Zanmbeel

Saturday, October 13, 2007

Advanced prostate cancer

INTRODUCTION — Over the last 20 years, more cases of prostate cancer have been detected in the early stages, when it is confined to the prostate gland. Prostate cancer that is confined within the prostate gland can be effectively treated and is often cured (show figure 1).

However, approximately 15 to 20 percent of newly diagnosed prostate cancers are advanced by the time they are detected, meaning that the cancer has spread outside the prostate gland (called locally advanced prostate cancer) and/or involved the lymph nodes or other organs (called metastatic prostate cancer).

Cases of advanced prostate cancer can also occur in men who are initially treated for localized disease and whose prostate cancer then recurs (commonly referred to as a relapse). Following treatment of early stage prostate cancer, men are routinely monitored with serum PSA levels. A rising PSA level suggests that prostate cancer has returned (termed a recurrence). Often, there is no evidence of metastatic cancer in the bones or other tissues at the time the PSA is rising, and the rising PSA is the only sign that the prostate cancer has recurred.

These men represent a unique category of advanced prostate cancer for two reasons: The average time it takes for signs of more advanced disease to appear (eg, bone metastases) may be as long as eight years, and in some men, symptomatic progression of prostate cancer will never occur. Despite this fact, many men are uncomfortable with an untreated rising serum PSA, and treatment is often considered, even if symptoms or signs of advanced disease are absent. Some men with a rising PSA as the only sign of disease recurrence may be curable with further local therapy (ie, radiation, surgery, or cryotherapy [freezing of the prostate gland]). Men who have the best chance of long-term control of the prostate cancer with local-only therapy are those who have less aggresive cancers (ie, lower Gleason grade and lower serum PSA level), and a slowly rising PSA level. (See "Salvage local therapy for a rising serum PSA after surgery or radiation" below).

This topic review will discuss the treatment of men with advanced prostate cancer. A separate topic review is available about the treatment of early stage prostate cancer. (See "Patient information: Treatment for early prostate cancer").

STAGING OF PROSTATE CANCER — Treatment for prostate cancer depends upon its "stage", which indicates how far the cancer has spread within the body. Prostate cancer is usually staged according to the system known as TNM (tumor, node, metastasis), in which the cancer is characterized by its extent within the prostate gland itself (tumor or T stage), whether the lymph nodes in the region are involved with cancer (node or N stage), and whether the cancer has metastasized to other parts of the body (metastasis or M stage, show table 1). Various combinations of T, N, and M stage are then grouped together to form stage groupings, from I to IV, which designate whether the cancer is considered localized (stage I and II), locally advanced (stage III), or metastatic (stage IV) (show table 2).

According to this system, T3 and T4 tumors that lack involvement of lymph nodes or distant organs are considered locally advanced, meaning that although the cancer is outside of the prostate gland, it has not extended beyond the tissues adjacent to the original tumor. On the other hand, metastatic (stage IV) prostate cancer has spread beyond the prostate to either the lymph nodes or to other organs or the bones.

TREATMENT OF METASTATIC (STAGE IV) PROSTATE CANCER — When cancer has spread beyond the prostate gland, androgen deprivation therapy (ADT) is usually recommended as the initial treatment. Metastatic prostate cancer is not considered a curable condition. However, treatment can prolong life, delay the progression of the cancer, relieve cancer-related symptoms, and improve quality of life.

Initial androgen deprivation therapy — The rationale for using ADT for advanced prostate cancer is that male hormones (androgens such as testosterone) promote or stimulate tumor growth. When deprived of male hormones, the cancerous cells of the prostate gland (as well as normal cells) die and the prostate gland shrinks in size. ADT is effective against cancer cells within the prostate gland and for any cancer cells that may have spread outside of the prostate.

There are several ways in which ADT can be accomplished:

Orchiectomy — ADT can be accomplished by removing the testicles, where most of the body's androgens are produced (this operation is called an orchiectomy). The penis and scrotum (skin pouch in which the testicles are located) remain intact.

GnRH agonists — An alternate way to accomplish ADT is to take a medication that disrupts androgen production in the body. These drugs work by interfering with gonadotropin releasing hormone (GnRH), which is the molecule that regulates the amount of androgen that a man's testicles make under normal conditions. Drugs in this class include leuprolide (Lupron®) and goserelin (Zoladex®). They are all administered by injection.

Guidelines for treatment of men with advanced prostate cancer from the American Society of Clinical Oncology (ASCO) recommend either orchiectomy or a GnRH agonist as the initial form of hormone therapy [11]. GnRH agonists and orchiectomy are similarly effective in men with advanced prostate cancer, and they share a similar side effect profile (see "Side effects of ADT" below). However, there are some differences which may influence an individual man's choice of one or the other. GnRH agonist therapy requires repeated physician visits for an injection every 3 to 6 months while orchiectomy is a one-time surgical procedure. For men without health insurance prescription drug coverage, GnRH agonist therapy can be expensive.

Combined androgen blockade (CAB) — Sometimes, a GnRH agonist or orchiectomy may be combined with drug of a different class called an antiandrogen. Examples include flutamide (Eulexin®) and bicalutamide (Casodex®). Antiandrogens take over the cell receptors that usually respond to androgens and prevent the body from using its own androgens. Antiandrgens alone are not considered a form of ADT because they do not lower the body's production of androgens.

While they are rarely used alone (see "Antiandrogen monotherapy" below), antiandrogens are often combined with a GnRH agonist or orchiectomy. Combined therapy is referred to as "combined androgen blockade", or CAB. Whether CAB provides better control of prostate cancer growth than either a GnRH alone or orchiectomy is controversial. Although CAB may slightly increase the likelihood that man with metastatic prostate cancer will still be alive in five years (by approximately 1 to 5 percent), there are also more treatment-related side effects, and the cost is much higher compared to single agent therapy. ASCO guidelines do not specifically recommend CAB over orchiectomy or a GnRH analog, but they suggest that this approach be considered [11].. (See side effects of ADT" below).

Timing of ADT — A major controversy for men with metastatic prostate cancer (particularly those with only a rising PSA and no other evidence of advanced disease) is the optimal timing of ADT. ADT can be started immediately (early ADT) or delayed until symptoms develop or there are obvious signs of tumor involvement in distant organs (metastases, most commonly involving the bones). Many doctors recommend initiating treatment at the time of diagnosis in the hope of delaying disease progression and possibly prolonging survival. Others have argued that early ADT is not curative and is associated with bothersome side effects, and that treatment is best deferred until symptoms develop.

Some research results suggest that earlier ADT decreases the likelihood of dying from prostate cancer and delays the onset of symptoms [7,8]. Neither of these studies was performed in men with a rising serum PSA as the only evidence of disease recurrence: In one trial, a higher proportion of men found to have lymph node involvement at the time of prostatectomy who received early ADT remained progression-free (77 versus 18 percent) and fewer died of prostate cancer (4 versus 31 percent) compared to those who were treated at a later time [7]. In the second study, which included men with locally advanced prostate cancer and those with metastatic disease (although without any symptoms from tumor involvement at any site), those undergoing early ADT had fewer complications related to prostate cancer (eg, painful bone metastases) [8]. However, the likelihood of surviving the prostate cancer was significantly better only for the group of men with nonmetastatic (ie, locally advanced) disease, and not for those with metastatic disease.

The only available data in men with a rising PSA as the only sign of advanced disease come from a review of 804 men with a rising PSA after radical prostatectomy [9]. Men who received early ADT survived just as long as those treated at the time when metastases became evident, although the time to develop metastases was longer for the men who received early ADT

Although controversial, many doctors suggest early treatment for the following reasons: It is associated with less disease progression and fewer complications of untreated disease (eg, urinary obstruction, painful bone metastases) There is a possible survival benefit, particularly in men with minimal disease. Many men are uncomfortable with delaying treatment, particularly if the PSA continues to rise.

Men should discuss the relative benefits and risks of early versus delayed ADT with their physician.

Duration of benefit of ADT — Most men with advanced prostate cancer initially respond well to ADT, but most have prostate cancer recurrence within two years. At this point, the cancer is termed androgen-resistant, meaning that ADT alone is no longer effective. Once this occurs, secondary hormone therapy is usually considered. Even when prostate cancer becomes resistant, some form of ADT is usually continued because at least a portion of the cancer cells may still be responsive to removing the influence of androgens (see "Secondary hormone therapy" below).

Side effects of ADT — Side effects from ADT are related to the lower levels of androgens in a man's body, and include decreased libido (interest in sex), impotence (ability to have an erection sufficient for sexual intercourse), hot flashes, and temporary enlargement of the breast tissue. (See "Patient information: Sexual problems in men").

ADT can also lead to a reduction in muscle and bone strength; loss of bone can lead to osteoporosis (thinning of the bones), and bone fractures. Studies show that regular injections of a bisphosphonate medication (eg, zoledronic acid, Zometa®) can prevent bone loss during long-term ADT [1], and regular exercise may also delay the loss of lean muscle. Most experts recommend that all men beginning ADT increase their calcium intake to 1200 to 1500 mg daily and take vitamin D supplements. (See "Patient information: Calcium for bone health" and see "Patient information: Osteoporosis causes, diagnosis, and screening").

