Archive for October 13th, 2007

Treatment of rectal cancer

Posted on October 13, 2007. Filed under: Unknown |

INTRODUCTION — The rectum is the section of the gastrointestinal system that connects the colon (large intestine) to the anus, where waste (fecal) matter passes out of the body (show figure 1). Like the colon, the rectum is part of the large intestine, and rectal and colon cancers are often referred to together as colorectal cancers. While the two conditions are part of the same disease process, the treatment of rectal cancer is different from colon cancer because of its unique anatomic location.

Like colon cancer, rectal cancer develops slowly over a period of years. Most cancers begin within a polyp, also called an adenoma. These are small growths of non-cancerous tissue that protrude from the lining of the large intestine. Over time, as these polyps grow, they can become cancerous and begin to invade the layers of tissue that form the wall of the rectum. At this point, they can spread to lymph nodes and to other organs such as the lung and liver, a process called metastasis.

RECTAL CANCER STAGING — Treatment and prognosis (outcome) depend upon the stage of the cancer. Staging of rectal cancer is based upon how far the cancer has penetrated into the wall of the rectum, whether the cancer has spread to lymph nodes located around the rectum, and whether the cancer has spread via the bloodstream to other organs (a situation called distant metastatic spread).

The initial evaluation of a rectal cancer usually involves a colonoscopy (a test in which a flexible tube with a camera is guided through the rectum and the rest of the colon). Abdominal and pelvic CT scans (specialized x-rays), and a chest x-ray are often recommended to look for evidence of cancer spread within the abdominal cavity and/or lungs. Other possible tests include a specialized rectal ultrasound or magnetic resonance imaging (MRI) scan.

The final stage of a rectal cancer is confirmed by the findings during surgery, which is the most accurate way to determine how far the tumor has spread.

There are two staging systems for rectal cancers: The TNM system (tumor, nodes, metastases) is most comonly used (show table 1) Less frequently, a modification of the Dukes system is used (show table 2)

A blood test for carcinoembryonic antigen (CEA, a substance produced by most colorectal cancers that circulates in the blood) should be obtained before a patient has his or her initial surgery. An elevated CEA level that does not return to a normal after surgery may be a sign of persistent disease and requires further evaluation.

RECTAL CANCER TREATMENT — The majority of rectal cancers are treated with a combination of surgery, radiation, and chemotherapy. Surgery alone may be curative for patients with stage I disease. For patients with stage II or III disease (see below), chemotherapy and radiation therapy are typically recommended following surgery (in which case, they are referered to as adjuvant therapy), or in some cases, before surgery (termed neoadjuvant therapy). Patients with stage IV (metastatic) rectal cancer are predominantly treated with chemotherapy, with or without surgery and radiation therapy. (See “Patient information: Treatment of metastatic colorectal cancer”).

SURGERY — Regardless of the extent of the disease, surgery has an important role in treating rectal cancer. For patients with tumors that have not spread beyond the rectum (“localized disease”), surgery permits the removal of the cancerous part of the rectum and the associated lymph nodes, and the surgeon can examine the abdominal area directly for signs of cancer spread. Sometimes an operation to remove the cancerous tumor from the rectum is performed even in patients who have metastases (stage IV rectal cancer, show table 1). This is done to prevent bleeding and obstruction of the intestine, two problems that can be caused by an untreated enlarging rectal cancer.

Types of surgery — Surgical treatment for rectal cancer varies according to the extent of tumor involvement and the location of the cancer. For example, some rectal cancers are very small and limited to the surface of the rectal lining while others have grown through the entire rectal wall and are adherent (stuck) to nearby structures and organs, such as the abdominal or pelvic wall, the sacrum, the bladder, or the prostate gland. The extent of surgery that will be needed to remove these two tumors is very different.

In general, there are four types of operations: Transanal excision Low anterior resection (LAR) Abdominoperineal resection (APR) Pelvic exenteration

Most rectal cancers require an open surgical procedure, meaning that an incision is made through the abdominal wall to gain access to the lower intestine so the tumor can be removed (resected). However, some early tumors can be removed without an abdominal incision in a procedure called transanal excision.

Transanal excision — The simplest type of surgery for rectal cancer is done without an abdominal incision by inserting instruments though the anal opening. This method can be used for removing large polyps and for removing tumors that are small and located relatively close to the anus (show figure 1). Most rectal tumors that can be succesfully treated in this way are stage I, and have a favorable appearance when they are examined under the microscope by the pathologist (ie, they are moderately-well or well differentiated rather than poorly differentiated). This means that the tissue forming the tumor is forming or beginning to form normal gland structures.

Superficial rectal cancers (T1, show table 1) are the most suitable for local excision, although selected patients with T2 tumors may be eligible for this approach as well.

When a rectal tumor is removed through a local excision, the tissue will be analyzed under the microscope to determine if further surgery is needed, and whether postoperative (adjuvant) therapy, which usually consists of a combination of radiation and chemotherapy, will or will not be recommended. These treatments are discussed below.

Low anterior resection — If an open approach is needed, the surgeon may be able to remove the tumor while leaving the anus intact if the tumor is located high enough in the rectum. This operation is called a low anterior resection (LAR) and requires an abdominal incision. LAR is used whenever possible in order to preserve rectal function. After removing cancerous tissue, the remaining colon is connected to the lower rectum, or in some cases, the upper anus, and the patient is able to have bowel movements in a normal fashion.

Sometimes, a temporary ileostomy or colostomy (in which the small intestine or colon is brought out to the skin of the abdominal wall allowing passage of the stool into an external bag) is necessary to allow the connected tissues to heal. After six to eight weeks, the ileostomy or colostomy is closed, an external bag is no longer needed to collect the stool, and the patient is able to have bowel movements in a normal fashion (from their anus).

During the LAR procedure, the surgeon will also remove all the lymph nodes (also called lymph glands) associated with the rectum. It is important to remove the lymph nodes when treating cancer because one way that cancer cells travel through the body is by using the lymphatic system. Lymph nodes contain special cells that trap cancer cells, and removing them helps to ensure that cancer cells from the primary tumor in the rectum are not able to spread beyond the lymph nodes. The tissue removed from the lymph nodes will also be examined to help determine whether further treatment is needed after surgery. A sufficient number of lymph nodes must be removed by the surgeon (typically at least 12) so that the pathologist can reliably determine whether nodal spread has occurred or not.

Abdominoperineal resection — Similar to the LAR, an abdominoperineal resection (APR) requires an abdominal incision and also requires an incision to remove the anus. This results in the need for a permanent colostomy (see “Life with a colostomy” below). The APR is used when tumors cannot be completely removed using LAR, most commonly because the tumor is too close to the anus. To remove enough surrounding tissue to ensure that the cancer is completely resected, the surgeon must remove the anus as well (show figure 2). During an APR, the lymph nodes in the vicinity of the rectum are removed, just as in the LAR.

Pelvic exenteration — If a cancer has invaded nearby organs, a more extensive operation may be needed. In this situation, it is often possible for the surgeon to remove a part of certain organs such as the bladder. If the function of these organs cannot be saved because of the extent of tumor involvement, the entire organ may need to be removed. Rarely, all of the tissues and organs within the pelvis (including the bladder, prostate [in men], and/or uterus [in women]), must be removed in order to successfully treat the cancer, a major operation called pelvic exenteration.

Most often, patients undergoing this procedure require a permanent colostomy. If the bladder is removed, the patient may also need a urostomy, an artificial opening on the front of the abdomen that allows urine to leave the body. Pelvic exenteration can cause a number of complications and may not result in a cure due to the widespread nature of the cancer.

For many patients with locally advanced rectal cancer, an alternative to pelvic exenteration is the administration of chemotherapy and radiation therapy before surgery. This can often shrink the tumor, allowing the surgeon to perform an LAR, an APR, or a more extensive operation, depending on how much cancer remains after chemotherapy and radiation therapy. This type of therapy is discussed in more detail below. (See “Preoperative (neoadjuvant) chemotherapy and radiation” below).

