By Alice McCarthy

When Howard Smith and Jane St. George were diagnosed with colon cancer‚ they joined approximately 100‚000 other people in the United States who receive the same news each year. An additional 40‚000 people are diagnosed with rectal cancer annually.

“When I was diagnosed‚ the cancer had spread‚” says 69–year–old St. George‚ who lives in the Bahamas. “I was told to get things in order.”

In contrast‚ Smith’s cancer was first classified as an early stage I cancer. “After the surgery‚ everything looked fine‚” says the 56–year–old from Philadelphia. “But about six months later‚ a CT scan showed it had gone to my liver.” Since their diagnoses‚ both have embarked on the road of colorectal cancer drug treatment.

Colorectal cancers are one of the most common cancers in men and women‚ making up about 10% of all diagnosed cancers. A strong genetic component explains why many people who develop colorectal cancer have a close blood relative with the disease. Similarly‚ risk is increased with a personal or family history of adenomatous polyps‚ precancerous growths on the inside of the colon.

In recent years‚ some new drugs have provided for modest advances in treatment of the disease. “Today is an encouraging time for patients with colorectal cancer‚” says Neal J. Meropol‚ MD‚ director of the Gastrointestinal Cancer Program‚ Fox Chase Cancer Center‚ Philadelphia.

“There are a number of new treatments in development that are likely to improve the outcome for patients‚” he says. Specifically‚ new targets have been identified in colorectal cancers‚ and drugs now in development work against them differently than traditional drugs. As a result‚ the hope is that these new medicines will be more active against colon and rectal cancers‚ especially when combined with other established drugs.

Traditional Treatments
Following surgery to remove colorectal cancer growths‚ many patients will receive chemotherapy or chemotherapy with radiation treatment to destroy any remaining cancer cells. In the United States‚ the most common treatment is the drug 5–fluorouracil (5–FU). In use for several decades‚ 5–FU acts by chemically killing cancer cells. Unfortunately‚ it also kills many healthy cells‚ which explains its many potential side effects‚ including diarrhea‚ mouth irritation‚ and lowered white blood cell counts—a side effect Smith says caused his doctors to reduce his 5–FU treatments. 5–FU is almost always given with leucovorin (also known as folinic acid)‚ which may make 5–FU more active against cancer cells‚ and is usually delivered to patients as an intravenous (I.V.) infusion or by injection.

For people with metastatic disease‚ or disease that has spread beyond the colon or rectum‚ traditional therapy includes 5–FU/leucovorin in combination with another cytotoxic (cell–killing) drug called Camptosar® (CPT–11 or irinotecan).

First available in the United States in 1996‚ the combination of Camptosar with leucovorin and 5–FU given via injection is sometimes called the Saltz regimen after Leonard Saltz‚ MD‚ Memorial Sloan–Kettering Cancer Center (MSKCC)‚ New York.

“Up until 1996 there was only one drug with any demonstrated effectiveness against colorectal cancer and that was 5–FU‚” says Dr. Saltz. Camptosar was approved as a second–line‚ or backup‚ drug to be used when 5–FU/leucovorin alone is ineffective. “Use of CPT–11 after 5–FU/leucovorin failure brought a modest survival advantage of a few months‚ and it shrank the tumor to less than half its original size in about 13–15% of patients‚” says Dr. Saltz. “This modest step forward was exciting progress considering we had had nothing new for 40 years.” Side effects with Camptosar can include diarrhea and low white blood cell counts.

Dr. Saltz says he believes today is an era of several exciting‚ modest steps forward‚ but he does not see a cure for colorectal cancer on the horizon. “Instead‚ what we have done over the past decade‚ and what I believe we will continue to do at an accelerated pace‚ is come up with new drugs that provide modest advantages and modest steps forward‚” he explains.

Dr. Meropol adds that treatment will change not by replacing drugs used today but by adding new drugs in new combinations‚ an opinion shared by others in the field.

New Chemotherapies
An oral pill called Xeloda® (capecitabine)‚ approved by the U.S. Food and Drug Administration (FDA)‚ is converted in the body to 5–FU. It is the first oral medication for metastatic colorectal cancer. Broken down to active 5–FU in cancer cells themselves‚ Xeloda has been available since 1998 for treatment of advanced breast cancer. As an oral drug‚ Xeloda has the potential to be as active as traditional 5–FU but with the convenience of a pill rather than I.V. infusions or injections‚ according to Dr. Meropol. For St. George‚ this means she has more flexibility to pursue her passion for thoroughbred horse breeding and racing.

