Thousands of cancer patients across the U.S. are getting bewildering news from their oncologists:
Proven curative regimens containing platinum-based drugs—cisplatin and carboplatin—have become largely unavailable because of a nationwide drug shortage. The institutions that have some supplies of cisplatin and carboplatin are setting up algorithms for rationing their dwindling stocks, which usually means giving top priority to patients treated with curative intent and denying standard-of-care treatment to patients who cannot be cured but who can still benefit from these drugs.
Cisplatin and carboplatin are old, generic drugs. Cisplatin was first described in medical literature in 1844 (The Cancer Letter, April 28, 2023). Both cisplatin and carboplatin have been widely used since the 1970s. Since platinum drugs are thoroughly studied and are a staple in oncology, this means they are often present in regimens on both the experimental and control arms of clinical trials.
A list of platinum-containing regimens compiled by The Cancer Letter shows that these drugs are used in 12 cancer types and are included in a massive number of regimens. A list of uses of these drugs, compiled based on the NCCN guidelines, appears below.
The shortage of platinum drugs affects an unprecedented number of patients, said Julie R. Gralow, chief medical officer and executive vice president of the American Society of Clinical Oncology.
“The FDA approval for these drugs is in ovarian, testicular, and bladder cancer. And so, if you take where there is actually an approved label, and you look at that and you take into account that testicular is only the advanced or metastatic that are getting platinum agents, it’s at least 100,000,” Gralow said.
Over decades of clinical research, platinum drugs have been tested in a large number of diseases, where they are often used off-label.
“[When] you add on top of where there’s a label, you’ve got cervical cancer, non-small cell lung cancer, head-and-neck cancers, for example. There are estimates that up to 500,000 patients possibly could have a stage and a diagnosis that would rely on a platinum agent,” Gralow said. “Although I think that 500,000 hasn’t [been] adjusted for stages where we wouldn’t use it. So, it’s somewhere between 100,000 and 500,000 of Americans each year would be diagnosed or have a cancer that this would be relevant to. That’s a lot of patients.”
Altogether, 1.8 million Americans are diagnosed with some form of cancer every year.
A conversation with Gralow appears here.
ASCO’s information on drug shortages is posted here.
The shortages of platinum-based drugs were first reported in February, and it’s anyone’s guess how long they will persist (The Cancer Letter, April 7, 2023). There is no shortage of these drugs in Europe, sources say.
Florida Cancer Specialists has been preparing for the shortage for the past three months.
“We started doing those rounding 5% to 10% down in the carboplatin cisplatin, especially for non-curative patients,” Lucio N. Gordan, president and managing physician at Florida Cancer Specialists, said to The Cancer Letter on May 24. “But as of yesterday, we had run out of carboplatin 12 days ago—so 12 days without any carboplatin at Florida Cancer Specialists. And as you know, we see about 1.3 or 1.5 million patients a year.
“It’s a pretty dire situation.”
Since platinum-based drugs are the mainstay of a lot of regimens, omitting them is not easy.
“For ovarian cancer, how can you not give platinum on the adjuvant ovarian cancer treatment?” Gordan said. “There isn’t an alternative. I guess we can do paclitaxel-gemcitabine—or whatever—but it’s not the same thing. You can’t say it’s the same.
“It’s very, very difficult.”
The situation is not better at Tennessee Oncology.
“We have about a month left of cisplatin, but carboplatin, we potentially have less than a week’s supply left,” said Stephen M. Schleicher, the group’s chief medical officer. “It’s bad. And I have a hundred docs whom we are trying to coach on what to do. Especially when, with curative breast cancer, the two most common neoadjuvant regimens, for triple-negative—KEYNOTE-522—and for HER-2-positive—TCHP—require carboplatin for curative regimens.
“And those are not uncommon diseases. So, we’re trying to shift everybody else away from carboplatin to preserve as much as we can for those patients. Which is huge. All of lung cancer uses carboplatin, gyn uses carboplatin. So, right now, we’re having to shift everybody over to cisplatin, which doesn’t work for everyone. If your kidneys aren’t great, it’s more toxic than carboplatin. A lot of physicians, especially the younger generation like me, have less experience with cisplatin, because we don’t use it that much outside of testicular, bladder, and head and neck.”
Oncologists across the U.S. are desperately looking for reasonable treatment options for their patients.
“The drug in greatest shortage right now is carboplatin, and it’s reserved for very few patients,” said Mark J. Ratain, the Leon O. Jacobson Professor of Medicine and director of the Center for Personalized Therapeutics at the University of Chicago. “It’s impacting patients that are on it already, receiving therapies, both on and outside of clinical trials. So, it’s having significant impact.