BOWEL FUNCTION AFTER SURGERY — Bowel function following rectal cancer surgery depends upon the specific operation that was performed and whether radiation therapy was also used (see below). Following a LAR, many patients experience initial difficulty with bowel control even if the anal sphincter (the valve that controls elimination of stool) has been preserved. You may feel a sense of bowel urgency and need to pass stool frequently. For most patients, bowel function improves over time, but it may not return to presurgery levels.

Patients in whom the connection between the colon and the anus was made very close to the anal opening have very little “rectal reservoir,” or room, to store fecal matter before needing to move the bowels. These patients may have an increased frequency of bowel movements and some difficulty with evacuation (emptying the bowels). Sometimes a larger reservoir can be created out of the colon (colonic J Pouch) prior to connecting it to the lower rectum or anus. This provides more space to store fecal matter, and can result in better bowel function.

Life with a colostomy — Having a colostomy can alter a patient’s body image, and this may be challenging, both physically and emotionally. However, with education and support about living with a colostomy, it is possible to lead an active life. A team effort that includes the colorectal surgeon, oncologist, and an enterostomal therapy (ET) nurse is vital to counsel and educate a patient and their family before surgery, and also in the care and rehabilitation following the procedure. The United Ostomy Associations of America is also a good source of information and support (www.uoaa.org).

CHEMOTHERAPY AND RADIATION — Chemotherapy and radiation therapy are recommended in addition to surgery for most patients with stage II or III rectal cancer. These treatments improve the likelihood of surviving the cancer. Even when all visible signs of cancer have been removed by the surgeon, between 20 and 50 percent of patients will have a recurrence of their cancer if it is treated with surgery alone.

One reason for this relatively high recurrence rate is that the area of the pelvis in which the rectum is located is a “tight space” and it is often difficult for the surgeon to remove a sufficient amount tissue around the tumor; this means that all of the cancer cells in the surrounding tissue may not be removed. In addition, tiny cancer cells may have “escaped” from the lymph nodes and spread to other organs. The combination of chemotherapy and radiation helps to reduce the chance of recurrence by targeting any remaining cancer cells.

There are two general ways to administer chemotherapy and radiation in patients who have rectal cancer:

Postoperative therapy — Postoperative (adjuvant) therapy is typically recommended for patients who have already undergone surgery. A commonly used treatment protocol (regimen) is as follows [1,2]: Two monthly courses of chemotherapy with the anticancer drug 5-fluorouracil (abbreviated 5-FU) given five days in a row, once per month. This is followed by: Radiation therapy over a five- or six-week period. During this time, a continuous intravenous infusion of 5-FU is administered. This approach requires that patients have a central venous access catheter (often termed a port) surgically inserted into one of the large blood vessels in the chest, and a portable chemotherapy pump at home (referred to as an ambulatory infusion pump). This pump is very small, battery-operated, and fits into a fanny pack that patients can wear around their waist to allow freedom of movement during therapy. Two further courses of chemotherapy with 5-FU given five days in a row, once per month.

For patients in whom ambulatory infusion pump therapy is not feasible, an alternative method of combining chemotherapy with radiation is to give one large dose (bolus) of 5-FU given into a vein in the arm for three days during the first and last weeks of radiation therapy. However, treatment-related toxic side effects may be greater with this approach [3]

Another increasingly popular alternative is to give a daily oral dose of the drug Xeloda (capecitabine). Although this regimen is more convenient for the patient, it has not yet been proven to be equivalent to therapy with infusional 5-FU.

Benefits — The use of combined chemotherapy and radiation after surgery reduces the risk of dying of rectal cancer by about 30 percent [4]. This benefit is relatively large, and as a result, adjuvant therapy with both chemotherapy and radiation is considered a standard approach in patients following rectal cancer surgery if the tumor involves the lymph nodes (stage III) or has grown through the entire bowel wall (stage II).

Preoperative (neoadjuvant) chemotherapy and radiation — Although often given after surgery, chemotherapy and radiation may be offered to a patient prior to the rectal operation, most commonly if the tumor is large or located low in the rectum. This is called neoadjuvant chemoradiotherapy. The purpose of such an approach is to try to shrink the tumor before the operation is performed.

Research indicates that, compared to the postoperative approach, neoadjuvant chemoradiotherapy provides better local control of the tumor, a twofold higher chance of avoiding a permanent colostomy, and fewer side effects of radiation, with no detrimental impact on survival [5].

The administration of chemotherapy in addition to radiation therapy is critical to the success of the approach. As in the postoperative setting (described above), the most common approach for preoperative chemotherapy and radiation is the administration of continuous intravenous 5-FU with an ambulatory infusion pump during the radiation.

An increasingly popular alternative to infusional 5-FU during radiation is to give a daily dose of oral Xeloda during radiation therapy, largely because it is more convenient for the patient. Although guidelines from the National Comprehensive Cancer Network (NCCN) endorse this approach as an acceptable alternative to infusional 5-FU, no study has shown that long-term outcomes are equivalent. Studies are underway to help answer this question.

Patients who undergo neoadjuvant chemotherapy and radiation therapy should receive an additional six months of chemotherapy alone after surgery. There are several reasonable options, including: Single agent 5-FU alone, given intravenously daily for five days every four weeks Oral therapy with the drug capecitabine (Xeloda®) A combination of 5-FU and leucovorin (with both drugs given once weekly for six of every eight weks) The addition of a third drug (oxaliplatin) to 5-FU and leucovorin (a regimen that is abbreviated FOLFOX)

Side effects — Both radiation and chemotherapy can cause side effects, particularly when used together.

Chemotherapy — The most common side effects with 5-FU are diarrhea, mucositis (soreness in the mouth), and temporary low blood counts. When 5-FU is given continuously, it can cause “hand-foot syndrome”, which causes soreness, redness and peeling of the skin of the palms and soles of the feet. Supplemental vitamin B6 (also called pyridoxine) may provide benefit in this situation.

Orally active 5-FU derivatives like Xeloda® share the same side effects as intravenous 5-FU, although diarrhea and mucositis is less common with Xeloda® while hand-foot syndrome is somewhat more common.

Most patients tolerate chemotherapy reasonably well and many are able to continue working during treatment, often with a reduced schedule of hours due to fatigue. Hair loss is an uncommon side effect of the chemotherapy drugs used for rectal cancer.

Combined chemotherapy and radiation — Possible side effects of 5-FU and radiation include diarrhea, irritation or inflammation of intestinal tissue leading to a sense of bowel urgency, bleeding and discomfort in passing stool, and skin irritation around the anus.

PROGNOSIS — Each patient with cancer is different, and it is impossible to predict what to expect in the future. Both before and after cancer treatment, it is important to discuss ongoing management, lifestyle changes, and future treatment options.

Prognosis generally depends upon the stage of the cancer at the time that it is removed. Cancer that is identified and treated early has the best prognosis. The likelihood of dying is greater with increasingly advanced cancer. The average five year survival by stage is approximately [6]: Stage I — 66 to 78 percent Stage II — 55 to 62 percent Stage III — 31 to 42 percent

FOLLOW-UP AFTER TREATMENT — The term surveillance refers to the follow-up testing after surgery for colon cancer that is performed to detect a cancer recurrence or a new colorectal cancer. The following are recommendations for posttreatment surveillance (show table 3) [7]. Patients should see their clinician every three to six months for the first three years and then yearly thereafter. A medical history is done to determine if there have been signs or symptoms suggestive of a cancer recurrence. The physical examination should include a rectal examination for patients who have undergone low anterior resection. A blood test for carcinoembryonic antigen (CEA, a substance produced by most colon cancers that circulates in the blood) should be obtained every one to three months in patients with stage II and III disease for at least the first three years after primary resection. An increase in the CEA may be the first sign of a recurrence of the cancer. This is true even if preoperative CEA levels were normal.

