Real-world impact of the platinum chemotherapy shortage on US patients with advanced cancer

Abstract

The recent cisplatin and carboplatin (“platinum”) chemotherapy shortage, first announced on February 10, 2023, has impacted cancer patients nationwide. Here, we quantify the extent to which the shortage affected platinum chemotherapy prescribing and short-term mortality. This cohort study included 11 797 adults with advanced solid cancers who initiated first-line therapy during the 1-year period before (February 1, 2022–February 9, 2023) or during (February 10, 2023–January 31, 2024) the platinum shortage. During the shortage, there was a 2.7% absolute reduction in platinum use (95% CI = −4.4% to −0.9%) compared to the previous year. At the peak of the shortage, there was a 15.1% absolute reduction in platinum prescribing (June 2023: 57.8% [95% CI = 53.6% to 62.0%]) compared to 1 year prior (June 2022: 72.9% [95% CI = 70.7% to 75.2%]). There was no difference in mortality before vs during the shortage (adjusted hazard ratio 1.00; 95% CI = 0.94 to 1.07) with median follow-up time of 7.6 months. Further research is required to study shortage impacts on long-term mortality.

Background

Cisplatin and carboplatin (“platinum”) chemotherapies are life-prolonging treatments for hundreds of thousands of US cancer patients each year.¹ The United States is currently experiencing a platinum shortage due to the shutdown of a single pharmaceutical manufacturing facility for quality control lapses.² The U.S. Food and Drug Administration (FDA) announced a cisplatin shortage on February 10, 2023, which resolved on June 27, 2024, and a carboplatin shortage on April 28, 2023, which is ongoing. The prolonged shortage of essential cancer therapies, a recurrent threat requiring policy and supply-chain interventions,^3,4 has created uncertainty for patients, clinicians, regulators, and biopharma.⁵ The real-world effects of this shortage on platinum prescribing and short-term mortality among US patients with advanced solid cancers have not been quantified.

Methods

This retrospective cohort study included adults with advanced-stage lung, head and neck, bladder, ovarian, and uterine cancers who initiated a first-line (1L) therapy in the 1-year period before (February 1, 2022–February 9, 2023) or during (February 10, 2023–January 31, 2024) the platinum shortage. The cisplatin and carboplatin shortages were announced 2 months apart, so we define the start of the shortage period from the first announcement. These cancer types were selected because platinum chemotherapy is a standard 1L option, and patients starting palliative therapy for advanced-stage cancer are more vulnerable to platinum rationing than those starting curative therapy for early-stage cancer. We used data from the Flatiron Health database, derived from de-identified electronic health records of patients receiving care in geographically diverse US oncology clinics.⁶ Those with multiple malignancies, molecular targeted therapy indications (eg, lung cancer EGFR alterations, for which there is a non-platinum 1L therapy), or on a clinical trial were excluded (Figure S1).

Among all 1L treatment initiators, we calculated unadjusted percentages of patients initiating a platinum-containing therapy before and during the shortage, as well as absolute differences. Adjusted probabilities of 1L platinum utilization were derived from multivariable logistic regression adjusted for cancer site, age, sex, self-reported race and ethnicity, body mass index, Eastern Cooperative Oncology Group (ECOG) performance status, creatinine clearance, programmed death-ligand 1 (PD-L1) biomarker expression (positive or negative), socioeconomic status quintile, census region, practice setting (community or academic), and insurance payer category, using marginal standardization.⁷ Each model included a binary indicator of period (before vs during the platinum shortage), and temporal trends were modeled using restricted cubic splines with 3 degrees of freedom. An adjusted hazard ratio (HR) for mortality in patients initiating treatment during, compared to before, the shortage was estimated using Cox regression.

Analyses were conducted using Stata version 18.0, and all tests used two-sided α = 0.05. The University of Pennsylvania’s institutional review board approved a waiver of informed consent.

Results

In the 2-year study period from February 2022 to January 2024, we identified 11 797 1L treatment initiators (44% [n = 5179] during and 56% [n = 6618] before the shortage period). Median age was 70 years; 57% (n = 6728) had non-small cell lung cancer, 50% were women (n = 5889), 80% were White (n = 7656), and 81% (n = 9579) received care at community practices. Baseline characteristics were well-balanced across groups (Table S1).

The unadjusted percentage receiving platinum was 68.7% (4547/6618) before and 66.1% (3421/5179) during the shortage, a 2.7% absolute reduction in platinum use (95% CI = −4.4% to −0.9%), corresponding to 137 fewer patients (95% CI = 49 to 226) than expected receiving platinum during the shortage. Cisplatin use increased from 5.8% (385/6618) to 6.2% (322/5179), a 0.4% absolute increase (95% CI = −0.5% to 1.3%) and carboplatin use decreased from 62.9% (4162/6618) to 59.8% (3099/5179), a 3.1% absolute decrease (95% CI = −4.8% to −1.3%) (Table 1). After adjusting for patient and practice factors, the peak of the platinum shortage in June 2023 was associated with a 15.1% absolute reduction in the probability of platinum prescribing (57.8% [95% CI = 53.6% to 62.0%]) compared to 1 year prior in June 2022 (72.9% [95% CI = 70.7% to 75.2%]) (Figure 1). There was no difference in mortality before vs during the shortage (adjusted HR 1.00; 95% CI = 0.94 to 1.07) with median follow-up time of 7.6 months.

