Which factors matter least and most

The most important point to remember about your prognosis is that what are used today as reliable prognostic indicators may become meaningless when new treatments that surmount old difficulties are engaged.

The order of the sections that follow does not imply a greater or lesser effect on outcome.

Stage

There are several staging systems, including the TNM, Dukes, the Modified Astler-Coller (MAC) staging schemas, and a separate staging system used just for analyzing CT scans prior to, or in the absence of, surgical surveillance. Many cancer centers have abandoned the older staging systems in favor of the TNM system. All are based on the invasiveness and spread of disease.

Some aspects of disease spread that contribute to prognosis are:

• The degree of penetration of the tumor through the bowel wall correlates to a worse prognosis. In Chapter 18 of Cohen's 1995 text, Cancer of the Colon, Rectum, and Anus, Hamilton writes: "Infiltration through the muscularis mucosae is virtually required for risk of metastasis in colorectal carcinoma… As a consequence, `in situ' and `intramucosal' adenocarcinomas of the large bowel … pose virtually no threat to the patient."

• The spread to other organs. The tumor burden the body is carrying is directly related to outcome, with higher tumor burden within many organs related to poorer outcome than disease spread only to one organ.

• Presence of bowel obstruction.

• Presence of disease in lymph nodes. An increasing number of nodal sites involved correlates to a poorer prognosis. Patients with less than four involved lymph nodes have significantly better survival odds than those with four or more involved nodes.

• Malignant ascites, a collection of tumor-cell bearing fluid in the abdomen, is associated with a poorer outcome.

• The existence of just one lesion predicts a good outcome. Primary tumors that develop together (synchronous) yield a prognosis that matches the behavior and stage of the most serious tumor. Multiple primary tumors are more easily eliminated than multiple or large metastases from one primary.

• Metastases to liver, lung, abdomen, or pelvis can in some cases be treated with surgery and chemotherapy, and may result in long-term survival for up to 30 percent of patients deemed eligible for a second surgery.

• Size, with primary tumors smaller than two centimeters in the largest dimension having a better prognosis.

• Well-differentiated tumors that resemble mature, normal cells are more successfully treated than poorly differentiated tumors. Often, poorly differentiated tumors are more aggressive than well-differentiated tumors.

• Infiltrating rectal tumors have a worse prognosis than those of the expanding type.

Individualized prognostic factors

Site of disease

• Peritoneal carcinomatosis, the implanting of numerous tumors on the inside lining of the abdomen and the pelvis, is considered a bad sign if many large tumors are found at surgery and cannot be completely removed. One study quantifies large tumors to be those greater than 5 centimeters; one medical reviewer specifies greater than 5 millimeters. Involvement of only one or two of the five abdominopelvic regions is considered a good sign.¹

• The portion of the intestine in which the tumor develops is thought to contribute to outcome: tumors arising in the appendix have better outcome than those arising in other parts of the colon;² right-side disease (excepting that in the appendix) may, in some patients, have a worse prognosis than left-side disease. Left-side disease expressed the desirable p53 gene more often.

• In females, the spread of large secondary tumors to the ovary is correlated to worse prognosis.

• Bone marrow involvement confers a worse prognosis.

• Tumors that adhere to adjacent structures are thought to be more likely to recur.

• If the spine is involved, the preoperative neurological status and the number of vertebrae affected correlates to a worsening prognosis.

Tumor aggressiveness (tumor grade)

• Histologic grade and the number of tumor cells actively dividing (percentage of S phase content) are thought to contribute to recurrence of disease.

• An unusually high number of blood vessels in a tumor, a sign of robust tumor growth, is thought to predict recurrence, even in node-negative disease. A tumor must grow beyond 2 millimeters in order to break apart and spread (metastasize). Tumors cannot grow beyond a few millimeters without an increased blood supply.³

• Poorly differentiated tumor cells, an indicator of rapid cell division, are correlated to higher tumor grade and greater aggressiveness. Poorly differentiated tumors connote a worse prognosis than well-differentiated tumors diagnosed at the same stage.

