Recurrent uterine cancer is cancer that has returned after primary treatment.  For most women, recurrent uterine cancer is incurable with currently available standard therapies.  The identification of a cancer driving genomic mutation may also help define treatment for some patients – ALL women should undergo genomic biomarker testing.

If a recurrence follows primary treatment with surgery alone and is detected early, cure is still attainable with additional surgery and/or radiation therapy. Unfortunately, the removal of all cancer cannot typically be achieved for the majority of patients with recurrent disease. For these patients, treatment of recurrent 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 recurrent uterine cancer is to reduce symptoms and prolong survival.

Genetic Mutations: Not all uterine cancer cells are alike. They may differ from one another based on what genes have mutations. Molecular testing should be performed to test for genetic mutations or the proteins they produce on ALL patients. By testing an individual’s uterine cancer for specific unique genomic- biomarkers doctors can offer a personalized treatment approach utilizing precision medicines. Uterine cancer mutations are being identified and new precision cancer medicines are being developed to target these mutations on an ongoing basis.

Precision Cancer Medicine Treatment

Individuals with the following biomarkers may have their uterine cancer treated differently using targeted precision cancer medicines.

Microsatellite Instability High (MSI-H): MSI-H is a DNA abnormality found in about 20% of uterine cancers. It is most often found in tumors associated with genetic syndromes like Lynch syndrome but can also occur sporadically. MSI-High uterine cancer can be more effectively treated with the precision cancer immunotherapy drugs called “checkpoint inhibitors.” Keytruda, and Opdivo have both been demonstrated to improve treatment of individuals with MSI-High disease.

Recurrence Following Treatment of Early Stage Cancer with Surgery

Women who initially had stage I or IIB cancer and experienced a recurrence after treatment with surgery alone are frequently cured with further surgery and the addition of radiation therapy. Radiation therapy is usually given as brachytherapy (placement of a radioactive isotope near the cancer) and external beam radiation therapy. This therapy is often successful since stage I and IIB patients treated initially with surgery alone have frequent follow-up examinations, which allow for detection of a recurrence early, when it is curable. For patients with bulky pelvic disease, radiation therapy consisting of a combination of brachytherapy and external-beam radiation therapy is frequently used. Radiation therapy can decrease symptoms and improve survival for patients with inoperable uterine cancer.

Recurrence Following Treatment of Early Stage Cancer with Surgery and Radiation

Further radiation therapy in women who experience a recurrence following initial radiation is usually not possible. However, some women will fail treatment that only included brachytherapy and these women could be treated with external beam radiation therapy if they develop a recurrence in the pelvis away from the site of isotope placement. For more information, go to Radiation Therapy and Cancer of the Uterus.

Primary Hormone Therapy

Hormonal treatment of cancers that have estrogen or progesterone receptors 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 tamoxifen (an anti-estrogen) may be better treatment than megestrol alone.

Chemotherapy

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). Several chemotherapy medications used alone or in combination can effectively induce remissions in ~ 30% to 70% of women with recurrent uterine cancer.

• Doxorubicin
• Doxil
• Platinol
• Hycamtin
• Gemcitabine
• Taxol
• Taxotere

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 have evaluated chemotherapy-hormonal therapy drug combinations; for example 74% of patients responded to treatment with the combination of Paraplatin®, methotrexate, fluorouracil and medroxyprogesterone. 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.

Surgery for Uterine Cancer

Surgery for uterine cancer is performed in order to remove the cancer and learn additional information about the stage or extent of spread of the cancer. A surgeon who specializes in treatment of disorders of the female reproductive tract is known as a gynecologist. Gynecologic oncologists are gynecologists who have special training in treatment of cancers of the female reproductive tract. Gynecologic oncologists have developed expertise in performing surgical treatment of uterine cancer.

The standard surgery for treatment of uterine cancers is a total abdominal hysterectomy (removal of the uterus) and bilateral salpingo-oophorectomy (removal of the fallopian tubes and ovaries). In addition to removing the uterus and ovaries, the surgeon will often sample or remove the pelvic and para-aortic lymph nodes to determine if cancer has spread.

Dilation and Curettage

Dilation and curettage (D&C) is a common diagnostic procedure used by gynecologists to obtain tissue from the wall of the uterus. During a D&C, the vagina is washed with an antiseptic and a local anesthetic is injected into or near the cervix. Injectable painkillers or general anesthesia can also be used. The opening of the cervix is gradually stretched. One after the other, a series of increasingly thick rods (dilators) are inserted into the cervical opening. The thickest dilator may be the width of a fountain pen. As an alternative, absorbent dilators can be used to stretch the cervical opening. These dilators absorb fluids from the cervical area and stretch the opening of the cervix as the dilators expand. Scraping (curetting) the lining of the uterus yields tissue, which can then be looked at under the microscope to determine if cancer is present. Rarely, if ever, is curettage used for the treatment of uterine cancer since only a superficial layer of the uterus is removed.

Hysterectomy and Pelvic Lymph Node Dissection

The standard treatment of stages I – III uterine cancer is a total abdominal hysterectomy (removal of the uterus) and bilateral salpingo-oophorectomy (removal of the fallopian tubes and ovaries) with or without removal of the pelvic and para-aortic lymph nodes. When the uterus is surgically removed, the cut ends of the vagina are surgically sewn together forming what is termed a “vaginal cuff”. The vaginal cuff is a site of local cancer recurrence following surgery alone.