The CEA level can help to detect recurrences that might be amenable to further curative surgery. Thus, periodic CEA levels may not be necessary in patients who would not be able to undergo resection for a recurrent cancer. All patients with rectal cancer should undergo a complete colonoscopy either before surgical resection or within a few months after resection. This will exclude polyps and other cancers that may be present in other areas of the colon. (See “Patient information: Colonoscopy”).

An additional screening colonoscopy is recommended one year later to evaluate for polyps or new cancers [8]. If none are detected, the next colonoscopy is recommended in three years, and then every five years thereafter. Any symptoms or laboratory values that suggest recurrence require immediate colonoscopy. For patients who have had an abdominopelvic resection, colonoscopy is performed through the colostomy. For patients who have undergone low anterior resection for rectal cancer, flexible sigmoidoscopy (scope examination of just the lower part of the intestine) is recommended every six months for five years for patients who have not received pelvic radiation therapy. Flexible sigmoidoscopy is not needed for patients who have received pelvic radiation therapy. (See “Patient information: Flexible sigmoidoscopy”). The 2005 American Society of Clinical Oncology guidelines suggest that patients with stage II or III should have an annual CT scan of the chest and abdomen for three years. If radiation was not administered, an annual pelvic CT scan is also recommended for the first three years after treatment [7]. As with the CEA levels (see above), CT scans are used to detect recurrences that might be treatable with further surgery. Thus, periodic CT scanning may not be necessary in patients who would not be able to undergo surgery for a recurrent cancer.

If the CEA becomes elevated or the patient develops symptoms that are worrisome (eg, abdominal pain, bloating, inability to pass stools), an abdominal CT is recommended to determine if there are metastases.

The following tests are not necessary for routine surveillance: Testing for microscopic amounts of blood in the stool (guiac or stool cards) Liver function tests (a panel of blood tests) Complete blood count (a blood test) Yearly chest x-ray

OPTIONS FOR RECURRENT CANCER — If a rectal cancer recurs in the area of the rectum, the best therapy is determined by several factors, including what treatments were used previously and where the new cancer is located. Treatment options are similar to those for primary tumors, and include surgery, chemotherapy, radiation therapy.

The treatment of patients with advanced rectal cancer depends upon the extent and location of the tumor involvement. Although the majority of patients cannot be cured by any therapy, some patients with limited involvement may be cured by further surgery. In other cases, chemotherapy is the best option. (See “Patient information: Treatment of metastatic colorectal cancer”).

CLINICAL TRIALS — Progress in treating cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

http://www.cancer.gov/clinical_trials/learning/
http://www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/

IMPLICATIONS FOR THE FAMILY — A diagnosis of rectal cancer can be devastating for the patient and also for their family. The best way to cope with all of these issues varies from person to person and among families. Do not underestimate the importance of good support; it is something that each patient should discuss with their healthcare team.

An important issue for close relatives (siblings, parents, or children) of a person with colorectal cancer is the risk of developing colon cancer themselves. This also applies to family of persons with specific types of polyps, called adenomatous polyps.

Relatives should understand the following information: People who have one first-degree relative (parent, brother, sister, or child) with colorectal cancer or adenomatous polyps at a young age (before the age of 60 years), or two first-degree relatives diagnosed at any age should begin colon cancer screening earlier, typically at age 40, or 10 years younger than the earliest diagnosis in their family, whichever comes first, and screening should be repeated every 5 years. (See “Patient information: Screening for colon cancer”). People who have one first-degree relative (parent, brother, sister, or child) who has experienced colorectal cancer or an adenomatous polyps at age 60 or later should begin screening at age 40, and screening should be repeated as for average risk people. People with a second-degree relative (grandparent, aunt, or uncle) or third-degree relative (great-grandparent or cousin) with colorectal cancer are screened as average-risk people.

Some conditions (such as hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis) are associated with an even higher risk of colonic polyps or cancer in family members, and require more aggressive screening for family members. Patients and their family should discuss these issues with a healthcare provider who is experienced in these areas.

WHERE TO GET MORE INFORMATION — Your healthcare provider is the best source of information for questions and concerns related to your medical problem. Because no two patients are exactly alike and recommendations can vary from one person to another, it is important to seek guidance from a provider who is familiar with your individual situation.

This discussion will be updated as needed every four months on our web site (www.patients.uptodate.com). Additional topics as well as selected discussions written for healthcare professionals are also available for those who would like more detailed information.

A number of web sites have information about medical problems and treatments, although it can be difficult to know which sites are reputable. Information provided by the National Institutes of Health, national medical societies and some other well-established organizations are often reliable sources of information, although the frequency with which they are updated is variable. People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute

1-800-4-CANCER
(www.cancer.gov)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
The American Gastroenterological Association

(www.gastro.org)
The American College of Gastroenterology

(www.acg.gi.org)

[1-7,9]

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. NIH consensus conference. Adjuvant therapy for patients with colon and rectal cancer. JAMA 1990; 264:1444.
2. O’Connell, MJ, Martenson, JA, Wieand, HS, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion 5-FU with radiation therapy after curative surgery. N Engl J Med 1994; 331:502.
3. Smalley, SR, Benedetti, JK, Williamson, SK, et al. Phase III trial of fluorouracil-based chemotherapy regimens plus radiotherapy in postoperative adjuvant rectal cancer: GI INT 0144. J Clin Oncol 2006; 24:3542.
4. Krook, JE, Moertel, CG, Gunderson, LL, et al. Effective surgical adjuvant therapy for high-risk rectal carcinoma. N Engl J Med 1991; 324:709.
5. Sauer, R, Becker, H, Hohenberger, W, et al. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 2004; 351:1731.
6. Jessup, JM, Stewart, AK, Menck, HR. The National Cancer Data Base report on patterns of care for adenocarcinoma of the rectum, 1985-95. Cancer 1998; 83:2408.
7. Desch, CE, Benson AB, 3rd, Somerfield, MR, et al. Colorectal cancer surveillance: 2005 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol 2005; 23:8512.
8. Rex, DK, Kahi, CJ, Levin, B, et al. Guidelines for colonoscopy surveillance after cancer resection: a consensus update by the American Cancer Society and the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology 2006; 130:1865.
9. Janjan, NA, Khoo, VS, Abbruzzese, J, et al. Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience. Int J Radiat Oncol Biol Phys 1999; 44:1027.

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Treatment of metastatic colorectal cancer

Posted on October 13, 2007. Filed under: Unknown |

INTRODUCTION — Despite early diagnosis and treatment, cancers involving the colon or rectum (together referred to as colorectal cancer) can reappear at a later time, even if the cancer was entirely removed during the initial treatment. This reappearance of the cancer is referred to as a recurrence or a relapse.

A colorectal cancer recurrence can be either local (confined to the large intestine or nearby tissues) or at a more distant site. Areas of distant tumor involvement are called metastases. Although most patients with metastatic colorectal cancer develop the tumor recurrence months to years after initial treatment, a small percentage already have metastatic cancer when their cancer is first discovered.

The treatment of patients with colorectal cancer that has spread or metastasized depends upon the extent and location of the tumor involvement. Cure is not possible for most patients with metastatic colorectal cancer, although some patients who have limited involvement (particularly involving the liver) may be cured by further surgery. For others, chemotherapy is the most appropriate option. Chemotherapy does not cure metastatic colorectal cancer, but it can improve symptoms and prolong life.

This topic review will discuss management of patients with metastatic colorectal cancer. Treatment for localized colon cancer and localized rectal cancer is discussed elsewhere (See “Patient information: Treatment of colon cancer” and see “Patient information: Treatment of rectal cancer”).

SURGERY FOR RESECTABLE ADVANCED DISEASE — Sometimes surgery can be considered for patients whose colorectal cancer has spread in a limited way outside of the intestine, to an area such as the liver. Up to 30 percent of patients may be cured if the tumor(s) in the liver can be completely removed or resected [1]. In order for this approach to succeed, there must be no cancer outside of the liver.