Alternatives to conventional ADT — Some men find that the side effects of ADT (particularly impotence, hot flashes and fatigue) significantly affect their quality of life. As a result, attempts have been made to find alternative hormone therapies that have fewer side effects. Many of these have been studied in men whose only evidence of advanced disease is a rising PSA.

Intermittent ADT — Intermittent ADT (called IAD) is given over a period of time and then stopped temporarily. It is a controversial alternative to continuous ADT. The main benefit is that some men have an improved sense of well-being and a return of libido and sexual ability (if these were present prior to treatment) while ADT is stopped.

Typically, IAD (with or without an antiandrogen) is continued until a maximal response is achieved (usually a predetermined, low value of serum PSA), stopped, then restarted when the serum PSA rises to a predetermined threshold (eg, 10 to 20 ng/mL).

Men receiving IAD can expect to spend approximately 35 to 50 percent of their time off-therapy. Time off treatment in the first cycle ranges from 6 to 15 months, and may be longer for men with less advanced disease compared to those with metastatic disease. Time off therapy decreases with each consecutive cycle [10].

The impact of this approach on long-term outcomes, particularly survival, is not yet known. The ASCO expert panel concluded that there was insufficient evidence to support the use of intermittent as compared to continuous ADT [11]. Some experts consider a temporary discontinuation of treatment if the serum PSA level becomes undetectable during initial ADT, and if side effects (usually hot flashes) are significant. However, a man who chooses IAD must understand that his survival may be reduced; further study is needed. Men who are interested in IAD are encouraged to enroll in a clinical trial testing the benefit of IAD versus conventional ADT. (See "Clinical trials" below).

Antiandrogen monotherapy — As noted above, antiandrogens alone are not considered a form of ADT because they do not lower the body's production of androgens and their effectiveness as sole therapy for advanced prostate cancer is controversial. However, antiandrogens alone are attractive as a treatment option for men with minimal advanced disease (eg, only a rising PSA after local therapy) because they can be given orally, and they are associated with a better quality of life during therapy than other forms of hormone therapy because they cause fewer problems with sexual dysfunction and loss of bone mass. ASCO guidelines suggest that monotherapy with an antiandrogen be discussed, but the guidelines do not specifically recommend this strategy over conventional methods of ADT (such as orchiectomy or a GnRH agonist) [11].

Oral sequential hormone therapy — Peripheral or sequential androgen blockade involves the use of an oral anti-androgen (usually flutamide or bicalutamide) combined with another oral drug that blocks the conversion of testosterone to dihydrotestosterone. Such drugs are called 5-alpha reductase inhibitors. Most studies have used finasteride (Proscar@), although dutasteride (Avodart@) is also available.

Although early studies of this regimen show promising results, long-term follow-up is lacking and the impact on survival is unknown. Furthermore, oral hormone therapy is associated with a high frequency of painful and progressive enlargement of breast tissue. This problem can be prevented with radiation therapy to the breasts prior to starting treatment. However, if breast enlargement develops, surgery may be required to remove excessive tissue. (See "Managing the side effects of androgen deprivation therapy").

Secondary hormone therapy — When advanced prostate cancer becomes androgen-resistant, other hormone treatments may be tried. Current guidelines recommend that the first approach should be to discontinue ADT, particularly antiandrogens. Research shows that withdrawal of antiandrogen therapy often results in improvements in the symptoms and signs of the disease. The time it takes for improvements to be noticed depends upon the drugs being used. When antiandrogens are withdrawn, a man must wait several weeks or months before knowing if this approach has been effective.

Another approach for androgen-resistant prostate cancer is to use a different type of antiandrogen. Cancer that is resistant to one antiandrogen treatment may not be resistant to another. There are two groups of antiandrogens, the steroidal antiandrogens and the nonsteroidal or "pure" antiandrogens. Steroidal antiandrogens include cyproterone acetate and megestrol acetate. Nonsteroidal antiandrogens include flutamide (Eulexin®), bicalutamide (Casodex®), and nilutamide (Nilandron®). All of these drugs block androgen receptors and alter the levels of other hormones in the body, eventually lowering the high testosterone levels that contribute to the growth of prostate cancer.

Other drugs that function to block the activity of androgen in the body can also be used to treat androgen-resistant prostate cancer, including estrogens, the antifungal medication ketoconazole, and corticosteroids (eg, dexamethasone [Decadron®] or prednisone).

Chemotherapy — Eventually, even with secondary hormone treatment, nearly all men with advanced prostate cancer stop responding to all forms of hormone treatment. This situation is referred to as hormone-refractory prostate cancer (HRPC). The next step in treatment is determined by an individual's characteristics and preferences, and often includes chemotherapy.

In the past, chemotherapy was considered ineffective in treating prostate cancer, but newer research suggests that this is not necessarily true. Newer chemotherapy regimens include active drugs such as docetaxel. In 2004, two landmark trials were published that showed that docetaxel-containing regimens were associated with significantly longer survival compared to other regimens [1,2].

Because of these data, most physicians consider docetaxel plus prednisone the standard chemotherapy regimen for men with HRPC.

SALVAGE LOCAL THERAPY FOR A RISING SERUM PSA AFTER SURGERY OR RADIATION — As noted above, some men with a rising PSA as the only sign of disease recurrence may be curable with further local therapy. Men who have the best chance of long-term control of the prostate cancer with local-only therapy are those who have less aggresive cancers (ie, lower Gleason grade and lower serum PSA level), and a slowly rising PSA level.

The best treatment for this situation depends upon a number of factors.

Salvage radiation — Some men who initially had prostate surgery may be successfully treated with radiation therapy, as long as immediate postoperative EBRT was not administered. The best candidates for this approach are men who meet all of the following criteria: A positive surgical margin, and/or Gleason score <8, and no evidence of lymph node involvement at the time of initial prostatectomy A low serum PSA (optimally 1.5 ng/mL) at the time of recurrence At least one year elapsed between the surgery and the rise in PSA

For men who had unfavorable risk factors at the time of radical prostatectomy (eg, PSA >10 ng/mL, Gleason score 8, T2b disease, show table 1), or if the post-prostatectomy PSA doubling time is 10 months, the addition of short-term androgen deprivation therapy (two months before and during salvage EBRT) may be recommended.

Men who do not meet these criteria are usually offered hormone therapy alone without radiation therapy (see "Androgen deprivation therapy" below).

Salvage prostatectomy — Selected men with a rising serum PSA following radiation therapy for a localized prostate cancer may be able to undergo prostatectomy (termed "salvage" prostatectomy). However, salvage prostatectomy can be associated with serious side effects, and all men are not good candidates.

Optimal candidates are men who are unlikely to have tumor spread outside the prostate, have a life expectancy of at least 10 years, and who had a Gleason score 6, a pretreatment serum PSA <10 ng/mL, and T1c or T2a tumor stage at initial diagnosis. At the time when the recurrence is found, similar conditions should also be met (ideally, with a serum PSA <4.0 ng/mL).

Men at the highest risk for having disease outside of the prostate include those with a rapid PSA doubling time (particularly less than three to six months), high Gleason score tumors, and a short interval between the original treatment and the time when the PSA begins to rise again; these men are not good candidates for salvage prostatectomy. These men may be offered cryotherapy or androgen deprivation therapy.

Cryotherapy — Cryotherapy is sometimes recommended for men who have a rising PSA after EBRT, and who meet the criteria for salvage prostatectomy, but have more advanced tumor in the region of the prostate (ie, T3 disease, show table 1) at the time of initial diagnosis or recurrence.

Androgen deprivation therapy — For men who are not suitable candidates for local therapy because they have metastases, a short PSA doubling time (3 months), significant underlying medical illness, or an unfavorable balance of risks and benefits for definitive salvage therapy, traditional androgen deprivation therapy (ADT) is usually the treatment of choice. The general aspects of ADT are discussed in detail above (see "Androgen deprivation therapy" above).

TREATMENT FOR LOCALLY ADVANCED CANCERS — Experts are not in complete agreement about the best way to manage locally advanced prostate cancer (most often T3 tumors; T4 disease is rare); treatment options include: External beam radiation treatment (EBRT) with or without brachytherapy (see "Radiation therapy" below). Transurethral resection of the prostate (TURP), a conservative type of surgery that aims only to relieve obstruction to the urine flow that is caused by the tumor Radical prostatectomy, in which the entire prostate gland is removed surgically in an attempt to provide a cure Hormone therapy that eliminates the effect of male hormones (androgens such as testosterone) on the growth of the prostate cancer cells. The term "hormone therapy" refers to any treatment that decreases the amount of androgens in a man's body or prevents the body (particularly the prostate cells) from responding to them. More commonly used terms for this type of therapy are androgen ablation or androgen deprivation therapy (ADT).

ADT alone is not a common form of therapy for men with locally advanced prostate cancer. However, it is often used in combination with radiation therapy, which is the most commonly recommended approach for men with locally advanced prostate cancer. Prostatectomy may be a reasonable option for young, otherwise healthy men. Your doctor will take into account your age, general health, and the particular characteristics of your cancer when making a treatment recommendation.

