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From OncoLog, April-May 2010, Vol. 55, No. 4-5

Compass: Early Uterine Papillary Serous Carcinoma
Treatment Options Tailored to Patient and Disease Characteristics

By Sunni Hosemann

Introduction

Uterine papillary serous carcinoma (UPSC) comprises 5%–10% of newly diagnosed endometrial cancers. Some UPSC tumors, when found early, will appear to be confined to a small uterine polyp, with no invasion into the wall of the uterus. Nonetheless, patients with such tumors should be referred to a gynecologic oncologist for a more extensive initial surgical staging and treatment planning than women with other uterine cancers may require.

Following surgery, a decision must be made about the next steps in treatment. The range of choices among current standards is wide, from no further treatment (observation) to radiation and/or chemotherapy. “It’s either nothing or a lot,” explained Karen Lu, M.D., a professor in the Department of Gynecologic Oncology at The University of Texas MD Anderson Cancer Center. The range of options for early-stage UPSC stems from the question: Which patients require substantial adjuvant (postoperative) therapy, and which patients should only be observed?

According to Lois Ramondetta, M.D., an associate professor in the Department of Gynecologic Oncology, the wide range of treatment choices is confusing and reflects the relative paucity of data specific to this variant of endometrial cancer. “Most large trials have combined all endometrial cancers, and owing to the relative rarity of individual histologic subtypes, it is difficult to accrue significant study populations in order to study a specific subtype,” Dr. Ramondetta said. In general, though, based on reviews of recent studies, physicians at MD Anderson rarely choose observation alone for women with early-stage UPSC and instead favor not one but a combination of adjuvant therapies.

Understanding UPSC

UPSC is associated with a high risk of recurrence and accounts for 39% of deaths resulting from endometrial cancer. That statistic suggests UPSC should be treated differently than other endometrial cancers, but deriving evidence-based guidelines for UPSC-specific treatments has been difficult. Because of the rarity of UPSC, few studies targeting this disease subtype have been conducted.

The more common variants of endometrial carcinoma are classified as type I cancers. They have an endometrioid histology, are more typically seen in younger women, and are associated with obesity and hyperestrogenism. UPSC is categorized as a type II endometrial cancer, is seen more commonly in older, thinner women, and is not historically associated with hormonal risk factors. The incidence of UPSC is also significantly higher in African-American women and in women who have had breast cancer. Type II endometrial cancers carry a worse prognosis than type I cancers, regardless of stage at presentation.

The most important difference between type I and type II endometrial cancers is their behavior. Type I endometrial tumors tend to progress by invading local tissues before metastasizing via the lymphatic and vascular systems. UPSC, on the other hand, spreads to peritoneal surfaces, much like ovarian cancer, and thus the depth of tumor invasion is not a reliable indicator of whether UPSC has metastasized. In fact, many UPSCs manifest as a polyp-like structure—a tumor on the end of a stalk—with no apparent invasion into endometrial tissue. Further, in some cases the disease appears to be confined to just a single polyp. This appearance belies the danger of UPSC: evidence of extrauterine disease is found in as many as 40% of patients in whom no myometrial invasion was present; and not only is the recurrence rate for stage I UPSC much higher than that for endometrioid tumors, but recurrence is also more likely to be distant than local.

When UPSC does recur at distant sites, it becomes more difficult to treat, Dr. Lu said. Recurrence of type I disease is most commonly local—within the pelvis—and is often treatable with radiation therapy.

Many endometrial tumors display a mixed histology. Although it was thought in the past that at least 10% papillary serous histology should be present to warrant a diagnosis of UPSC, studies have demonstrated that the tendency to recur and survival are related not to the percentage of tumor that has papillary serous histology but rather to the presence of any papillary serous component. Therefore, specialists at MD Anderson believe that endometrial tumors with any papillary serous component, no matter how small, should be treated as UPSC.

Initial Treatment

Treatment of all endometrial cancers begins with surgery, including a total hysterectomy; removal of ovaries, fallopian tubes, and aortic and pelvic lymph nodes; and examination of the abdomen for evidence of extrauterine disease. For UPSC, the surgery may be more extensive, and like the surgical staging of ovarian cancer, it includes removal of the omentum, scrutiny of all peritoneal surfaces for evidence of tumor, excision of all noted disease (“debulking”), and washings and biopsies for pathologic examination. This is an extensive operation that, like many operations for gynecologic cancers, should be performed by a gynecologic oncologist.

When UPSC is confirmed by surgical-pathologic staging to be stage I, standard options for further treatment range from observation to adjuvant chemotherapy and/or radiation therapy.

Adjuvant Treatment Decisions

Overview
At MD Anderson, a patient’s general health status is the overarching determinant of the approach to treating UPSC. Lymph node status and tumor characteristics are considered in the assessment of recurrence risk but are less reliable indicators of recurrence risk in UPSC than in some other endometrial cancers. These characteristics may, however, help the physician tailor therapy, particularly radiation treatments.

Observation
Currently, many guidelines and standard treatment recommendations include the option of observation following surgery for stage IA UPSC. In light of recent studies, however, physicians at MD Anderson recommend adjuvant treatment for all patients with a diagnosis of UPSC, unless the patient has concomitant medical issues that would significantly tip the risk/benefit ratio—in other words, a comorbidity or performance status that would make additional therapy less feasible.

