Chemotherapy Treatment for Recurrence

1. What every clinician should know Are you sure your patient has the disease? What should you expect to find?

Although an early presentation of abnormal vaginal bleeding often allows for a cure with surgery alone for women with endometrial cancer, some patients do present with advanced disease, and a fraction of those with early stage cancer have high risk features, and subsequently develop metastatic or locoregionally recurrent disease. A systematic review revealed an overall recurrence risk of 13% for all patients and 3% or less for patients at low risk.

The majority of recurrences occur within the first three years of diagnosis, and are associated with symptoms such as pain, weight loss, vaginal bleeding, abdominal bloating, or sometimes cough if lung metastases are present. Risk factors for recurrence include advanced stage (e.g., positive lymph nodes), and for stage I disease include high grade histology, deep myometrial invasion, presence of lymphovascular invasion, advanced age, particularly over 70 years, and serous or clear cell subtype. The importance of positive cytology in washings taken at the time of initial surgery remains unclear, and this is no longer part of the FIGO endometrial cancer staging system.

Clear cell and serous tumors are more likely to present at an advanced stage at diagnosis. Women of African American descent have a worse prognosis. They are more likely to present with advanced stage disease, and more likely to have disease with high-risk histology. SEER data show that for all cancers of the uterine corpus, relative five-year survival for white women aged 70 years or older is 80.6%, whereas for black women aged 70 years or older it is only 48.7%.

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Local recurrences most commonly occur in the vaginal vault in patients treated with surgery alone for early stage disease, while patients initially treated with multimodality therapy are more likely to develop recurrent disease at distant sites. The following statistics were reported in a study of 379 patients with recurrent adenocarcinoma of the endometrium:

  • Approximately 50% had locally recurrent disease, 28% had distant metastases, and 21% had both.

  • Recurrence was asymptomatic in 32% of patients.

  • The median time interval between primary therapy and disease recurrence was 14 months for patients with local recurrence and 19 months for patients with distant metastases.

  • Approximately 34% of recurrences were detected within 1 year and 76% within 3 years of primary therapy.

Routine radiologic surveillance for women with early stage disease is not recommended, and many women are diagnosed with recurrence based on symptoms, which will depend on the site of metastasis. Isolated vaginal recurrences are curable, and therefore regular pelvic exams are critical in the first 2-3 years after surgery, particularly for women who were not treated with radiotherapy. Median survival for women with measureable recurrent or metastatic disease is only 12-15 months.

2. Diagnosis and differential diagnosis

A diagnosis ofrecurrent endometrial cancer should be suspected when an individual previously treated for early stage disease presents with symptoms such as abdominal or pelvic pain, vaginal bleeding, weight loss, or cough. Vaginal recurrences may be detected on pelvic examination. The diagnosis of metastatic disease is sometimes made on the basis of radiologic features alone; however, tissue diagnosis is usually warranted, particularly in the case of isolated metastasis, metastasis in an unusual location, or apparent metastasis after a protracted disease-free interval.

Lung lesions are occasionally caused by a second lung primary cancer, or by a nonmalignant cause such as sarcoidosis. Tissue diagnosis may be made by a biopsy of accessible lesions. Pathologic assessment may include re-assessment of histologic type and progesterone receptor expression, as the latter is of therapeutic importance.

A re-staging should be completed at the time of any recurrence, and should include pelvic exam and CT scan of chest/abdomen/pelvis. A bone scan is not included as part of standard guidelines but may be indicated if bony symptoms are present. There may also be a role for FDG PET/CT in diagnosis and staging of recurrent endometrial cancer. One study showed sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 100, 94.7, 92.3, 100, and 96.8%, respectively. CA-125 may be elevated in women with endometrial cancer, and is sometimes helpful in following metastatic disease.

Applicable consult services include interventional radiology for tissue biopsy.

3. Management

A. What therapies should you initiate immediately, i.e., emergently?

Emergent therapies are not typically necessary for recurrent endometrial carcinoma per se but may be necessary for associated organ damage or dysfunction. Examples of therapies that may be required are:

  • Ureteral stenting or nephrostomy for relief of urinary obstruction.

