Zanmbeel

Saturday, October 13, 2007

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;

Myelodysplastic syndromes (MDS)

INTRODUCTION — The myelodysplastic syndromes (MDS, myelodysplasia) are not one specific disease, but include a series of blood disorders, all characterized by chronic deficiencies of certain components of the blood and abnormal growth of blood cells. MDS can cause infections, bleeding, anemia (low level of red blood cells), and can progress to acute leukemia, which is often difficult to treat. MDS may occur on its own or years after exposure to chemotherapy. The risk of developing MDS increases with age and is very rare in childhood.

SIGNS AND SYMPTOMS — MDS usually causes a low number of red blood cells, white blood cells, and/or platelets. Each cell type performs a number of functions, including the following: Red blood cells carry oxygen throughout the body White blood cells help to protect the body from infection Platelets helps blood to clot normally

Anemia is almost always present in MDS and is generally associated with a slow regrowth of red blood cells. A low total white blood cell count is found in approximately 50 percent of patients with MDS at the time of diagnosis, which increases a person's risk of developing infections.

A low platelet count is found in roughly 25 percent of people with MDS. An increase in the platelet count is less common, but occurs in association with a specific abnormality in chromosome 5, called the 5q-syndrome. Abnormalities of the immune system may be found in patients with MDS in a minority of cases. There is usually an excess of bone marrow blast cells in MDS; often bone marrow cells are deformed and have abnormal growth and maturation.

A microscopic study of blood and bone marrow cells is necessary to diagnose MDS.

TYPES OF MYELODYSPLASTIC SYNDROME — MDS is classified according to the type and number of red blood cells. Refractory anemia (RA) causes a lack of red blood cells and is resistant (refractory) to standard treatment; RA occurs in approximately 21 percent of MDS patients. Refractory anemia with ringed sideroblasts (RARS) causes a lack of red blood cells, along with the presence of "ringed" deposits of iron in bone marrow cells under a microscope. RARS is also resistant (refractory) to standard treatment and occurs in approximately 17 percent of MDS patients. Refractory anemia with excess blasts (RAEB): a lack of red blood cells, and a bone marrow examination which shows a slight excess of bone marrow blast (leukemic) cells under a microscope and is resistant (refractory) to standard treatment; RAEB occurs in approximately 37 percent of MDS patients. Refractory anemia with excess blasts in transformation (RAEB-t) causes a lack of red blood cells, which shows a greater excess of bone marrow blast cells (greater than in RAEB) under a microscope and is resistant (refractory) to standard treatment. There may be little difference between RAEB-t and acute myeloid leukemia. RAEB-t occurs in approximately 13 percent of MDS patients. Chronic myelomonocytic leukemia (CMML) is a type of chronic leukemia with an excessive number of monocytes (a type of white blood cell); CMML occurs in approximately 12 percent of MDS patients. Most people with CMML have an elevated white blood cell count.

Some cases of MDS are not readily categorized. This is particularly true for people with treatment-related MDS. In such cases, the terms "unclassifiable MDS" or "refractory anemia with dysplasia" have been used.

TREATMENT — Treatment of patients with MDS includes four major goals: Control of symptoms - this goal is easily achieved Improving quality of life and minimizing the side effects of therapy - this goal is frequently achievable Decreasing progression to acute leukemia - we are currently unable to achieve this goal Improving overall survival - with good medical care and judicious use of growth factors we can have an impact here

Practice guidelines of the National Comprehensive Cancer Network (NCCN) suggest that treatment should be based upon three features (show table 3): Age of the patient Performance status, a measure of how well a patient can perform normal daily tasks Risk category, as defined by the IPSS system

High versus low intensity treatment — The NCCN has characterized treatment as being either of "high" or "low" intensity, as follows: High intensity treatment requires hospitalization and includes intensive combination chemotherapy with or without bone marrow transplantation. Low intensity treatment includes outpatient treatments, such as hematopoietic growth factors, differentiation-inducing agents, biologic response modifiers, and low intensity chemotherapy.

Treatment recommendations — MDS treatment guidelines include the following (show table 3): Patients less than 61 years of age who have minimal disease symptoms and who are in the IPSS intermediate-2 or high risk categories (expected survival 0.3 to 1.8 years) are generally treated with high intensity therapies. Patients in the low or intermediate-1 category (expected survival 5 to 12 years) are generally treated with low intensity therapy. Patients >60 years of age with good performance status (expected survival 0.4 to 5 years), are generally treated with low intensity therapy, although selected patients may be candidates for high intensity therapies. For patients with a limited life expectancy, supportive care or low intensity therapies are recommended. Supportive care includes transfusion of red cells or platelets, antibiotics, and hematopoietic growth factors.

Due to the advanced age of most patients with MDS, the chronic nature of the disease and its symptoms, supportive care is an important part of treatment for all patients.

Virtually all of the treatments discussed below are still considered to be experimental. Comparative clinical trials with the critical involvement of MDS patients are still needed in order to determine the relative value of each of the treatments described below.

Hematopoietic growth factors — The hematopoietic growth factors, recombinant human granulocyte colony-stimulating factor (G-CSF) and recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) do not improve survival or prevent infection in people with MDS. Recombinant human erythropoietin (EPO) promotes the growth of red cells, and decreases the need for red cell transfusions in 20 percent of MDS patients.