“Our pharmacy has worked with some of our physicians to develop a set of criteria. And if the patient doesn’t meet the criteria, they’re not allowed access to the drug or drugs.
“Criterion one: Is the treatment being administered with intent or reasonable expectation of cure? And two, are there any alternatives that are as effective? So, the highest priority is for patients for whom there’s no alternative. The second highest is for patients who are being treated for cure, but for whom there may be an inferior alternative.
“And this is also driving up costs. For example, paclitaxel is also in shortage, so some patients are being switched to nab-paclitaxel, which is not in shortage. It’s been suggested some patients get immunotherapy if the chemotherapy drugs are not available,” Ratain said.
“It’s very good for brand name companies. There’s absolutely no shortage of expensive drugs.”
Across the U.S., institutions are distributing instructions for prioritization and conservation of dwindling supplies of platinum-based drugs and putting together talking points for describing this desperate situation to patients. These documents are usually not being made available outside the institutions.
One institution’s instructions to oncologists state that while no strict restrictions (i.e. curative intent only) have been made as of yet, it is anticipated that they will be coming, and carboplatin should not be used for patients for whom there are alternatives.
One set of instructions for oncologists specializing in prostate cancer includes the following:
- Omit carboplatin for patients with aggressive disease who are receiving in combination with taxane,
- You can reincorporate/add when shortage is resolved,
- Prioritize olaparib/rucaparib over carboplatin in patients with BRCA/DDR mutation,
- Prioritize cisplatin/etoposide when able for small cell/neuroendocrine prostate cancer.
“There are big ethical issues, and we are hearing from our ASCO members that they need help in how to talk to patients, and they’re having their own mental health issues related to having to have conversations like this,” Gralow said. “[We are] supplying our members and their patients with alternative regimens, ways to preserve the limited amount of drug they have.”
Clinical trials groups are working on guidelines, too.
Last month, NRG Oncology published the following statement to member institutions:
The approach for delays and/or modifications in therapy for patients already enrolled in the research without prior IRB approval is permissible under the Department of Health and Human Services (HHS) regulations 45 CFR 46.103(b)(4)(iii) since the modifications are being made to eliminate immediate apparent hazards to study participants. In the instance of drug shortage, appropriate delays and/or modifications in study treatment may be made when the commercial agent is not available. The participant must be informed of delays or modifications in therapy due to supply shortage and potential risks. The discussion must also be documented in the participant’s medical record and reported as an unanticipated problem to the IRB.
NRG Oncology is updating the guidance. A communique published by Society of Gynecologic Oncology, the Foundation for Women’s Cancer, and The GOG Foundation Inc. is available here.
“ECOG-ACRIN has developed guidelines for the cisplatin shortage to allow patients to continue on study, potentially even allowing brief use of an alternative chemotherapy, “ Peter O’Dwyer, co-chair of the ECOG-ACRIN Cancer Research Group, said to The Cancer Letter. “We have used this strategy in the past with unexpected drug shortages.”
“Our guidelines are study-specific and provide for substitution with alternative platinum agents where available. In diseases in which substitution of carboplatin is potentially less effective, we emphasize allocation of cisplatin selectively for such patients,” said ECOG-ACRIN Executive Officer Bruce Giantonio.
Charles Blanke, chair of SWOG Cancer Research Network, said three of the group’s studies are affected by the cisplatin shortage.
“It’s optional in two, so not a big deal, and the one where it is required is nearing completion anyway,” Blanke said. “We are sending out a memo advising: (1) Investigators ensure enough CDDP is on hand for full treatment, before enrolling a patient, (2) We will issue study-specific guidance, as it comes up, and (3) We generally recommend following ASCO guidelines, though we don’t allow modifying dose or schedule unless already permitted in the protocol.”
The issue of drug shortages has been discussed ad nauseum. Some blame the drug pricing system, others accuse the group purchasing organizations (The Cancer Letter, May 20, 2022).
“The market has failed,” said UChicago’s Ratain, voicing a widely shared view of the problem. “I think we have to acknowledge the market has failed, and when the market fails, the government needs to step in, and the government needs to contract to have these inexpensive drugs manufactured, and then stockpile them. There are vaccines stockpiles, and stockpiles of other things that are necessary, such as energy. And so, we need to create a government stockpile of essential drugs that are in shortage or expected to go into shortage. It’s not an expensive undertaking, because if these were expensive drugs, people would be making them.”
As of yesterday, we had run out of carboplatin 12 days ago—so 12 days without any carboplatin at Florida Cancer Specialists. And as you know, we see about 1.3 or 1.5 million patients a year. It’s a pretty dire situation.Lucio N. Gordan
This latest shortage is a national public health calamity that requires government action, said Gordan, of Florida Cancer Specialists.