  • Biliary stenting for relief of biliary obstruction.

  • Blood transfusion for anemia resulting from vaginal bleeding.

  • Analgesic therapy for abdominal or pelvic pain.

  • Antibiotics for infection, such as urosepsis.

Occasionally, a recurrence may present with severe bleeding. If this cannot be controlled with local measures, uterine artery embolization can be considered. Gynecologic oncology and radiation oncology evaluation may also be helpful for institution of appropriate emergent therapies. In women with no prior radiotherapy, radiation will often control bleeding. Radiation therapy can also provide palliation for brain and bone metastases.

B. What should the initial definitive therapy for the cancer be?

Initial therapy for recurrent endometrial carcinoma is dependent on features such as number and location of metastatic deposits, tumor grade, and presence of progesterone receptor expression. Isolated vaginal recurrences or nodal recurrences (such as an isolated para-aortic node) in a non-irradiated field may be treated with radiation therapy with curative intent, while vaginal recurrences in a previously radiated field and solitary distant metastases, such a lung nodule, may occasionally be amenable to surgical resection with a possibility of cure.

Whether chemotherapy should be added to radiation in the treatment of vaginal/pelvic recurrences is not clear. There is currently an ongoing randomized clinical trial, GOG 238, testing pelvic irradiation with our without concomitant weekly cisplatin in patients with pelvic-only recurrence of endometrial carcinoma.

More extensive recurrence and multiple distant metastases are treated with hormonal therapy or cytotoxic chemotherapy. Progestins, such as megestrol acetate, are the mainstay of hormonal therapy. Overall response rates are modest; the highest response rates are seen in women whose tumors are low grade and progesterone receptor positive, who have a small volume of tumor, and have had a protracted disease-free interval.

The highest response rate to date (27%) reported by the Gynecologic Oncology Group has been with a regimen alternating megestrol acetate and tamoxifen. Megestrol acetate is given for three weeks at a dose of 160 mg/day, typically in 2-4 divided doses, alternating with tamoxifen 20 mg twice a day for three weeks. This regimen was based on the observation that continuous progestin therapy downregulates the progesterone receptor, which was hypothesized to decrease the activity of progestins over time. Tamoxifen upregulates the progesterone receptor. There are, however, no randomized data showing the alternating regimen to be superior to single agent progestin therapy.

Cytotoxic chemotherapy is currently the mainstay of treatment for metastatic or recurrent endometrial carcinoma. Several agents, particularly taxanes, platinum drugs, and anthracyclines, have shown single-agent activity (response rates over 20%) in recurrent endometrial carcinoma, and may be used alone or in combination. As with other advanced or recurrent solid tumors, combination chemotherapy for endometrial cancer often results in a higher response rate (RR) than single agent therapy, but toxicities are more pronounced and overall survival benefits are often small or nonexistent. Interestingly, there is currently no evidence to support the use of an alternate chemotherapeutic regimen for serous carcinomas, even though they are biologically very different from the more common endometrioid tumors.

The most common front-line chemotherapy regimen used is carboplatin/paclitaxel. This was shown in a large phase III trial, GOG 209, to be noninferior to the triple-drug regimen of TAP (doxorubicin and cisplatin on day 1, paclitaxel on day 2, and granulocyte-colony stimulating factor (G-CSF) starting on day 3). The TAP combination had previously shown a superior RR, progression-free survival (PFS), and overall survival (OS) when compared to a doxorubicin-cisplatin doublet (median OS 15.3 vs. 12.3 months). Another doublet studied in a phase II trial is carboplatin and pegylated liposomal doxorubicin (PLD), which is an option for patients at high risk for neuropathy.

Newer agents showing some promise include bevacizumab, and temsirolimus. Agents affecting the PI3K pathway, such as temsirolimus, have been of particular theoretical interest in endometrial cancer, because of the frequency of PTEN and PI3KCA aberrations in these tumors. However, response rates to mTOR inhibitors have been modest, as a front-line trial of temsirolimus reported only a 14% major response rate, and no particular biomarker to predict for benefit has yet been found. It is possible that benefit will be greater when it is used in combination with other agents. A completed GOG front line trial (86P) randomly assigned patients to carboplatin/paclitaxel/bevacizumab, carboplatin/paclitaxel/temsirolimus, or carboplatin/ixabepilone/bevacizumab. Results should be available soon.

