Insurance makes a difference for people with rectal cancer.

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.

Some colon cancer patients don’t benefit from treatment with 5-FU based chemotherapy and may even have worse outcomes than if they no chemo at all.

Of every 100 people with colon cancer, about 15 will have cancers that arise when mistakes in DNA during cell division are not caught and fixed.  Scientists call this defective mismatch repair or dMMR.

More often, colon cancer occurs when mutations in chromosomes accumulate but DNA repair pathways remain intact and mismatch repair is proficient (pMMR). This is true for about 85 percent of colon cancer.

Both prognosis and the potential benefit from FU-based chemotherapy appear to be very different for these two types of colon cancer. Knowing mismatch repair status of colon tumors can help patients and their doctors make better treatment decisions.

Patients with defective mismatch repair have better disease-free and overall survival and don’t seem to benefit from 5-FU at either stage II or stage III.  Stage II patients with dMMR have significantly poorer overall survival if they get chemo after surgery.

Caution:  These results come from studies of 5-FU plus levamisole or 5-FU plus leucovorin.  They don’t include any information from the current standard treatments of FOLFOX or FLOX which contain oxaliplatin in addition to 5-FU and leucovorin.

Defective mismatch repair is uncovered when either tumors have microsatellite instability (MSI) or immunohistochemical tests can’t find the proteins that are expressed by genes that control mismatch repair — MLH1, MSH2, MSH6, and PMS2.  Measuring either MSI or lack of MLH1 or MSH2 expression gives similar results in deciding whether a tumor is mismatch defective or proficient.

Almost all defective mismatch repair tumors are located in the right side of the colon.  They are poorly differentiated, often have lots of mucus, and tend to be infiltrated with immune-system cells (lymphocytes). Some scientists speculate that it is this improved immune-response that gives them their survival advantage.

Daniel Sargent, Ph.D., and his team analyzed mismatch repair status in the tumors of 457 patients in five different clinical trials with stage II or III colon cancer who had received either FU-based chemotherapy after surgery to remove their cancer or surgery alone.  They then pooled their information with a group of 570 patients who had been analyzed earlier.  The entire set included 1,027 patients, including 165 (16 percent) with defective mismatch repair.

They analyzed the impact of either proficient or defective mismatch repair as both a prognosis marker (its effect on survival despite treatment) and predictive marker (if chemotherapy treatment changes outcomes).

Pooled Results

Mismatch Repair Status as a Prognostic Marker

• Patients with defective mismatch repair (dMMR) who didn’t get 5-FU had significantly better disease-free and overall survival than patients with proficient mismatch repair (pMMR).
• When patients got chemotherapy, mismatch repair status had no impact on survival.

Mismatch Repair Status as a Predictive Marker for FU- based chemotherapy

• There was no benefit of FU-based chemotherapy for either stage II or stage III colon cancer patients with defective mismatch repair.
• There was no benefit of FU chemo for stage II patients with proficient mismatch repair.
• Stage III patients with pMMR did benefit from chemotherapy with 5-FU.
• Stage II patients with dMMR had worse overall survival when they got 5-FU than when they had surgery alone.

Graph of Predictive Value of dMMR in Adjuvant Colon Cancer

A — Stage II, dMMR
B–  StageIII dMMR
C — Stage II pMMR
D — Stage III pMMR

Click on graph to enlarge it.

Dr. Sargent’s analysis confirmed an earlier study reported in 2003 in the New England Journal of Medicine by Christine Ribic that found no benefit to treatment with 5-FU for patients with stage II or III colon cancer with high microsatellite stability, who may possibly be harmed by  5-FU-based chemotherapy and have a better overall prognosis after diagnosis.

His team concluded,

In conclusion, this prospectively specified analysis of data from randomized, clinical trials provides independent, supportive evidence of the following: dMMR colon cancers have a favorable stage adjusted prognosis compared with the majority of colon cancers; and patients with dMMR colon cancers do not benefit from FU based adjuvant therapy.

Further, they point out,

These findings support the conclusion that average-risk patients with colon cancer who are considered for FU based adjuvant therapy should have the tumor MMR status assessed to inform the likelihood of patient benefit of chemotherapy. Our conclusions are restricted to patients being considered for single agent, fluoropyrimidine-based therapy (ie, patients with stage II disease), and the conclusions provide guidance as to who should not be treated (ie, the dMMR subset). We believe that dMMR status in the setting of stage II disease should be considered a clinically useful marker of tumor biology and represents an additional step in individualized cancer therapy.

SOURCE: Sargent et al.,  Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of Fluorouracil-Based Adjuvant Therapy in Colon Cancer. Journal of Clinical Oncology, Volume 28, Number 20, pages 3219-3226,July 10, 2010.

Image:  Figure #2, Sargent et al., JCO

By studying changes in tumor tissue from colon cancer patients whose cancers had not spread to distant organs, researchers were able to isolate a gene mutation that led to a poor outcome.

Stage I through III colon cancer patients whose tumors had a mutation in the PIK3CA gene were more likely to die of colon cancer that patients with normal or wild-type PIK3CA.  About 1 in 5 patients had that mutation in tumor tissue.

After adjusting for other variables that affect death from colon cancer, patients with a PIK3CA mutation were more than twice as likely to die from colon cancer.  This was especially true in KRAS wild-type tumors where a PIK3CA mutation increased risk of death almost four times.  However, in KRAS mutated tumors, the presence of PIK3CA made little difference in cancer-specific survival.

Five years after surgery, 9 out of 10 patients whose tumors didn’t have PIK3CA mutations had not died of colon cancer compared to a little more than 8 out of 10 (84 percent) with mutated PIK3CA.

Image from Journal of Clinical Oncology -- Yellow Line is Mutated PIK3CA

The study included 450 patients drawn from two large groups of both men and women who have been followed for many years.  Women in the Nurse’s Health Study have been followed since 1976 with questionnaires every two years. Men from the Health Professionals Follow-up Study completed the biennial questionnaires since 1986.

Tumors were analyzed for a number of genetic changes including KRAS, BRAF, p53, MSI, CIMP, and LINE-1 methylation.  The research team also recorded the age, sex, and body mass index of each patient, along with the year the cancer was diagnosis and its stage, location, and grade.

They found PIK3CA mutations in 18 percent of the tumors.  PIK3CA mutations were more likely to be found along with KRAS mutations, but less likely to show expression of p53.  There was no connection between PIK3CA and any clinical features of the cancers.

PIK3CA mutations activate a pathway in cancer cells that leads to cell division, cell survival, invasion of other tissues, and the development of new blood cells.  Studies in colon cancer cells have found drugs that block PIK3 also have anti-tumor activity.

Shugi Ogino and colleagues at Dana Farber Cancer Institute in Boston concluded,

Among patients who undergo a curative resection of colon cancer, PIK3CA mutation is associated with shorter cancer-specific survival. The adverse effect of PIK3CA mutation may be potentially limited to patients with KRAS wild-type tumors.

SOURCE: Ogino et al., Journal of Clinical Oncology, Volume 27, Number 9, March 20, 2009.