In some cases, intravenous chemotherapy may be recommended prior to attempted surgical removal of the liver metastases. This approach might permit some patients who have liver metastases that are initially unresectable or borderline resectable (because of size or location) to have successful surgery [2].

It is not clear if additional chemotherapy is beneficial after successful surgical removal of liver metastases. Although several clinical trials have studied this issue, none have shown that survival is better in patients who get chemotherapy after liver surgery compared to those who do not. However, none of the studies used what would be considered to be “modern” chemotherapy regimens. Treatment guidelines suggest that six months of treatment with chemotherapy or observation alone are both reasonable options [3]. Contemporary chemotherapy regimens for metastatic colorectal cancer are described in detail below (See “First-line chemotherapy” below).

At some institutions, the chemotherapy is given directly into the liver (an approach called hepatic intraarterial chemotherapy) with or without additional chemotherapy given into the veins (intravenous chemotherapy) [4]. However, whether this approach is better than intravenous chemotherapy alone is unclear, and the most commonly used approach is intravenous chemotherapy.

CHEMOTHERAPY FOR UNRESECTABLE DISEASE — As noted above, surgery is the only way to cure a patient who has metastatic colorectal cancer. If surgery is not possible, then chemotherapy is generally recommended. Chemotherapy clearly benefits patients by improving symptoms and prolonging survival; it is not intended to cure the cancer.

Conventional chemotherapy — The conventional chemotherapy drugs used to treat metastatic colorectal cancer include: 5-fluorouracil (abbreviated 5-FU), which is usually given into the vein with a second drug called leucovorin, which enhances its activity Orally active 5-FU-like drugs such as capecitabine (Xeloda®) Oxaliplatin (Eloxatin®), which is given intravenously Irinotecan (Camptosar®), also given intravenously

These drugs work by interfering with the ability of rapidly growing cells (like cancer cells) to divide or reproduce themselves. Because most of an adult’s normal cells are not actively growing, they are less affected by chemotherapy, with the exception of bone marrow (where the blood cells are produced), the hair, and the lining of the gastrointestinal tract. Effects of chemotherapy on these and other normal tissues cause side effects during treatment. (See “Chemotherapy side effects” below).

Targeted therapies — Three other drugs that are active in metastatic colorectal cancer, called bevacizumab (Avastin®), cetuximab (Erbitux®), and panitumumab (Vectibix®) work by a different mechanism. All three are referred to as “targeted chemotherapy agents” since they are antibodies (a type of protein) that work to inhibit a protein that is important for the growth and/or survival of colon cancer cells: Avastin binds a protein called vascular endothelial growth factor (VEGF). VEGF is involved in the development of a blood supply within a growing cancer; this blood supply is essential for the tumor to grow and spread. Avastin also enhance the antitumor effect of other chemotherapy drugs. Erbitux targets a different protein, the epidermal growth factor receptor (EGFR), which is found in approximately 80 percent of colorectal cancers. Erbitux is effective even if EGFR is not detected within a person’s tumor, possibly because the test is not sensitive in detecting a small number of receptors. Vectibix also targets the EGFR, but in a different way than Erbitux.

Because these drugs do not directly inhibit rapidly dividing cells, they do not have the usual side effects of conventional chemotherapy drugs such as irinotecan, oxaliplatin, and 5-FU. However, they have other unique side effects, which are described in detail below. (See “Chemotherapy side effects” below).

Avastin is not effective when given by itself, without other anticancer drugs. It is used only in combination with 5-FU and irinotecan or oxaliplatin. On the other hand, Erbitux can be used alone or in combination with irinotecan. Ongoing trials are currently evaluating Erbitux and Avastin (both alone and together) with other chemotherapeutic agents in an attempt to find more active combinations.

In the United States, Vectibix is only approved as a “last resort” treatment of metastatic colorectal cancer, after other drugs have failed. Its role in combination with chemotherapy and Avastin is under study.

Assessment during therapy — Regardless of the particular drugs that are chosen, the response to chemotherapy is typically assessed using periodic x-ray studies (such as CT scans), often recommended after every two to three cycles of therapy, and by measuring blood levels of a tumor marker called carcinoembryonic antigen (CEA). CEA levels are typically high in patients who have advanced colorectal cancer, and levels are checked every one to three months during therapy. Persistently rising CEA levels suggest that disease is progressing and that a change in therapy is warranted. However, disease progression should be confirmed with radiographic testing (eg, CT scan) or biopsy before a change in treatment is recommended.

FIRST-LINE CHEMOTHERAPY — Conventional chemotherapy drugs and targeted agents are generally used in combination for patients with newly diagnosed, previously untreated metastatic colorectal cancer. Many different combinations have been developed, and studies are ongoing to determine which combinations and schedules are best. Several different combinations are currently recommended for initial (first-line) treatment.

FOLFOX and FOLFIRI — Two different combination regimens are considered standard approaches for the initial treatment for patients with metastatic colorectal cancer [5,6]. Each of these regimens consists of three drugs, used together in a specific way: Oxaliplatin plus 5-FU and leucovorin (referred to as FOLFOX) Irinotecan plus 5-FU and leucovorin (referred to as FOLFIRI)

In both regimens, the oxaliplatin or irinotecan are typically administered intravenously all at once on the first day of treatment (day 1). The leucovorin and 5-FU are administered on two consecutive days (day 1 and 2) with an initial intravenous bolus (rapidly infused) dose of leucovorin and 5-FU, followed by a continuous infusion of 5-FU administered into the vein over 22 hours. The same doses and schedule of all three drugs are repeated every two weeks. Frequently, the delivery of 5-FU is modified so that the infusion runs for 46 instead of 22 hours, thus eliminating the need for patients to come in for the bolus infusion of 5-FU and leucovorin on day 2.

Both the FOLFOX and FOLFIRI regimens require that patients have a central venous access catheter (often termed a “port”) surgically inserted into one of the large blood vessels in the chest and a portable chemotherapy pump at home (referred to as an ambulatory infusion pump). This pump is actually very small, and it fits into a fanny pack that can be worn around the patient’s waist.

Both FOLFIRI and FOLFOX have similar outcomes when used as first-line therapy [5,6] and the choice between them is sometimes based upon expected side effects with each regimen (see “Chemotherapy side effects” below). At least in the United States, most patients are offered first-line FOLFOX, and FOLFIRI is reserved for second-line therapy unless there are coexisting medical conditions (such as neuropathy) that might favor the initial use of FOLFIRI.

For patients in whom ambulatory infusion pump therapy is not feasible, the combination of the oral drug Xeloda plus oxaliplatin is an acceptable alternative to the infusional regimens FOLFOX. This regimen is more convenient for the patient, and probably similarly effective for first-line therapy as FOLFOX. However, some side effects (including diarrhea and redness, tenderness, and peeling of the skin of the palms and soles of the feet) may be more pronounced than with FOLFOX.

Combinations of Xeloda with irinotecan may not be as effective and are more toxic than FOLFIRI. As a result, they are usually not recommended.

Benefit of adding Avastin — Encouraging results have been reported when bevacizumab (Avastin®) is combined with 5-FU plus leucovorin and either oxaliplatin or irinotecan (FOLFOX or FOLFIRI). Adding Avastin results in a significantly higher likelihood of a tumor response, and it prolongs survival compared to treatment without Avastin. As long as there are not reasons Avastin should not be used, it is recommended for first-line treatment in persons who receive either FOLFIRI or FOLFOX. Avastin is administered intravenously once every two weeks.

Patients who can’t tolerate irinotecan or oxaliplatin — For patients who are not appropriate candidates for an aggressive chemotherapy regimen like FOLFOX or FOLFIRI (for example, because of their age, physical condition or coexisting medical problems), intravenous 5-FU plus leucovorin with or without Avastin may be a reasonable, less toxic alternative. In this regimen, both agents are administered as a short injection weekly for six of every eight weeks.

