SGO, FWC and GOG-F Communique: Considerations When Treating Persons with Endometrial Malignancies in the Setting of Cisplatin and Carboplatin Shortages

A platinum drug shortage in the U.S. was first reported to the FDA on February 10th, 2023. Please refer to the SGO Rapid Communique dated April 21st, 2023, for details and guidance regarding platinum dosing and sparing strategies. This communication provides guidance for treating patients with endometrial malignancies in the context of limited drug availability.

Hospital systems or similar organizations are encouraged to facilitate open and frequent communication among multi-specialty teams, including gynecologic, medical and radiation oncologists, pharmacists, infusion managers, advanced practitioners, and patient advocates. In doing so, the goal is to create institution- and population-specific strategies to overcome anticipated treatment challenges.

Importantly, cancer care disparities may emerge or worsen in times of resource scarcity. As treatment recommendations are adjusted during this shortage, identifying patients at risk for experiencing structural barriers to care – and having a plan to mitigate those barriers – must be considered as part of each institution’s strategic plan. Therefore, the allocation of limited-supply drugs must be prioritized in a transparent and data-driven fashion to ensure thoughtful and equitable distribution. Additionally, considerable operational workflow resources must be facilitated by hospital leadership, administrators, pharmacists, and payors to ensure adequate and equitable patient care.

General Principles

1. For the treatment of endometrial cancer, carboplatin/paclitaxel-based therapy is recommended in evidence-based guidelines as the first-line standard of care for^[1]:
   1. Patients with high-risk early-stage disease (e.g., uterine serous carcinoma, carcinosarcoma, clear cell carcinoma, de-differentiated carcinoma);
   2. All patients with advanced-stage disease; and the
   3. First-line treatment of patients with recurrent disease who are chemotherapy-naïve or have experienced a platinum-free interval of >/=6-12 months.
2. In the setting of chemotherapy shortages, cisplatin and carboplatin should be prioritized for endometrial cancer treatment with curative intent or in settings when prolonged clinical benefit is anticipated, namely, to treat patients with high-risk early-stage disease, newly diagnosed metastatic disease, or chemotherapy naïve, recurrent disease^{[1, 2]}.In cases where the cisplatin and carboplatin drug supply is in critical shortage, radiotherapy is acceptable for patients with high intermediate risk, early-stage disease^[3] (Level of Evidence 1). Adjuvant radiotherapy with or without brachytherapy should be administered per standard protocols at the discretion of the care team based on surgical pathology and tumoral molecular profile.
3. When carboplatin is not available, cisplatin is the preferred drug alternative. Acceptable regimens to treat advanced or first-line recurrent disease include: a) cisplatin 50 mg/m2 IV on Day 1 and paclitaxel 135-160 mg/m2 IV paclitaxel on Day 2 plus granulocyte colony stimulating factor (G-CSF) support every 21 days, or b) cisplatin 50 mg/m2 IV and doxorubicin 45 mg/m2 IV on Day 1 and paclitaxel 160 mg/m2 IV paclitaxel on Day 2 plus G-CSF support every 21 days^{[2, 4]} (Level of Evidence 1).
   1. In the setting of administering cisplatin-based therapy and either targeted therapies (e.g., trastuzumab for HER2 positive tumors) or immunotherapy (e.g., pembrolizumab or dostarlimab for mismatch repair proficient/ deficient tumors), cisplatin 50 mg/m2 IV on Day 1 and paclitaxel 135-160 mg/m2 Day 2 is preferred.
   2. Oxaliplatin has not been evaluated in the primary treatment of endometrial cancer. It was evaluated as a single agent in patients with recurrent endometrial cancer in GOG 129K^[5] (Level of Evidence 2). Based on extrapolation from treatment trials in patients with other gynecologic cancers, oxaliplatin* (75-85 mg/m2 IV every 21 days) can be considered in combination with paclitaxel if carboplatin and cisplatin are not available. Vigilance is needed to monitor for neuropathy in this setting; consider utilizing docetaxel instead of paclitaxel.
      1. For patients with HER2 positive endometrial cancer, no prospective data exists utilizing of an oxaliplatin, taxane and trastuzumab regimen. However, in a small Phase II trial of patients with HER2 positive gastric carcinoma, docetaxel 70 mg/m2 combined with oxaliplatin 130 mg/m2 IV on Day 1, and continuous infusion 5-fluorouracil mg/m2 IV Days 1–5 plus trastuzumab 6 mg/kg IV on Day 1, every 21 days was well tolerated^[6] (Level of Evidence 3).
   3. If platinum isn’t available but anticipated, it is also reasonable to omit platinum from the regimen for one cycle and initiate treatment with the remainder of the regimen (e.g., administer paclitaxel and pembrolizumab only).
4. Alternative treatment regimens for advanced disease include the combination of doxorubicin/paclitaxel (doxorubicin 50 mg/m2 IV D1 followed by D2 paclitaxel 150 mg/m2 IV plus GCSF support every 3 weeks)^[7] and for carcinosarcoma specifically, ifosfamide/paclitaxel (ifosfamide 1600mg/m2 IV Days 1 to 3, mesna IV or oral, and paclitaxel 135mg/m2 IV on Day 1) plus G-CSF support^[8].
5. For those patients with low-grade endometrioid, ER+ endometrial cancer, hormonal-based therapy provides an additional treatment option. Megesterol acetate combined with tamoxifen and everolimus combined with letrozole are listed by the NCCN as preferred hormonal regimens for select patients with recurrent or metastatic disease^[1].
6. Although pembrolizumab monotherapy is currently being compared to platinum-based chemotherapy in randomized clinical trials of patients with newly diagnosed dMMR endometrial cancer, it has demonstrated superiority to chemotherapy in patients with dMMRd colorectal cancer^[9]. However, use of immune checkpoint inhibition alone in patients with treatment naïve dMMR endometrial cancer has not been prospectively examined and should be used with caution and appropriate counseling when alternate options do not exist.
7. When unfamiliar with an alternative chemotherapy regimen, consider consultations with your institutional pharmacist and other gynecologic or medical oncology colleagues.
8. Seek prompt institutional approval and implementation of order sets for alternative treatment regimens.

