SGO, FWC, and GOG-F* Communique: Considerations When Treating Persons with Ovarian, Fallopian Tube, and Peritoneal Cancers 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 ovarian, fallopian tube and peritoneal cancers 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.
The term “ovarian cancer” includes ovarian, fallopian tube and primary peritoneal cancers.
- For the treatment of epithelial ovarian cancer, carboplatin-based regimens are the recommended standard of care[1, 2] for patients with
- high-grade, early-stage disease
- advanced-stage disease
- platinum-sensitive recurrence. (Level of Evidence I)
- Cisplatin and carboplatin should be prioritized for curative intent or in settings where prolonged clinical benefit is anticipated for patients with
- high-grade, early-stage epithelial ovarian cancer
- advanced-stage epithelial ovarian cancer
- metastatic or high-grade germ cell cancers
- select sex-cord stromal tumors
- platinum sensitive recurrence.
- When possible, consider patient enrollment in clinical trials. Visit www.gog.org to search GOG Partners and NRG Oncology Clinical Trials.
- To preserve platinum drug at institutions in short supply:
- Prioritize intravenous (IV) regimens over intraperitoneal (IV/IP) or heated intraperitoneal chemotherapy (HIPEC) regimens given that the latter regimens require more platinum per cycle than IV regimens. Cisplatin 75-100 mg/m2 is the only preferred HIPEC agent. HIPEC should be reserved for select patients at interval cytoreductive surgery (e.g., those with Stage III disease who had a response or stable disease following neoadjuvant chemotherapy).
- Round dose down to the nearest vial size as a first step to ensure efficient use.
- Increase the interval between cycles and reduce the total platinum dose when clinically acceptable to do so. Where National Comprehensive Cancer Network (NCCN) guidelines state a range for cycle duration, default to the lower end of that range (e.g., if platinum is recommended every 3 to 4 weeks, default to every 4 weeks). Where guidelines state a range of dosing, default to the lowest therapeutically appropriate dose.
- Consider Carboplatin AUC 4-5 rather than AUC 6 dosing.
- Consider short interval imaging for patients with measurable disease (i.e., after two rather than three cycles so a platinum drug can be discontinued if ineffective).
- Avoid weekly carboplatin (AUC 2) dosing.
- For patients who had a secondary or tertiary cytoreductive surgery to no gross residual for a platinum-sensitive, oligometastatic recurrence, consider reducing the total number of planned postoperative platinum-based cycles to 3-4.
- Strongly consider minimizing, omitting, or postponing cisplatin or carboplatin from the treatment of platinum-resistant or refractory disease. If an alternative agent with comparable efficacy and safety is available, then cisplatin or carboplatin should not be ordered. Consider clinical trials for these patients or refer to the NCCN standard of care guidelines for non-platinum containing regimens for recurrent disease.
- Patients with rare, low-grade tumors (e.g., low-grade serous, mucinous, granulosa cell subtypes etc.) may exhibit relative chemoresistance to platinum-containing treatment regimens, and alternative agents may be considered in the setting of platinum drug shortages. Additional information is provided below (e.g., consider endocrine therapy for hormone-sensitive tumors such as FIGO grade 1 endometrioid or granulosa subtypes and recurrent low-grade serous cancer).
- The standard of care for patients with high-grade, early- or advanced-stage epithelial ovarian cancer is carboplatin-taxane-based IV regimens. In the event of a carboplatin shortage, consider the following:
Note: Observation after surgery is an acceptable consideration for patients with Stage I clear cell, mucinous, FIGO grade 1 endometrioid and low-grade serous ovarian carcinomas who are adequately surgically staged (NCCN alternative, Level of Evidence IV). If platinum is given for Stage I high-grade disease, administer 3 instead of 6 cycles (Level of Evidence I).
- Preferred regimen: Cisplatin 75 mg/m2 IV 21 days (in addition to paclitaxel 135 mg/m2 IV +/- bevacizumab 15 mg/kg IV +/- maintenance therapy with PARP inhibitor +/- bevacizumab 15 mg/kg IV): Because cisplatin and carboplatin shortages may not overlap, cisplatin combination therapy is the preferred alternative platinum regimen when available (Level of Evidence 1).
- Additional regimen to consider**: Oxaliplatin 85 mg/m2 IV, docetaxel 75 mg/m2 IV and bevacizumab followed by bevacizumab maintenance 15 mg/kg IV: The single-arm, phase II TEACO trial of 132 patients with Stage IC-Stage IV ovarian cancer +/- measurable disease following initial surgery demonstrated a median progression-free (PFS) of 16.3 months and median overall survival (OS) of 47 months. There was a 42.4% rate of grade 3/4 neutropenia. Adverse events associated with oxaliplatin (increased lacrimation-26.5% and blurred vision-7.8%)) were observed. In the event of neutropenia colony-stimulating factors should be considered. (Level of Evidence II)
- For patients with advanced-stage, rare and low-grade epithelial and sex cord stromal ovarian cancers, consider the following:
- Low-grade serous ovarian carcinoma and endometrioid adenocarcinoma first-line therapy
- Letrozole 2.5 mg PO daily monotherapy: For patients with Stage II-IV disease, NCCN guidelines support the use of either chemotherapy followed by letrozole maintenance therapy or letrozole monotherapy after cytoreductive surgery (Level of Evidence III and category 2B NCCN recommendations).
- Mucinous ovarian carcinoma
- Consider observation in patients with Stage I disease.