Another alternative is Xeloda alone, which is taken in pill form twice daily for 14 of every 21 days. Xeloda has about the same level of effectiveness as intravenous 5-FU plus leucovorin. These regimens are slightly less effective than oxaliplatin or irinotecan-containing chemotherapy regimens (FOLFOX or FOLFIRI), but in general, they have fewer side effects and do not require a central venous access catheter or ambulatory infusion pump.

SECOND-LINE THERAPY — If the cancer continues to grow despite chemotherapy, or it begins to enlarge again after an initial response to the first-line chemotherapy regimen, a different chemotherapy combination may be tried (if the patient is well enough to tolerate additional therapy). Because survival can be prolonged by second-line (as well as third-line) therapy, exposure to all of the most active medications at some point in the treatment (ie, 5-FU, oxaliplatin, irinotecan, Avastin, Erbitux, Vectibix) is thought to be more important than the specific sequence or order of drug administration.

The choice of second-line treatment typically depends on what was given originally. Two different approaches may be considered, but it is unknown whether either approach is superior to the other: If FOLFOX (or Xeloda plus oxaliplatin) plus Avastin was the first-line regimen, patients are typically switched to FOLFIRI with or without Avastin. If FOLFIRI plus Avastin was given as the first-line therapy, the patient is usually switched to FOLFOX or Xeloda plus oxaliplatin with or without Avastin.

Whether or not Avastin should be continued with the second-line regimen is a very controversial area, and should be discussed with a physician.

Erbitux — Adding Erbitux to irinotecan can shrink tumors in patients who stop responding to irinotecan-containing chemotherapy combinations (such as FOLFIRI or even irinotecan alone). Most often, the combination of Erbitux plus irinotecan is used for third-line therapy after failure of both FOLFOX and FOLFIRI. However, it is also sometimes used as second line therapy if there is progression on FOLFIRI plus Avastin.

Erbitux is also approved for use as a single agent to treat metastatic colorectal cancer in patients who cannot tolerate irinotecan-based chemotherapy.

Vectibix — In the United States, panitumamab (Vectibix®) is approved as a “last resort” treatment of metastatic CRC, after other drugs have failed. In one trial, patients receiving panitumumab after failing irinotecan and oxaliplatin-containing chemotherapy were significantly more likely to be alive and disease-free 8 weeks after treatment, than were those who had supportive care only without further chemotherapy (49 versus 30 percent). Combinations of panitumumab with conventional chemotherapy and bevacizumab are currently being studied.

CHEMOTHERAPY SIDE EFFECTS — The side effects of chemotherapy depend upon the type, combination, and schedule of drugs that are administered. The most common side effects of each agent are listed below, but is important to review all of the potential side effects of any therapy with the healthcare team.

5-FU and leucovorin — The most common side effects are diarrhea, mucositis (soreness in the mouth), and temporary low blood counts. In general, diarrhea and mucositis are more likely when 5-FU and leucovorin are given five days in a row (rather than weekly), especially in older patients. For this reason, most oncologists prefer the weekly regimen. Hair loss is less common with 5-FU plus leucovorin than with combinations of irinotecan or oxaliplatin plus 5-FU/leucovorin.

Xeloda — The most common side effect of Xeloda is hand-foot syndrome, a condition that causes soreness, redness and peeling of the skin of the palms and soles of the feet. Otherwise, oral 5-FU-like drugs such as Xeloda have the same side effects as intravenous 5-FU, although diarrhea and mucositis are somewhat less common.

Irinotecan — Irinotecan usually causes more diarrhea, lower blood counts, more fatigue, and more hair loss compared to 5-FU. When irinotecan is combined with 5-FU and leucovorin (FOLFIRI), the most common side effect is diarrhea. Patients should call their healthcare provider immediately if severe diarrhea develops.

Oxaliplatin — Oxaliplatin can cause numbness and tingling of the hands and feet, and this is more likely with longer durations of therapy. This drug can also cause an unusual sensitivity to cold temperatures. This can result in painful spasms of the throat while inhaling cold air or ingesting cold liquids. Patients should not drink cold fluids in the several days surrounding their oxaliplatin infusions, avoid inhaling cold air, and avoid exposing the hands and feet to cold when possible.

Avastin — Avastin can rarely cause an allergic reaction. If the reaction is severe, the drug may need to be stopped. Because there is a small risk that Avastin can impair wound healing, surgery should be avoided for at least four weeks before and after Avastin (if possible) to avoid this potential side effect.

Avastin may also cause bleeding or, uncommonly, perforation of the bowel during treatment. It can also increase blood pressure or cause protein in the urine. Close monitoring is necessary to detect these problems early so that they can be effectively treated.

There is an increased risk of blood clots for patients using Avastin in combination with 5-FU. Approximately 5 percent of patients have serious events such as strokes and heart attacks during therapy. The risk appears to be highest in patients with prior heart problems, and in those over the age of 65.

Erbitux — Erbitux can cause allergic reactions slightly more frequently than Avastin. If severe, treatment with Erbitux may be stopped. Patients will be closely monitored for allergic reactions during and after their infusion.

Other side effects include a skin rash that resembles acne, and low blood levels of magnesium. Low magnesium levels can cause weakness, heart rhythm abnormalities, and lead to low levels of other components of the blood, such as potassium and calcium.

Vectibix — Vectibix can also cause allergic reactions which, if severe, may require that drug treatment be stopped. Other side effects are similar to those with Erbitux, including skin rash, which may be severe and accompanied by infection, and low blood levels of magnesium.

http://www.cancer.gov/clinical_trials/learning/
http://www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/

website of the American Society of Clinical Oncology
(http://www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
National Cancer Institute

1-800-4-CANCER
(www.cancer.gov)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
The American Gastroenterological Association

(www.gastro.org)
The American College of Gastroenterology

(www.acg.gi.org)

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Goldberg, RM, Fleming, TR, Tangen, CM, et al. Surgery for recurrent colon cancer: Strategies for identifying resectable recurrence and success rates after resection. Eastern Cooperative Oncology Group, the North Central Cancer Treatment Group, and the Southwest Oncology Group. Ann Intern Med 1998; 129:27.
2. Adam, R, Delvart, V, Pascal, G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg 2004; 240:644.
3. National Comprehensive Cancer Network (NCCN) guidelines available online at http://www.nccn.org/patients/patient_gls.asp.
4. Kemeny, N, Huang, Y, Cohen, AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Engl J Med 1999; 341:2039.
5. Goldberg, RM, Sargent, DJ, Morton, RF, et al. A randomized controlled trial of Fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22:23.
6. Tournigand, C, Andre, T, Achille, E, et al. FOLFIRI Followed by FOLFOX6 or the Reverse Sequence in Advanced Colorectal Cancer: A Randomized GERCOR Study. J Clin Oncol 2004; 22:229.

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Treatment for early prostate cancer

Posted on October 13, 2007. Filed under: Unknown |

INTRODUCTION — Prostate cancer is a malignancy of the prostate gland, an organ that forms a ring around the urethra, near its connection to the bladder (show figure 1). The urethra is the tube that carries urine from the bladder to the outside of the body.

Prostate cancer is the most common cancer affecting men. Every year, more than 200,000 American men are diagnosed with prostate cancer, and nearly 30,000 die from this disease. Over the last 15 years, the increasing use of prostate cancer screening with blood levels of prostate-specific antigen (PSA) has led to more cases being diagnosed at an early stage, when the cancer is still limited to the prostate gland and is highly curable.

There are three standard approaches to treating early prostate cancer: surgical removal of the prostate gland, radiation therapy with or without hormone therapy, and “active surveillance,” a term that describes the decision to delay definitive treatment while carefully monitoring for evidence of progression or growth of the cancer. Hormone therapy has traditionally been reserved for men with advanced or metastatic prostate cancer, although new applications of hormonal therapy as a supplement to active surveillance, surgery, or radiation show promise.