As noted above, antiandrogen therapy is rarely used alone (ie, without a GnRH antagonist) in men with locally advanced prostate cancer. ADT is not as effective as radiation or surgery for local tumor control, and there is a high risk of developing urinary obstruction from an enlarging prostatic tumor if ADT is used alone.

Radiation therapy — There are two forms of radiation therapy used to treat prostate cancer: external beam radiation therapy (EBRT) and brachytherapy (also called interstitial implantation).

External beam radiation therapy — The majority of men with locally advanced prostate cancer are treated with EBRT, usually in conjunction with ADT (see "ADT plus EBRT" below). EBRT uses an accelerator, which makes x-rays and then delivers radiation to the area of the prostate and pelvis (where the regional lymph nodes are located) from outside of the patient. The level or dose of EBRT that is directed to the prostate is important; higher doses may give better results.

EBRT does not require hospitalization and men can usually continue with normal activities during the course of treatment, typically administered once daily for approximately eight weeks. Although the radiation therapist attempts to limit the amount of radiation that hits healthy tissue, this is difficult; noncancerous tissue around the prostate (such as the rectum or bladder) may be damaged during treatment.

The most precise way to give higher doses of EBRT to the prostate uses a method called intensity modulated radiation therapy or IMRT. This technique uses sophisticated computer modeling to precisely outline the tumor, allowing larger doses of radiation to be delivered precisely to the tumor while minimizing damage to surrounding normal tissues. This technique is more expensive than conventional EBRT, and is not available in all radiation treatment facilities. Although it has not yet been proven to be more effective at controlling prostate cancer, IMRT is associated with fewer side effects, particularly bowel problems.

Side effects of EBRT — Side effects of EBRT can include urinary urgency, frequency, bladder pain, bowel problems, sexual impotence (inability to have an erection sufficient for intercourse), and proctitis (inflammation of the rectum, resulting in rectal pain or bleeding). Compared to men undergoing radical prostatectomy for prostate cancer, urinary problems tend to be less common after EBRT, but bowel problems such as diarrhea, bowel urgency, and painful hemorrhoids may be more common.

ADT plus EBRT — Most men who have EBRT for locally advanced prostate cancer also receive androgen deprivation therapy (ADT). The benefits of combined therapy include better control of disease within the prostate, better control throughout the rest of the body, and improved survival [14].

The optimal duration of ADT in this setting is controversial; some studies suggest that four months is sufficient (two months before and during EBRT) while others show benefit from an additional two or three years of ADT following EBRT. Some research findings suggest that men with more aggressive prostate cancers (those men with a higher Gleason grade and higher pretreatment serum PSA level) may benefit from a longer duration of ADT [].

EBRT plus brachytherapy — Brachytherapy is a several hour-long procedure done in the hospital. Brachytherapy is given after the man receives anesthesia, and involves placement of a radioactive source directly into the prostate gland with ultrasound guidance. There are two types: low-dose-rate (LDR) brachytherapy implants many radioactive seeds or pellets (each about the size of a grain of rice) into the prostate. These emit radiation within the gland for a specified period of time and then become inactive. This type of brachytherapy is most commonly used for men with earlier stage disease. This procedure rarely requires an overnight stay in the hospital.

In contrast, men with locally advanced prostate cancer are more likely to be offered high-dose rate (HDR) brachytherapy. This typically requires general anesthesia and an overnight hospital stay. With HDR brachytherapy, a catheter or needle is inserted into the prostate temporarily to deliver radiation to the prostate gland for a period of several hours. HDR brachytherapy is not considered effective in treating locally advanced prostate cancer when used alone; it must be combined with EBRT.

Whether combining HDR brachytherapy with EBRT (with or without ADT) is better than treating a man with optimal doses of EBRT plus ADT is controversial. Although combined brachytherapy plus EBRT has the advantage of a shorter course of EBRT (4 to 5 weeks versus 8.5 weeks if EBRT is given without brachytherapy), it is also more likely to cause urinary side effects.

Side effects of brachytherapy — Complications of brachytherapy are predominantly urinary. Men who undergo this treatment may experience inflammation and swelling of the prostate gland, which can cause an inability to pass urine (urinary retention). Thus, men with a very large prostate gland (particularly those with significant urinary symptoms or a high "urinary symptom score", show table 2) are not good candidates for brachytherapy.

Surgery

Transurethral resection of the prostate — Commonly referred to as a TURP, this form of surgery involves removal of a part of the prostate gland by inserting thin instruments into the urethral canal of the penis. This procedure can prevent the prostate tumor from growing for a time, and helps relieve the blockage of urine flow caused by the tumor. However, this provides only a temporary fix, and studies show that TURP is not as effective over the long-term compared to radical prostatectomy.

Radical prostatectomy — Radical prostatectomy refers to complete surgical removal of the prostate gland. Although this treatment option is widely used in cases of early prostate cancer, it is not used as often for men with locally advanced prostate cancer for two reasons: it is more difficult to remove all the cancer, and it is more likely that the cancer has already spread to the lymph nodes or other tissues. If this happens, the chance of radical surgery curing the cancer is extremely low.

Nonetheless, in selected healthy men with locally advanced prostate cancer, radical prostatectomy may be an appropriate option. In one of the largest studies to date, 842 men with locally advanced prostate cancer underwent prostatectomy; two thirds were still alive without evidence of spread of their prostate cancer at 15 years, although more than one-half had a rising PSA []. This is an early indicator of cancer recurrence.

It is possible to select those men who have the greatest chance of benefiting from radical surgery. Men who have a pretreatment serum PSA below 10 ng/mL, a low to moderate Gleason score (a measure of the microscopic degree of tumor aggressiveness), and no evidence of tumor spread to the seminal vesicles (an area that lies above the prostate gland) have the best long-term outcomes with radical prostatectomy. The likelihood of a successful outcome with radical prostatectomy is twice as high for men with these characteristics compared to men without them [,].

Some men who undergo prostatectomy for locally advanced prostate cancer may be offered postoperative radiation therapy, particularly if the tumor could not be removed entirely (often termed positive margins). Although this approach decreases the chance of a tumor recurrence, its influence on survival is less clear, and there is some disagreement as to whether the benefits outweigh the risks.

Side effects of prostate surgery — Serious or life-threatening complications from prostate surgery are rare. The most common complications are urinary incontinence and sexual impotence. Rates of incontinence and impotence are highest immediately after surgery and tend to improve over time. In recent years, advances in surgical techniques have reduced the incidence of both of these conditions by avoiding (sparing) the nerves responsible for urinary and sexual function, although this nerve-sparing surgery is not always an appropriate option for men with locally advanced prostate cancer.

Age is an important factor in the risk of urinary incontinence after prostatectomy. Older men are more likely to have problems. The likelihood of impotence after radical prostatectomy also increases with age. A man's previous level of sexual functioning and the use of nerve-sparing surgery also influence this complication. Several treatments have been shown to be effective for men who experience impotence after surgery, including sildenafil (Viagra®), vardenafil (Levitra®) and tadalafil (Cialis®). (See "Patient information: Sexual problems in men").

Hormone therapy — The rationale for using androgen deprivation therapy (ADT) for locally advanced prostate cancer is the same as for metastatic disease. Male hormones (androgens such as testosterone) promote or stimulate tumor growth; when deprived of these hormones, the cancerous cells of the prostate gland (as well as normal cells) die and the prostate gland shrinks in size. ADT is effective against cancer cells within the prostate gland as well as for any cancer cells that may have spread outside of the prostate.

ADT is rarely used alone (ie, without any form of local treatment) in men with locally advanced prostate cancer. ADT is not as effective as radiation or surgery for local tumor control, and there is a high risk of developing urinary obstruction from an enlarging prostatic tumor if ADT is used alone. More commonly, ADT is used in conjunction with RT. (See "ADT plus EBRT" above).

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:

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

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)
National Library of Medicine

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

(www.ustoo.com)

[13,14]

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Smith, MR, McGovern, FJ, Zietman, AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001; 345:948.
2. Bolla, M, Gonzalez, D, Warde, P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337:295.
3. Roach, M, Lu, J, Pilepich, MV, et al. Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on Radiation Therapy Oncology Group clinical trials. Int J Radiat Oncol Biol Phys 2000; 47:609.
4. Ward, JF, Slezak, JM, Blute, ML, et al. Radical prostatectomy for clinically advanced (cT3) prostate cancer since the advent of prostate-specific antigen testing: 15-year outcome. BJU Int 2005; 95:751.
5. Van Poppel, H, Goethuys, H, Callewaert, P, et al. Radical prostatectomy can provide a cure for well-selected clinical stage T3 prostate cancer. Eur Urol 2000; 38:372.
6. Gerber, GS, Thisted, RA, Chodak, GW, et al. Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis. Eur Urol 1997; 32:385.
7. Messing, EM, Manola, J, Sarosdy, M, et al. Immediate hormonal therapy vs. observation for node positive prostate cancer following radical prostatectomy and pelvic lymphadenectomy: A randomized Phase III Eastern Cooperative Oncology Group trial. N Engl J Med 1999; 341:1781.
8. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. The Medical Research Council Prostate Cancer Working Party Investigators Group. Br J Urol 1997; 79:235.
9. Dotan, ZA, Cho, D, Rhee, AC, et al. The role of hormonal treatment for biochemical recurrence in patients following radical prostatectomy (abstract). Proc Amer Soc Clin Oncol 2003; 22:381a.
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12. Picus, J, Halabi, S, Hussain, M, et al. Long term efficacy of peripheral androgen blockade on prostate cancer: results of CALGB 9782 (abstract). J Clin Oncol 2006; 24:234s. (Abstract available online at www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD, accessed August 22, 2006).
13. Tannock, IF, de Wit, R, Berry, WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351:1502.
14. Petrylak, DP, Tangen, CM, Hussain, MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351:1513.