“People need to get on the ball with this as far as legislation, as far as government action, and we started a grassroots effort,” Gordan said. “Most of our physicians, nurses and staff members, wrote to our legislators on the state level and the national level. I wrote letters to everybody. I wrote letters to the White House—President Biden—and haven’t heard much back.
“We also started grassroots efforts with the patients. We emailed 200,000 or so patients that we have email addresses for and urged them to reach out to their state and federal legislators to tell them to get on the ball.”
Recently, four House members circulated a sign-on letter to HHS Secretary Xavier Becerra and FDA Commissioner Robert M. Califf. The letter, circulated by Reps. Ami Bera (D-CA), Brian Fitzpatrick (R-PA), Derek Kilmer (D-WA), and Mike Kelly (R-PA), reads:
Dear Secretary Becerra and Commissioner Califf:
Thank you for your leadership in addressing ongoing drug shortages and ensuring Americans have access to the medications and devices they need. We especially appreciate the FDA’s recent actions to address current shortages of key oncology drugs. We are writing to you today expressing our concerns with the impact these shortages have on patients, particularly in cancer care. We’d like to request additional information about how the U.S. Food and Drug Administration (FDA) is working to resolve these issues and ways in which Congress can assist in these efforts.
For years, the medical community has experienced shortages of critical drugs that are used to treat a variety of conditions. These shortages are caused by a multitude of factors, including but not limited to quality issues, manufacturer business decisions, disruptions to active pharmaceutical ingredients (APIs) and excipient supplies, natural disasters, and other emergencies that take place in countries that house critical drug manufacturing facilities. In recent years, the United States has experienced shortages in broadly used essential products, as well as to products critical to smaller patient populations.
Within the oncology pharmaceutical supply chain, patients and providers continue to face shortages of potentially curative treatments. A recent survey of U.S. Oncology Pharmacists found that oncology drug shortages occurred frequently in 2020 and led to delays in chemotherapy and changes in treatment or omission, complicated clinical research, and increased risk of medication errors and adverse outcomes. Of the 136 drugs currently in shortage, as reported by the FDA, 15 are oncology drugs.
Shortages of these 15 drugs, such as carboplatin and cisplatin, are causing care disruptions across the country. While we cannot quantify the direct impact to patients, estimates show that shortages in cisplatin and fluorouracil could impact 500,000 and 275,000 patients respectively. These drugs are used in the treatment of multiple common cancers, including lung, breast, ovarian, testicular, head and neck cancer, endometrial cancer, and many types of cancers impacting children.
Drug shortages also place children at risk across the United States. Drugs affected by shortage are often critical for treatment, and there are limited or no alternatives. Many childhood cancers are highly treatable, often curable, but in many cases certain drugs are essential for cure. In both adult and pediatric settings, some community cancer centers are unable to treat patients due to shortages in carboplatin and cisplatin, while some large academic cancer centers have reported having less than two weeks supply of the drugs on hand.
As a result, doctors are forced to choose between inferior or potentially ineffective therapies to protect their patients. Health providers may also be forced to make treatment decisions that prioritize the most curable patients, rather than administering these drugs to all who need them. Ultimately, shortages of critical drugs lead to worse health outcomes.
The FDA has existing authority to monitor and collect data on current and potential drug shortages, including Section 510(j)(3) of the Federal Food, Drug, and Cosmetics Act (FD&C Act) which requires registrants of drug establishments to report on numbers of drugs manufactured for commercial distribution.
FDA has pursued these drug shortage mitigation goals and issued guidance requiring manufacturers to notify the FDA of discontinuances or interruptions in drug manufacturing, create risk management plans for drugs, and report quantities of drugs manufactured.
It is our understanding, however, that many manufacturers are currently non-compliant with these guidelines. We also understand that neither the federal government nor industry has end-to-end visibility into the pharmaceutical supply chain. Together, we believe these factors may limit the federal government’s ability to proactively identify and mitigate drug shortages.
Given this, we request responses to the following inquiries:
- In the past two years, the FDA has helped prevent over 500 shortages due to early notifications and intervention. In instances where manufacturers have been compliant with FDA reporting guidelines, how has that data allowed the agency to work with manufacturers to mitigate drug shortages? How could this existing required reporting be strengthened?
- What steps is FDA taking to ensure manufacturers not in compliance with existing guidelines become compliant? What challenges exist in FDA’s ability to leverage its oversight authorities?
- Does FDA have sufficient transparency and visibility into the supply chain necessary to identify potential shortages, including visibility into root suppliers for raw materials used in API manufacture and other suppliers more than one step removed from finished-product manufacture?