The ultimate choice of treatment is dependent upon several factors. The likelihood that the prostate cancer is confined to the prostate gland and therefore, potentially curable The volume and histologic grade (ie, degree of aggressiveness) of the cancer A man’s age and overall health, including any other medical conditions The outcomes and potential side effects associated with the different forms of treatment

This topic discusses the evaluation of men with early prostate cancer, and describe the available treatment options, outcomes from therapy, and treatment-related side effects. A separate topic review is available about advanced prostate cancer. (See “Patient information: Advanced prostate cancer”).

PRETREATMENT EVALUATION — Prior to selecting the best treatment option, it is critically important that the disease extent be determined. Although this is most accurately determined by surgically removing the prostate, several pretreatment factors can be used to predict whether a prostate cancer is likely to be confined to the prostate gland itself (termed organ-confined disease) or spread beyond the prostate gland, and therefore, more advanced.

The most important pretreatment factors are the clinical stage, the level of the serum PSA, the tumor volume (as determined by the number of positive biopsy samples, and the extent of cancer involvement within each biopsy sample) and the degree of aggressiveness of the tumor, referred to as the Gleason grade.

Prostate cancer stage — Physicians use a common notation to describe the extent, or stage of a cancer. The tumor-node-metastasis (TNM) system is the most common method used to stage prostate cancer (show table 1).

In this system, T1 tumors are microscopic and cannot be felt during rectal examination (show figure 2) T2 tumors can be felt with a rectal examination, but appear to be confined to the prostate gland T3 tumors have grown beyond the prostate into the capsule of connective tissue that surrounds the gland, or into the seminal vesicles (glands near the prostate that secrete fluid into the reproductive tract) (show figure 1) T4 tumors have grown locally beyond the prostate, and involve nearby tissues

The finding of a T3 or T4 tumor suggests a more advanced tumor that is not likely to be cured, even with aggressive surgery. The stage assigned by a rectal examination is termed a clinical or “c” stage, while a man who has undergone surgical removal of the prostate with microscopic evaluation will be assigned a pathologic, or “p” stage.

Endorectal coil MRI — Endorectal coil MRI uses magnetic resonance imaging to assess the prostate and its surrounding tissues. Although this technique is not yet widely available, it has been shown to be particularly helpful in evaluating the possibility of extension outside of the prostate capsule or into the seminal vesicles in men who are considering surgery. This procedure may also help to determine if a nerve-sparing prostate operation is appropriate.

Serum PSA level — The vast majority of men with prostate cancer have elevated levels of PSA in the blood. The PSA level at the time of diagnosis provides important information about the likelihood of finding that prostate cancer has spread beyond the prostate. As PSA levels increase, the likelihood of disease spread to tissues beyond the prostate gland rises. Men with a PSA concentration less than 10 ng/mL have a 70 to 80 percent chance of having organ-confined disease, compared to 50 percent for those with PSA levels 10 to 50 ng/L, and only 25 percent with higher PSA levels [1].

The pretreatment PSA level can also predict the likelihood of a cancer recurrence after treatment. Men with a lower PSA concentration are more likely to be cancer-free five years after treatment than those with a higher pretreatment PSA level.

Biopsy grade — A prostate biopsy, in which a small amount of tissue is removed from the prostate and examined under a microscope, is performed when prostate cancer is suspected. This examination allows the physician to confirm the diagnosis, and also assess the volume and level of aggressiveness (called the Gleason grade) of the tumor.

The pathologist typically reports a primary grade (between 1 to 5) and a secondary grade, also between 1 and 5. The higher the Gleason grade, the more aggressive (fast-growing) the tumor appears. These two numbers are then combined together to form the Gleason score. If the cancerous tissue shows primarily grade 3 and secondarily grade 4 areas of tumor involvement, the combined Gleason score is “3 plus 4” or 7. Gleason score 2 to 4 tumors are typically referred to as low grade (also called well-differentiated), Gleason 8 to 10 tumors are high grade (or poorly differentiated), and the Gleason scores between 5 to 7 are referred to as intermediate grade.

Predictive models — These pretreatment factors, and combinations of these factors can be used by physicians in two ways: they are useful to predict the likelihood that a man has an organ-confined cancer that may be potentially curable, and they can also be used to predict the outcome of either surgery or radiation therapy.

Predicting organ-confined cancer — Combinations of pretreatment factors are more accurate than any one of the individual factors to predict the likelihood of a man having organ-confined disease. One such predictive model combines the clinical tumor (T) stage, the Gleason score from the tumor biopsy, and the serum PSA to construct tables that allow an estimation of the likelihood of finding organ-confined, and thus, potentially curable disease at the time of surgery (show table 2).

Another potentially useful tool to estimate outcome of therapy is a nomogram or graph, which consists of parallel scales that are calibrated for different prognostic variables. Once the numerical risk is calculated for each variable, a final single calibrated scale is then used to determine the overall risk of prostate cancer recurrence based upon all of the factors. Many of these published nomograms are designed for use after therapy such as surgery (show table 3), but some use pretreatment variables.

Predicting treatment outcome — In addition to predicting the likelihood of organ-confined disease, pretreatment models utilizing PSA, biopsy Gleason score, and clinical T stage can also be used to predict the chance of being cancer-free following either surgery or radiation. In general, these models stratify patients into one of three defined prognostic groups: Low-risk — Clinical stage T1c or T2a, serum PSA concentration 20 ng/mL, and a biopsy Gleason score of 8 or higher. Men with high-risk prostate cancer have an approximately 33 percent chance of being cancer-free five years after treatment.

TREATMENT OPTIONS — The three standard therapies for men with organ-confined prostate cancer are surgery (radical prostatectomy), RT, and active surveillance. To date, no good study has directly compared these three options. Young, healthy men are typically encouraged to undergo radical prostatectomy, while older patients tend to be steered toward RT or observation. This fact makes it difficult to compare outcomes in men treated with either surgery or radiation.

Radical prostatectomy — Radical prostatectomy (referred to as prostatectomy) is a complete removal of the prostate gland. This treatment is thought to offer the best chance for long-term survival (beyond ten years). Selected men with low-risk early stage prostate cancer who undergo prostatectomy have an 80 to 85 percent chance of remaining cancer-free up to 15 years after surgery.

During a prostatectomy, the surgeon removes the entire prostate and then reconnects the urethra and bladder. The prostate gland may be removed from two different approaches: the perineal approach (through the perineum, the tissue between the penis and anus), or the retropubic approach (through the lower abdomen). One advantage of the retropubic approach is that it allows tissue to be removed from the lymph nodes in the pelvis prior to removal of the prostate. Men with low-risk disease may not need a lymph node dissection, since there is a low likelihood that disease has spread to these nodes.

Newer prostatectomy techniques include the use of a laparoscope (an instrument in inserted through a small incision) or a robotic arm. These methods do not have a proven advantage over the open approach, except for possibly less blood loss.

Complications — The most common complications of prostatectomy are urinary incontinence (uncontrolled leakage of urine) and erectile dysfunction (ED, the inability to have an erection sufficient for sexual intercourse). Most men have some degree of urinary incontinence and ED immediately following surgery, although both usually improve over time.

Age is an important factor in the risk of urinary incontinence after prostatectomy. In a large study, severe urinary incontinence was experienced by almost 14 percent of men between 75 and 79, but in fewer than 4 percent of younger men [2]. Almost one-half of the affected men had only occasional incontinence, often related to stresses on the bladder such as sneezing, coughing, or laughing.