Combination therapy, using G-CSF along with EPO, may be more effective than EPO alone, especially in those with low serum levels of EPO and low transfusion requirements.

Immunosuppressive drugs — In some patients with MDS, the immune system may encourage a decreased production of blood cells. This may be especially true in people with a reduced number of cells in the bone marrow.

Some of these patients, particularly those who are younger, with normal blood cells, reduced cell content of the marrow, and early disease, respond to immunosuppressive therapies, which weaken the immune system. Examples of immunosuppressive therapies include antithymocyte globulin (ATG) and cyclosporine.

Most everyone who is treated with ATG develops serum sickness, which causes hives, swelling, and fever. This reaction can be reduced by giving steroids along with the ATG.

Thalidomide and its derivatives — Responses to thalidomide occur in 20 percent of patients with MDS, but side effects such as fatigue and constipation can be formidable.

Second generation thalidomide-like drugs (eg, Revlimid, lenalidomide) may be more active and more tolerable for treatment of anemia. In early studies, this agent has been particularly effective in patients with abnormalities of chromosome 5 (called the 5q minus syndrome).

Low and intermediate dose chemotherapy — Low doses of chemotherapy have been used in selected patients with MDS. This approach is a good option in older patients (show table 3).

Cytarabine has been the most widely studied drug, although rates of complete remission are below 20 percent. The drug 5-azacytidine has shown activity in MDS, and may lengthen survival, although the improvement is modest. 5-aza-2-deoxycytidine may be more effective than 5-azacytidine.

High intensity chemotherapy — Aggressive chemotherapy has generally not been as effective in people with MDS as in people with acute leukemia. In one study, patients <60 years of age with a good performance status underwent aggressive chemotherapy followed by bone marrow transplantation [2]. Survival of these patients was comparable to, or better than, that of patients treated with only supportive care and nonintensive treatment approaches.

Ongoing studies are evaluating new drugs (eg, clofarabine combined with cytarabine). Such chemotherapy programs entail a significant risk, especially in people with other serious medical conditions, such as the elderly. This risk would only be justified if the new agents appeared much more effective than the older treatment programs.

Inhibitors of tumor necrosis factor-alpha — Some of the diminished production of blood cells is thought to be due to an excess production of tumor necrosis factor (TNF)-alpha, a protein which usually has anticancer activity, but, in excess, can cause a deficiency of red blood cells and some of the necessary components in the blood. Clinical trials are ongoing using etanercept, a protein that binds to TNF-alpha and prevents it from having harmful effects.

STEM CELL TRANSPLANTATION — In the past, patients over age 50 were not considered for hematopoeitic stem cell transplantation (also called bone marrow transplantation), mostly due to the risk of transplant-related complications. Improvements in technique and supportive care have allowed the upper age limit for BMT to expand to people age 60 or more. However, approximately 75 percent of patients with MDS are older than 60 at diagnosis, so conventional BMT can only be offered to a minority of individuals. (See "Patient information: Overview of bone marrow transplantation").

One study from Seattle evaluated the outcome after BMT in 50 patients between the ages of 55 and 66 [3], and found that survival in all categories was inversely related to their IPSS risk score. For example, a person in this age group with a high risk score was less likely to survive than a person with a low risk score. Thus, age alone might not be the only determining factor in the decision to undergo BMT.

However, patients who are less than 60 years with the most favorable IPSS scores have median survivals of 5 to 12 years with standard (supportive) care only. This group also has the highest success rate following BMT, although the median survival is approximately five years, which takes into account those patients "cured" of MDS as well as those dying early as a result of the transplantation procedure itself. Thus, survival following transplantation may be lower than that achieved with supportive care alone. Accordingly, the decision to undergo transplantation is difficult.

Patients with MDS who are under the age of 60 and who have a tissue-matched sibling donor of bone marrow should be considered for a BMT. The decision to have BMT depends upon a number of criteria, including the IPSS score and the risk of disease progression and the overall health of the patient. Although there is a significant chance of cure after BMT in low and intermediate risk patients (approximately 60 and 40 percent, respectively), transplant-related deaths and the relapse rate at five years are also high (as high as 40 percent).

One study described the outcome after BMT in 93 patients with MDS [4,5]. After four years, 41 percent of patients were alive and free of disease, 28 percent had relapsed, and 43 percent died of transplant-related complications. As expected, those patients who had the best overall result were younger (<40 years). A 1998 update of this study included 251 patients with MDS; 60, 36, and 28 percent of patients in the low and intermediate-1, intermediate-2, and high risk groups, respectively, were disease free after five years [6]. Based upon this data, BMT is recommended for patients with intermediate-1, intermediate-2, and high risk MDS, but not for patients with low risk disease.

The use of tissue-matched unrelated donors for patients with MDS has been limited. One study found that age was a factor with unrelated bone marrow transplants; younger patients had better survival than older patients.

Use of reduced intensity treatment before transplantation, also called "mini-transplants", have allowed some patients with MDS, who would not otherwise be eligible, to receive a transplant with a lower incidence of transplant-related complications. This is an area of intense research interest.

Children — BMT is the treatment of choice for children with MDS. BMT allows for long term survival for a high percentage of those with tissue-matched sibling donors.