Clinical trials show that Xeloda is as effective as I.V. 5–FU and has more acceptable side effects. While it is hoped that Xeloda will prove at least equivalent to I.V. 5–FU when used with other drugs‚ the clinical tests supporting this are not complete.

A side effect called hand–foot syndrome—swelling‚ dryness‚ cracking of the skin on the palms and feet—can necessitate decreasing the dosage or interrupting treatment. This condition also can occur with I.V. 5–FU but usually only when given as a prolonged infusion.

One of the most eagerly anticipated new drugs is Eloxatin™ (oxaliplatin)‚ just approved by the FDA in August 2002 in combination with 5–FU/leucovorin (though available in Europe since 1999). “There is no question oxaliplatin has activity against co–lorectal cancer‚” says Dr. Meropol. “Its widespread availability will be an important step forward for patients.”

Like 5–FU and Camptosar‚ Eloxatin is a cytotoxic drug. The FDA made its decision from a study that found that in patients whose tumors had grown after previous Camptosar therapy‚ combination treatment of Eloxatin plus infused 5–FU/leucovorin was more effective in shrinking tumors and delaying cancer growth than either Eloxatin or 5–FU/leucovorin alone.

Yet the larger clinical trial story with Eloxatin in the United States continues to evolve. A recent study in people with metastatic colorectal cancer compared a treatment regimen called FOLFOX (Eloxatin in combination with infused 5–FU and leucovorin) against the Saltz treatment strategy (Camptosar plus injected 5–FU and leucovorin).

People on the FOLFOX regimen survived an average of 4.5 months longer‚ but there were several cautions tempering these results. “First‚ 5–FU was administered in a different fashion in both regimens‚” says Dr. Meropol. And patients on the FOLFOX regimen had access to Camptosar as a backup if treatment failed. But very few people on the Saltz regimen had access to the FOLFOX treatment if their treatment was not successful. Three times as many people got second–line treatment with CPT–11 when FOLFOX failed‚ says Dr. Saltz‚ so researchers cannot say yet with certainty why people on FOLFOX lived longer. The FDA has only approved Eloxatin for patients who have failed treatment with Camptosar.

Eloxatin has the potential side effect of neurologic toxicity. It is characterized both by sensitivity to cold‚ which occurs shortly after the I.V. infusion‚ and also as a cumulative sensory nerve damage‚ which can result in numbness of the hands and feet after prolonged use of the drug. In most cases the cold sensitivity tends to resolve completely and the neurologic toxicity tends to abate in terms of frequency and intensity over time.

Designer Drugs
Along with Eloxatin‚ researchers are also enthused about Avastin™ (bevacizumab). “The results are eagerly awaited because the scientific basis for the development of Avastin and the early clinical results are provocative‚” says Dr. Meropol. Avastin stops the process of angiogenesis‚ the development and growth of new blood vessels that feed the tumor. It is an antibody that targets an important protein called vascular endothelial growth factor (VEGF)‚ which is responsible for new blood vessel growth in normal cells as well as cancerous tumors. Once bound to VEGF‚ Avastin interrupts vessel growth‚ preventing tumor growth and spread.

“I liked the whole idea of starving the tumor of blood vessels‚” says St. George‚ who was one of the first people involved in the clinical trials for Avastin. “It made a lot of sense to me.” Smith decided to enroll in the Avastin trial after his doctor suggested it because he liked the idea of attacking the cancer two ways. “The 5–FU and CPT–11 poisons and kills the cancer cells while the VEGF drug starves it from growing more‚” he says.

A 900–person phase III study is under way comparing chemotherapy alone to chemotherapy plus Avastin‚ and “we’re anxiously awaiting results from that study‚” adds Dr. Saltz. “It is a very reasonable‚ encouraging approach.” St. George and Smith‚ who both remain on Avastin treatment‚ have had very positive results from their clinical trial experience. “Four years ago‚ I wasn’t expected to live more than six months‚” says St. George‚ who also remains on Xeloda. ”But today my tumors have either shrunk or remained stable and people say I’ve never looked better.” Smith’s CT scans reveal a similar story—a reduction in the size of his tumor. He says he feels “absolutely great.”

Earlier studies have shown that adding Avastin to the Saltz regimen for advanced colorectal cancer does not add significant additional side effects. Both St. George and Smith say they experience minimal or no side effects after their Avastin treatments. “The only thing I notice is that it can send my blood pressure zooming‚” says St. George.