*Addendum:

Oxaliplatin: Administration and Toxicity Concerns

Administration:
Infuse oxaliplatin at a rate of 1mg/m2/minute to a maximum of 2 hours (i.e., a dose of 130mg/m2 will be infused over 2 hours). To reduce localized pain during peripheral IV infusion, increase the rate of a compatible IV fluid or decrease the rate of oxaliplatin infusion.

Toxicity:
Oxaliplatin is associated with peripheral neuropathy. Patients should be monitored for hypersensitivity reactions. Patients frequently report transient paresthesia or dysesthesia that is exacerbated by cold temperatures. In the event of cold sensitivity patients should be advised to avoid cold food or drinks and to drink through a straw for up to 72 hours post oxaliplatin. In cold weather patients should dress warmly and cover extremities by wearing socks and gloves especially if walking on cold floors or reaching into the freezer.

This document is subject to updating as additional information becomes available.

*These recommendations are not meant to be a substitute for clinical judgment at the individual patient level, nor should they supersede other policies at the institutional level. All decisions should be made in the context of the unique circumstances where members practice, including other local resource considerations. We encourage members to work closely with their institutions to meet patients’ needs and advocate for transparent allocation of limited drug supply. Sites participating on clinical trials should contact study sponsors (if applicable).

The SGO, FWC and GOG-F wish to acknowledge the following members and professionals for their contributions to this communique: Amanda Fader, MD; Brian Slomovitz, MD; Ramez Eskander, MD; Renata Urban, MD; Roisin O’Cearbhaill, MD; Matthew Powell, MD; Peter Rose, MD; Angeles Alvarez Secord, MD, MHSc; Thomas Herzog, MD; Deborah Armstrong, MD; Catheryn Yashar, MD; Ginger Gardner, MD; Ms. Katie Campbell; Ms. Jenna Cummins; Ms. Elizabeth Kix; Ms. Katie Martino; Ms. Kayla Nixon; Ms. Jessica Oldham; Ms. Traci Schwendner.

For questions or further guidance, please email sgo@sgo.org.

References:

1. Abu-Rustum, N.R., et al., NCCN Clinical Practice Guidelines, Uterine Neoplasms. Version 2.2023
2. Dimopoulos, M.A.., et al., Paclitaxel and cisplatin in advanced or recurrent carcinoma of the endometrium: long term results of a phase II multicenter study. Gynecol Oncol. 2000. 78(1): p. 52-7.
3. Randall M.E.., et al., Phase III Trial: Adjuvant Pelvic Radiation Therapy Versus Vaginal Brachytherapy Plus Paclitaxel/Carboplatin in High-Intermediate and High-Risk Early-Stage Endometrial Cancer J Clin Oncol. 2019 Jul 20; 37(21): 1810-1818.
4. Miller, D.S., et al., Carboplatin and paclitaxel for advanced endometrial cancer: Final overall survival and adverse events analysis of a phase III trial (NRG Oncology/GOG0209). J Clin Oncol. 2020. 38(33): p. 3841-3850.
5. Fracasso, P.M., et al., Phase II study of oxaliplatin as second-line chemotherapy in endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2006. 103(2): p. 523-6.
6. Fleming, G.F., et al., Phase III randomized trial of doxorubicin + cisplatin versus doxorubicin + 24-h paclitaxel + filgrastim in endometrial carcinoma: a Gynecologic Oncology Group study. Ann Oncol. 2004. 15(8): p. 1173-8.
7. Roviello G., et al., Docetaxel, oxaliplatin, 5FU, and trastuzumab as first-line therapy in patients with HER2-positive advanced gastric or gastroesophageal junction cancer. Medicine (Baltimore). May 2018. 97(20): e10745.
8. Powell M., et al., Randomized Phase III Trial of Paclitaxel and Carboplatin Versus Paclitaxel and Ifosfamide in Patients With Carcinosarcoma of the Uterus or Ovary: An NRG Oncology Trial. J Clin Oncol. 2022 Mar 20;40(9):968-977.
9. André, T., et al. KEYNOTE-177 Investigators. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med, 2020. 383(23): p. 2207-2218.