Rectal Cell

Stage IV Rectal Cancer Overview Following clinical evaluation of rectal cancer, the cancer is referred to as stage IV (D) rectal cancer if the final evaluation shows that the cancer has spread to distant locations in the body, which may include the liver, lungs, bones or other sites. A variety of factors ultimately influence a patient's decision to receive treatment of cancer. The purpose of receiving cancer treatment may be to improve symptoms through local control of the cancer, increase a patient's chance of cure, or prolong a patient's survival. The potential benefits of receiving cancer treatment must be carefully balanced with the potential risks of receiving cancer treatment. The following is a general overview of the treatment of stage IV rectal cancer. Circumstances unique to your situation and prognostic factors of your cancer may ultimately influence how these general treatment principles are applied. The information on this Web site is intended to help educate you about your treatment options and to facilitate a mutual or shared decision-making process with your treating cancer physician. Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of this cancer. Clinical trials are available for most stages of cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits of clinical trials with their physician. To ensure that you are receiving the optimal treatment of your cancer, it is important to stay informed and follow the cancer news in order to learn about new treatments and the results of clinical trials. Patients diagnosed with stage IV rectal cancer have been perceived to have few treatment options. Certain patients, however, can still be cured of their cancer and others derive meaningful palliative benefit from additional treatment. Patients with stage IV rectal cancer can be broadly divided into two groups: those with cancer that is localized to a single site and those with more widespread cancer. Treatment of Non-Localized Stage IV Rectal Cancer While some patients have a single site of cancer that can be treated with curative intent, the majority of patients with stage IV rectal cancer have unresectable or widespread cancer. Historically, these patients have been considered incurable and were offered treatment with chemotherapy for the purpose of prolonging their duration of survival and alleviating symptoms from progressive cancer. Single-agent 5-fluorouracil chemotherapy with or without leucovorin was the standard treatment approach for over 30 years. Treatment with 5-fluorouracil chemotherapy regimens induce a remission or shrinkage of the cancer in 15-45% of patients and the average patient survives approximately one year from treatment. Continuous infusion 5-fluorouracil appears to have less toxicity and provides more benefit than intermittent, rapid intravenous infusion 5-fluorouracil therapy. The biologic agent interferon has also been combined with 5-fluorouracil and leucovorin and evaluated in clinical trials. The addition of interferon did not prolong survival and may have diminished quality of life.

Patients electing to receive treatment with 5-fluorouracil should discuss the potential side effects from treatment, as they vary considerably across the many different 5-fluorouracil chemotherapy regimens. More recently, several newer chemotherapeutic drugs have demonstrated a substantial ability to kill rectal cancer cells in patients with recurrent cancer. Developing and exploring single or multi-agent chemotherapy agents as a treatment approach for patients with widespread rectal cancer is an area of active investigation. A newer chemotherapy drug, Camptosar�, has been compared to the best supportive care available in patients with colorectal cancer that no longer responded to chemotherapy with 5-fluorouracil. In this direct comparison, patients receiving Camptosar� treatment were 2.6 times more likely to be alive after one year of treatment. This clinical study established Camptosar� as a standard treatment for patients with colorectal cancer that had stopped responding to 5-FU. More recently, French researchers assigned 387 previously untreated patients with advanced colon or rectal cancer to receive either A) fluorouracil and calcium folinate plus Camptosar� or B) fluorouracil and calcium folinate alone. The results showed a response rate of 49% for patients receiving both Camptosar� and fluorouracil, compared with 31% for patients receiving fluorouracil alone. The time it took for the cancer to progress (begin growing again) was also more delayed in patients receiving the Camptosar� (6.7 versus 4.4 months). The average survival time was 17.4 months for patients receiving Camptosar� and fluorouracil, compared with 14.1 months for those receiving fluorouracil alone. The Camptosar� regimen had more side effects; however, all were manageable and reversible. These findings show response rates in patients receiving Camptosar� plus fluorouracil/calcium folinate that are superior to those in patients receiving fluorouracil/calcium folinate alone. There were also modest increases in the time it took for the cancer to progress and in duration of survival in patients receiving Camptosar�. The researchers concluded that this new regimen should be considered an option for the initial treatment of advanced colorectal cancer. Treatment of Metastatic Rectal Cancer to a Single Site Rectal cancer may spread or metastasize to the liver, lung or other locations in the body. When the site of metastasis is a single organ, such as the liver, patients may benefit from local treatment directed at that single site of metastasis. The most common location of metastasis for patients with rectal cancer is the liver. Highly selected patients with isolated areas of rectal cancer can be cured if the primary cancer in the rectum and the isolated area of cancer outside the rectum can be surgically removed. Several clinical trials have reported that patients who have isolated areas of rectal cancer in the liver or lungs that is surgically removed are cured in approximately 25% of circumstances. Surgical removal of cancer can be accomplished with acceptable side effects in many community cancer centers, with mortality rates of approximately 2%. Liver-Directed Therapies For patients with disease confined to the liver who are not surgical candidates, several other liver-directed treatments approaches have been developed. The goal of liver-directed therapies is to inject chemotherapy directly into the blood supply of the liver, thereby delivering chemotherapy directly to the cancer and/or to block the flow of blood to the liver to further "starve" the cancer cells by preventing the necessary blood flow. Hepatic artery infusion (HAI) refers to chemotherapy that is injected directly into the hepatic artery. This procedure has the potential advantage of delivering