A few patients will be candidates for front-line hormonal therapy based on disease characteristics. We recommend that combination chemotherapy be considered as an initial therapy for most patients with minimal co-morbidities and good performance status. Options for combination chemotherapy, dosages, and outcomes observed in clinical trials are listed below:

  • Paclitaxel 175 mg/m 2 + carboplatin AUC 5-6 every 3 weeks (RR = 35 to 73%).

  • PLD 40 mg/m 2 + carboplatin AUC 5 every 4 weeks (RR = 60%)

It is very important to realize that patients who are elderly or have previously received pelvic radiotherapy will often need to start with reduced doses and/or with G-CSF. For example, the AGO-OVAR trial of the PLD/carboplatin regimen cited above excluded patients with prior pelvic irradiation. Combination chemotherapy can produce complete response rates in the range of 20%. Although the categories “platinum sensitive disease” and “platinum resistant disease” are not as well defined for women with endometrial carcinoma as for those with ovarian cancer, it is clear that the women with a more prolonged time since prior adjuvant chemotherapy (if it was given) will have a higher response rate to their first chemotherapy for metastatic disease. In addition, the minority of women who have a complete response and a prolonged (six or more months) interval between the completion of their first chemotherapy for metastatic disease and reappearance of their cancer will often respond well to second-line therapy. A regimen that is similar to that initially used will often produce a second response. Patients who do not have a response to their initial chemotherapy have a poor prognosis, and subsequent chemotherapy regimens are often ineffective. For these women a clinical trial is often the best option, if there is one available.

Single agent therapy is often appropriate for older/sicker patients, or in the second-line setting. Growth factor support can be used as appropriate. Some preferred single agents and dosages that may be used are listed below:

  • Paclitaxel 175 mg/m 2 every 3 weeks or 80 mg/m 2 weekly.

  • Docetaxel 60 -75 mg/m 2 every 3 weeks or 35 mg/m 2 weekly for 3 weeks with 1 week off . In breast cancer, weekly docetaxel appears to be less well tolerated (fatigue, tear duct and nail toxicity) than weekly paclitaxel, and less active than every three week docetaxel. However, weekly docetaxel does not usually cause alopecia, and the modest hematological toxicity is attractive in some cases.

  • PLD 40 – 50 mg/m 2 every 4 weeks (unfortunately trials of PLD have yielded response rates that are lower than those seen with doxorubicin, and the drug is not approved for the treatment of endometrial cancer; however, responses can be seen and the modest hematologic and GI toxicity make it relatively easy to use in frail patients).

  • Carboplatin AUC 5 every 3 weeks (lower AUC of 5 is better tolerated by pre-treated patients).

Single agent cisplatin is active, but toxic, and carboplatin is usually preferred. Other single agents may be considered but tend to have lower response rates and more toxicity. Doxorubicin is active as a first line agent, but appears to have minimal activity in the second-line setting. Other agents that occasionally produce responses include topotecan, ifosfamide, vincristine, and 5-fluorouracil, bevacizumab and ixabepilone. None of these are FDA-approved for treatment of endometrial cancer.

In those women with bone metastases, it is appropriate to use either zoledronic acid or denosumab along with chemotherapy to delay the onset of bony complications. For both, daily vitamin D and calcium supplementation are essential. Dosages are as follows:

  • Zoledronic acid 4 mg intravenously every 3-4 weeks (provided serum creatinine is within 10% of baseline).

  • Denosumab 120 mg subcutaneously every 4 weeks (as a result of a higher likelihood of hypocalcemia, serum calcium monitoring may be required).

4. Complications

A. What complications could arise as a consequence of the condition? Are there strategies to lower the risk of complications?

Complications from recurrent endometrial cancer may result from progressive organ infiltration and compression of intra-abdominal and pelvic structures. In some women, particularly those with serous tumors, the spread is predominantly intraperitoneal, and they are at significant risk for bowel obstruction. Care should be taken to use laxatives as needed, particularly when using constipating medications, such as narcotics or serotonin 5HT3 receptor antagonist antiemetic therapy.