Histology

• Mucinous adenocarcinoma has been shown in some studies to be a poor risk factor, but not in other studies.⁴

• Signet-ring cell carcinomas appear to have a worse prognosis than ordinary colon adenocarcinoma.⁵ This correlation might be attributable to the more common presence of signet-ring carcinoma in those under age 40 and the fact that younger people often are diagnosed at a later stage. Another study notes that those with signet-ring histology are not diagnosed until disease is advanced.⁶

• Poorly differentiated tumors connote a worse prognosis than well-differentiated tumor when stages are equal.

Immunophenotype

The science of immunophenotyping, or immunotyping, is a rapidly advancing subfield of cancer research. Some researchers say that advances in this method of analyzing tumor cells will provide us with the most meaningful information possible for designing patient- and tumor-specific anticancer products.

Thus far, immunophenotyping has concentrated mainly on identifying cell surface antigens--that is, proteins that protrude from the cell's surface and act as identifying signals and attractants to other cells and to other molecules. All cells have these surface antigens, which are proteins and which cancer cells produce in greater abundance or in different quality from normal cells. This allows cancerous cells to be sensed, measured, or treated, separately from healthy cells, using new tools being developed. Some can be detected in blood; others can be detected only in tumor tissue that has been biopsied.

Your doctor can look for certain antigens in your blood to let him know if you might be experiencing a recurrence of disease. For example, your doctor might ask for blood tests every three, six, or twelve months, looking for one of more of these substances.

At this time, CEA (carcinoembryonic antigen) is the most commonly followed blood antigen for detecting disease recurrence, as a majority of colorectal cancer survivors show elevated CEA levels upon recurrence of disease. The routine use of antigen detection alone for monitoring response to treatment and continued absence of disease, however, is not recommended. A single blood test showing an increase in CEA is not considered a reliable indicator of recurrence in the absence of other findings. CEA can become elevated as a result of other bodily or disease processes, or as a result of changes in smoking or alcohol consumption habits. Tumors that are either highly or poorly differentiated are less likely than moderately well-differentiated tumors to produce abnormally high levels of CEA; mucinous tumors or tumors that are localized are less likely to elevate blood levels of CEA. One study has shown that liver metastases are more likely to elevate CEA than tumors in other locations.⁷ Some clinicians find that CEA might not become elevated upon recurrence, even when gross metastatic disease is present, and that changes from initial test values often are meaningful, even if the patient's CEA level remains within normal laboratory ranges. Different laboratories sometimes use different manufacturers' assays to measure CEA levels, and their results cannot always be compared with accuracy. Thus, some clinicians say that at least two consecutive increases in CEA must be found before recurrence is likely. In summary, tests such as colonoscopies, chest x-rays, and magnetic resonance imaging (MRI) along with CEA blood testing all contribute to the total picture either of continuing health or of a recurrence of disease.

Radioimmunoguided surgery (RIGS) is a combination of imaging and surgical technique. One study has shown that five-year survival of those who were treated with RIGS was 60 percent; a matched group treated without RIGS experienced 0 percent survival after five years. Additional studies are needed to replicate these results. RIGS is based on the fact that an antigen called TAG72 on the surface of cancer cells can be detected with monoclonal antibodies. Antigens are unique protein tags that extend from the cell's surface; monoclonal antibodies are manmade proteins that are identical to those our bodies make, and are manufactured to target preferentially tumor cells by recognizing their cell surface antigens. These antibodies, which have a safe radioactive isotope attached to them, are injected a few weeks before surgery and subsequently attach to TAG72 on tumor cells. During surgery, a hand-held gamma counter is used by the surgeon to spot otherwise invisible sites of disease.

Other examples of experimental cell surface antigens that appear to correlate to tumor activity for colorectal cancer follow. Please note that, because new tumor markers are discovered regularly, this list is not exhaustive. Moreover, to date, none has been shown to be more accurate than CEA in tracking tumor activity. Some have been reported as the result of just one or two research studies, and need further scrutiny before becoming useful in the clinic. Nonetheless, you may see some of these biochemical markers on pathology reports in the future:

• Antigen CO17-1A is detectable with monoclonal antibodies when colorectal cancer is present. This antigen, also the target of treatment involving a monoclonal antibody that is now in clinical trials, can be used to highlight cancer cells in imaging studies using a scintigraphic agent connected to a monoclonal antibody that attaches to this antigen.

