SGO, FWC, and GOG-F* Communique: Considerations When Treating Cervical, Vulvar, and Vaginal Cancers in the Setting of Cisplatin and Carboplatin Shortages

A platinum drug shortage in the US was first reported to the FDA on February 10th, 2023. Please refer to the SGO Rapid Communique dated April 21^st, 2023 for details and guidance regarding platinum dosing and sparing strategies. This communication provides guidance for treating patients with cervical, vulvar, or vaginal 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.

Cervical Cancer

For the treatment of cervical cancer, cisplatin or carboplatin is recommended in evidence-based guidelines as the first-line standard of care, including chemoradiation, adjuvant, and recurrent treatment algorithms^[1,2] (Level of Evidence I).

1. Cisplatin and carboplatin should be reserved for cervical cancer treatment with curative intent, namely for those patients receiving concomitant chemoradiotherapy to treat early-stage, high-risk or locally advanced cervical cancer; or when prolonged clinical benefit is anticipated.
2. The use of concomitant platinum-based chemoradiotherapy as adjuvant therapy following radical hysterectomy should be restricted to patients with early-stage, high-risk disease (e.g., those with positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium)^[1].
3. Cisplatin or carboplatin may be omitted from radiotherapy in intermediate-risk cervical cancer patients when the drug supply is limited^[3]. Adjuvant radiotherapy with or without brachytherapy should be administered per standard protocols at the discretion of the care team based on surgical pathology and patient-specific factors.
4. For patients receiving concomitant chemoradiation for locally advanced cervical cancer, cisplatin 40 mg/m² (capped at 70mg) IV weekly remains the preferred chemotherapy drug^[2].
5. When possible, consider patient enrollment on clinical trials.
6. When cisplatin is not available, consider alternative radiosensitizing agents. A meta-analysis and Cochrane Database systematic review of chemoradiation versus radiation for cervical cancer treatment demonstrated asurvival benefit of platinum and non–platinum-based regimens^[2]. When unfamiliar with an alternative chemotherapy regimen, consider consultations with your institutional pharmacist and other gynecologic or medical oncology colleagues. It is important that the use of alternative radiosensitizing chemotherapy regimens does not delay or impair the ability to deliver radiotherapy.
   1. Preferred alternative regimens
      1. Carboplatin AUC 2 IV weekly:
         Although cisplatin is the preferred radiosensitizing agent, preclinical and clinical data (including a meta-analysis of 12 studies) suggest that carboplatin may have similar efficacy to cisplatin as a radiosensitizer in cervical cancer^[4-7]. Confer with your institutional pharmacy regarding availability. (Level of evidence II)
      2. Capecitabine (Oral Fluorouracil) and Mitomycin IV (See Addendum for dosing schedules and toxicity considerations)**:
         In a randomized, four-arm study of patients with locally advanced cervical cancer, patients who received concomitant oral fluorouracil and IV mitomycin together with external beam radiation therapy showed an improved disease-free survival rate when compared with radiation alone^[8]. The regimen was relatively well tolerated by study patients. (Level of Evidence I)
         NOTE: Fluorouracil alone is not an appropriate alternative^[9].
   2. Additional regimens to consider
      1. Gemcitabine 300 mg/m2 IV weekly:
         Preclinical^{[10, 11]} and early-phase clinical trials data demonstrate the efficacy and tolerability of concomitant chemoradiation with gemcitabine in treating locally advanced cervical cancer^{[12, 13]}. (Level of Evidence II)
      2. Paclitaxel 30-40 mg/m2 IV weekly:
         Paclitaxel demonstrated synergistic activity in vitro with radiotherapy in squamous cell cancers of the head and neck, vulva, and cervix^[14,15]. A small, prospective pilot study in patients with locally advanced cervical cancer demonstrated favorable responses and toxicity profiles; however, efficacy in larger populations and long-term outcomes data is unavailable^[16,17].
7. When selecting alternative radiosensitizing agents, regimen toxicity, intensity, ease of administration, and cost must be considered.
   1. Advocating for and increasing access to support services such as transportation assistance, nutritious foods, and financial assistance, as well as minimizing wait times, may mitigate an exacerbation in cancer care disparities during this drug shortage, especially for those with cancers linked to poverty^[18,19].
   2. In the absence of concurrent chemotherapy, timely completion of radiation therapy, including brachytherapy, is particularly important^[20].
8. For patients with recurrent or persistent cervical cancer following primary chemoradiation or primary metastatic cervical cancer, consider the following:
   1. Preferred regimens
      1. Platinum-based therapy, either cisplatin 50 mg/m2 IV or carboplatin AUC 5 day 1, with paclitaxel 175 mg/m2 IV day 1, bevacizumab 15 mg/m2 IV day 1, and with or without pembrolizumab 200 mg IV day 1^[21] (Level of Evidence 1). Because cisplatin and carboplatin shortages may not overlap, cisplatin combination therapy is preferred for those who have not previously received cisplatin-based chemoradiation. In contrast, carboplatin is recommended for those previously receiving cisplatin-based chemoradiation^[22].
      2. The preferred non-platinum-based regimen is topotecan 0.75 mg/m2 IV days 1 to 3, paclitaxel 175 mg/m2 IV day 1, plus bevacizumab 15 mg/m2 IV day 1^[23]: Extrapolation from a recent KEYNOTE trial and adding pembrolizumab 200 mg IV day 1 in the setting of tumoral PDL1 positivity is reasonable^[21].
   2. Additional regimens to consider
      1. Substitution of oxaliplatin 130 mg/m² day 1 every 21 days for carboplatin or cisplatin in multi-agent regimens may be considered^[24,25]. (Level of Evidence II)
      2. Consider additional non-platinum containing second-line agents based upon NCCN standard of care guidelines^[25].