Pancreatic cancer

INTRODUCTION — More than 37,000 Americans develop cancer of the pancreas each year; it is the fourth leading cause of cancer-related death in the United States [1]. Two types of cancer can affect the pancreas: The most common, cancer of the exocrine pancreas (hereafter referred to as pancreatic cancer), originates in the pancreatic ducts. The ducts are responsible for carrying pancreatic juice to the intestines, where it assists in the digestion of food. This type of pancreatic cancer is discussed in this topic review. Another type of cancer consists of a group of tumors that originate from the cells that make hormones such as insulin. Like pancreatic juice, these hormones are made by the pancreas, but instead of traveling through the pancreatic ducts, they are secreted directly into the blood. These tumors are collectively referred to as pancreatic endocrine tumors, and are not addressed here.

PANCREAS ANATOMY AND PHYSIOLOGY — A brief review of the anatomy and physiology of the pancreas and surrounding structures will help in the understanding of pancreatic cancer.

The pancreas is a large gland that is located in the abdomen near the stomach, liver, and a part of the small intestine called the duodenum (show figure 1). Glands are organs that manufacture and secrete fluids that the body needs in order to function. The pancreas makes insulin, a hormone needed for sugar metabolism, and pancreatic juices, which are secreted into the intestines and aid in the digestion of food, particularly fats.

Pancreatic juices are carried to the digestive tract through a series of tubes or "ducts," that join together to form the main pancreatic duct. The pancreatic duct then joins the common bile duct (show figure 1) before they empty together into the small intestine at a point called the papilla of Vater (not pictured in the figure). The common bile duct drains bile into the intestines after it is made in the liver and stored in the gallbladder. The ampulla of Vater is located inside the duodenum, the first part of the small intestine near the head of the pancreas.

The pancreas has three main parts: the head (which is the part closest to the duodenum and the common bile duct), the body (the middle portion), and the tail. Cancer can develop in any of these parts. Cancers that surround or are close to the ampulla of Vater may be referred to as "periampullary tumors", and sometimes it is difficult to know whether they arose from the pancreas, the ampulla of Vater, or the duodenum.

RISK FACTORS — A number of factors increase the risk of developing pancreatic cancer including smoking, chronic pancreatitis (chronic inflammation of the pancreas), and possibly diabetes mellitus. The majority of studies do not support a relationship between coffee intake and pancreatic cancer. Pancreatic cancer can cause diabetes mellitus in many patients, and this makes it difficult to interpret many of the studies that examine the relationship between diabetes mellitus and pancreatic cancer. (See "Patient information: Chronic pancreatitis").

Many patients with pancreatic cancer have a family history of chronic pancreatitis. A small number of these families have an inherited condition that predisposes them to pancreatic cancer, sometimes in conjunction with chronic pancreatitis (inflammation of the pancreas).

SIGNS AND SYMPTOMS — Most patients with pancreatic cancer experience pain, weight loss, and/or jaundice (yellowing of the skin). Pain is common, and is usually felt in the upper abdomen as a dull ache that radiates to the back. It may be intermittent (comes and goes), and it may be worsened by eating. Weight loss can be profound. Some people lose weight because of loss of appetite, the sensation of felling full after eating only a small amount of food, or diarrhea. If the pancreatic duct is blocked by the cancer and the pancreatic juice cannot enter the intestines, the stools may seem greasy and tend to float in the toilet bowl because they contain undigested fat. Jaundice is a sign of high levels of bilirubin (the main component of bile) in the blood. People with jaundice have yellow skin, whites of the eyes, and urine. A build-up of bilirubin in the blood can be caused by cancers in and around the pancreas, which block the ducts that drain bile from the liver into the intestines. As a result, bowel movements may not be a normal brown color, and instead have a grayish appearance, described as clay-colored stools.

Symptoms vary depending upon where the pancreatic cancer is located. Cancers that develop in the head of the pancreas tend to block the drainage of bile from the liver to the intestines, and typically cause jaundice. In contrast, tumors that arise in the body or tail are less likely to cause jaundice, and more often cause abdominal pain, weight loss, and diarrhea.

Other signs of pancreatic cancer include a recent and unusual onset of diabetes mellitus, a history of recent but unexplained blood clots in the legs (thrombophlebitis), or a previous unexplained attack of pancreatitis.

DIAGNOSIS — If a patient's signs and symptoms suggest the possibility of pancreatic cancer, a number of different tests can be done to help pinpoint the diagnosis. All tests are not needed in every patient. Three main questions that testing can help to answer are: Are the symptoms/signs caused by a problem with the pancreas? If so, is it pancreatic cancer? If it is pancreatic cancer, can it be surgically removed?

Ultrasound of the abdomen — Patients with jaundice will typically have an ultrasound as a first step in the diagnostic process. An ultrasound uses sound waves that are transmitted through a wand-like instrument (a transducer) that applied to the abdomen. The purpose of this ultrasound is to determine whether the bile system is blocked, and to identify where the blockage appears to be located.

CT scan — CT scan, which uses x-rays and a computer to take detailed pictures of the body, may be the initial test ordered in patients who have abdominal pain or unexplained weight loss, particularly if the person is not jaundiced. CT may reveal a blockage of the bile and/or pancreatic ducts, a mass within the pancreas or in the periampullary area (where the bile duct, pancreas, and duodenum come together), and/or evidence of cancer spread beyond the pancreas (for example, to the liver). An injection of dye is usually given during the CT to allow the blood vessels surrounding the pancreas to be studied. The nature and extent of blood vessel involvement helps the surgeon to decide whether or not an operation should be performed.

Endoscopic retrograde cholangiopancreatography (ERCP) — ERCP is a dye study that may be used to outline the pancreatic duct system and bile duct system. It is performed by a gastroenterologist by inserting a small tube (called an endoscope) through the esophagus into the stomach, and then threading it through the duodenum to the papilla of Vater. Dye is then injected through the endoscope into the bile and pancreatic ducts. (See "Patient information: ERCP (endoscopic retrograde cholangiopancreatography)").

The ERCP may help to pinpoint the cause of jaundice, but is usually used only if less invasive tests do not provide enough information. An additional benefit of the ERCP is that if a blockage is identified in one of the bile ducts, it may be possible to place a flexible tube or catheter (also called a "stent") through the area that is blocked. This procedure can relieve the bile duct obstruction, allowing the bile to once again flow into the intestines, and lowering the amount of bilirubin within the blood. Whether or not this drainage procedure should be performed before a planned operation for pancreatic cancer in patients who present with jaundice is controversial.

Percutaneous transhepatic cholangiopancreatography (PTC) — PTC is an alternative way of visualizing the bile ducts to determine where a blockage is located. Instead of threading a tube into the bile system via the esophagus, a specially trained radiologist threads a tube into the bile ducts by inserting a needle into the liver from outside of the body, and then threading a catheter (over the needle) into the hepatic ducts (show figure 1). As with the ERCP, if a blockage is identified in one of the bile ducts, it may be possible to place a stent across the area that is blocked, thus relieving the bile duct obstruction.

Magnetic resonance cholangiopancreatography (MRCP) — MRCP is an MRI focusing on the bile ducts and pancreas. MRI uses magnetic fields and radio waves to produce detailed pictures of the body. It can create a very detailed three dimensional image of the pancreas, biliary ducts, liver, and surrounding blood vessels without the need for injection of dye. MRCP is sometimes done if an ERCP or PTC is not technically possible, or if the information provided by the ERCP and CT is incomplete and/or confusing.

Endoscopic ultrasound (EUS) — In this test, ultrasound is done from inside the body by placing the ultrasound transducer on the tip of an endoscope which is then passed into the duodenum by going down the esophagus. EUS is sometimes done if a small tumor is suspected, or to get more information about whether a pancreatic tumor can be removed by surgery.

Biopsy — A biopsy refers to the surgical removal of a small piece of tissue for examination under a microscope, looking for evidence of cancer. For patients suspected of having pancreatic cancer, a biopsy can be performed by inserting a biopsy needle into the area of abnormality. The needle can be inserted into a pancreatic tumor through the skin of the abdominal wall under guidance of a CT scan, or as part of an EUS procedure. Although a biopsy may be recommended if the diagnosis of pancreatic cancer is in doubt, or to confirm the diagnosis in patients who will not be having surgery, it may not be needed if the patient is thought to be a good candidate for surgery.