• Variants of CD44, an antigen on the surface of white blood cells, are higher in patients with active colorectal cancer. Variants 8 and 10 are higher in all patients; variant 6 is higher in primary tumors, but not in liver metastases.

• SLX (sialyl Lewis X antigen) rises with tumor activity. Patients with tumors that are negative for SLX have the best prognosis. In one study, increasing SLX levels correlate to disease recurrence and depth of tumor invasion.

• Lower levels of alfa-catenin are linked to poorly differentiated tumors with a higher potential to spread, and a worse prognosis.

• Lower levels of P-selectin correlate to lower tumor growth and fewer metastases.

• Increased levels of the ICAM-1 antigen in blood are linked to higher stages of colorectal cancer. Blood levels of ICAM-1 were higher in patients with liver metastases.

• Levels of ELAM-1 were higher in those with lung metastases.

• Tumors that do not express the MRP1/CD9 antigen have a significantly higher frequency of blood-vessel penetration of the tumor, and of liver metastasis. These findings were independent of the presence or absence of disease in lymph nodes.

Genetic characteristics

Colorectal tumors are often, but not always, tested for genetic abnormalities. Some genetic abnormalities may be present in all tumor samples from the same patient; some present in one sample but not in others; some are present at diagnosis but others accumulate as time progresses.

There have been many studies for many cancers that indicate a statistical correlation between certain kinds of genetic damage and outcome. The prognostic significance of some genetic aberrations is not entirely clear. Some have been detected in only one study and need to be confirmed with further research. Moreover, a correlation alone is never strong enough evidence to prove causality:

• Damage to one of the cell-death genes, p53, which resides on chromosome 17, appears to affect negatively the outcome of many cancers, including colorectal cancer, but at least one study has found that it does not affect prognosis in colorectal cancer.

• Absence of DCC, the "deleted in colon cancer" gene protein, appears to have a negative effect on survival.

• Extra copies of chromosomes 7, 13, or 20 have been correlated with a worse prognosis for colorectal cancer survivors.

• Loss of one copy of chromosome 11 is correlated with a lower incidence of spread of colorectal cancer to lymph nodes.

• Losses of chromosomes 8 or 18, or of the long arm of chromosome 18 (18q), have been correlated with a worse prognosis for colorectal cancer.

• Loss of genes at positions (loci) 32 or 36 on the short arm of chromosome 1 (indicated as 1p32, 1p36) are linked to a worse prognosis for colorectal cancer survivors.

• Loss of the gene at position 13 on chromosome 17, indicated as 17p13.3, was found in one half of colorectal cancer tumors biopsied by one group of researchers.

• Rearrangements of genes on chromosome 8 are found in some precancerous polyps. This implies that chromosome 8 plays a part in the development of colorectal cancer.

• Those with hereditary nonpolyposis colon cancer are less likely to have extra copies of chromosomes, or missing copies of chromosomes, than those with sporadic colorectal cancer.

• Tumors that are positive for the RER gene have a better prognosis.

• Mutations of the K-ras gene are linked to a worse prognosis, as these tumors tend to be nonresponsive to the chemotherapy drug CPT-11 (irinotecan).

• An increase in the expression of the c-myc gene is accompanied by a failure to respond to the chemotherapy drugs 5-fluorouracil and leucovorin.

Byproducts of tumor metabolism

Some of the substances described below have been detected only in one study. More research is needed to strengthen their meaning regarding prognosis; a correlation alone is never strong enough evidence to prove causality:

• P-glycoprotein (P-gp) which is expressed by tumors that have become resistant to many chemotherapy drugs (multiple drug resistance or MDR) is correlated to a higher risk of recurrence in those staged at Dukes B2.⁸

• Cytokeratin-producing cells that are found in the bone marrow when no signs of metastases exist upon physical examination have been linked to higher risk of recurrence of disease in the liver and in the lungs.⁹

• One form of the growth factor VEGF, type 3, increases when liver metastases are present. VEGF type 3 is found in the presence of new blood vessels in growth; tumor growth is accompanied by the growth of new blood vessels to feed the tumor.