Progression to acute leukemia prior to BMT — If a patient's MDS evolves into acute leukemia prior to a bone marrow transplantation procedure, many physicians choose to perform the transplant immediately, rather than administering pretransplant chemotherapy. Pre-BMT chemotherapy can increase a patient's risk of developing complications such as infections, especially fungal disease, and organ damage.

Other considerations — Patients with MDS are chronically immunosuppressed and are at risk for a variety of infections. They are also at high risk for a relapse of MDS following effective treatment. The risk of relapse may be as high as 40 percent at five years.

Recommendations for BMT — The above studies indicate that a subset of patients with MDS can be cured following BMT. This is in contrast to all other treatments, none of which has provided a significant chance for cure.

BMT should be considered for people with MDS who are under the age of 60 who have a tissue-matched sibling donor. The decision to undergo BMT depends upon a number of criteria, including the IPSS score, the risk of disease progression, underlying infections, and the overall health of the patient.

Although there is a significant chance of cure after BMT in low and intermediate risk patients (approximately 60 and 40 percent, respectively), transplant-related death is also high (as much as 40 percent). In addition, even five years after successful BMT, the risk of relapse of MDS is about 40 percent. Patients and their physicians should balance these competing issues and compare the outcomes of BMT and supportive care only.

TREATMENT-RELATED MDS — Treatment-related MDS (t-MDS) is an extremely serious complication of chemotherapy, and is usually fatal even with standard treatment. In one study, survival was strongly dependent upon the chemotherapy used immediately prior to BMT. Five-year survival after BMT for patients with treatment-related MDS is lower than that of patients with spontaneously-occurring MDS.

PROGNOSIS

IPSS Prognostic model — A prognostic system (model) was devised, called the International prognostic scoring system (IPSS), which considers variables such as age, type of blood abnormality present, as well as studies of the genetic makeup of the abnormal cells. The IPSS system is helpful to determine the prognosis of patients. Based on these criteria, four risk groups for survival and likelihood of progression to acute leukemia were defined: low, intermediate-1, intermediate-2, and high risk groups (show table 2): Overall median survival was longer for those in the low risk category compared to those in the intermediate and high risk categories. These were 5.7, 3.5, 1.2, and 0.4 years for patients with low, intermediate-1, intermediate-2, and high risk, respectively. The time for 25 percent of the patients to develop acute leukemia was longer for those in the low risk category than those in the intermediate and high risk categories: 9.4, 3.3, 1.1, and 0.2 years, for patients with low, intermediate-1, intermediate-2, and high risk, respectively. Survival of high risk patients was independent of age, being approximately 0.3 to 0.5 years for all age groups. Survival of low risk patients was strongly dependent on age: 11.8, 4.8, and 3.9 years in patients 60, >60, and >70 years of age, respectively.

The survival times noted above are averages; there is considerable variation from patient to patient, especially in the low-risk group.

Using the classification system, patients with RAEB and RAEB-t have relatively poor outcomes, with median survivals ranging from 5 to 12 months. In contrast, those with RA and RARS had median survivals of approximately three to six years.

The proportion of individuals whose disease progressed to acute myeloid leukemia (AML) varies similarly; 40 to 50 percent of patients with RAEB and RAEB-t progress to AML, compared to 5 to 15 percent of patients with RA and RARS (show table 1). RAEB-t usually progresses to AML faster than the other subgroups.

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 Library of Medicine

(www.nlm.nih.gov/medlineplus)
The Leukemia & Lymphoma Society

(www.leukemia-lymphoma.org)
National Marrow Donor Program

(www.marrow.org)
Aplastic Anemia and MDS International Foundation, Inc.

(www.aamds.org)
People Living With Cancer: The official patient information

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

[1-6]

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Bennett, JM, Catovsky, D, Daniel, MT, et al. FAB Cooperative Group: Proposal for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51:189.
2. de Witte, T, Suciu, S, Verhoef, G, et al. Intensive chemotherapy followed by allogeneic or autologous stem cell transplantation for patients with myelodysplastic syndromes (MDSs) and acute myeloid leukemia following MDS. Blood 2001; 98:2326.
3. Deeg, HJ, Shulman, HM, Anderson, JE, et al. Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood 2000; 95:1188.
4. Anderson, JE, Appelbaum, FR, Fisher, LD, et al. Allogeneic bone marrow transplantation for 93 patients with myelodysplastic syndrome. Blood 1993; 82:677.
5. Appelbaum, FR, Barrall, J, Storb, R, et al. Bone marrow transplantation for patients with myelodysplasia. Pretreatment variables and outcome. Ann Intern Med 1990; 112:590.
6. Appelbaum, FR, Anderson, J. Allogeneic bone marrow transplantation for myelodysplastic syndrome: outcomes analysis according to IPSS score. Leukemia 1998; 12 Suppl 1:S25.

Myelodysplastic syndromes (MDS)

Multiple myeloma

INTRODUCTION — Multiple myeloma (MM) is a cancer of plasma cells in the bone marrow. Normally, plasma cells produce antibodies and play a key role in immune function. However, uncontrolled growth of these cells leads to bone pain and fractures, anemia, infections, and other complications.

In the United States, about 4 out of 100,000 individuals are diagnosed with MM each year. This condition is slightly more common among men than women, and almost twice as common among blacks as among whites. The average age at diagnosis is 65 to 70 years.

