce the risk of local recurrence and chemotherapy can improve overall survival.  Cancer researchers are working on ways to improve treatment for rectal cancer, reducing recurrences and increasing the percentage of patients who are cured.

E5204

Phase III Randomized Study of Adjuvant Oxaliplatin, Leucovorin Calcium, and Fluorouracil With or Without Bevacizumab in Patients Who Have Undergone Surgery and Neoadjuvant Chemoradiotherapy for Stage II or III Rectal Cancer.

What is the goal of E5204?

The primary objective is to improve survival after treatment for rectal cancer.  In addition, researchers will be looking at  rates of local recurrence and side effects of treatment including long-term bowel function, diarrhea, and neuropathy.  They will also be measuring a number of molecular markers to determine what effect they may have on survival.

Who can participate in E5204?

Stage II or III rectal cancer patients are eligible if they

• completed chemoradiotherapy before surgery
• had surgery to remove the rectal tumor between 4 and 8 weeks previously
• don’t have cancer that has spread to distant sites (metastasized)
• have no medical conditions  or history that would make study treatment unsafe

How will the trial be conducted?

After understanding and signing an informed consent, patients will be assigned randomly (by chance) to one of two treatment arms:

• FOLFOX chemotherapy given every two weeks:  intravenous oxaliplatin, leucovorin, and 5-FU on the first day followed by continuous infusion of 5-FU over the next 46 hours.  Treatments are repeated every two weeks for 12 cycles (six months).
• FOLFOX chemotherapy plus intravenous Avastin (bevacizumab) on the first day.

You can find a site near you where the study is being conducted.

Under a special program, Medicare will pay for any additional costs that are involved in this trial for patients who have Medicare benefits.  Ordinarily Medicare covers the cost of routine care during clinical trials.  Private insurance may or may not cover routine medical care associated with a clinical trial, so check with your insurance about study coverage.

Why is this study important?

This trial and NSABP R-04, a clinical trial of chemoradiotherapy before surgery, are trying to discover if we can improve survival and other outcomes for patients with rectal cancer.  Patients who have taken part in NSABP R-04 are also eligible for E5204, but you don’t have to have been in R-04 to enroll in this study after your surgery.

Al Benson, M.D.

Dr. Al Benson, who is leading the trial says,

These two trials are intended to help define the best way to administer neoadjuvant and adjuvant treatment for rectal cancer. We hope to extend the benefits we have seen recently in adjuvant treatment for colon cancer to patients with rectal cancer.