- Could FDA benefit from additional manufacturer reporting requirements, such as, when a manufacturer identifies increased demand for their specific product(s)?
- The device shortage reporting requirements ended with the end of the COVID-19 Public Health Emergency (PHE) on May 11, 2023 (section 506J of the Federal Food, Drug and Cosmetic Act (FD&C Act); mandatory reporting during a PHE). FDA no longer has the statutory authority to require companies responsible for manufacturing devices that are critical for health to notify the FDA of supply disruptions. Are there ways Congress can strengthen the ability of FDA to mitigate potential device supply shortages whether with data collection or other tools?
- Beyond increased visibility into the drug supply chain, are there other policy recommendations for how Congress can help mitigate drug shortages? Does the FDA have the necessary statutory authority to assist in mitigating drug shortages? If not, how can the agency’s current authority be strengthened to secure the pharmaceutical supply chain?
- How can the FDA improve communications with healthcare stakeholders such as hospitals, providers, and pharmacies, in the short-term to help address drug shortages?
Patients, physicians, and pharmacists are often the last to know when an essential drug will no longer be available, yet, are affected by these shortages the most. We strive to ensure patients, physicians, and pharmacists never have to experience shortages of essential medications, but when shortages do occur it is vital that these individuals are made aware as quickly as possible so that they can better prepare.
We appreciate the actions FDA has already taken to address the ongoing cancer drug shortage and encourage you to take all appropriate steps to protect this vulnerable population. We stand ready to assist you in any way possible.
Thank you very much for your attention to this important issue.
Cisplatin and carboplatin uses by disease site
Compiled from NCCN Guidelines
Head and neck
Cisplatin and carboplatin, single agent, is used as a radiosensitizer for local and regional disease.
For recurrent, unresectable or metastatic disease with radiation therapy option:
- Cisplatin or carboplatin/docetaxel or paclitaxel
- Cisplatin/gemcitabine +pembrolizumab or nivolumab
Cisplatin and carboplatin can also be used as a single agent for metastatic disease in the very ill.
Chemosensitizer for localized disease:
- Paclitaxel and carboplatin
- Cisplatin and 5-FU
Oxaliplatin is already replacing some use of cisplatin or carboplatin for quality-of-life reasons.
For metastatic disease:
- Paclitaxel with carboplatin or cisplatin is still used especially in squamous
- Cisplatin and fluorouracil is used in adenocarcinoma
Carboplatin, a taxane, and pembrolizumab are used for some regimens especially in triple-negative disease.
Neoadjuvant and adjuvant regimens include:
- Paclitaxel and carboplatin +/- trastuzumab
- Docetaxel and carboplatin +/- trastuzumab
Non small cell lung
With concurrent chemo radiation:
- Carboplatin pemetrexed
- Cisplatin pemetrexed
- Carboplatin paclitaxel
Neoadjuvant and adjuvant platinum doublets include:
- Carboplatin pemetrexed
- Carboplatin gemcitabine
- Carboplatin paclitaxel
- Cisplatin pemetrexed
- Cisplatin gemcitabine
- Cisplatin paclitaxel
- Cisplatin docetaxel
- Cisplatin etoposide
- Cisplatin vinorelbine
These doublets are often used for metastatic disease along with:
- Carboplatin or cisplatin and pemetrexed and pembrolizumab
- Carboplatin and paclitaxel and bevacizumab and atezolizumab
Small cell lung
- Carboplatin and etopiside
- Cisplatin and etopiside
Oxaliplatin is replacing cisplatin due to lower toxicity, but cisplatin is still used.
- 5-FU and cisplatin with trastuzumab and pembrolizumab
- Capecitabine and cisplatin with trastuzumab and pembrolizumab
Gemcitabine and cisplatin as locally advanced first line therapy with known BRCA ½ or PALB2 mutations
- Carboplatin/paclitaxel (weekly)
- Carboplatin/gemcitabine ± bevacizumab
- Carboplatin/liposomal doxorubicin ± bevacizumab
- Carboplatin/paclitaxel ± bevacizumab
For locally advanced and metastatic bladder cancer, cisplatin is preferred, but carboplatin is used when cisplatin is not tolerated well:
- Gemcitabine and cisplatin
- Carboplatin and gemcitabine
Aggressive metastatic prostate is often treated with:
- Taxotere and carboplatin
- Cabazitaxel and carboplatin
Cisplatin is preferred over carboplatin:
- Cisplatin etopiside
- Bleomycin, etoposide, cisplatin (BEP)
- Paclitaxel ifosfamide cisplatin
- Etopiside cisplatin
Carboplatin and etoposide is one of many regimens