“But it is extremely important for people to know that these particular cases‚ as encouraging as they are‚ are highly atypical‚” cautions St. George’s doctor‚ Herbert Hurwitz‚ MD‚ Duke University‚ Durham‚ North Carolina. “This is not the cure we’re all waiting for.” Dr. Hurwitz says the overwhelming majority of his patients involved in the VEGF trial have not been as fortunate as Smith and St. George and have had a mediocre‚ minimal‚ or absent response.

Other antiangiogenesis agents targeting VEGF are in the works for colorectal cancer. One such drug is Angiozyme®‚ a ribozyme therapy now in early phase II testing. Ribozymes are molecular “scissors” that act like enzymes and ultimately prevent production of unwanted proteins.

“The theory behind angiogenesis inhibitors is that if you can turn off VEGF‚ or whatever growth factor you’re targeting‚ you inhibit the ability of cancers to regenerate or recover‚” theorizes Alan Venook‚ MD‚ director‚ Clinical Research Office‚ University of California San Francisco Cancer Center. He is also the lead scientist for the current 75–patient Angiozyme/Saltz treatment clinical study. Similar to Dr. Hurwitz‚ Dr. Venook advises measured patience when assessing the future of any particular antiangiogenesis medications‚ highlighting the recent disappointment in clinical studies with another antiangiogenesis colorectal cancer drug‚ semaxanib (su5416). Semaxanib—either with or without chemotherapy—failed to prove effective in people with advanced colorectal cancer.

Erbitux™ (cetuximab or C225) is a monoclonal antibody like Avastin‚ but it acts by targeting a protein found on cancer cells called the epidermal growth factor (EGF) receptor. Many malignant tumor cell types‚ including colorectal cancer‚ overproduce the EGF receptor (EGFR) by as much as a 100–fold compared with a normal cell. “There are several drugs in development targeting EGFR‚” says Dr. Meropol. The limit with this approach‚ according to Dr. Meropol‚ is that only about 50–70% of colorectal cancers have this receptor‚ restricting the drug’s activity only to those tumors. For these cancers‚ studies show that Erbitux‚ an I.V. medication‚ has modest activity used in combination with Camptosar and also by itself. Rash is the most common side effect.

Small Molecules
Joining the ranks of chemotherapies‚ antibodies‚ and ribozymes are small molecules‚ designed to interfere with growth–promoting compounds involved in cancer cell development. Researchers have identified a complicated network of compounds that signal a cell‚ whether normal or cancerous‚ to grow. “We know now of many compounds involved in the signaling cascade‚” says Rachel Humphrey‚ MD‚ director‚ Global Clinical Strategy‚ Oncology‚ Bayer Corporation‚ and a practicing medical oncologist. Some cancers develop due to an abnormal change within the normal signaling network.

Small molecules designed to attack this process include Bayer’s BAY 43–9006‚ an oral drug currently in phase I testing. “We are very encouraged by the phase I results and plan to evaluate BAY 43–9006 in phase II studies in a variety of cancer types‚ including colorectal‚” says Dr. Humphrey. BAY 43–9006 inhibits an enzyme involved in the cancer signaling process‚ called Raf kinase.

“Raf kinase is thought to be an important growth signal in many cancers‚” says Dr. Humphrey. But she cautions that more than one signaling compound may need to be inhibited to achieve full and complete cancer inhibition. Also‚ these cell growth cascades may be normal and important for blood vessel and blood cell formation. “If you inhibit too many of them or too many fundamental ones‚ toxicity could develop‚” she cautions.

Echoing opinions about most of the other new colorectal cancer drugs‚ Dr. Humphrey adds that it is uncertain the extent to which any of the therapies under evaluation will‚ if ultimately approved by the FDA‚ be used as a single agent or in combination with other agents. “This is true for all small molecule inhibitors in development today‚” she says. “And it’s very important not to overanalyze results from any phase I trial for any drug.”

Patients in these trials may not represent what the drug will do in the general pool of people with colorectal cancer‚ explaining why additional studies are necessary.

Two other small molecule drugs of interest in colorectal cancer‚ Tarceva® (erlotinib or OSI–774) and Iressa® (gefitinib or ZD1839)‚ and one monoclonal antibody‚ ABX–EGF‚ also target the EGFR. As with Erbitux‚ they might have potential efficacy only for those cancer cells that possess the EGFR. Unlike Erbitux‚ however‚ Tarceva and Iressa are oral medicines.

Prevention Still Essential
“When colorectal cancer does occur‚ the new drugs available now and the newer ones under development will continue to make treatment options better and safer for the people who need them‚” says Dr. Saltz. “But proper screening can make this preventable disease far less common.”