The current treatment options for MM include watchful waiting (for early or smoldering multiple myeloma), chemotherapy, immune-modulating drugs, and stem cell transplantation. Multiple myeloma is seldom cured, but treatment can relieve symptoms, induce remission, and prolong life.

The cause of MM is unknown. Exposure to radiation, organic chemicals (such as benzene), herbicides, and insecticides may play a role. Genetic factors and viral infection may also influence the risk of developing multiple myeloma.

FEATURES — Multiple myeloma can produce a wide variety of symptoms.

Bone symptoms — Most individuals develop bone pain in the back or chest or, less commonly, the arms and legs, at the time of diagnosis. The pain is usually triggered by movement and is absent at night, except when changing positions.

MM causes both generalized bone loss throughout the body as well as bone erosions (lytic lesions on x-ray) in specific areas. The bone loss and erosions can lead to osteoporosis and fractures. Many individuals with multiple myeloma experience fractures of the vertebrae (the bones of the spine), which can lead to a loss of height; about 30 percent of individuals experience fractures in other bones, often with little or no preceding trauma. For this reason they are called "pathologic fractures."

High blood calcium levels — Because bones contain large amounts of calcium, the breakdown of bone in MM can lead to high blood calcium levels (called hypercalcemia). High blood calcium levels occur in 10 to 15 percent of individuals, and the symptoms may include loss of appetite, nausea, vomiting, frequent urination, increased thirst, constipation, weakness, confusion, stupor, or coma.

Anemia — About two thirds of individuals have anemia (low red cell count) at the time of diagnosis, and anemia eventually occurs in almost all individuals. The signs and symptoms of anemia include paleness, weakness, and fatigue.

Impaired kidney function — The excess proteins and high blood calcium levels associated with MM can damage the kidneys. Kidney function is abnormal at diagnosis in about half of individuals with multiple myeloma. Occasionally, kidney failure is the first symptom of MM.

Thickened blood — The excessive production of proteins by the malignant plasma cells in MM can cause a thickening of the blood (called hyperviscosity syndrome). The symptoms may include bleeding from the nose and mouth, blurred vision, neurologic symptoms, and congestive heart failure.

Neurologic symptoms — Fractures of the vertebrae can lead to increased pressure on the nerve roots where they exit the spine, causing neurologic symptoms (called radiculopathy). This complication of multiple myeloma most commonly affects the chest, lower back, or legs, and the symptoms may include odd sensations (numbness or tingling), pain, or muscle weakness.

Occasionally, neurologic symptoms occur because plasma cells grow within the spinal canal and press on the spinal cord. The symptoms may include severe back pain, muscle weakness, especially of the legs, numbness or tingling, and loss of control of bowel or bladder function (incontinence). Spinal cord compression is a medical emergency and requires immediate treatment to relieve the pressure and prevent permanent damage.

Generalized symptoms — The generalized symptoms of MM include an increased susceptibility to infections (especially during chemotherapy) and weight loss. Occasionally, it causes increased bleeding or tumors of the ribs. In individuals with advanced MM, tumor cells may accumulate beneath the skin, causing large purple-colored bumps.

DIAGNOSTIC TESTING — The diagnosis of MM is based upon the presence of characteristic signs and symptoms of the disease and on the results of tests of the blood and bone marrow. Several different tests are used to determine the presence and severity of MM. In some individuals with early MM or related conditions, it may be necessary to repeat these tests periodically until the diagnosis is certain.

After MM is confirmed, additional tests are used to check for the presence of impaired kidney function, anemia, thickening of the blood, and other complications of multiple myeloma.

Blood and urine tests for monoclonal protein — An abnormal protein produced by the plasma cells, called a monoclonal (M) protein (sometimes called a "paraprotein"), can be found in the blood or urine of almost all patients with MM, which helps establish the diagnosis. These proteins serve no useful function, and may be responsible for increases in the thickness of the blood, kidney damage, or bleeding problems.

However, it is important to remember that not everyone with a monoclonal protein has MM. The diagnosis requires, in addition to the monoclonal protein, one or more abnormalities such as anemia, bone lesions (see "X-rays" below), kidney failure, or high calcium levels in the blood (see "Criteria for diagnosis" below).

Bone marrow examination — In most individuals with MM, a bone marrow aspiration and biopsy (a collection of a small sample of bone marrow for laboratory analysis, usually taken from the hip) shows that plasma cells comprise an abnormally high percentage of bone marrow cells (more than 10 percent). It may be necessary to collect samples from different areas because MM may affect the marrow of some bones but not others.

X-rays — In about 80 percent of individuals, routine x-rays show distinct, round (lytic) areas of bone erosion; generalized thinning of the bones; and/or fractures at the time of diagnosis. The bones most commonly involved are the vertebrae, the ribs, the pelvic bones, and the bones of the thigh and upper arm.

Genetic and chromosomal tests — Specialized tests may reveal genetic or chromosomal abnormalities of the plasma cells in individuals with MM. In general, such abnormalities are associated with a poorer prognosis. The results of these tests are helpful for predicting the response to treatment and survival.