A hysterectomy is most effective if the exploration during surgery shows the cancer has not spread beyond the uterus. Some patients, however, will have cancer that has spread outside the uterus into the lymph nodes in the pelvis. Before the hysterectomy is done, the doctor will sometimes perform a pelvic lymph node dissection. During a pelvic lymph node dissection, the surgeon removes lymph nodes to determine whether they contain cancer. If the lymph nodes contain cancer, the surgeon may not proceed with the hysterectomy. Another form of treatment, usually radiation therapy and chemotherapy, is generally recommended.

Despite the surgical removal of the uterine cancer, some patients may experience recurrence of their cancer. It is important to realize that some patients with uterine cancer already have small amounts of cancer that have spread outside the uterus and were not removed by surgery. These cancer cells cannot be detected with any of the currently available tests. Undetectable areas of cancer outside the cervix are referred to as micrometastases. The presence of these microscopic areas of cancer causes recurrence following the initial treatment. External beam radiation therapy with or without implant radiation and chemotherapy are often recommended to cleanse the body of micrometastases in order to improve the cure rate achieved with surgical removal of the cancer.

“Debulking” Surgery for Inoperable Cancer of the Uterus

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 and patients who did not undergo debulking surgery. The average survival for optimal surgical debulking (less than 2 cm remaining) 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.

Role of Para-aortic Lymphadenectomy

When uterine cancer spreads, it leaves the uterus and travels into lymph nodes in the pelvis near the uterus. From the pelvic lymph nodes it spreads to lymph nodes around the main artery from the heart called the aorta. These lymph nodes are called para-aortic lymph nodes.

During surgery, the pelvic lymph nodes are often removed, but the value of removing the para-aortic lymph nodes is less clear. If removal of para-aortic lymph nodes improved the chance of cure and/or prolonged survival, it would be beneficial. On the other hand, if para-aortic lymph node removal merely increases the side effects of surgery, it would be unadvisable.

Surgeons have attempted to evaluate whether para-aortic lymph node removal is beneficial. In a clinical study of 137 women at high-risk for para-aortic lymph node involvement, the cancer recurrence rate was 38% and the 5-year survival rate was 71% for those who did not have lymph nodes removed, compared to a recurrence rate of 23% and survival of 85% for those who did have lymph nodes removed. These doctors suggest that patients at high risk for lymph node spread should consider surgical removal of the para-aortic lymph nodes as well as the pelvic lymph nodes.

Side Effects of Surgery

Women undergoing a hysterectomy may experience lower abdominal incisional pain, bleeding or infection after the operation because it may reduce the risk of cancer recurrence and prolong survival. Difficulty with urination or problems with bladder control can also occur in women treated with surgery. Less commonly, injury to the rectum or tubes which drain the kidneys (ureters) or bladder occurs. This may be in the form of a “fistula” or abnormal connection to the vagina. For women of childbearing age, the effects of surgery are drastic, since the uterus and both ovaries are removed. Obviously, such surgery precludes childbirth. In addition, the removal of both ovaries precipitates menopause and the need for consideration of hormone replacement.

Surgical removal of the pelvic or para-aortic lymph nodes may cause lower-body lymphedema in some women.¹ Lymphedema is the buildup of lymph fluid in the tissues just under the skin, resulting in swelling, tightness and discomfort in the affected part of the body. Damage to or blockage of the lymph system is the cause of lymphedema.

Strategies to Improve Treatment

The progress that has been made in the treatment of uterine cancer has resulted from improved development of treatments in patients with more advanced stages of cancer and participation in clinical trials. Future progress in the treatment of uterine cancer will result from continued participation in appropriate clinical trials. Currently, there are several areas of active exploration aimed at improving the treatment of uterine cancer.

Laparoscopic Surgery for Uterine Cancer: A laparoscope is a lighted tube inserted through the skin into the abdomen that allows the surgeon to visualize, photograph and sample tissue for examination under the microscope. Some surgical procedures including hysterectomy and pelvic and para-aortic lymphadenectomy can be performed laparoscopically, obviating the need for an abdominal incision. This may reduce complications of surgery, especially in obese women. The Gynecologic Oncology Study Group is currently performing a clinical trial that directly compares laparoscopic hysterectomy to the standard technique involving an abdominal incision in order to evaluate which procedure is most beneficial.

Role of Para-Aortic Lymph Nodes Dissection: Currently, the routine removal of para-aortic lymph nodes is not agreed upon. Although some uncontrolled clinical trials suggest removal of para-aortic lymph nodes prolongs survival, other trials are ongoing to define the role of para-aortic lymph node dissection.

Next: Radiation Therapy

References:

1 Abu-Rustam NR, Alektiar K, Iasonos A et al. The Incidence of Symptomatic Lower-extremity Lymphedema Following Treatment of Uterine Corpus Malignancies: A 12-year Experience at Memorial Sloan-Kettering Cancer Center. Gynecologic Oncology 2006;103:714-718.

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