- The preferred regimen is CAPOX (also known as CapeOx)**; Oxaliplatin 130 mg/m2 IV day 1 and capecitabine 850 mg/m2 PO twice daily days 1 to 14 +/- bevacizumab 15 mg/kg IV day 1 followed by bevacizumab maintenance 15 mg/kg IV. Repeat every 21 days: Based on a retrospective series of patients with Stage I-IV mucinous ovarian carcinoma, additional data extrapolated from randomized colorectal cancer trial data, and the limited data from the 50 patients enrolled in the phase II GOG 241 trial (closed prematurely due to poor accrual), this is the preferred regimen over carboplatin/paclitaxel for mucinous carcinoma.[7, 8] (Level of Evidence III)
- FOLFOX**; 5-Fluorouracil with leucovorin and oxaliplatin +/- bevacizumab 15 mg/kg IV day 1 followed by bevacizumab maintenance 15 mg/kg IV. Repeat every 21 days: Based on a retrospective series of patients with Stage I-IV mucinous ovarian cancer and additional data extrapolated from randomized colorectal cancer trial data. Note: the American Society of Health-System Pharmacists declared a fluorouracil shortage on May 5th, 2023, so discuss drug supply with your institutional pharmacist. (Level of Evidence III).
- Granulosa cell ovarian cancer
- Consider observation with Stage I-II disease. For Stage III-IV disease adjuvant or second line therapy, may consider hormone therapy (e.g., aromatase inhibitor, leuprolide or fulvestrant) or bevacizumab.[4,10]
- Low-grade serous ovarian carcinoma and endometrioid adenocarcinoma first-line therapy
- For patients with malignant germ cells tumors, cisplatin and carboplatin should be prioritized for curative intent treatment. (Level of Evidence II). In the event of severe platinum shortage, consult with other gynecologic oncology or medical oncology colleagues.
Note: Patients with Stage I dysgerminoma and select patients with Stage I, grade 1-2 immature teratoma may be observed after staging surgery. (Level of Evidence III).
- When unfamiliar with an alternative chemotherapy regimen, consider consultations with your institutional pharmacist and other gynecologic oncology or medical oncology colleagues.
- Seek prompt institutional approval and implementation of order sets for alternative treatment regimens.
*Organizations involved in production of this communique include the Society of Gynecologic Oncology, the Foundation for Women’s Cancer, and The GOG Foundation, Inc.
- Administration: Given the concern for neurotoxicity, a dose of 50-75 mg/m2 cisplatin may be given with 3-hour paclitaxel either as a 2-day regimen (with paclitaxel on Day 1 and cisplatin on Day 2) or both drugs on the same day separated out by 1-2 hours with standard hydration protocols.
- Toxicity: The combination of cisplatin and paclitaxel may be associated with significant neurotoxicity.
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.
Capecitabine: Administration and Toxicity Concerns
- Administration: Available as 150mg and 500mg tablets. Tablets should be taken within 30 minutes after a meal and swallowed whole with a full glass of water. Doses should be taken at the same time each day about 12 hours apart. In the event of vomiting the dose should not be repeated.
- Toxicity: It is associated with gastrointestinal toxicity, hand-foot syndrome, and may rarely cause coronary artery vasospasm. It is a major inhibitor of CYP2D6; thus, concurrent administration with other CYP2D6 inhibitors/inducers should be avoided. It may increase serum levels of warfarin and phenytoin.
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: Roisin O’Cearbhaill, MD; Amanda Fader, MD; Bhavana Pothuri, MD; Angeles Alvarez Secord, MD, MHSc; Thomas Herzog, MD; Deborah Armstrong, MD; David Gershenson, MD; Renata Urban, 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 email@example.com.
- Kyrgiou, M., et al., Survival benefits with diverse chemotherapy regimens for ovarian cancer: meta-analysis of multiple treatments. J Natl Cancer Inst, 2006. 98(22): p. 1655-63.
- Ozols, R.F., et al., Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol, 2003. 21(17): p. 3194-200.
- van Driel, W.J., et al., Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. N Engl J Med, 2018. 378(3): p. 230-240.
- Armstrong, D.K., et al., NCCN Guidelines(R) Insights: Ovarian Cancer, Version 3.2022. J Natl Compr Canc Netw, 2022. 20(9): p. 972-980.
- Bell, J., et al., Randomized phase III trial of three versus six cycles of adjuvant carboplatin and paclitaxel in early stage epithelial ovarian carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol, 2006. 102(3): p. 432-9.
- Herzog, T.J., et al., A phase II trial of oxaliplatin, docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary, peritoneum, and fallopian tube. Gynecologic Oncology, 2014. 132(3): p. 517-525.
- Gore, M.E., et al., Multicentre trial of carboplatin/paclitaxel versus oxaliplatin/capecitabine, each with/without bevacizumab, as first line chemotherapy for patients with mucinous epithelial ovarian cancer (mEOC). Journal of Clinical Oncology, 2015. 33(15).
- Kurnit, K.C., et al., Effects of Gastrointestinal-Type Chemotherapy in Women With Ovarian Mucinous Carcinoma. Obstet Gynecol, 2019. 134(6): p. 1253-1259.
- Ledermann, J.A., et al., Gynecologic Cancer InterGroup (GCIG) consensus review for mucinous ovarian carcinoma. Int J Gynecol Cancer, 2014. 24(9 Suppl 3): p. S14-9.
- Brown, J., et al., Efficacy and safety of bevacizumab in recurrent sex cord-stromal ovarian tumors: results of a phase 2 trial of the Gynecologic Oncology Group. Cancer, 2014. 120(3): p. 344-51.
- Park, J.Y., et al., Outcomes of Surgery Alone and Surveillance Strategy in Young Women With Stage I Malignant Ovarian Germ Cell Tumors. Int J Gynecol Cancer, 2016. 26(5): p. 859-64.