Vulvar/Vaginal Cancers

Standard treatment regimens for cancers of the vulva and vagina include platinum-based chemotherapy as radiosensitizing agents and as part of multi-agent chemotherapy treatments^[26-28]. However, without randomized data delineating a preferred adjuvant modality, adjuvant radiation therapy without chemotherapy is also acceptable. When possible, consider patient enrollment on clinical trials.

1. In the treatment of vulvar cancer, allocation of cisplatin should be prioritized to regimens administered with curative intent in high-risk patients treated either in the neoadjuvant (Level of Evidence II) or adjuvant (Level of Evidence III) settings^[26-28]; or when prolonged clinical benefit is anticipated. When considering alternative radiosensitizing treatments, careful consideration of potential efficacy, toxicity, workflow, and cost, is critical, as discussed above.
2. In treating vaginal cancer, retrospective series have shown improved survival with concomitant cisplatin and radiation therapy^[29,30]. Because of the poor prognosis with radiation alone, the combined use of radiation and concurrent chemotherapy should be prioritized as is recommended in cervical cancer treatment algorithms^[31,32]. (Level of Evidence III)

*Organizations involved in production of this communique include the Society of Gynecologic Oncology, the Foundation for Women’s Cancer, and The GOG Foundation, Inc.

**Addendum:

Capecitabine (Oral Fluorouracil) and Mitomycin IV: Dosing Schedules and Toxicity Concerns

1. Dosing Schedules:
   Option 1: Capecitabine (oral fluorouracil) 300 mg/day (two tablets of 150mg) administered on days 1 through 14 and days 29 through 42 and mitomycin 10 mg/m² (consider capping at 20 mg) IV push administered on days 1 and 29 during external beam radiation therapy^[8]
   Option 2: Capecitabine (oral fluorouracil) 300 mg/day (two tablets of 150mg) administered on Monday through Friday every week during external beam radiation therapy and mitomycin 10 mg/m² (consider capping at 20 mg) IV push administered on days 1 and 29 during external beam radiation therapy^[8]
   Note: In routine practice, the day 29 mitomycin dose is often omitted due to toxicity. The capecitabine/mitomycin regimen is routinely given for the treatment of anal cancer; consider consulting with gastroenterology oncology colleagues if needed.

2. Toxicity:
   Mitomycin: This drug is a vesicant and is associated with a risk of hematologic toxicity (e.g., leukopenia, thrombocytopenia, microangiopathic hemolytic anemia).
   Capecitabine: It is associated with gastrointestinal toxicity, hand-foot syndrome, and may rarely cause coronary artery vasospasm. Tablets should be taken within 30 minutes after a meal. 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.

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

As additional information becomes available this is subject to updating. These recommendations are not meant to serve as 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.

The SGO, FWC, and GOG-F wish to acknowledge the following members and professionals for their contributions to this communique: Lisa Gabor, MD; Mark Einstein, MD; Roisin O’Cearbhaill, MD; Leslie Randall, MD; Peter Rose, MD; Amanda Fader, MD; Angeles Alvarez Secord, MD; Renata Urban, MD; Deborah Armstrong, MD; Wendy Brewster, MD, PhD; Eloise Chapman-Davis, MD; Thomas Herzog, MD; Navya Nair, MD; Bobbie J. Rimel, MD; Akila Viswanathan, MD; Catheryn Yashar, MD; Ms. Elizabeth Kix; Ms. Katie Martino; Ms. Kayla Nixon; Ms Jessica Oldham; Ms. Traci Schwendner

References:

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