higher doses of anti-cancer therapy directly to the cancer cells in the liver, while avoiding the side effects of chemotherapy delivered systemically. Techniques that interrupt blood flow to the cancer cells in the liver can simply block (chemoemobilization) or close the hepatic artery (hepatic artery ligation). These liver-directed treatment approaches are all highly specialized procedures and when performed by experienced individuals in highly selected patients have produced some encouraging treatment results. In order for these procedures to become widely used, the risk and benefit of liver-directed therapies must outweigh the risk and benefit from standard surgical removal of isolated liver lesions and systemic chemotherapy. Hepatic Artery Infusion: Hepatic artery infusion has been the most widely evaluated of the liver-directed treatment strategies. The most commonly used chemotherapeutic agent infused into the hepatic artery is FUdR. A clinical study in patients with cancer confined to the liver compared hepatic artery infusion with FUdR to no additional treatment. The study demonstrated that patients treated with hepatic artery infusion survived on average 13.5 months, compared to 7.5 months for patients who received no additional treatment. Hepatic Artery Infusion and Systemic Chemotherapy: When rectal cancer has spread to the liver, it is likely that cancer may exist elsewhere in the body; therefore, many doctors have advocated giving systemic chemotherapy over hepatic artery infusion chemotherapy directed exclusively to the cancer cells in the liver. Several clinical studies have been performed in patients with cancer metastatic to the liver that compare hepatic artery infusion with FUdR to treatment with systemic 5-fluorouracil-based chemotherapy. An analysis of all of these trials together has demonstrated that hepatic artery infusion produces a higher remission rate than systemic chemotherapy; however, the average overall survival is not significantly improved. Patients treated with hepatic artery infusion lived on average 16 months, compared to 12 months for patients treated with systemic 5fluorouracil chemotherapy. One clinical trial has compared the effectiveness of hepatic artery infusion plus systemic infusion of chemotherapy versus systemic infusion chemotherapy alone. Physicians randomly allocated 156 patients with colorectal cancer to two groups. One group received 6 cycles of chemotherapy into the hepatic artery and systemic chemotherapy, while the other group only received systemic chemotherapy. Two years following treatment, 86% of patients who received the combination treatment with HAI and systemic chemotherapy survived, compared to 72% of patients who received systemic chemotherapy alone. The average survival was 72 months for patients who received the combined treatment and 59 months for those who received systemic chemotherapy treatment alone. Only 10% of patients receiving combined treatment developed a cancer recurrence, compared to 60% of patients receiving the systemic chemotherapy treatment alone. The combined therapy did not lead to an increased treatment-related mortality. In summary, for patients with rectal cancer isolated to the liver who are unable to undergo surgical removal of the cancer, hepatic artery infusion improves response rates and prolongs survival when compared to no treatment and may produce a minor survival advantage compared to patients treated with systemic 5fluorouracil chemotherapy. In addition, the combination of HAI plus systemic chemotherapy appears to offer improved responses compared to HAI or systemic chemotherapy alone. Strategies to Improve Treatment While some progress has been made in the treatment of Stage IV rectal cancer, the majority of patients still succumb to cancer and better treatment strategies are clearly needed. Future progress in the treatment of rectal cancer will result from

continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of rectal cancer. New Chemotherapy Regimens: Development of new multi-drug chemotherapy treatment regimens that incorporate new or additional anti-cancer therapies is an active area of clinical research. Several new chemotherapy drugs show promising activity for the treatment of colorectal cancer. Camptosar� and oxaliplatin are being evaluated in clinical trials in combination with other chemotherapy drugs and at other doses and schedules of administration with the hope that this will further improve the treatment of patients with rectal cancer. Oral Chemotherapy Agents: Several new chemotherapy agents are being developed that can be taken orally. The most common are the fluoropyramidines, which may provide the same or greater benefit as intravenous 5-fluorouracil without requiring intravenous administration. Angiogenesis: Angiogenesis, a scientific term for the formation of blood vessels, is crucial to the development of cancer and other diseases that require the development of new blood vessels to supply them with essential nutrients for growth. Angiogenesis-dependent diseases form new blood vessels by sending out certain proteins, such as VEGF (vascular endothelial growth factor) that cause endothelial cells within existing nearby blood vessels to proliferate and migrate secreting enzymes called matrix metaproteinases or MMP's, which create an opening in the surrounding matrix, enabling these endothelial cells to form new blood vessels that reach out to the disease. Vascular endothelial growth factor (VEGF) plays a crucial role in the progression of cancer by stimulating the new growth of blood vessels. In essence, VEGF stimulates the body to provide a blood supply for a newly developing cancer. Researchers have developed a type of antibody, a recombinant humanized monoclonal antibody called rhuMAb VEGF, that inhibits the effects of VEGF in the body. This monoclonal antibody has now been studied in patients with metastatic rectal cancer. Researchers assigned 104 patients with metastatic colon or rectal cancer to receive treatment with either fluorouracil and leucovorin alone or fluorouracil, leucovorin and rhuMAb VEGF. The results indicated that 34% of patients who received the rhuMAb VEGF had a response to treatment, compared with only 21% of those who received chemotherapy alone. The average time it took for the cancer to begin growing again (called time to progression) was 6.8 to 7.3 months in patients who received the rhuMAb VEGF and 5.4 months in those who received the chemotherapy alone. RhuMAb VEGF and other anti-angiogenesis components are being evaluated alone or in combination with chemotherapy. Liver-Directed Therapies: Continued development and refinement of hepatic artery infusion, chemoembolization and other liver-directed therapies is ongoing. For patients with liver dominant disease, these strategies are being utilized to shrink the cancer and increase the number of patients eligible for surgical removal of their cancer. Radiofrequency Ablation:Radiofrequency ablation entails the use of high-energy radio waves that can be administered through the skin using a probe, about the size of a needle, into the tumor(s) in the liver. The doctor uses an imaging scan, such as an ultrasound or a computerized tomography (CT) scan, to guide the probe to the right spot(s) in the liver. The high-energy radio waves heat the cancer

cells such that they later become coagulated and are destroyed. The radio waves can also be delivered into the tumor as part of a surgical procedure. Researchers have demonstrated that radiofrequency ablation is safe and effective in primary liver tumors and are currently evaluating this technique in patients with metastases to the liver. Biological Modifier Therapy: Biologic response modifiers are naturally occurring or synthesized substances that direct, facilitate or enhance the body's normal immune defenses. Biologic response modifiers include interferons, interleukins, vaccines and monoclonal antibodies. In an attempt to improve survival rates, these and other agents are being tested alone or in combination with chemotherapy in clinical trials. Monoclonal Antibodies: Another approach is to deliver additional treatment directed specifically to the cancer cells and avoid harming the normal cells. Monoclonal antibodies are a treatment that can locate cancer cells and kill them directly. Monoclonal antibodies are being evaluated alone or in combination with chemotherapy to determine whether they can improve cure rates. Vaccines: One strategy for stimulating the immune system to attack cancer cells is the use of vaccines. Cancer cells often display certain small proteins and/or carbohydrates (antigens) on their surface that are not displayed by healthy cells. Vaccines are often comprised of these specific antigens, which can be taken directly from the patient�s cancer cells, other patient�s cells or produced in a laboratory. If these antigens are injected into the patient, the immune system recognizes them as �foreign� and will attack the cancer cells displaying the antigens. Researchers are now evaluating various strategies to enhance the immune response against the injected antigens, including combining the patient�s own immune cells with the specific antigens in a laboratory prior to injection. Phase I Trials: New chemotherapy drugs continue to be developed and evaluated in patients with recurrent cancers in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the best way of administering the drug and whether the drug has any anti-cancer activity in patients.