Medically Reviewed by Dr. C.H. Weaver M.D. Medical Editor (08/2018)
Stage IV uterine cancer involves the bladder, bowel or distant locations in the body. Stage IVA cancer has invaded the bladder and/or bowel and IVB disease has spread to distant locations in the body.
The following is a general overview of the treatment of stage IV uterine cancer. Optimal treatment of patients with stage IV uterine cancer often requires more than one therapeutic approach. Thus, it is important for patients to be treated at a medical center that can offer multi-modality treatment involving gynecologic oncologists and radiation oncologists.
For early stage uterine cancers, all visible cancer can be removed during surgery. Unfortunately, the removal of all cancer cannot typically be achieved in patients with stage IV disease. Treatment of stage IV uterine cancer is dictated by the site of metastatic cancer and symptoms related to the spread of cancer. The goal of treatment for women with stage IV uterine cancer is to reduce symptoms and prolong survival.
“Debulking” Surgery for Inoperable Uterine Cancer
When the cancer cannot be completely removed, an appropriate question to ask is whether surgical removal of as much cancer as possible is beneficial. This is referred to as a “debulking surgery,” and is often performed so that radiation therapy and/or chemotherapy will have fewer cancer cells to kill. This, however, is major surgery and has many potential complications. The value of debulking surgery has not been clearly demonstrated in controlled clinical studies; however, researchers have evaluated the outcomes of women with advanced uterine cancer who underwent debulking surgery. Patients with less than 2 centimeters of cancer remaining after debulking surgery were compared to patients who had more than 2 centimeters of cancer remaining after debulking surgery and to patients who did not undergo debulking surgery. The average survival for optimal surgical debulking was 32 months, compared to 12 and 13 months for women with inadequate or no debulking. Thus, there may be a role for surgically removing as much cancer as possible in women with widespread uterine cancer.
For bulky pelvic disease, radiation therapy consisting of a combination of brachytherapy (intracavitary placement of a radioactive isotope) and external-beam radiation therapy is frequently used. Radiation therapy can decrease symptoms and improve survival for patients with inoperable uterine cancer.
Primary Hormone Therapy
Cancers that have estrogen or progesterone receptors (small proteins on the surface of the cells) can be treated with hormonal therapy, which can delay cancer progression and prolong survival, especially in patients with small amounts of cancer not involving the lung or liver. Estrogen and progesterone are female hormones produced mainly by the ovaries and are found circulating in the blood. Many organs in the body are composed of cells that respond to or are regulated by exposure to these hormones. Cells in the breast, uterus and other female organs have estrogen and progesterone receptors and when exposed to these hormones, are stimulated to grow. When cells that have these receptors become cancerous, the growth of these cancer cells can be increased by exposure to the female hormones.
The basis of hormonal therapy as a treatment for uterine cancer is to block or prevent the cancer cells from being exposed to estrogen and progesterone hormones. Removal of the ovaries, the organ chiefly responsible for producing these hormones, is one effective approach to eliminating hormone production and is commonly used in many countries. Another approach is to utilize drugs that can accomplish a similar effect without removing the ovaries.
Progestational agents have long been used in the treatment of advanced or recurrent uterine cancer because of the presence of receptors for these agents on the cancer cells. Well-differentiated cancers respond better to progestational agents than undifferentiated cancers. Progestational agents that have been used include hydroxyprogesterone, medroxyprogesterone and megestrol. These agents produce a partial or complete disappearance of cancer in 20-29% of women with advanced or recurrent uterine cancer. The combination of a progestional agent (megestrol) and Nolvadex® (an anti-estrogen) may be better treatment than megestrol alone. In one study performed by the Gynecology Oncology Group, 61 patients with advanced or recurrent uterine cancer were treated with megestrol and Nolvadex®. The complete response rate was 21% and 5.4% had a partial response. The average survival was 14 months. Toxicity was moderate and there were no treatment related deaths. Of those who responded, 50% sustained this response for an average of 20 months. It was noted that, overall, younger women had better responses to the treatment than older women. From these findings, the researchers concluded that megestrol and Nolvadex® appears to be an active combination against advanced and recurrent endometrial cancers. More recently, hormone treatment is being used in earlier stages of this disease.
Chemotherapy is the use of chemicals (drugs or medications) to kill cancer cells. Numerous chemicals have been developed for this purpose and most act to injure the DNA of cells. When the DNA is injured, the cells cannot grow or survive. Successful chemotherapy depends on the cancer cells being at least somewhat more sensitive to the chemicals than the normal cells. Because the cells of the bone marrow, the intestinal tract, the skin and hair follicles are also very sensitive to these chemicals, injury to these organs are common side effects of chemotherapy (i.e., mouth sores, diarrhea, rashes and hair loss).