Plasma cell labeling index — The plasma cell labeling index determines how rapidly the abnormal plasma cells are growing and dividing. Patients in whom the labeling index is low tend to have slower disease progression than those with high values. This test is also useful for distinguishing MM from related conditions that generally have a better prognosis. A normal plasma cell labeling index suggests that MM is less likely, while an elevated index suggests that multiple myeloma is more likely. However, this test is not generally available.

Criteria for diagnosis — The diagnosis of multiple myeloma requires the following: A bone marrow aspirate or biopsy showing that at least 10 percent of the cells are plasma cells or the presence of a plasma cell tumor (called a plasmacytoma), plus: M protein in the blood or urine, or Evidence of damage to the body as a result of the plasma cell growth, such as destructive bone lesions, kidney failure, anemia, or high calcium in the blood.

STAGING AND PROGNOSIS — The simplest measure of prognosis in MM is based on blood levels of two markers: beta-2-microglobulin and albumin. In general, higher levels of beta-2-microglobulin and lower levels of albumin are associated with a poorer prognosis. This staging system is referred to as the International Staging System, or ISS.

The older Durie-Salmon staging system divided patients into three stages: Stages I, II, and III, corresponding to low, intermediate, and high cell mass, depending on such factors as the degree of anemia, calcium level, kidney function, presence or absence of bone lesions, and the amount of the abnormal protein. It is best used as a measure of the overall amounts of malignant plasma cells present in the patient, and is less useful as a measure of prognosis.

TREATMENT OVERVIEW — The treatment of MM is complex because of rapid advances in stem cell transplantation, medications, and better supportive care. The main options for therapy include: Chemotherapy Stem cell (bone marrow) transplantation

Each option needs to be weighed carefully. Because current therapy is rarely curative, patients will likely go through many treatment options during the course of their illness. Stem cell transplantation may not be an option for many patients because of advanced age, presence of other serious illness, or other physical limitations (see "Stem cell transplantation" below).

CHEMOTHERAPY — Chemotherapy is usually the first treatment recommended. In most individuals, chemotherapy partially controls MM; rarely, chemotherapy leads to complete remission. The response to initial chemotherapy also helps to estimate how long an individual will survive.

A person who "responds" to chemotherapy must have a 50 percent reduction in blood and urine levels of the abnormal M protein and an improvement of symptoms. Individuals who have any response to chemotherapy (even if it does not meet the above definition) survive approximately three years, while individuals who do not have a response survive approximately one to two years.

The treatment of MM is tailored to a variety of individual factors, including the stage of MM, age, overall health, and personal preferences.

Timing of chemotherapy — Multiple myeloma can remain stable for prolonged periods of time. Individuals with early myeloma (stage I: low cell mass by the Durie-Salmon staging system) who have no symptoms (often called smoldering or indolent myeloma) may be advised to wait months to years before considering chemotherapy.

Individuals with a related condition, called monoclonal gammopathy of undetermined significance (MGUS), do not require treatment, although long-term follow-up is needed; a percentage of patients with MGUS will eventually develop full-blown myeloma.

Chemotherapy is recommended for individuals who have symptoms of multiple myeloma at the time of diagnosis.

Initial chemotherapy options — The type of chemotherapy initially recommended for treatment of MM depends upon the patient's age, underlying medical illnesses, and the likelihood of undergoing stem cell transplantation in the future. Melphalan prednisone (MP) chemotherapy is usually recommended first for individuals over the age of 75 and younger individuals who will not be undergoing stem cell (bone marrow) transplantation at a later time because of associated illnesses or poor health. If later transplantation is a possibility, stem cells should be collected before the start of melphalan chemotherapy because this drug can cause long-lasting damage to stem cells. For individuals between 65 and 75 years who do not plan to undergo stem cell transplantation, melphalan, prednisone, and thalidomide (MPT) is recommended. This is also recommended if a rapid response is needed.

For either of the above groups, chemotherapy is usually continued until the patient reaches a plateau phase (see "Plateau phase" below). For individuals who hope to undergo stem cell transplantation, treatment with dexamethasone plus thalidomide is recommended (thal/dex) or another similar regimen is recommended. These treatments do not interfere with later collection of stem cells. For individuals who have renal failure at the time initial chemotherapy is needed, treatment with dexamethasone alone or dexamethasone plus thalidomide is often preferred.

Melphalan prednisone (MP) chemotherapy — Melphalan (Alkeran, a drug in the alkylating agent class of chemotherapy drugs) and prednisone (a steroid) are taken by mouth three times daily for seven days; this is repeated every four to six weeks. A one week dose is called a cycle. It may take 6 to 12 months or even longer for blood tests to reflect the full effects of this chemotherapy on multiple myeloma.

Between 50 and 60 percent of individuals with MM have a response to melphalan-prednisone chemotherapy. The average survival among individuals treated with this chemotherapy is three years.

During melphalan-prednisone chemotherapy, periodic blood tests are needed to ensure that an individual has adequate levels of white blood cells (cells that fight infection) and platelets (blood components that are important for clotting). The dose of melphalan must be adjusted based on these findings.

Thalidomide — Thalidomide (Thalomid®) is an immune-modulating drug that is effective in the treatment of relapsed MM, either alone or in combination with steroids such as dexamethasone or chemotherapy. Thalidomide is not yet approved for the initial treatment of myeloma, but is commonly used "off label" for this purpose.