PANCREATIC CANCER STAGING — Treatment and prognosis for individual cancers depends upon the extent or "stage" of disease. The most commonly used pancreatic cancer staging system is the TNM ("Tumor, nodes, metastases") system (show table 1). It is based upon tumor size and how far the cancer has penetrated into the structures surrounding the pancreas, whether the cancer involves lymph nodes adjacent to the pancreas, and whether the cancer has spread to other organs. These factors are then combined to assign a "stage grouping" from I to IV, with stage I cancers being the earliest and least advanced stage disease and stage IV the most advanced. The final staging of a pancreatic cancer often depends upon the findings during surgery.

TREATMENT — Several approaches to treatment of pancreatic cancer are available. For patients whose cancer has not spread significantly and who are strong enough to withstand an operation, doctors will attempt to remove the cancer surgically. Surgery provides the only opportunity for cure. Surgery is not possible in many patients because the disease is often advanced at the time of diagnosis.

In some cases, chemotherapy and/or radiation therapy will be recommended following surgery while in others it may be offered before surgery (termed neoadjuvant therapy). For patients who are not candidates for surgery, radiation and/or chemotherapy may be offered. In addition, other treatments are available to relieve the symptoms of pancreatic cancer (see "Treating signs and symptoms" below).

Laparoscopy — In some centers, laparoscopy is recommended before attempted surgical removal of a pancreatic cancer to get more information about the location and extent of cancer involvement. During a laparoscopy, the surgeon inserts a narrow tube into small incisions and uses a camera within the tube to view the inside of the abdominal cavity. If the surgeon finds evidence of cancer spread, the patient may be spared the complications and long recovery time of a major operation that would not likely cure the cancer. Postoperative recovery after a laparoscopy is faster than with a standard open surgical procedure because the incisions are smaller.

Surgery for tumors in the head of the pancreas — The standard operation for tumors located in the head of the pancreas is a Whipple procedure (a pancreaticoduodenectomy) [2]. In this procedure, the surgeon removes the pancreatic head, the duodenum (first part of the small intestine), part of the jejunum (the next part of the small intestine), the common bile duct, the gallbladder, and part of the stomach (show figure 2). A modification of the Whipple procedure (a pylorus-preserving Whipple procedure) has been developed that preserves the part of the stomach (the pylorus) that is important for stomach emptying [3].

In the past, complications and deaths following this operation were high, and cure rates were less than 10 percent. However, more recent results suggest better outcomes: In experienced hands, the death rate following surgery is less than 4 percent [4,5]. The long-term outlook for patients undergoing this surgery varies, depending in part on whether the cancer has affected the lymph nodes. Between 10 and 30 percent of patients undergoing a Whipple procedure for pancreatic cancer will be alive and cancer-free five years after the operation [4-9].

Better outcomes are achieved in hospitals that perform a large number of Whipple procedures and when the surgeon is experienced with the procedure [10] (see "Adjuvant therapy after surgery" below).

Surgery for tumors in the body or tail of the pancreas — Because tumors in the body or tail of the pancreas do not cause the same symptoms as those in the head of the pancreas, these cancers tend to be discovered at a later stage, when they are more advanced. If the patient has a tumor that can be removed surgically, a laparoscopic exploration is usually done first to make sure the cancer has not spread within the abdominal cavity. If surgery is still an option, part of the pancreas is removed, usually along with the spleen. However, long-term outcome for these patients is usually poor.

Adjuvant therapy after surgery — Adjuvant (additional) therapy refers to chemotherapy, radiation, or a combination of both that is recommended for patients who are thought to be at high risk of having cancer reappear (termed a recurrence or a relapse) after a tumor has been removed surgically. Even if the tumor has been completely removed, tiny cancer cells may remain in the body and grow, causing relapse after surgery. For such patients, adjuvant therapy can prevent relapse and prolong survival by eradicating the tiny cancer cells before they have had a chance to grow [6-9].

Many different studies have been done to evaluate the benefits and risks of these treatments, and more are underway. Despite the widespread opinion that adjuvant therapy is beneficial for patients who have undergone surgery for stage II or III pancreatic cancer (show table 1), research to date has not indicated the best way to give such therapy. Two different approaches may be recommended, including: Chemotherapy alone (typically with the drug gemcitabine) A combined approach of chemotherapy (either gemcitabine or 5-FU) given in conjunction with radiation therapy and also a period (usually four to six months) of chemotherapy alone (usually gemcitabine). This strategy is called chemoradiotherapy.

Whether either of these approaches is superior is unclear, and both are acceptable forms of adjuvant therapy. In the United States, a combined approach is recommended for most patients. However, outside of the United States, patients are frequently offered chemotherapy alone. Until more research is done, the best way to use these adjuvant therapies in particular cases will not be known. Many patients will be asked to participate in clinical trials that compare different approaches or that explore new strategies. (See "Clinical trials" below).

Treatment of locally advanced pancreatic cancer — Locally advanced pancreatic cancer has not yet spread to distant locations in the body, but has extended into surrounding organs or structures, making surgical removal impossible. The best therapy for locally advanced pancreatic cancer is unknown. Options include chemotherapy alone or a combination of radiation therapy with chemotherapy. This approach increases the average survival for patients with locally advanced cancer by about one year compared to no treatment, but rarely results in long-term survival.

A major unanswered question is: which patients benefit from the use of radiation therapy? Researchers have tried a new strategy, which uses radiotherapy in a selected group. With this strategy, chemotherapy alone (usually gemcitabine) is given to all patients for three months. Chemoradiotherapy is then added if the cancer has not progressed during that time. Although this approach reserves radiation therapy for the subgroup of patients who seem most likely to benefit, the survival benefit of adding radiation therapy to chemotherapy remains uncertain.

Chemotherapy — Patients with metastatic pancreatic cancer (stage IV) have a poor prognosis, with survival averaging only three to six months. Chemotherapy may be offered as a means of slowing the spread of the disease or to relieve disease-related symptoms.

Many different chemotherapeutic drugs and drug combinations have been studied. To date, none has consistently been proven to be more effective than single agent gemcitabine. The combination of gemcitabine with a second drug (a tablet called erlotinib [Tarceva®]) was compared to gemcitabine alone in one trial. The preliminary results showed that gemcitabine plus erlotinib was associated with longer survival [11], but the length of added survival was short (approximately two weeks). In addition, the cost of erlotinib ($3,000 per month) may be prohibitive in some cases.

As a result, gemcitabine alone is considered the standard first-line treatment for advanced pancreatic cancer by most oncologists. Gemcitabine is typically administered once per week for three of every four weeks. On average, about 25 percent of patients benefit, in that they feel better and possibly gain weight. Importantly, single agent gemcitabine is reasonably well tolerated, with little nausea, vomiting, hair loss, or bone marrow suppression (lowering of the blood counts, which may increase the risk of an infection). Still, the average survival for patients treated with gemcitabine is approximately 6 months, and only 10 to 20 percent will live for one year or longer.

Patients with advanced disease should talk with their health care providers about the benefits and side effects of chemotherapy. Many patients will be asked to participate in clinical trials that compare different chemotherapy drugs or combinations or that explore new strategies. (See "Clinical trials" below).

TREATING SIGNS AND SYMPTOMS — Treatment for pancreatic cancer may include a number of other therapies to improve disease-related symptoms. The symptoms that are most often treated include jaundice, bowel obstruction, pain, and weight loss.

Jaundice — Jaundice is caused by an obstruction to the flow of bile through the common bile duct into the intestine (show figure 1). The most common treatment is the placement of a stent, which is a small tubular device that is inserted into a duct to keep it open. The stent can usually be placed through an endoscope during an ERCP procedure (see "Endoscopic retrograde cholangiopancreatography (ERCP)" above). Initially, a plastic stent is placed, particularly if surgical removal of the cancer is possible. However, plastic stents often get clogged by debris and may become infected and require replacement. Once a decision is made that surgery is not possible, the plastic stent is replaced with a metal one.

If stenting is not possible due to technical reasons, bypass surgery can be done to create a detour around the blockage and restore the drainage of bile. However, this is rarely necessary.

Bowel (duodenal) obstruction — About 15 to 20 percent of patients with pancreatic cancer will develop an obstruction in the duodenum caused by growth of tumor into this part of the small intestine, or from compression from a growing tumor which is outside of the duodenum in the head of the pancreas (show figure 1). A preventive bypass surgery may be performed to create a detour between the stomach and a lower part of the intestine.

An alternative to bypass surgery for some patients is placement of a stent in the duodenum through an endoscope. Stents are effective, less expensive than surgery, and are a reasonable option, provided that they are place by an experienced endoscopist familiar with the technique. Bypass may be required if a stent cannot be placed or if stenting fails to relieve the obstruction.

Pain — Many patients with pancreatic cancer have abdominal pain because the pancreas lies in front of the celiac plexus, the nerve center for many of the abdominal organs. Cancers affecting the pancreas can grow locally and invade this structure, causing severe pain that can be difficult to control. In some patients, medication alone is enough to control the discomfort. Radiation therapy may also help alleviate pain in some cases by shrinking the tumor.