Because women with endometrial cancer are often obese, and may have pelvic recurrences causing lower extremity edema, they are at significant risk for deep venous thrombosis and pulmonary embolus, and clinical suspicion for those complications should always be high. Hormonal therapy with tamoxifen and megestrol acetate may also increase thrombotic risk. One recent phase II clinical trial of the combination of megestrol acetate alternating with tamoxifen and temsirolimus was halted after the first stage because of an excess of venous thrombotic events (seven events in 22 patients).

In cancer patients in general, low molecular weight heparin (LMWH) is believed to be more effective than warfarin. It is also decreases the difficulties in maintaining a therapeutic level that can occur in cancer patients who have variable oral intake during warfarin treatment. If renal function is normal and the patient is not too obese, LMWH is often the preferred treatment for venous thrombosis in women with metastatic endometrial cancer.

As discussed above, progressive pelvic/vaginal disease can occasionally result in bleeding that is difficult to control, and radiation therapy (if not previously used) or consultation with interventional radiologists for embolization of the feeding arteries can be helpful.

B. What complications could arise as a consequence of the management – chemo, radiation and surgical?

Some possible serious side effects from chemotherapy are listed below, while agents most commonly associated with each side effect are indicated in parentheses:

  • Nausea and vomiting (cisplatin, carboplatin, and doxorubicin).

  • Nephrotoxicity (cisplatin and renal obstruction from pelvic masses).

  • Peripheral neuropathy (cisplatin and paclitaxel).

  • Cardiomyopathy (doxorubicin and epirubicin).

  • Myelosuppression, causing anemia and neutropenia (all agents to varying degrees).

  • Infection resulting from neutropenia (all agents to varying degrees).

  • Bony pain (paclitaxel and G-CSF).

As mentioned above, G-CSF can be very helpful in older patients and those with prior pelvic radiotherapy. Many endometrial cancer patients are diabetic, putting them at increased risk for neuropathy, and they should be monitored carefully for this complication. Decreasing the paclitaxel dose or substituting docetaxel for paclitaxel can often minimize the risk of this complication. The steroids used for nausea and the prevention of hypersensitivity reactions may worsen diabetes, and attention should be paid to reasonable control of glucose levels. Bony pain can be treated with steroids, narcotics or nonsteroidal anti-inflammatory agents (assuming renal function and platelet number are adequate).

C. What other therapies are helpful for reducing complications?

Supportive and ancillary therapies may significantly reduce the likelihood of side effects from chemotherapy. A few examples are:

  • Anti-emetics: substance P antagonists, such as aprepitant, serotonin 5HT3 receptor antagonists, such as ondansetron, glucocorticoids, dopamine D2 receptor antagonists, and short-acting benzodiazepines.

  • Intravenous hydration prior to cisplatin therapy.

  • G-CSF therapy to reduce the duration of neutropenia.

  • Zoledronic acid of denosumab to reduce bony complications.

  • Laxatives to reduce constipation.

5. Prognosis and outcome

A. What would you tell a patient and family about the prognosis?

Aside from cases of isolated recurrences, such as a vaginal recurrence in a patient with no prior irradiation or a solitary distant metastatic deposit which may be cured by surgical resection, recurrent endometrial cancer is not curable and eventually leads to death. Single or combination chemotherapy serves a palliative role and improves progression-free and overall survival. While there are some women who do well for a number of years, the overall prognosis for women with measurable recurrent/metastatic endometrial cancer is poor, with a median survival of about 12 to 15 months.

B. "What if" scenarios

Recurrent endometrial cancer may fail to respond to first line therapy, in which case an alternative regimen or treatment via clinical trial can be considered, but likelihood of response is low. Therapy is often continued until disease progression, unacceptable toxicity, or complete clinical or radiologic response. However, patients with a good partial response can also be considered for a “chemotherapy holiday,” as there are no data that this will shorten survival.

