• Gynecology Cancer Disease Site Group. Gawlik C, Carey M, Faught W, Fung Kee Fung M, Chambers A. Systemic therapy for advanced or recurrent endometrial cancer, and advanced or recurrent uterine papillary serous carcinoma [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2004 Aug 17. 31 p. (Practice guideline report; no. 4-8). [53 references]

Advanced or recurrent endometrial cancer (excluding sarcomas and squamous cell carcinomas) or uterine papillary serous carcinoma

Assessment of Therapeutic Effectiveness
Treatment

Obstetrics and Gynecology
Oncology

Physicians

• To evaluate the chemotherapeutic and hormonal therapy options for women with advanced or recurrent endometrial cancer (excluding sarcomas and squamous cell carcinomas)
• To evaluate the chemotherapeutic options for women with advanced or recurrent uterine papillary serous carcinoma

Adult patients diagnosed with advanced stage or recurrent endometrial cancer (excluding sarcomas and squamous cell carcinomas) or uterine papillary serous carcinoma.

Treatment

Chemotherapy Regimens

1. Doxorubicin/cisplatin versus doxorubicin/cisplatin/paclitaxel, doxorubicin alone, radiotherapy, carboplatin/paclitaxel, and doxorubicin/paclitaxel
2. Ifosfamide versus cyclophosphamide
3. Methotrexate/vinblastine/doxorubicin/cisplatin versus doxorubicin/cisplatin
4. Doxorubicin/cyclophosphamide versus doxorubicin alone
5. Doxorubicin/cyclophosphamide/cisplatin versus cisplatin alone
6. Doxorubicin versus cyclophosphamide

Chemotherapy Plus Hormonal Therapy

1. Cyclophosphamide/doxorubicin/5-fluorouracil/megestrol versus melphalan/5-fluorouracil/megestrol
2. Doxorubicin/cyclophosphamide/megestrol versus cyclophosphamide/doxorubicin/5-fluorouracil/megestrol

Hormonal Therapy

1. Megestrol versus megestrol/tamoxifen
2. Medroxyprogesterone acetate (200 mg/day versus 1,000 mg/day)
3. Medroxyprogesterone acetate versus tamoxifen
4. Gonadotrophin-releasing hormone and lutenizing hormone-releasing hormone analogs
5. Aromatase inhibitors
6. LY353381 (selective estrogen receptor modulator)

Systemic Therapy

1. Platinum plus paclitaxel
2. Paclitaxel alone
3. Cisplatin/doxorubicin/cyclophosphamide

Other Agents

1. Oral etoposide
2. Dactinomycin
3. Topotecan
4. Liposomal doxorubicin
5. Vinorelbine

• Median survival
• Tumour response (complete response, partial response, response rate)
• Quality of life
• Adverse events

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

17 randomized controlled trials, 26 phase II studies, and 4 non-comparative studies were reviewed.

Expert Consensus (Committee)

Not applicable

Systematic Review with Evidence Tables

The Gynecology Cancer Disease Site Group (DSG) identified 17 randomized controlled trials (RCTs) that compared various chemotherapy regimens for the treatment of advanced or recurrent endometrial cancer, including abstracts and randomized phase II trials. The results of randomized controlled trials could not be pooled because of the differences among the studies in terms of:

1. The number of advanced versus recurrent cases. Advanced cases actually have a poorer prognosis with a shorter expected survival than most patients presenting with recurrence.
2. The greater proportion of patients previously treated with radiation therapy and documentation with respect to the site of recurrence (either in or out of the radiated field). Patients with disease in the radiated field are known to have lower response rates to systemic chemotherapy than patients with disease outside the field.
3. The inclusion or exclusion of adverse histologic subtypes. Trials differed with respect to the inclusion or exclusion of patients with adverse histologic subtypes. It was only within the last three to five years that the Gynecologic Oncology Group (GOG) decided to separate patients with serous carcinomas as a distinct entity in subsequent Gynecologic Oncology Group studies.
4. The inclusion criteria concerning previous systemic therapy. There were marked differences among studies with respect to the number of prior chemo-hormonal regimens administered to patients.