An additional treatment that is being used with increasing frequency is celiac plexus neurolysis (CPN). In this procedure, nerves that transmit pain signals from the area of the tumor are injected with alcohol so that they are unable to transmit signals normally. This procedure can be performed in one of three ways: in the operating room at the time of the initial surgical exploration, by a radiologist using a needle that is inserted into the area of the celiac plexus from outside of the body under CT guidance, or through an endoscope by a specially trained gastroenterologist, using endoscopic ultrasound.

Weight loss — Weight loss is common in patients with pancreatic cancer. There can be many causes. One cause is related to a decrease in the absorption of food due to a lack of the pancreatic enzymes that are found in pancreatic juice. Some patients benefit from taking pancreatic enzyme replacement. Other causes of weight loss, such as vomiting or depression, can also be addressed and treated.

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:

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

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. National Cancer Institute

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)
The American Gastroenterological Association

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

(www.acg.gi.org)

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Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Jemal, A, Siegel, R, Ward, E, et al. Cancer statistics, 2007. CA Cancer J Clin 2007; 57:43.
2. Strasberg, SM, Drebin, JA, Soper, NJ. Evolution and current status of the Whipple procedure: An update for gastroenterologists. Gastroenterology 1997; 113:983.
3. Seiler, CA, Wagner, M, Sadowski, C, et al. Randomized prospective trial of pylorus-preserving vs. Classic duodenopancreatectomy (Whipple procedure): initial clinical results. J Gastrointest Surg 2000; 4:443.
4. Yeo, CJ, Cameron, JL, Sohn, TA, et al. Six hundred fifty consecutive pancreaticoduodenectomies in the 1990s: pathology, complications, and outcomes. Ann Surg 1997; 226:248.
5. Geer, RJ, Brennan, MF. Prognostic indicators for survival after resection of pancreatic adenocarcinoma. Am J Surg 1993; 165:68.
6. Yeo, CJ, Abrams, RA, Grochow, LB, et al. Pancreaticoduodenectomy for pancreatic adenocarcinoma: Postoperative adjuvant chemoradiation improves survival. A prospective, single-institution experience. Ann Surg 1997; 225:621.
7. Neoptolemos, JP, Stocken, DD, Friess, H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med 2004; 350:1200.
8. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Gastrointestinal Tumor Study Group. Cancer 1987; 59:2006.
9. Lim, JE, Chien, MW, Earle, CC. Prognostic factors following curative resection for pancreatic adenocarcinoma: a population-based, linked database analysis of 396 patients. Ann Surg 2003; 237:74.
10. Birkmeyer, JD, Stukel, TA, Siewers, AE, et al. Surgeon volume and operative mortality in the United States. N Engl J Med 2003; 349:2117.
11. Moore, M, Goldstein, D, Hamm, J, et al. Erlotinib plus compared to gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group (NCNC-CTG) (abstract). J Clin Oncol 2005; 23:1s. Abstract available online at www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRDvmview=abst_detail_viewconfID=34index=yabstractID=33471 (Accessed August 9, 2006).

Pancreatic cancer

Ovarian cancer treatment

INTRODUCTION — Ovarian cancer is the seventh most common cancer among women in the United States, and it occurs most frequently in women who are between 40 and 65 years of age. The lifetime risk of developing ovarian cancer is 1.4 to 1.8 percent for women living in the United States. The following factors increase the risk of ovarian cancer: Being a white person Never being pregnant Early age of menarche (the onset of the menstrual periods) or late age of menopause Family history of ovarian, breast, or endometrial (uterine) cancer Presence of inherited BRCA1 or BRCA2 mutations (See "Patient information: Genetic testing for breast and ovarian cancer") Family history of hereditary nonpolyposis colorectal cancer (HNPCC). Women in families with this trait have up to a 60 percent chance of endometrial cancer and a 10 to 12 percent chance of ovarian cancer [1].

Although there are several different types of cancer that can arise in the ovary, epithelial ovarian cancer (hereafter referred to as ovarian cancer) is the most common, and will be the subject of this review.

SIGNS AND SYMPTOMS — During the early stages of ovarian cancer, symptoms are often vague and ill-defined. They may include pelvic or abdominal discomfort, bloating, difficulty eating, increased abdominal size, urinary symptoms (urgency and frequency), constipation, irregular menstrual cycles, or fatigue.

In some women, ovarian cancer is first suspected when a mass or lump is felt during a routine pelvic (internal) examination. However, a mass is not always detectable in the early stages of ovarian cancer. Furthermore, even when a mass is detected, it does not necessarily indicate the presence of an ovarian cancer, as a number of other conditions (some of which are not cancerous, such as cysts) may also present in a similar way.

Because the initial symptoms are vague and nonspecific, ovarian cancer often goes undetected during its early stages. The majority of women have disease that is at an advanced stage by the time it is diagnosed. At this point, the woman may have more significant symptoms such as abdominal distention (swelling), nausea, or a significant loss of appetite.

DIAGNOSIS — If ovarian cancer is suspected because of symptoms and/or an abnormal physical examination, imaging tests (such as a CT scan or MRI) are usually performed to obtain more information. Although these tests may provide important information about the location and/or extent of a possible cancer, they are insufficient to make the diagnosis of an ovarian cancer.

The only way to diagnose ovarian cancer is to have surgery. During surgery, abnormal areas are examined and a small piece is removed (biopsied).The tissue is then examined with a microscope.

Tumor markers (CA 125) — Prior to surgery, most women with suspected ovarian cancer have a blood test to measure the level of a tumor marker called CA 125. This marker is normally <35>65 U/mL) in 80 percent of women with ovarian cancer, particularly in those with advanced stage disease (see below).

Measurement of levels of CA 125 in the blood (actually the serum, the clear fluid component of the blood) may be useful in one of two ways: as a laboratory test that supports the diagnosis of ovarian cancer, and as a marker of ovarian cancer activity during treatment. Measurement of serum levels of CA 125 prior to surgery provides a baseline value that can be used to monitor the success of treatment (if ovarian cancer is found).

When considering the usefulness of the serum CA 125 concentration as an aid to the diagnosis of ovarian cancer, a number of issues must be kept in mind: Elevated levels of CA 125 may be found in women without ovarian cancer (show table 1). This tumor marker is also elevated in patients with other cancers (eg, endometrial cancer, and certain pancreatic cancers), in a variety of non-cancerous conditions (eg, endometriosis, uterine fibroids, and pelvic inflammatory disease), and in approximately 1 percent of normal healthy women. Thus, CA 125 is not currently recommended as a screening test for ovarian cancer in healthy women. For premenopausal (ie, menstruating) women, CA 125 is less useful as a marker of ovarian cancer, especially when it is increased by only a small amount. Cancer is rare in this age group, and small elevations in serum CA 125 are often not related to the presence of an ovarian cancer. Testing is more useful in postmenopausal women, in whom an elevated value is more likely to indicate the presence of a cancer.

Initial surgery — In a woman suspected of having ovarian cancer (even advanced disease), a procedure called exploratory laparotomy is typically performed. In this procedure, a vertical abdominal incision is made, and the surgeon examines the organs in the pelvis and abdomen for signs of cancer. Any fluid that is found within the abdominal cavity (also referred to as the peritoneal cavity), tissue from the ovary, neighboring lymph nodes, other abdominal organs, and the mesentery (the apron of fat that covers and connects the organs of the abdomen and pelvis), are sampled and sent to the pathology laboratory for testing.

If a diagnosis of ovarian cancer is confirmed by the pathologist, the surgeon then removes as much of the cancerous tissue as possible (this is termed "debulking" or cytoreduction, and is an important first step in the treatment of ovarian cancer). Treatment outcomes are best in women whose debulking surgery removes all visible tumor (termed optimal debulking). This is best performed by a gynecologic oncologist, who has received specialized surgical training.

In most cases, the uterus, both fallopian tubes, and both ovaries are also removed. However, in some young women who wish to preserve their ability to bear children in the future, it may be possible to leave the uterus, one fallopian tube, and one ovary in place if these structures seem to be unaffected by the cancer. The doctor and patient should discuss this option before surgery. If the cancer has spread to other organs, those organs, or affected portions of them, may be removed as well.

In some patients, a less invasive procedure called exploratory laparoscopy may be performed. In this procedure, a flexible tube is inserted through a small incision in the abdomen. A camera located in the tip of the tube allows the surgeon to visualize the contents of the abdomen and pelvis. This less invasive approach may be chosen in a young woman who has a mass that is unlikely to be ovarian cancer. In general, however, the open laparotomy is preferred as it allows the surgeon to more easily and completely visualize the abdominal contents and remove any suspicious masses.

STAGING — Based upon the findings during exploratory surgery, a tumor stage between I and IV is assigned (show table 2). Staging is a means of formally defining the extent and location of any cancer, including ovarian cancer, in order to determine the prognosis (outcome) and appropriate selection of further treatment. In general, the stage designations I, II, III, and IV refer to the location of tumor involvement, while the subdivisions A, B, and C further refine the extent of tumor involvement. A higher stage of disease indicates more extensive tumor involvement.