The likelihood of experiencing ED after prostatectomy also increases with age. In one review, the potency rate after surgery was 100 percent for men in their 40s, and 55, 43, and 0 percent for men in their 50s, 60s, and 70s, respectively [3]. Men who have nerve-sparing surgery and who had a high level of sexual functioning before surgery are less likely to have ED after surgery (see “Nerve sparing procedures” below). Medications (eg, Viagra®, sildenafil) are effective in the majority of men. Early, preventive use of these drugs may also promote the return of a man’s ability to have an erection. (See “Patient information: Sexual problems in men”).

Nerve sparing procedures — A procedure that avoids the nerves responsible for urinary and sexual function (called nerve-sparing prostatectomy) has reduced the incidence of these conditions. However, this procedure is not recommended for all men, including men with large tumors, high Gleason grade cancers, or a high PSA before treatment. With these exceptions, there is no evidence that a nerve-sparing operation compromises control of the cancer.

Radiation therapy (RT) — Two forms of RT are used to treat prostate cancer: external beam RT and interstitial implantation, also called brachytherapy.

External beam radiation — External beam RT (EBRT) uses a machine called a linear accelerator that moves around the patient, directing x-rays (also called gamma rays) at the pelvis. EBRT is typically administered daily, five days per week. Treatment lasts five to eight weeks, depending upon whether it is used alone or in combination with other treatments. EBRT can be done on an outpatient basis, and men can usually continue their normal activities during treatment. The dose of radiation delivered to the prostate tumor is important, and is determined in part by the pretreatment factors discussed above.

Whether results with EBRT are comparable to those obtained with surgery is controversial. It is difficult to compare outcomes among similar groups of men who have received these two different treatments for the following reasons: As noted above, young, healthy men are typically encouraged to undergo surgery, while older men often receive RT. During prostatectomy, the pelvic lymph nodes and the tissues around the prostate gland can be directly evaluated for evidence of cancer spread, but this is not possible in men undergoing RT. As a result, men receiving RT may actually have more extensive disease than expected from the pretreatment evaluation, compared to those undergoing surgery.

Nevertheless, some generalizations can be made. For men with low-risk, organ-confined prostate cancer, surgery and EBRT result in approximately equivalent rates of cancer control at five years, approximately 80 percent [4]. Men with high-risk organ-confined tumors (eg, high pretreatment serum PSA and high Gleason score) may do better with surgery. In the same report, 62 percent of surgically treated men with high-risk tumors were cancer-free at five years, compared to only 26 percent after EBRT[4]. However, these men were treated with relatively low doses of EBRT, and at least one study suggests that higher doses of RT preferentially benefit men with high-risk disease [5]. Furthermore, other reports show that long-term treatment results from surgery and RT are similar in men with either low-risk or high-risk disease when higher doses of EBRT are used (72 Gray or higher) (show table 4) [6]. Complications — Clinicians are careful to limit the amount of radiation that is directed at healthy tissue around the prostate tumor, although some surrounding normal tissues can be damaged. The risk of damage may be lower when newer treatment planning techniques such as conformal RT are utilized (see “Conformal radiation” below).

Possible side effects of EBRT include urinary urgency and/or frequency, bladder pain, sexual impotence (erectile dysfunction, ED), and bowel problems such as proctitis (inflammation of the rectum). Compared to prostatectomy, urinary problems and ED are less common following RT, but bowel problems such as diarrhea, bowel urgency, and painful hemorrhoids are more common. In contrast to surgically treated men, ED rates increase over time after RT.

These differences in treatment-related complications continue to be evident up to five year following treatment [7,8]. As an example, in one study, men undergoing prostatectomy had a more than twofold higher risk of urinary incontinence compared to those treated with EBRT (9.6 versus 3.5 percent) and were more likely to have ED (80 versus 62 percent) [7]. On the other hand, men receiving EBRT reported more difficulties with bowel function (diarrhea, bowel urgency, and painful hemorrhoids).

Viagra and other related drugs may be beneficial for men with radiation-related ED.

Conformal radiation — Three-dimensional conformal radiation therapy, or 3D-CRT, uses sophisticated computer modeling to precisely outline the tumor and deliver larger doses of RT while minimizing damage to surrounding normal tissues. This technique is more expensive than EBRT, and has not been proven more effective than conventional RT. However, it may allow a higher dose to be given to the prostate, which produces fewer side effects, particularly bowel problems.

Intensity modulated radiation therapy — Intensity modulated radiation therapy (IMRT) is an advanced form of 3D-CRT in which the radiation dose to the prostate gland, a complex and irregular target, is varied by changing the intensity of the beam during therapy. The major advantage of IMRT over 3D-CRT is a reduction in the dose received by nearby organs, particularly the bowel, resulting in fewer side effects. The advantage may be greatest in men who require RT of the pelvic lymph nodes in addition to the prostate gland. IMRT requires special expertise and equipment, and is becoming more available in treatment centers within the United States.

Brachytherapy — Brachytherapy involves placing a radioactive source directly into the prostate gland under ultrasound guidance. The procedure is done with general anesthesia (the patient is given medicine to induce sleep) or regional anesthesia (epidural or spinal medications block pain below the waist). There are two types of brachytherapy. Low-dose-rate (LDR) brachytherapy implants rice-sized radioactive seeds or pellets into the prostate, which emit radiation from within the gland for a specified period of time. The radioactivity of the seeds diminishes over time, and the dose of radiation to surrounding tissues is limited.

Some men have questions or fears about the possibility of exposing family members to unsafe levels of radiation. The risk of radiation exposure to people around the patient after the seeds are placed is not clearly understood. However, radiation exposure to family members is thought to be low. One study examined radiation levels in the home of a man who had undergone seed placement [9]. Radiation levels were measured in four rooms of the man’s home for three weeks. The study revealed that, even for spouses living in the same home, the level of radiation exposure was low, and similar to that of a transcontinental airplane flight.

Nevertheless, as an added margin of safety, most men are advised to avoid prolonged, direct contact with children and pregnant women (eg, by sitting on the patient’s lap) for three months after seed placement. High-dose rate (HDR) brachytherapy uses a catheter or needle inserted into the prostate to temporarily implant a radioactive source into the prostate gland over a period of several hours. The catheter or needle is placed while a patient is under general anesthesia, but anesthesia not necessary to load the radioactive source or while the source is in place. There is no risk of radiation exposure to family or friends after the catheter/needle is removed.

When it is used, HDR brachytherapy is usually combined with EBRT. At least one study suggests that there are fewer side effects with HDR as compared to LDR brachytherapy [10]. However, HDR brachytherapy is not as widely available as LDR brachytherapy.

Brachytherapy versus EBRT — The major advantage of brachytherapy over EBRT is convenience; brachytherapy (at least the more common LDR procedure) is a one-time procedure while EBRT requires five to eight weeks of treatment. Brachytherapy is often used alone in men with low-risk disease, and has effectiveness similar to other treatments for this group of men. Up to 86 percent of men with a Gleason score less than 7 and serum PSA less than 10 ng/mL remain free of progression for up to 15 years [11]. Brachytherapy is usually combined with EBRT for men with higher risk disease.

Complications — Men who undergo brachytherapy usually experience inflammation and swelling of the prostate gland, which can lead to urinary urgency (needing to void urgently), frequency (needing to void frequently), and burning, and occasionally retention of urine (being unable to empty the bladder completely, which requires temporary use of a catheter). In addition, damage to nearby tissue can cause bowel urgency and frequency, rectal bleeding, and the development of rectal ulcers; these symptoms are rare when brachytherapy is used alone.

The risk of short-term urinary incontinence may be less with brachytherapy than with EBRT as long as pati are selected carefully. Selection criteria have been developed by the American Brachytherapy Society on the basis of pretreatment clinical features [12]. The guidelines suggest that the combination of clinical stage T2a or better, biopsy Gleason score of 6 or less, and serum PSA less than 10 ng/mL identifies a group of low-risk patients who are most likely to have excellent long-term oncologic outcomes. Most men who have brachytherapy-related urinary and bowel symptoms improve significantly over time, whereas symptoms may become more severe in men who have EBRT. The risk of ED is similar to other treatments.