Expert Consensus

Not stated

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

Practitioner feedback was obtained through a mailed survey of 81 practitioners in Ontario (11 gynecologists, 39 medical oncologists, 18 radiation oncologists, and 13 surgeons). The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations above should be approved as a practice guideline. Written comments were invited. The practitioner feedback survey was mailed out on October 27, 2003. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The Gynecology Cancer Disease Site Group (DSG) reviewed the results of the survey.

The practice guideline report was circulated to members of the Practice Guidelines Coordinating Committee (PGCC) for review and approval. Seven of 14 members of the PGCC returned ballots. Four PGCC members approved the practice guideline report as written, and one member approved the report with a minor editorial change to the recommendations required. One member approved the report conditional on the Gynecology DSG clarifying the recommendations. One PGCC member did not approve the report because the member was concerned that the guideline placed too much emphasis on the abstract by Fleming et al comparing doxorubicin/cisplatin to doxorubicin/paclitaxel/cisplatin. The PGCC member thought that the Gynecology DSG should wait until the randomized controlled trial (RCT) was reported in a full publication before making recommendations based on the trial.

Final approval of the practice guideline report is obtained from the Practice Guidelines Coordinating Committee.

For women with advanced or recurrent endometrial cancer:

• Combination chemotherapy is favoured over single agent chemotherapy because of higher response rates.
• Paclitaxel in combination with cisplatin/doxorubicin chemotherapy improves both response rate and median survival; however, the use of this three-drug combination is associated with increased toxicity.
• Hormonal therapy may be a therapeutic option for those patients with minimal symptoms or non-life threatening advanced or recurrent endometrial cancer.

For women with uterine papillary serous carcinoma:

• Evidence supporting or refuting various chemotherapy regimens for uterine papillary serous carcinoma is limited.
• Patients should be encouraged to participate in randomized trials.

None provided

The recommendations are supported by randomized controlled trials.

Improved understanding of the chemotherapeutic and hormonal therapy options for women with advanced or recurrent endometrial cancer or recurrent uterine papillary serous carcinoma

• Neuropathy, hematological, and gastrointestinal toxicities were the most common adverse effects reported; toxicity increased in incidence with the increase in the number of agents used.
• Hormonal agents were well tolerated: adverse effects were reported at less than 5%.

• The decision to use the three-drug combination, consisting of cisplatin/doxorubicin/paclitaxel, should be made in consultation with the patient. Consideration needs to be given to both the greater toxicity and the three-month increase in median survival time achieved with the three-drug combination in comparison with the two-drug doxorubicin/cisplatin regimen.
• For uterine papillary serous carcinoma treatment (UPSC), the most studied regimen is a paclitaxel/platinum combination. The addition of paclitaxel in small, non-comparative studies is associated with improved response rates and survival compared to non-platinum containing regimens.
• Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult the practice guideline is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or warranties of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way.

An implementation strategy was not provided.

Living with Illness

Effectiveness

• Gynecology Cancer Disease Site Group. Gawlik C, Carey M, Faught W, Fung Kee Fung M, Chambers A. Systemic therapy for advanced or recurrent endometrial cancer, and advanced or recurrent uterine papillary serous carcinoma [full report]. Toronto (ON): Cancer Care Ontario (CCO); 2004 Aug 17. 31 p. (Practice guideline report; no. 4-8). [53 references]

Not applicable: The guideline was not adapted from another source.

2004 Aug 17

Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]

The Practice Guidelines Initiative (PGI) is the main project of the Program in Evidence-based Care (PEBC), a Province of Ontario initiative sponsored by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Cancer Care Ontario
Ontario Ministry of Health and Long-Term Care

Provincial Gynecology Cancer Disease Site Group

Members of the Gynecology Cancer Disease Site Group (DSG) disclosed potential conflict of interest information.

None available

This summary was completed by ECRI on October 6, 2004. The information was verified by the guideline developer on October 20, 2004.