• A substance known as guanylyl C cyclase is found in lymph nodes when colorectal cancer cells exist in extraintestinal tissue.

• When increasing levels of soluble urokinase receptor (suPAR) can be detected in blood, a recurrence of colorectal cancer may be unfolding.

• The substance tenascin (TN) is associated with thick bands around well-differentiated tumors, but only with interstitial bands in poorly differentiated tumors. The pattern of tenascin might be useful in distinguishing less aggressive from highly aggressive tumors. In general, aggressive tumors correlate to a worse prognosis.

• Increased amounts of matrix metalloproteinase-1 (MMP-1) appear to correlate to a worse prognosis, independent of Dukes staging. Matrix metalloproteinase-1 is part of the process by which tumors spread and attach to new areas.

• Decreasing levels of C-adherin have been linked in some studies, but not others, to spread of disease. C-adherin is a component of the cellular glue that keeps an organ intact. When tumor cells begin to spread (metastasize), this glue breaks down.

• Serum levels of hepatocyte growth factor (HGF) increase when liver or lymph node metastases are present, and as tumor size increases.

Patient characteristics

Age

Many studies have shown that younger patients, those under age 40, are more likely to experience a recurrence of disease after curative surgery than those over age 40. Reasons proposed for this include:

• A more deadly form of the disease, with or without a family history of colon disease

• Later diagnosis, owing to neither young people nor their physicians suspecting colorectal cancer as the cause of symptoms

Race

Weight

Physical ability

Pregnancy

Other patient characteristics

• Presence of adhesions after curative surgery is thought to contribute to recurrence.¹⁰

• Reduced levels (reduced expression) of HLA class I antigens--antigens detectable on white blood cells during an immune-system response--correlate to increased aggressiveness, higher grade, and passage of the tumor through the intestinal wall. In other words, a reduced immune system response to tumor appears to be linked to tumor aggressiveness and spread.¹¹

• Increased levels of HLA II antigen HLA-DR--another white blood cell antigen detectable during an immune response--along with relatively low PCNA-LI levels, occur in patients with the best prognosis.

• Untreated anemia and resulting low hemoglobin levels are correlated with a worse prognosis.

Blood transfusions

Notes

1. P. H. Sugarbaker et al., "Peritoneal carcinomatosis from adenocarcinoma of the colon," World Journal of Surgery 5 (20 June 1996): 585-91; discussion 592.

2. S. Y. Hsieh et al., "A clinical study on pseudomyxoma peritonei," Journal of Gastroenterology and Hepatology 10, no. 1 (January-February 1995): 86-91.

3. S. R. Harris and U. P. Thorgeirsson, "Tumor angiogenesis: biology and therapeutic prospects," In Vivo 12, no. 6 (November-December 1998): 563-70.

4. S. Hamilton, "Pathologic Features of Colorectal Cancer," Cancer of the Colon, Rectum, and Anus, Chapter 18.

5. G. B. Secco, "Primary mucinous adenocarcinomas and signet-ring cell carcinomas of colon and rectum," Oncology 51, no. 1 (January-February 1994): 30-4.

6. T. Anthony et al., "Primary signet-ring cell carcinoma of the colon and rectum," Annals of Surgical Oncology 3, no. 4 (July 1996): 344-8.

7. G. Li Destri et al., "Monitoring carcinoembryonic antigen in colorectal cancer: is it still useful?" Surgery Today 28, no. 12 (1998): 1233-6.

8. F. A. Sinicrope et al., "Relationship of P-glycoprotein and carcinoembryonic antigen expression in human colon carcinoma to local invasion, DNA ploidy, and disease relapse," Cancer 74, no. 11 (1 December 1994): 2908-17.

9. S. Braun and K. Pantel, "Immunodiagnosis and immunotherapy of isolated tumor cells disseminated to bone marrow of patients with colorectal cancer," Tumor 81, 3 Supplement (May-June 1995): 78-83.

10. D. Nori, "Tumor ploidy as a risk factor for disease recurrence and short survival in surgically treated Dukes' B2 colon cancer patients," Tumour Biology 17, no. 2 (1996): 75-80.

11. S. Hamilton, "Pathologic Features of Colorectal Cancer."