Active surveillance — Some men elect to delay treatment in favor of a program of observation, also called active surveillance (previously called watchful waiting). Active surveillance may be preferred over treatment to avoid treatment-related side effects. However, prostate cancer itself can cause urinary incontinence, sexual impotence, and obstruction of the flow of urine as the tumor grows and the cancer progresses. In the United States, less than 10 percent of men with early stage prostate cancer choose active surveillance.

A large study from Sweden directly compared surgery to active surveillance, and showed that men who chose active surveillance were significantly more likely to die within 10 years [13]. The risk of dying was highest among men 65 years of age and younger who chose active surveillance. In addition, many fewer surgically treated men developed metastatic prostate cancer at 10 years (15 versus 25 percent). Despite the fact that many men who delay treatment do not die of prostate cancer, even those with low-grade cancers are at risk of developing incurable bone metastases.

When is active surveillance appropriate? — Active surveillance is most appropriate for men with a limited life expectancy (less than 10 years, based upon their age) who have small tumors, low Gleason scores (less than 7), and a slowly rising PSA level, particularly if they have another medical condition that might limit their life expectancy to less than 15 years. Younger men and men over the age of 70 who are otherwise healthy and who have aggressive (eg, Gleason score 7) or large tumors should be encouraged to receive immediate treatment. These men have more rapid tumor growth, and are more likely to die of prostate cancer if their disease is left untreated.

Monitoring during active surveillance — Men who choose active surveillance should have monitoring every three to six months, including a rectal examination and blood test to determine PSA level. A repeat prostate biopsy should be done within the first year after the initial diagnosis to make certain that a more aggressive tumor (ie, with a higher Gleason grade) was not missed.

There are no guidelines in place that define what, if any, criteria should be used to decide when to intervene with treatment. Definitive therapy (ie, radiation or surgery) may be recommended if there is a significant change in the PSA level, rectal examination, or Gleason grade on follow-up biopsy. Some clinicians use a PSA doubling time of less than three years as a trigger to prompt therapy. However, none of these criteria are firm recommendations based upon scientific studies.

In reality, many men will go on to receive treatment because of anxiety about the continually rising PSA level. Approximately 50 percent of men who choose active surveillance will proceed to treatment within three years, either because of disease progression or anxiety.

Androgen deprivation therapy — Male hormones (androgens, the most common of which is testosterone) fuel the growth of prostate cancer. Treatments that decrease the body’s levels of androgens (androgen deprivation therapy, ADT) decrease the size of a normal prostate and prostate cancer. ADT can be accomplished either by removing the testicles, where many of the body’s androgens are produced (called an orchiectomy), or by using medicines that interfere with androgen production or its action in the body.

The available data suggest that ADT is useful for men who are undergoing RT. The addition of ADT to EBRT improves outcomes for men with intermediate-risk and high-risk localized prostate cancer, but not those with low-risk disease. The optimal duration of therapy is controversial, but men with intermediate-risk disease (see “Biopsy grade” above) appear to benefit from four to six months of ADT, given for two months before and during EBRT, while those with higher-risk disease benefit from an additional two years of ADT after completing EBRT.

ADT alone versus active surveillance — The use of ADT alone (rather than active surveillance) in men with early stage disease has risks and benefits that are not completely understood. ADT alone is increasingly recommended to men who prefer to avoid surgery and radiation therapy, and some studies suggest that this offers modest cancer control.

However, these studies do not consider treatment-related side effects and long-term follow up data are not yet available. Potential side effects of long-term ADT are sexual dysfunction, breast tenderness and enlargement, hot flashes, muscle loss, osteoporotic bone fractures, and accelerated coronary artery disease.

Side effects of ADT — Side effects of ADT are related to the decreased levels of male hormones, and include decreased libido (sex drive), impotence (erectile dysfunction), and symptoms similar to those of menopause (eg, hot flashes, temporary enlargement of the breast tissue). ADT can also lead to loss of muscle and bone, the latter resulting in osteoporosis (thinning of the bones) and an increased risk of bone fractures. Treatments are available to reduce the risk of osteoporosis. (See “Patient information: Osteoporosis prevention and treatment”).

Cryotherapy — Cryotherapy is a local treatment for prostate cancer in which tumor cell destruction is accomplished by freezing. Although early trials showed unacceptably high complication rates, there has been a resurgence of interest in cryotherapy because of improvements in technique that have reduced treatment-related side effects, and possibly improved outcomes [14].

Cryotherapy is performed in the operating room under anesthesia. Using ultrasound guidance, multiple cryoprobes (thin needles) are placed within the prostate gland. Liquid nitrogen or argon gas is then infused into the gland, freezing the tissues. After the gland has been frozen and allowed to thaw, the tumor is refrozen and again allowed to thaw (the “double freeze-thaw” technique). Following therapy, men are discharged home with a urinary catheter in place for at least three weeks.

The available data suggest that with newer techniques, the same men who benefit from radical prostatectomy or RT (ie, those with low-risk disease) are likely to have favorable outcomes from cryotherapy. However, cryotherapy cannot be recommended with the same sense of confidence as radical prostatectomy or RT because long-term data on outcomes are not available.

CLINICAL TRIALS — Progress in treating prostate cancer requires that better treatments be identified through clinical trials, which are conducted all over the world. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies. Ask for more information about clinical trials, or read about clinical trials at:

http://www.cancer.gov/clinical_trials/learning/
http://www.cancer.gov/clinical_trials/
http://clinicaltrials.gov/

SUMMARY Surgery and RT offer fairly equivalent survival outcomes in well selected patients for the first ten years or so after therapy; beyond that time, there may be a higher risk of recurrence with RT. However, radiation techniques continue to improve, and it is likely that results using higher doses, more precise delivery techniques, and combined use with androgen deprivation therapy (for men with higher risk disease) will improve outcomes (see “Intensity modulated radiation therapy” above). Often, the decision between radiation and surgery is a matter of patient preference. The pattern of treatment-related toxicity is different. Surgery is associated with more early urinary and sexual side effects, which tend to improve over time, while RT causes more bowel problems, and worse urinary and sexual dysfunction over time. Although brachytherapy alone offers some advantages over external beam radiotherapy, it is best reserved for men with low-risk disease and those with small prostate glands. Men with higher-risk disease who choose brachytherapy are usually treated with a combination of brachytherapy and external beam RT (see “Brachytherapy” above).. Watchful waiting (active surveillance) is appropriate only for older men (over the age of 70 or 75) with a small tumor, a low Gleason score, and a life expectancy of 15 years or less. Monitoring with PSA blood tests, a rectal examination, and follow up biopsies are recommended at regular intervals during active surveillance. Treatment with surgery or radiation may be recommended if the tumor is thought to be rapidly growing (see “Active surveillance” above). Clinical trials (particularly those that compare surgery to different forms of radiation therapy) are needed to improve outcomes among men with clinically localized prostate cancer (see “Clinical trials” above).

1-800-4-CANCER
(www.cancer.gov)
People Living With Cancer: The official patient information

website of the American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
American Cancer Society

1-800-ACS-2345
(www.cancer.org)
National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
US TOO! International, Inc

(www.ustoo.org)

[1-8,10,11,13-18]

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Partin, AW, Yoo, J, Carter, HB, et al. The use of prostate specific antigen: Clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993; 150:110.
2. Stanford, JL, Feng, Z, Hamilton, AS, et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA 2000; 283:354.
3. Naitoh, J, Zeiner, RL, Dekernion, JB. Diagnosis and treatment of prostate cancer [see comments]. Am Fam Physician 1998; 57:1531.
4. Kupelian, P, Katcher, J, Levin, H, et al. External beam radiotherapy versus radical prostatectomy for clinical stage T1-2 prostate cancer: Therapeutic implications of stratification by pretreatment PSA levels and biopsy Gleason scores. Cancer J Sci Am 1997; 3:78.
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