Cancer Surgery

a)How Tumors Grow

b)Removing One Tumor May Stimulate the Growth of Many More

c)How to Enter Clinical Trials

d)The First Anti-angiogenesis Drug Is Approved

e)Protecting Against Surgery-Induced Immune Suppression

f)Avoid Analgesic Drugs That Promote Metastasis

g)Summary

Surgery poses many risks to a cancer patient. The known side effects associated with the surgical removal of tumors include anesthesia complications, infections, and immune suppression.

A surgery side effect of concern to cancer patients is that the removal of the primary tumor may directly stimulate cancer spread (the propagation of metastatic lesions). Metastatic tumors require the formation of new tumor blood vessels (called angiogenesis) to grow.

Once the primary tumor has been surgically removed, the amount of endostatin and angiostatin to control new tumor blood vessel growth is drastically reduced, and metastasized lesions begin proliferating out of control. If the immune depression that surgery induces is factored in, the failure of surgery to meaningfully prolong the life of cancer patients becomes quite understandable. Surgery reduces growth control factors (endostatin and angiostatin) while simultaneously weakening the immune surveillance that might be keeping metastatic lesions under some degree of control (Oliver et al. 1996).

Cancer has long baffled medical science. Until recently, scientists did not fully understand why the disease so often begins rapidly spreading throughout the body after surgery. This protocol identifies previously unknown factors involved in the long-term failure of cancer surgeries. The educated patient now has access to drugs to facilitate systemic control of cancer rather than to promote metastasis.

Even more exciting is the news that drugs such as endostatin and angiostatin are in clinical trials. If the FDA approves these drugs, the surgical removal of a large primary tumor might actually "cure" many more cancer patients. In the meantime, there are other anti - angiogenesis drugs that may help prevent the rapid growth of metastatic lesions after the primary tumor is removed.


How Tumors Grow

Almost every tissue in the body derives blood from the thinner-than-a-hair capillaries that lace our tissues. Through capillaries, nutrients, oxygen, and various signaling molecules diffuse into cells. These mechanisms maintain health, fight disease, and allow the body to flourish and grow.

Tumors start out without a vascular circulation. In the early stages of tumor development, they are limited to nutrients that can diffuse from the nearest capillaries. Then, tumors begin to stimulate healthy tissue to make thousands of new blood vessels to supply the cancerous growth--a process called angiogenesis. Without this ability to nourish itself and grow, a tumor cannot enlarge. If the blood supply can be reduced or cut off, the tumor will shrink or die.


Removing One Tumor May Stimulate the Growth of Many More

Recurrence is the point when cancer cells from the primary tumor are detected following the primary treatment for the cancer.

Ipsilateral breast tumor recurrence following conservative surgery and radiation for early stage invasive cancer occurs in approximately 15% of all patients at 10 years and is reduced with surgical excisions which achieve negative margins (Fowble 1999). Local recurrence continues to be a major problem following surgical treatment for rectal cancer, because of the frequency with which it occurs (varying from 4% to 51%), its impact on quality of life, the fact that treatment is rarely successful (McLeod 1997), and the proposed ways of reducing this remain controversial ( McCall et al. 1995).

All patients undergoing laparoscopic surgery for malignancies should have careful follow-up with special attention to the port sites, as port-site metastasis after laparoscopic lymphadenectomy is a phenomenon that occurs following this type of cancer surgery ( Tjalma et al. 2001).

Several drugs--including interferons, steroids, and certain hormonal agents--have been developed to stop or slow angiogenesis. In fact, at least 11 anti-angiogenic drugs are in clinical trials, and three have proved effective enough to make it to the final phase.

Some of the drugs, like endostatin, are derived from natural proteins, while others are based on smaller molecules. Ironically, one promising drug in clinical trials is thalidomide, which once was sold as a sedative that caused notorious birth defects.

Another drug, 2-methoxyestradiol (2-ME), is a natural estrogen metabolite believed to be an inhibitor of angiogenesis and also an anti - tumor agent.

In addition, researchers are investigating a drug called Col-3 and are negotiating with several biotechnology companies to examine other anticancer compounds.

Of all the anti - angiogenic drugs, endostatin and angiostatin appear to hold the greatest potential for saving lives. These drugs are nontoxic and have shown efficacy against every type of cancer tested. These drugs suppressed metastatic tumor growth rates by 90% (Hajitou et al. 2002). Another study showed primary tumors regressing to become dormant microscopic lesions (O'Reilly et al. 1997).

Based on this new information, angiostatin and endostatin may greatly increase the number of cancer patients who become disease-free after surgery.


How to Enter Clinical Trials

Endostatin was the first endogenous angiogenesis inhibitor to enter into clinical trials. Endostatin given to 21 advanced solid tumor patients daily as a 1-hour intravenous infusion (for 28 days) was well - tolerated (Thomas et al 2003).

The safety and efficacy of recombinant human Angiostatin protein administered in combination with chemotherapy (paclitaxel and carboplatin) to patients with non-small-cell lung cancer is currently being investigated in a clinical trial: http://clinicaltrials.gov/ct/search?term=angiostatin

For more information about cancer clinical trials call the Cancer Information Service, (800) 4-CANCER.

Physicians may request information about trials from the PDQ Search Service by calling (800) 345-3300, faxing (800) 380-1575, or e-mailing pdqsearch@icicc.nci.nih.gov.

There are many anti - angiogenesis drugs in clinical studies. In some cases, the FDA may allow an unapproved drug to be released before it is officially approved. Here are some of the anti - angiogenesis drugs being tested and the sponsoring companies:

The First anti-angiogenesis drug is approved