Among individuals treated with thalidomide alone for relapsed myeloma, 58 percent survive at least one year, and, on average, 48 percent survive at least two years. The possible side effects of thalidomide, when used for prolonged periods of time, include nerve damage, usually involving the sensory and motor functions of nerves serving the arms and legs, which may not be reversible.

Thalidomide is taken orally. The main side effects are sleepiness, constipation, skin rash, and nerve damage. The use of this medicine in combination with dexamethasone or chemotherapy increases the chance of developing blood clots, and may require the use of anticoagulants ("blood thinners") to prevent this from happening. Thalidomide causes severe birth defects and it is absolutely unsafe (contraindicated) for pregnant women.

Lenalidomide (Revlimid®) is a closely related drug (analogue) of thalidomide. It is currently available as a second line treatment, and is being evaluated as a first line treatment in clinical research trials. It has shown clinical activity in MM with fewer side effects than thalidomide (see "Clinical trials" below).

Bortezomib — Bortezomib (Velcade™) is a proteasome inhibitor that is effective in treating patients with refractory MM and other tumors. It is currently available as a second line treatment, and is being evaluated as a first line treatment in clinical research trials. It is given intravenously, and its main side effects are low blood counts and nerve damage.

Chemotherapy-related infections — There is an increased risk of infection during the first two months of chemotherapy. Infections often require stopping chemotherapy. Therefore, daily antibiotics may be recommended for individuals starting chemotherapy to reduce the risk of infection and the severity of infections that do occur.

Plateau phase — Chemotherapy is usually continued until MM enters a stable (plateau) phase. The plateau phase is reached when the myeloma becomes stable and shows no signs of progressing. Although this phase is usually temporary, it typically lasts six months or longer. The plateau phase occurs in about one half of individuals after chemotherapy.

Achieving this phase usually requires at least six cycles of chemotherapy, but it may require additional cycles. Additional chemotherapy is not needed or recommended during the plateau phase.

STEM CELL TRANSPLANTATION — Stem cell or bone marrow transplantation is a treatment option for some individuals with MM. There are three types of transplantation, based on the source of the stem cells: Autologous transplantation: the stem cells are obtained from the individual with MM. This is the type of transplantation that is most commonly recommended. Allogeneic transplantation: the stem cells or bone marrow are obtained from a donor with a tissue type matching that of the patient. This type of transplantation carries very high risks and is not recommended for most individuals with MM. Syngeneic transplantation: the stem cells or bone marrow are obtained from an identical twin of the individual. This is the optimal form of transplant at this time, but only rare individuals with MM have an available identical twin who can serve as a donor.

Transplantation, when successful, prolongs survival, leads to a remission, and, infrequently, cures MM. However, transplantation has several limitations. The high-dose chemotherapy (even with radiation) given before transplantation usually fails to kill all of plasma cells, allowing the condition to relapse. Such treatment also puts the patient at risk for serious infections and bleeding, which might be fatal. (See "Patient information: Overview of bone marrow transplantation").

Autologous stem cell transplantation — Autologous stem cell transplantation refers to transplantation with an individual's own stem cells. During this procedure, stem cells are collected and frozen for later use. High-dose chemotherapy is then given to kill as many plasma cells as possible, and the stem cells are thawed and returned to the patient. Stem cells obtained from the peripheral blood of the patient are preferred over bone marrow, because peripheral blood stem cells take up residence in tissues more quickly and are less likely to be contaminated with residual malignant plasma cells.

At present, autologous stem cell (or bone marrow) transplantation is appropriate for up to 50 percent of individuals with multiple myeloma.

Procedure — After initial therapy with a regimen such as thalidomide/dexamethasone for about four months, an individual is given granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) to stimulate the production of stem cells. Stem cells are then collected from the blood, frozen, and stored for later use.

After an individual recovers from the stem cell collection, he or she is given high-dose chemotherapy with melphalan (or similar drugs) to kill as many of the malignant plasma cells as possible; then the previously collected stem cells are thawed and returned to the patient. In about one-half of patients, this procedure can be done on an outpatient basis.

Alternatively, after stem cell collection, an individual may be given standard chemotherapy with melphalan (or similar drugs) to achieve a plateau phase. At the time of relapse, high doses of melphalan (or similar drugs) are given, and the previously collected stem cells are returned to the patient ("delayed transplantation").

Role of age and stage of myeloma — Because autologous transplantation has serious side effects, it is generally not recommended for individuals over the age of 70. However, this procedure may be an option for some individuals over the age of 70 who are otherwise healthy. The likelihood of a good response to transplantation is somewhat lower for older adults than for younger adults, but the effects of age on survival after transplantation are still uncertain.

Autologous stem cell transplantation is not recommended for individuals with early stage (Durie-Salmon stage I) or smoldering myeloma.

Importance of prior treatment — Autologous transplantation is not recommended for individuals who have received prolonged chemotherapy with alkylating drugs (such as melphalan). In such instances, it is very difficult to collect a sufficient number of healthy stem cells for transplantation.

If transplantation is a possibility, initial therapy with dexamethasone alone or thalidomide plus dexamethasone is usually recommended. In contrast to alkylating drugs such as melphalan, these agents do not cause damage to the stem cells.

Effectiveness — About one to two percent of individuals die from complications related to transplantation. However, compared with chemotherapy, autologous stem cell transplantation is more likely to produce a response, and is associated with survival approximately 12 months longer than that produced by chemotherapy alone.