Stage I and II disease are considered early stage ovarian cancer. For women with stage I disease, tumor involvement is generally limited to one or both ovaries. In stage IA and IB disease, the cancer is limited to one or both or ovaries, and the capsule or membrane covering the ovaries has not been broken by the cancer's growth. In contrast, with stage IC disease, the capsule may have ruptured, or there may be signs suggesting that cancer cells have begun to spread within the pelvis. In stage II disease, other pelvic organs such as the uterus or fallopian tubes are involved with the tumor, and there may be early signs that the cancer has spread beyond the pelvis.

In stage III disease, the cancer is confined to the abdomen and retroperitoneal lymph nodes. In stage IV disease, the cancer has spread to distant sites such as the liver or lungs.

As noted previously, ovarian cancer is uncommonly detected during its early stages. Most women (about 75 percent) have stage III disease at the time the cancer is diagnosed.

TREATMENT OF NEWLY DIAGNOSED OVARIAN CANCER — Treatment focuses on eliminating cancerous tissue and preventing disease recurrence.

Surgery — As noted above, the usual first step in treating ovarian cancer is the removal of as much cancerous tissue as possible at the time of initial surgery. A woman is more likely to have optimal cytoreduction, staging, and a higher cure rate if her initial surgery is performed by a gynecologic oncologist.

For selected women with stage IA and IB disease (show table 1), surgery alone is effective in treating the disease, and no additional therapy is recommended. In almost all other cases, however, chemotherapy is recommended in conjunction with surgery.

Chemotherapy

What is chemotherapy? — Chemotherapy refers to the use of medicines to stop or slow the growth of cancer cells. Chemotherapy works by interfering with the ability of rapidly growing cells (such as cancer cells) to divide or reproduce themselves. Because most of an adult's normal cells are not rapidly growing, they are not 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 give rise to side effects during treatment.

In general, side effects are more frequent when two or more drugs are administered simultaneously (termed combination chemotherapy, see below), and with higher as compared to lower doses of chemotherapy. Most chemotherapy drugs are administered into the vein, although some agents can be given by mouth. A newer alternative treatment strategy involves giving chemotherapy directly into the abdominal (peritoneal) cavity. This is called intraperitoneal or IP chemotherapy, and is discussed in detail below (see "Intraperitoneal chemotherapy" below).

In general, regardless of the route by which they are given, chemotherapy drugs are administered in carefully defined sequence and doses over a period of several months. Chemotherapy drugs are usually not administered daily but periodically, in cycles. A cycle of chemotherapy refers to the time it takes to give the treatment and then allow the body to recover from the effects of the medicines. While receiving these medications, patients are closely monitored for signs of drug toxicity and serious side effects. In most cases, chemotherapy is given after surgery.

Neoadjuvant chemotherapy — Occasionally, it is too risky or technically difficult to perform surgery because of the extensive nature of the cancer. In this case, chemotherapy may be recommended as a first step in the treatment process; this is referred to as neoadjuvant therapy. Neoaduvant therapy is often recommended prior to surgery for women with advanced stage ovarian cancer who have a buildup of fluid in the abdominal cavity (called ascites) or evidence of cancer spread to the lungs, liver, or other distant organs. Some women who receive neoadjuvant chemotherapy are able to have surgery at a later date.

In one study, women with spread of tumor outside the pelvis who received carboplatin and paclitaxel neoadjuvant chemotherapy had a longer period before the cancer progressed. These women also lived longer, compared to women who initially had surgery for stage IV disease [2].

Selection of treatment — Among the chemotherapy agents most commonly used in the treatment of ovarian cancer are paclitaxel (Taxol®), and one of the platinum-type agents (carboplatin or cisplatin). Research suggests that these drugs are effective in preventing recurrence of ovarian cancer, and improving a woman's chance of surviving her cancer.

In the United States, combination chemotherapy using intravenous paclitaxel plus carboplatin is commonly used to treat newly diagnosed ovarian cancer. At least three research trials support the superiority of paclitaxel-containing chemotherapy, in contrast to regimens that do not contain paclitaxel [3-5]. The combination of a platinum-type drug (usually carboplatin) and paclitaxel is standard therapy for the first-line treatment of women with ovarian cancer who require chemotherapy. Carboplatin appears to be as effective as cisplatin, and has fewer side effects.

A potentially less toxic alternative is single agent therapy with carboplatin alone, although this approach is more controversial. It is used more often in Europe than in the United States [6].

Intraperitoneal chemotherapy — In contrast to almost all other cancers, ovarian cancer typically does not spread through the bloodstream. Instead, tumor growth is often limited to the abdominal (peritoneal) cavity, even in advanced cases. Because the bulk of cancerous tissue is found within the peritoneum, newer treatment approaches have tried administering chemotherapy directly into this area (called intraperitoneal or IP therapy). The advantage of IP administration is that higher doses of the drugs can be given, compared to the intravenous (IV) route.

IP chemotherapy is administered through a small, soft, flexible catheter, which is placed in the peritoneal cavity The catheter may be left in place for several weeks or months at a time. The catheter is surgically placed into the peritoneum; the procedure can be done in a hospital or clinic setting, and patients are usually able to go home the same day. A helpful website with educational materials about intraperitoneal catheters and IP chemotherapy is available from the Gynecologic Oncology Group (www.gog.org/IPChemoEd/ipchemoed.html) [7]. Benefits — Benefit for administering chemotherapy directly into the abdomen in women with ovarian cancer was suggested in two early trials [8,9]. The question of whether IP chemotherapy is better than intravenous chemotherapy for women with advanced ovarian cancer was the subject of a study that was conducted in several American hospitals [10]. In this study, IP chemotherapy using cisplatin and paclitaxel was given in combination with intravenous paclitaxel, and compared to the standard intravenous regimen of paclitaxel plus cisplatin in women with optimally debulked stage III ovarian cancer (see "Initial surgery" above). Women who received IP chemotherapy had a 16 month longer survival as compared to women who received intravenous chemotherapy only, even though most of them did not receive the entire six courses of IP treatment because of complications. Risks — However, this benefit was counterbalanced by a higher number of treatment-related complications in the IP group. These included both catheter-related complications (infection, blockage or leakage of the catheter) as well as non-catheter-related problems (low white and red blood cell counts, nausea and vomiting, abdominal pain, and neurologic side effects such as numbness and tingling of the fingers and toes). Recommendation for IP chemotherapy — The National Cancer Institute recommends that IP chemotherapy be strongly considered for women who are left with small volume residual tumor after optimal debulking for stage III disease (show table 1). However, at least for the present, a standard intravenous regimen of paclitaxel plus carboplatin is an acceptable alternative to IP therapy for these patients because of toxicity issues. Patients should discuss the risks and benefits of IP versus IV chemotherapy with their physician.

Maintenance or consolidation chemotherapy — The high likelihood of cancer recurrence after initial chemotherapy has led to efforts to improve outcomes by increasing either the duration and/or the intensity of chemotherapy. There are no data to support a benefit from increasing the chemotherapy dose.

Increasing the duration of first-line chemotherapy may delay cancer progression. This was illustrated in a study of 277 women with stage III or IV ovarian cancer who had achieved a complete response to first-line intravenous chemotherapy [11]. Women who were given 12 additional months of paclitaxel alone had a seven month delay in disease progression compared to those who only received three months of continued paclitaxel [12]. However, whether more women were cured by the longer course of chemotherapy is not clear. Moreover, this benefit was achieved at the cost of more treatment-related side effects with longer treatment.

Because of these issues, some experts regard these results as inconclusive. Nevertheless, the issue of maintenance chemotherapy should be discussed with your physician.

PROGNOSIS — A number of factors influence the success of treatment for ovarian cancer. Treatment tends to be more successful when the cancer is diagnosed at an early stage and at a younger age (below the age of 67). One of the most important factors influencing the outcome of treatment is the amount of tumor that remains after the initial surgery. This is the reason why the goal of the initial exploration is to remove as much of the cancerous tissue as possible.

At the end of treatment, a patient is considered to have a complete response if the physical examination is normal, there is no evidence of disease on radiologic studies (such as a CT scan), and the serum CA 125 level is normal. However, even when all of these criteria are met, microscopic amounts of residual cancer can still be present. In some women, surgery (termed a second look laparotomy) may be performed to more conclusively evaluate the response to treatment. The benefit of second look surgery is controversial, and it is not routinely recommended for all women.

Even when a complete response is obtained (as determined by physical examination, x-ray studies, or second look surgery), ovarian cancer can recur at a later time. The likelihood of tumor recurrence is highest in women with more advanced stage disease at diagnosis, particularly if the debulking surgery was unable to remove all visible tumor. Recurrence of ovarian cancer may be suggested by the development of new symptoms, a rising level of serum CA 125, or new areas of abnormality seen on CT scan. Any of these findings may prompt a reevaluation for disease recurrence. Further treatment may not necessarily be recommended for an isolated rise in the serum CA 125 if symptoms are absent and CT scans show no new growth.