The driving force behind treatment decisions for UPSC is its propensity to recur. As previously mentioned, UPSC’s recurrence risk is not indicated by tumor size, extent, or depth of invasion. According to Dr. Lu, serous malignancies can be aggressive regardless of the amount of tumor present. “The recurrence risk and patterns are the main reason why we would be very nervous about recommending observation alone,” she explained. “Even when there is no sign of invasion, we know now that UPSC spreads in other ways and has a high recurrence rate.” However, added Dr. Ramondetta, “It’s hard to tell a patient who has a disease confined to a polyp that she needs extensive treatment, especially if there is just a small percentage of serous histology present.”

But recurrences of UPSC are likely to occur at distant sites such as the lung—a much greater threat than local recurrence. Treatment decisions for an individual patient, therefore, include weighing her tolerance for adjuvant treatments against the possibility of an incurable recurrence.

Chemotherapy
Until recently, chemotherapy was rarely used for early-stage endometrial cancer that appeared to be confined to the uterus. However, since chemotherapy offers the best chance of eradicating distant disease and since UPSC is associated with distant recurrence, chemotherapy is now a part of the standard adjuvant therapy for all stages of UPSC except stage IA. For stage IA UPSC, chemotherapy is recommended as an adjuvant therapy.

Radiation
Radiation therapy is a traditional adjuvant treatment for endometrial cancers and is known to reduce the incidence of recurrence in the pelvis. For stage I UPSC, there are several options for adjuvant radiation therapy, including abdominopelvic or pelvic radiation with or without vaginal brachytherapy (which provides a vaginal “boost” dose of radiation) or vaginal brachytherapy alone.

National Comprehensive Cancer Network guidelines recommend tumor-directed radiation therapy (defined as radiation to the area of tumor involvement but not to the whole abdomen) as an option for stage IA UPSC. For stage IB and IC UPSC, the guidelines recommend either pelvic or abdominopelvic radiation, with or without vaginal brachytherapy. According to Anuja Jhingran, M.D., a professor in MD Anderson’s Department of Radiation Oncology, the vagina is the most common site for local recurrences of UPSC, and therefore vaginal brachytherapy is considered an important adjunct to improve local control.

Vaginal brachytherapy is delivered via an inserted cuff; a typical regimen includes a total of 5 treatments, administered every other day, compared to 5 weeks of daily treatment for pelvic or abdominopelvic radiation. “The toxicity of pelvic radiation is a key consideration,” Dr. Jhingran said. “With the vaginal cuff, there are minimal side effects since the bladder, rectum, and small bowel are not irradiated.”

Combination Therapy
Based on results from a recently completed prospective phase II study of patients with stages I-IIIA UPSC, physicians at MD Anderson now favor a combination approach of concurrent chemotherapy and radiation therapy followed by a course of chemotherapy for all patients with stages IIIIA UPSC as a means of providing both local and systemic disease control.

The chemoradiation phase of treatment in the trial consisted of weekly paclitaxel plus pelvic radiation followed by vaginal brachytherapy. This was followed by a course of four cycles of paclitaxel. Improvements in overall survival and disease-free survival using this approach were seen in all stages compared to historical and published data.

Whether there are patients with early-stage UPSC who can safely forego chemotherapy or part of the radiation treatment remains to be determined. According to Dr. Jhingran, a new multicenter trial by the Gynecologic Oncology Group, a national cooperative group of the National Cancer Institute, aims to determine whether vaginal brachytherapy may be used instead of pelvic radiation therapy in select patients with early-stage UPSC. Patients in this trial will receive chemotherapy in addition to radiation.

Currently, Dr. Jhingran would consider vaginal brachytherapy with or without systemic chemotherapy in patients with stage IA or minimally invasive IB UPSC if more than 10 lymph nodes are removed at surgery and are negative for disease. In particular, this option would be considered if tolerance for additional therapy is in question based on performance status, especially in view of vaginal brachytherapy’s low morbidity and relative convenience for the patient.

Conclusion

Choosing from the rather substantial UPSC treatment options—an extensive surgery, radiation therapy, and chemotherapy, all of which carry their own risks for morbidity—remains a challenge. “We always weigh the possible consequences of treatment in conjunction with opportunities for improved overall survival for each individual patient,” Dr. Ramondetta said. “Treatment is always tailored according to what the patient can tolerate while minimizing her risk and maximizing chance for cure.”

References
National Comprehensive Cancer Network: Clinical Practice Guidelines in Oncology, Uterine Neoplasms V1.2010. http://www.nccn.org/professionals/physician_gls/PDF/uterine.pdf
B.M. Slomovitz, T.W. Burke, P.J. Eifel, L.M. Ramondetta, E.G. Silva, A. Jhingran, et al. Uterine papillary serous carcinoma (UPSC): a single institution review of 129 cases, Gynecol Oncol 91 (2003), pp. 463–469.
D.M. Boruta, P.A. Gehrig, A.N. Fader, and A.B. Olawaiye. Management of women with papillary serous cancer: a Society of Gynecologic Oncology (SGO) Review, Gynecol Oncol 115 (2009), pp. 142–153.

Contributing Faculty
The University of Texas MD Anderson Cancer Center

Anuja Jhingran, M.D.
Professor, Radiation Oncology

Karen H. Lu, M.D.
Professor, Gynecologic Oncology

Lois M. Ramondetta, M.D.
Associate Professor, Gynecologic Oncology

For more information on this topic or for questions about MD Anderson’s treatments, programs, or services, call askMDAnderson at (877) MDA-6789.

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