6. Follow up surveillance and therapy management of recurrences

In the event of a complete response with first-line therapy, it is reasonable to discontinue therapy. Surveillance should include symptom evaluation and physical exam, and may also include periodic imaging, usually with CT scans. In some patients, CA-125 is a good disease marker and may also be useful.

7. What is the evidence for specific management and treatment recommendations?

Fung-Kee-Fung, M, Dodge, J, Elit, L. “Follow-up after primary therapy for endometrial cancer: a systematic review”. Gynecol Oncol. vol. 101. 2006. pp. 520-9. (This study evaluated 16 non-comparative retrospective studies of potentially curative treatments of endometrial cancer.)

Aalders, JG, Abeler, V, Kolstad, P. “Recurrent adenocarcinoma of the endometrium: a clinical and histopathological study of 379 patients”. Gynecol Oncol. vol. 17. 1984. pp. 85(A study of clinicopathologic features among 379 patients with recurrent endometrial cancer.)

Haie-Meder, C, Mazeron, R, Magne, N. “Clinical evidence on PET-CT for radiation therapy planning in cervix and endometrial cancers”. Radiother Oncol. vol. 96. 2010. pp. 351-5. (A study of the diagnostic use of PET-CT for recurrent endometrial cancer.)

Fiorica, JV, Brunetto, VL, Hanjani, P. “Phase II trial of alternating courses of megestrol acetate and tamoxifen in advanced endometrial carcinoma: a Gynecologic Oncology Group study”. Gynecol Oncol. vol. 92. 2004. pp. 10-4. (A GOG study designed to estimate the objective response rate and toxicity associated with alternating megestrol acetate and tamoxifen.)

Fleming, GF, Brunetto, VL, Cella, D. “Phase III trial of doxorubicin plus cisplatin with or without paclitaxel plus filgrastim in advanced endometrial carcinoma: a Gynecologic Oncology Group study”. J Clin Oncol. vol. 22. 2004. pp. 2159-66. (This demonstrated the activity and superiority of TAP compared to cisplatin/doxorubicin for first line therapy of recurrent endometrial carcinoma.)

Du Bois, A, Pfisterer, J, Burchardi, N. “Combination therapy with pegylated liposomal doxorubicin and carboplatin in gynecologic malignancies: a prospective phase II study of the Arbeirsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and Kommission Uterus (AGO-K-Ut)”. Gynecol Oncol. vol. 107. 2007. pp. 518-25. (Demonstrated the efficacy of carboplatin/PLD doublet for recurrent endometrial carcinoma.)

Gebbia, V, Testa, A, Borsellino, N. “Cisplatin and vinorelbine in advanced and/or metastatic adenocarcinoma of the endometrium: a new highly active chemotherapeutic regimen”. Ann Oncol. vol. 12. 2001. pp. 767-72. (Demonstrated the activity of cisplatin/vinorelbine in recurrent endometrial carcinoma.)

Oza, AM, Elit, L, Tsao, MS. “Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: A trial of the NCIC Clinical Trials Group”. J Clin Oncol. vol. 29. 2011. pp. 3278-85. (This study demonstrated modest response rates with single-agent temsirolimus.)

Lincoln, S, Blessing, JA, Lee, RB. “Activity of paclitaxel as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study”. Gynecol Oncol. vol. 88. 2003. pp. 277-81. (This demonstrated the activity of paclitaxel in the second-line setting.)

Katsumata, N, Noda, K, Nozawa, S. “Phase II trial of docetaxel in advanced or metastatic endometrial cancer: a Japanese Cooperative Study”. Br J Cancer. vol. 93. 2005. pp. 999-1004. (This demonstrated the activity of 3-weekly docetaxel in the first- and second-line settings.)

Miller, D, Filiaci, V, Fleming, G, Mannel, R, Cohn, D, Matsumoto, T, Teard, K, DiSilvestro, P, Pearl, M, Zaino, R. “Randomized phase III noninferiority trial of first line chemotherapy for metastatic or recurent endometrial carcinoma: A Gynecologic Oncology Group study”. Gynecol Oncol. vol. 125. 2012. pp. 771(This showed the noninferiority of carboplatin/paclitaxel to doxorubicin/cisplatin/paclitaxel.)

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