SECOND-LINE TREATMENT — Women with recurrent ovarian cancer and those who do not respond well to initial chemotherapy are candidates for further chemotherapy (often called "second-line chemotherapy").

Chemotherapy — The choice of chemotherapy agents for second-line treatment depends on whether, and how well, the patient responded to first-line treatment with paclitaxel and one of the platinum-type agents. If a good response was obtained that lasted for at least six months, the same or a similar regimen may be used again. Research has shown that such patients may obtain a good response with a second course of a platinum agent plus paclitaxel. In fact, if the initial response lasted longer than 24 months, up to one-fourth of patients may achieve a complete response to second-line chemotherapy.

For women who have relapse at least six months following initial treatment who have persistent neurologic side effects related to prior paclitaxel and a platinum agent, an alternative regimen includes the combination of gemcitabine plus carboplatin [13].

If a patient did not respond well to first-line therapy with paclitaxel and a platinum agent or if she relapses within six months of completing such therapy, a different non-platinum-containing regimen may be considered. Usually, a single drug rather than combination chemotherapy is recommended in these patients. A variety of agents may be considered, including docetaxel, oral etoposide, liposomal doxorubicin, topotecan, gemcitabine, vinorelbine, ifosfamide, leucovorin-modulated 5-fluorouracil, and tamoxifen.

Molecularly targeted therapy — A different type of therapy, referred to as molecularly targeted therapy, may also be of benefit. The drug bevacizumab (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 enhances the antitumor effect of other anticancer drugs, and is used in combination chemotherapy regimens for the treatment of metastatic colorectal, breast, non-small cell lung, and renal cell cancer.

Avastin is an active agent in the treated of ovarian cancer, and it may be considered for women with platinum-resistant ovarian cancer, either alone or in combination with chemotherapy. However, a major problem is the risk of bowel perforations during treatment (approximately 10 percent in two reports [14,15]). Patients with preexisting tumor involvement of the GI tract (eg, obstruction or bowel wall thickening) appear to be at greater risk for this complication [15].

Timing of second-line therapy — An area of major controversy is the optimal timing of second-line therapy. Immediate treatment is reasonable for women with a symptomatic recurrence, with the specific goal of palliation (improvement) of symptoms. In contrast, the optimal timing of second-line therapy in women who are asymptomatic, but who have either a rising level of the tumor marker CA 125 or an abnormal CT scan, is uncertain.

Some experts believe that treatment should be delayed or deferred until the woman has symptoms because therapy is unlikely to result in a cure. Others argue that women with a smaller volume of disease have a better response to chemotherapy, and that responders almost always do better than nonresponders.

Recommendation — One approach to recurrent ovarian cancer takes into account the response to first-line therapy, and the duration of the recurrence-free interval. Immediate therapy at initial discovery of recurrence could be considered for women with disease who responded well to initial platinum-containing chemotherapy and who had a recurrence-free interval of longer than 24 months. Response rates up to 60 percent and average survival durations as long as two years have been reported in such women [16]. In contrast, response rates are relatively low and survival durations are short in women who have disease that is resistant to chemotherapy (ie, an incomplete response to first-line chemotherapy and/or a recurrence-free interval of 12 months or less). In such patients, treatment could be reasonably deferred until actual masses are observed on CT scans or symptoms develop. A rising serum CA 125 concentration would indicate the likelihood of progressive disease and the need for further evaluation.

Surgery — In some cases, surgery may also be beneficial, particularly if the tissue can be easily removed and the patient has been free of disease recurrence for more than 6 to 12 months. Surgery can also be helpful in relieving symptoms and discomfort caused by the growth of cancerous tumors.

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:

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

OVARIAN CANCER SCREENING — A screening test is one that is able to detect a disease, such as a precancer or cancer in the early stages, when it is most likely to respond to treatment. An example of a commonly used screening test is the Pap smear, which is used to detect cervical precancers and cancers. A screening test must be both sensitive and specific, meaning that it is able to accurately identify most people with a specific condition and avoids mistakenly identifying people who do not have the condition. This is especially important for ovarian cancer, since a positive screening test usually requires surgery to obtain a biopsy.

High risk family history — Women who have a high-risk family history of ovarian or breast cancer should meet with a genetic counselor to discuss genetic testing for BRCA1 and BRCA2. Characteristics of a high risk family history are described in table 3 (show table 3). Genetic testing and management after a positive or negative genetic test result are discussed in a separate topic review. (See "Patient information: Genetic testing for breast and ovarian cancer").

Family history of ovarian cancer — Women with a family history of ovarian cancer but who do not meet the criteria for a high-risk family history should discuss their individual risk factors (age, number of children, and history of oral contraceptive pill use) with a healthcare provider. A woman is said to have a family history if she has one first degree relative (eg, mother, sister) or two second-degree relatives (eg, grandmother, aunt) with ovarian cancer.

Screening for ovarian cancer in this group has not proven to prevent death related to ovarian cancer. In addition, there are potential risks of screening, including the need for surgery if screening is positive. However, selected postmenopausal women with a family history of ovarian cancer may benefit from screening. An optimal screening strategy for this group has not yet been defined; one screening approach includes an annual CA 125 blood test; transvaginal ultrasound is recommended if the CA 125 level is above 30 U/mL.

Trials are currently underway to better identify the risks and benefits of screening low and high-risk women, and also to determine the most accurate combination of screening tests.

Average risk women — Women with an "average risk" of ovarian cancer include those with no history of ovarian cancer or BRCA mutation in a first or second degree relative (mother, sister, grandmother, aunt). Screening for ovarian cancer is not recommended in average risk women because of the increased risk of an inaccurate result.

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 ofthe American Society of Clinical Oncology
(www.plwc.org/portal/site/PLWC)
The Women's Cancer Network

(www.wcn.org)
National Comprehensive Cancer Network

(www.nccn.org/patients/patient_gls.asp)
Gynecologic Oncology Group

(www.gog.org/gynecologiccancerinformation.html)
National Cancer Institute

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

1-800-ACS-2345
(www.cancer.org)
National Ovarian Cancer Coalition

(www.ovarian.org)

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Schmeler, K, Lynch, HT, Chen, LM. Prophylactic surgery to reduce the risk of gynecologic cancers in the Lynch syndrome. N Engl J Med 2006; 354:261.
2. Hou, JY, Kelly, MG, Yu, H, et al. Neoadjuvant chemotherapy lessens surgical morbidity in advanced ovarian cancer and leads to improved survival in stage IV disease. Gynecol Oncol 2007; 105:211.
3. McGuire, WP, Hoskins, WJ, Brady, MF, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996; 334:1.
4. Piccart, MJ, Bertelsen, K, James, K, et al. Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advancd epithelial ovarian cancer: three-year results. J Natl Cancer Inst 2000; 92:699.
5. Muggia, FM, Braly, PS, Brady, MF, et al. Phase III randomized study of cisplatin versus paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 2000; 18:106.
6. Paclitaxel plus carboplatin versus standard chemotehrapy with either single agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: the ICON3 randomised trial. The International Collaborative Ovarian Neoplasm (ICON) group. Lancet 2002; 360:505.
7. Patient-oriented information on intraperitoneal chemotherapy from the Gynecologic Oncology Group (GOG) available online at www.gog.org/IPChemoEd/ipchemoed.html. (Accessed on August 21, 2006).
8. Alberts, DS, Liu, PY, Hannigan, EV, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996; 335:1950.
9. Markman, M, Bundy, BN, Alberts, DS, et al. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 2001; 19:1001.
10. Armstrong, DK, Bundy, B, Wenzel, L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006; 354:34.
11. Markman, M, Liu, PY, Wilczynski, S, et al. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 2003; 21:2460.
12. Parmar, MK, Ledermann, JA, Colombo, N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 2003; 361:2099.
13. Pfisterer, J, Plante, M, Vergote, I, et al. Gemcitabine/carboplatin (GC) vs. carboplatin (C) in platnum sensitive recurrent ovarian cancer (OVCA). Results of a Gynecologic Cancer Intergroup randomized phase III trial of the AGO OVar, the NCIC CTG and the EORTC GCG (abstract). Proc Am Soc Clin Oncol 2004; 23:449s.
14. Cannistra, SA, Matulonis, U, Penson, R, et al. Bevacizumab in patients with advancecd platinum-refractory ovarian cancer (abstract). J Clin Oncol 2006; 24:257s. (Abstract available online at www.asco.org/portal/site/ASCO/menuitem.34d60f5624ba07fd506fe310ee37a01d/?vgnextoid=76f8201eb61a7010VgnVCM100000ed730ad1RCRD, accessed July 20, 2006).
15. Wright, JD, Hagemann, A, Rader, JS, et al. Bevacizumab combination therapy in recurrent, platinum-refractory, epithelial ovarian carcinoma: A retrospective analysis. Cancer 2006; 107:83.
16. Cantu, MG, Buda, A, Parma, G, et al. Randomized controlled trial of single-agent Paclitaxel versus cyclophosphamide, Doxorubicin, and Cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens. J Clin Oncol 2002;

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