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Doxorubicin was the standard chemotherapy treatment for women with advanced or recurrent uterine cancer for over a decade. When doxorubicin is administered as a single agent, it reduces the amount of cancer in about 25% of women with advanced or recurrent uterine cancer. Doxorubicin is now being administered in combination with other chemotherapy agents. A comparison of doxorubicin administered alone to doxorubicin plus Platinol® in women with uterine cancer showed that the combination reduced the amount of cancer in 45% of women, compared to only 27% for doxorubicin alone. Thus, doxorubicin and Platinol® became the standard chemotherapy drug combination for treatment of women with advanced or recurrent uterine cancer.
The Gynecologic Oncology Group compared the standard doxorubicin and Platinol® treatment regimen to doxorubicin and paclitaxel. This study randomly allocated 314 women with advanced or recurrent uterine cancer to receive doxorubicin combined with either Platinol® or paclitaxel. Paclitaxel was given with Neupogen® to hasten recovery of blood counts. Side effects were similar between both treatments. The response rate following doxorubicin and Platinol® was 40% and 15% of these were complete responses. The response rate following doxorubicin and paclitaxel was 43% and 17% of these were complete responses. Longer follow-up is required to determine whether either treatment prolonged survival.
Chemotherapy and Hormonal Therapy
Chemotherapy and hormonal therapy prevent cancer cells from growing by different methods. Combining chemotherapy with hormonal therapy may reduce cancer cell growth more than either treatment administered alone. Researchers in Greece have evaluated a four-drug combination of Paraplatin®, methotrexate, fluorouracil and medroxyprogesterone. These physicians treated 23 patients with advanced or recurrent uterine cancer. None of the patients had received prior chemotherapy or hormonal therapy and 10 had received prior radiation therapy. Responses were observed in 74% of women, with two long-lasting complete remissions. The average duration of response was over 10 months and the average survival was over 16 months. This regimen was administered on an outpatient basis and was well tolerated. These doctors concluded that this was an active treatment regimen for women with advanced or recurrent uterine cancer.
Strategies to Improve Treatment
The progress that has been made in the treatment of stage IV uterine cancer has resulted from improved hormonal treatments, chemotherapy treatments and doctor and patient participation in clinical studies. Currently, there are several areas of active exploration aimed at improving the treatment of stage IV uterine cancer.
Hormonal Agents: Researchers are continuing to design new agents that take advantage of the hormone sensitivity of some uterine cancers. SERM LY353381 binds to the estrogen receptor and has been shown to prevent growth of uterine cancer. A novel agent, SERM LY353381, was evaluated in 35 women with progesterone sensitive uterine cancer. Most patients in this study had failed surgery and radiation therapy. Twenty-two percent of patients experienced a partial disappearance of cancer following treatment. The major side effects were hot flashes, swelling and sweating. The importance of this study is that a new hormonal agent with a different mechanism of action is now available for further evaluation in patients with advanced or recurrent uterine cancer.
New Chemotherapy Regimens: Development of new multi-drug chemotherapy treatment regimens that incorporate new or additional anti-cancer therapies for use as treatment is an active area of clinical research carried out in phase II clinical trials. These studies are performed in patients with stage IV or recurrent uterine cancer. One drug combination currently under investigation is Platinol® and Hycamtin®.
Phase I Trials: New chemotherapy drugs continue to be developed and evaluated in phase I clinical trials. The purpose of phase I trials is to evaluate new drugs in order to determine the best way of administering the drug and to determine whether the drug has any anti-cancer activity in patients with uterine cancer.
Miller DS, Fleming G, Randall ME. Chemo- and radiotherapy in adjuvant management of optimally debulked endometrial cancer. Journal of the National Comprehensive Cancer Network. 2009;7:535-541.
Randall ME, Filiaci VL, Muss H et al. Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: A Gynecologic Oncology Group study. Journal of Clinical Oncology. 2006;24:36-44.
Maggi R, Lissoni A, Spina F et al. Adjuvant chemotherapy vs radiotherapy in high-risk endometrial carcinoma: results of a randomized trial. British Journal of Cancer. 2006;95:266-271.
Hogberg T, Rosenberg P, Kristensen G et al. A randomized phase-III study on adjuvant treatment with radiation (RT) ± chemotherapy (CT) in early-stage high-risk endometrial cancer (NSGO-EC-9501/EORTC 55991). Presented at the 2007 annual meeting of the American Society of Clinical Oncology. Abstract 5503.