Single versus double autologous transplantation — Double autologous transplantation (two consecutive autologous transplantations) may be more effective than single autologous transplantation if the first transplant has not produced a complete or near complete response. The second transplantation is usually performed within six months of the first.

Among individuals undergoing double transplantation, 51 percent have a complete response, lasting, on average, 50 months. One study has shown that double transplantation improves long-term survival relative to single transplantation with the greatest benefit seen in patients who have not achieved an excellent response with the first transplant.

Allogeneic bone marrow transplantation — An allogeneic stem cell or bone marrow transplantation is a treatment option for only 5 to 10 percent of individuals with multiple myeloma. This type of transplantation has two advantages over autologous transplantation: the donated stem cells do not contain any malignant plasma cells, and the transplanted cells may target and help control any remaining myeloma cells. This latter beneficial effect is called the "graft versus tumor" effect. However, allogeneic transplantation is also associated with a "graft versus host" effect, in which cells from the donor attack tissues of the host, resulting in damage to various organs, such as the skin, liver, and intestines.

Allogeneic transplantation requires bone marrow or stem cells from a donor with a matching tissue type. Under the best conditions, a sibling may qualify as a donor; otherwise national bone marrow donor banks may be employed to find a donor with a matching tissue type. The donated bone marrow or stem cells are given to the patient after he/she receives appropriate doses of high-dose chemotherapy and radiation to reduce the number of malignant plasma cells.

About one half of individuals have a complete response after allogeneic transplantation. Thirty percent of individuals live for at least four years, and 20 percent of individuals live for at least 10 years. The likelihood of a complete response to allogeneic bone marrow transplantation is highest in individuals with a lower number of myeloma cells and in individuals who have had a complete response to the initial chemotherapy.

Although multiple myeloma usually relapses after allogeneic transplantation, some individuals are cured of multiple myeloma after this type of transplantation.

Unfortunately, approximately 25 percent of individuals who undergo allogeneic transplantation die from transplant-related complications, such as infection, lung inflammation, and graft-versus-host disease. Thus, the potential benefit of allogeneic transplantation (long-term disease control or cure) must be weighed against the potential for immediate morbidity and mortality. Primarily because of this toxicity, allogeneic transplantation is seldom used for the treatment of myeloma.

Nonmyeloablative allogeneic transplantation — Because autologous transplantation is not often curative and allogeneic transplantation carries a high mortality, other solutions have been sought. These include nonmyeloablative allogeneic transplants (often called "mini transplants") in which the patient receives a lower dose of chemotherapy prior to an allogeneic transplant.

The best results have been seen when a nonmyeloablative allogeneic transplantation is conducted following an initial autologous transplantation. However, the best preparative regimen and the control of graft versus host disease are evolving. We believe that this procedure should be done only in a research setting.

Donor lymphocyte infusion — Donor lymphocyte infusion is an experimental procedure that is a good option for individuals who have a relapse of multiple myeloma after allogeneic stem cell transplantation. During this procedure, lymphocytes collected from the original donor are given to the individual; these lymphocytes target the myeloma cells and may produce a beneficial "graft versus tumor" effect. Fifty-two percent of individuals have a response to this procedure, and 22 percent of individuals have a complete response.

Syngeneic transplantation — A syngeneic transplantation refers to a transplantation between identical twins. For individuals who have an identical twin, this treatment option is more effective than either autologous or allogeneic transplantation.

Remission after transplantation — The strict definition of remission requires that there are no signs or symptoms of multiple myeloma and that highly sensitive tests do not detect any abnormal plasma cells. This type of remission occurs in about 4 percent of individuals after autologous transplantation and about 19 percent of individuals after allogeneic transplantation.

TREATMENT OF COMPLICATIONS — Multiple myeloma can cause a variety of complications, some of which are life-threatening. It is important to treat these complications in addition to treating MM itself.

High blood calcium levels — High blood calcium levels develop as bone is lost. Individuals with MM should remain as active as possible because physical activity helps counter bone loss.

The treatment of high blood calcium levels usually includes use of intravenous fluids and prednisone. If this treatment is not effective, treatment with drugs that counter bone loss, such as zoledronic acid (Zometa™) or pamidronate (Aredia™), a class of drugs called bisphosphonates, may be recommended.

Impaired kidney function — Kidney function becomes impaired in about one half of individuals with multiple myeloma. The treatment of impaired kidney function is aimed at the specific underlying cause.

Treatment usually includes intravenous fluids; it may also include dialysis (a type of blood filtration used for kidney failure), prednisone (a steroid that can indirectly lower blood calcium levels), and allopurinol, a drug that can lower blood levels of uric acid, a waste product from the increased turnover of the malignant plasma cells, which can damage the kidneys.

Patients are advised to stay well-hydrated and should drink enough fluid to produce three liters of urine daily if they have Bence Jones proteinuria (increased light chains in the urine). They should also avoid using any nonsteroidal anti-inflammatory drugs (NSAIDs, such as Advil®, Motrin®, Aleve®) because these drugs might worsen kidney function.

If impaired kidney function has progressed to kidney failure, the treatment options include hemodialysis or peritoneal dialysis. Advanced degrees of kidney failure are usually not reversible even if the multiple myeloma later responds to treatment. (See "Patient information: Renal replacement therapy").