Table 1.

Difference in unadjusted percentage of patients initiating platinum chemotherapy during the shortage compared to the year before the shortage.

1L Therapy	Patients initiating before shortage (%), n = 6618	Patients initiating during shortage (%), n = 5179	Absolute difference, % (95% CI)
Either platinum	4547 (68.7)	3421 (66.1)	−2.7 (−4.4 to −0.9)
Cisplatin	385 (5.8)	322 (6.2)	+0.4 (−0.5 to 1.3)
Carboplatin	4162 (62.9)	3099 (59.8)	−3.1 (−4.8 to −1.3)

Abbreviation: 1L = first-line.

Figure 1.

Adjusted probability of initiating platinum chemotherapy. The adjusted probabilities of platinum first-line therapy use were based on a multivariable logistic regression model, which included date of first-line therapy initiation (restricted cubic spline) and a binary indicator of before vs during the shortage beginning February 10, 2023 and adjusted for cancer type, age, sex, self-reported race and ethnicity, body mass index, Eastern Cooperative Oncology Group (ECOG) performance status, creatinine clearance, programmed death-ligand 1 (PD-L1) biomarker expression (positive or negative), socioeconomic status quintile, census region, practice setting (community or academic), and insurance payer category. Adjusted probabilities were obtained from this model via marginal standardization. Shaded areas denote 95% confidence intervals. The vertical line marks the date the U.S. Food and Drug Administration (FDA) announced the cisplatin shortage, the start of the platinum shortage period.

Discussion

In a large US cohort, during the year following the FDA’s announcement of the platinum shortage, we observed a modest absolute decrease in platinum prescribing (∼3%) and a larger absolute decrease at peak shortage (∼15%). In contrast to carboplatin, cisplatin prescribing was not significantly different, consistent with a national survey reporting cancer centers experienced less cisplatin shortage.⁸ There was no difference in short-term mortality, likely due to the use of effective evidence-based non-platinum alternatives, as recommended by society guidelines (Table S2).¹ Even so, substitutions made for platinum therapies are generally more expensive and carry different, and potentially more toxic, side-effect profiles. Limitations of our study include limited follow-up to study longer-term mortality and inability to study potential harms of alternative therapies, specifically increased drug toxicity and acute care utilization, financial burden, emotional and psychological stress, and time spent counseling patients. Understanding the role of mitigation strategies, such as waste minimization (ie, dose rounding), selection of alternative treatment regimens proposed by oncologic societies, and importation efforts by regulators⁹ will offer important policy insight for future chemotherapy shortage crises.

Author contributions

Jacob B. Reibel, MD (Conceptualization; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Visualization; Writing—original draft; Writing—review & editing), Lova L. Sun, MD, MSCE (Conceptualization; Methodology; Writing—review & editing), Ravi B. Parikh, MD, MPP (Conceptualization; Writing—review & editing), Nadim Mahmud, MD, MS, MPH, MSCE (Formal analysis; Methodology; Visualization), Lainie P. Martin, MD (Conceptualization; Writing—review & editing), Rebecca A. Hubbard, PhD (Formal analysis; Investigation; Methodology; Supervision; Writing—review & editing), and Ronac Mamtani, MD, MSCE (Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Supervision; Writing—review & editing).

Supplementary material

Supplementary material is available at JNCI: Journal of the National Cancer Institute online.

Funding

This work was supported by the National Institutes of Health (T32CA009679 to J.B.R.).

Conflicts of interest

Dr L.L.S. reported research support from Blueprint, Seagen, IO Biotech, and Erasca as well as personal fees from Sanofi Genzyme, Regeneron, Seagen, and Bayer outside the submitted work. Dr R.B.P. reported receiving grants from the National Institutes of Health (NIH), Prostate Cancer Foundation, National Palliative Care Research Center, National Comprehensive Cancer Network Foundation, Conquer Cancer Foundation, Humana, Emerson Collective, and Veterans Health Administration; receiving personal fees and equity from GNS Healthcare, Thyme Care, and Onc.AI; receiving personal fees from the Cancer Study Group, Biofourmis, ConcertAI, CreditSuisse, Humana, and Nanology; receiving honoraria from Flatiron and Medscape; being an unpaid board member of the Coalition to Transform Advanced Care and American Cancer Society; and serving on a leadership consortium (unpaid) at the National Quality Forum outside the submitted work. Dr N.M. reported receiving grants from Grifols. Dr L.P.M. reported receiving grants from Agenus, AstraZeneca, Sutro bioPharma, and Immunogen; and is in a consulting or advisory role for Sutro Biopharma, Elucida Oncology, and GlaxoSmithKline. Dr R.M. reported receiving grants from Merck and Astellas and personal fees from Astellas, Seattle Genetics, Flatiron Health, Bristol Myers-Squibb, and Roche outside the submitted work. No other disclosures were reported.

Data availability

The data that support the findings of this study are from Flatiron Health, Inc. These de-identified data may be made available on request and are subject to a license agreement with Flatiron Health. Interested researchers should contact DataAccess@flatiron.com to determine licensing terms.