Infection — Bacterial infections, often indicated by the presence of fever, require prompt treatment with antibiotics. Daily use of the antibiotic trimethoprim-sulfamethoxazole (Bactrim) can help prevent infections. Individuals who get frequent infections may be advised to take penicillin daily or rarely to have periodic intravenous infusions of gamma globulin.

All individuals with MM should receive the pneumococcal vaccine (which reduces the likelihood of pneumonia) and the influenza vaccine (which reduces the likelihood of flu). (See "Patient information: Influenza").

Bone pain and fractures — Physical activity, with careful avoidance of injury, can promote bone strength in individuals with MM. The bone pain associated with MM can be controlled with chemotherapy, analgesics (pain relieving drugs), radiation, and bone strengthening drugs such as zoledronic acid (Zometa™) or pamidronate (Aredia™) (commonly referred to as bisphosphonates) that can also reduce the likelihood of fractures.

In individuals who have early signs of bone erosion, bisphosphonates reduce the risk of fractures and reduce bone pain. Therefore, bisphosphonates are recommended for all individuals who have early signs of bone erosions on x-rays. Bisphosphonates are usually given by intravenous infusion every four weeks; this treatment is continued for approximately two years. Zoledronic acid requires infusion times as short as 15 to 30 minutes. These medications may affect kidney function, which should be monitored on a regular basis to avoid this complication.

Dental procedures, such as root canal or extraction of teeth, may be associated with infection or osteonecrosis of the jaw in patients treated with intravenous bisphosphonates. Accordingly, patients should avoid such procedures while taking these agents; any needed dental procedures should be performed before these agents are started.

Spinal cord compression — Spinal cord compression is a medical emergency that requires prompt treatment to prevent irreversible damage, such as paralysis. Initial treatment may consist of radiation and dexamethasone (a steroid) to reduce swelling around the spinal cord; if these measures are not effective, surgery is needed to relieve pressure on the spinal cord.

Anemia — Anemia that is causing symptoms can be treated with erythropoietin (EPO), a substance that stimulates the production of red blood cells. Erythropoietin is usually given by injection one to three times per week. This treatment effectively increases levels of hemoglobin (the protein in red blood cells that helps carry oxygen to the tissues), improves symptoms, and reduces the need for blood transfusion.

Thickening of the blood — Thickening of the blood (called hyperviscosity syndrome) rarely occurs in individuals with MM. This complication is treated with plasmapheresis, a type of blood filtration that removes the excess monoclonal proteins responsible for the increased viscosity.

TREATMENT OF RELAPSED OR REFRACTORY DISEASE — Almost all patients with MM who survive their first cycle of treatment eventually relapse, and a modest percentage are resistant to initial treatment.

MM that responds poorly or not at all to melphalan-prednisone or other chemotherapy is called refractory MM. This condition can occur during initial chemotherapy or during chemotherapy given after a relapse. Refractory MM is more difficult to treat.

Thalidomide, bortezomib, and lenalidomide have all shown significant single-agent activity in relapsed or refractory MM; together with alkylators and corticosteroids, they form the major treatment options for relapsed or resistant disease. Relapses occurring more than six months after completing chemotherapy are usually treated by resuming the initial chemotherapy. Most individuals will again have a response to chemotherapy when it is given a second time, but the response is usually shorter and less marked than the original response. Selected patients can consider autologous or allogeneic stem cell transplantation. The lack of response to initial induction chemotherapy does not always mean that the person will not have good response to autologous hematopoietic cell transplantation. Said another way, if a person does not respond to induction chemotherapy, he or she may still respond to autologous stem cell transplantation.

CLINICAL TRIALS — Progress in treating multiple myeloma requires that better treatments be identified through clinical trials. A clinical trial is a carefully controlled way to study the effectiveness of new treatments or new combinations of known therapies; clinical trials are conducted all over the world. 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. The International Myeloma Foundation

(www.myeloma.org)
Multiple Myeloma Research Foundation

(www.multiplemyeloma.org)
National Library of Medicine

(www.nlm.nih.gov/medlineplus/healthtopics.html)
National Cancer Institute

(www.cancer.gov)
American Cancer Society

(www.cancer.org)
The Leukemia & Lymphoma Society

(www.leukemia-lymphoma.org)
National Marrow Donor Program

(www.marrow.org)
People Living With Cancer: The official patient information

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

[1-5]

Use of UpToDate is subject to the Subscription and License Agreement. REFERENCES 1. Diagnosis and management of multiple myeloma. Br J Haematol 2001; 115:522.
2. Kyle, RA. Multiple myeloma: an odyssey of discovery. Br J Haematol 2000; 111:1035.
3. Riedel, DA, Pottern, LM. The epidemiology of multiple myeloma. Hematol Oncol Clin North Am 1992; 6:225.
4. Kyle, RA, Rajkumar, SV. Multiple Myeloma. N Engl J Med 2004; 351:1860.
5. Rajkumar, SV, Kyle, RA. Multiple Myeloma: Diagnosis and Treatment. Mayo Clin Proc 2005; 80:1371.

Pages

Saturday, October 13, 2007

Ovarian cancer treatment

Myelodysplastic syndromes (MDS)

Myelodysplastic syndromes (MDS)

Multiple myeloma