Why drug shortages are having an outsize impact on ovarian cancer patients

Sarah Evans considers herself a lucky ovarian cancer patient, though she is dealing with the second recurrence of the disease since she was first diagnosed in February 2018.

She is grateful that, even by her third round of chemo in March of this year, her cancer was still responding to carboplatin treatment — the most common first line of treatment for ovarian cancer, and one Evans tolerates without unbearable side effects. Patients often become resistant to carboplatin, especially after repeat treatments, in which case they require different drugs that may be less effective, or have more side effects.

But in May of this year, Evans, who at age 68 has stage three cancer, received a call from the hospital: Due to a national shortage of generic drugs, there was no carboplatin available for her. She was going to be treated with cisplatin this time.

“When they called me, I was shocked,” said Evans, who lives in Syracuse, N.Y. “I knew that there was a shortage. But […] I never really thought that it would happen to me.”

Cancer patients, doctors, and patient advocates alike are struggling with the wide-ranging effects of the ongoing chemotherapy drug shortages. The platinum-based drugs carboplatin and cisplatin have been hard to keep in stock for months now, affecting most U.S. cancer centers: 93% have reported carboplatin shortages, and 70% have reported shortages of cisplatin.

While patients with various types of cancer have been impacted by the shortages, those with ovarian cancer are among the groups most affected — both because the disease is relatively common, with women having a 1 in 78 chance of getting it in their lifetime, and because the drugs that are most effective in treating it are the ones now in short supply.

While there are alternatives to the use of platinum drugs to treat ovarian cancer, none of them work quite as well. Carboplatin in particular — in combination with the chemotherapy drug paclitaxel — has remained unchallenged as the go-to for ovarian cancer, in particular when the treatment could be curative, rather than palliative.

The lack of good alternatives to platinum drugs for ovarian cancer patients “reflects the fact that it does work so well,” said Michael Birrer, director of the Winthrop Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences. As a single agent, he said, platinum has a response rate of close to 60% or 70%, and combined with paclitaxel, it can reach 80%. No newer treatments have been able to deliver similar results. “Because platinum is so good, it drives the whole field and nobody is willing to second guess it,” he said.

“These are first-line drugs. These are the bread and butter of treatment for cancer,” said Stephanie Blank, the director of gynecologic oncology for the Mount Sinai Health System. “These are the ones that the evidence shows are the most important drugs for treating ovarian cancer.”

The differences between carboplatin and cisplatin

Carboplatin and cisplatin have both been in use for decades. Cisplatin received Food and Drug Administration approval for ovarian cancer treatment in 1978. Carboplatin, which received FDA approval in 1989, was developed as an analog drug to cisplatin with lower toxicity for the kidney.

Compared to cisplatin, carboplatin tends to cause less vomiting and have milder side effects. In some cases, doctors may still use cisplatin to treat patients — for instance, in those who are hypersensitive to carboplatin. But it’s not the preferred option, as it is much more taxing on the body.

For Evans, switching from carboplatin to cisplatin meant taking steroids ahead of the treatment and changing her routine afterward to incorporate electrolytes whenever she drank water. The lasting side effects were even more challenging.

“I just did not feel right,” she said. “It took me almost two weeks to kind of get back into my usual routine. […] I was much more tired and just had a fog about me.” After her carboplatin treatments, she said, she typically experienced a level of discomfort of three out of ten. With cisplatin, she felt much worse — seven out of ten.

Since she was first diagnosed with ovarian cancer, Evans — a single mother who retired after three decades with the postal service, where she worked nights for 12 years while raising her three sons — has tried to keep up her usual life. She works with the homeless making sandwiches for a hundred people every Saturday, and has a rich social life. But when her friends came to visit her from out of town shortly after her cisplatin treatment, she didn’t feel like leaving the house.

Thankfully, for her following treatments, in June and July, carboplatin was available again. “I don’t know how they got it, but I was really glad because I didn’t want to go through another month of [cisplatin side effects],” she said. “It was a more negative experience for me — and I was mad, you know, how could you not have cancer drugs?”

Why platinum-based drugs are still the standard for ovarian cancer treatment

The causes behind the cancer drug shortage are systemic, and require policy reforms that would take time to be implemented even if they were approved. For now, more than a decade since the first shortages became a problem in the U.S. there is no end in sight.

The shortages mean that doctors have to make hard choices about which patients have a higher need for carboplatin or cisplatin. “Somebody getting treatment for ovarian cancer would probably be somebody that we’d prioritize and hopefully would get it,” said Blank. However, she has heard of patients who were unable to remain on a steady schedule, because the drug supplies were late.

Then there are the cases where patients have to be given alternative treatments altogether. In those cases, doctors may use other drugs such as bevacizumab, particularly for patients who have had recurrent cancer and for whom treatment is unlikely to be curative.“We’re really just trying to figure out the best way to give our patients the best outcomes in these circumstances, which are really unfortunate,” said Blank.

The efficacy of platinum-based drugs in the treatment of ovarian cancer is unmatched, and unlikely to have a strong alternative soon, said Birrer. “In terms of randomized trials and where the field is going, there’s not a lot of testing, unfortunately, to try to replace platinum,” he said. “I don’t think the shortage has changed that.”

Nor should it, according to Birrer. The solution to the lack of platinum drugs, he said, is a better portfolio of companies that can provide cheap oncology drugs, likely through some measure of government intervention, rather than focusing on developing new drugs that are just as effective but more expensive — and therefore more lucrative for drugmakers.

This doesn’t mean there is no value in researching new ovarian cancer treatments, especially when it comes to specific situations, such as patients with BRCA gene mutations. “The upfront therapy for ovarian cancer is still evolving and we’re trying to get it to be better and better,” Birrer said.

And  there are reasons beyond the shortage to look for alternatives to platinum drugs. When patients treated with carboplatin experience recurrences, they can die from what is known as “platinum resistant disease,” which occurs because the platinum can also mutate bone marrow as it targets cancer cells. “And when you get resistant clones growing out, those tumors are so heavily mutated that they’re not going to respond to much else. So it’s a double-edged sword,” said Birrer.

In the meantime, oncologists are navigating a delicate balance in how to frame the problem of drug shortages to their patients. On the one hand, patients need to be reassured. “There have been guidelines put together by big brains in the field so that their care will be disrupted to the least amount possible,” said Blank.

On the other hand, it’s hard to know for sure whether any of these disruptions will have actual impacts on the success of the treatment. It might take up to two years to see whether those who can’t complete their first round of treatment with carboplatin or cisplatin because of the shortage will have worse treatment results, and more recurrence, than those who had full access to the drugs, she said.

Tracy Moore, who heads patients programs at the Ovarian Cancer Research Alliance (OCRA),  said that she’s spoken with patients who, like Evans, had to switch from carboplatin to another treatment and experienced worse side effects. The shortages are cause for concern even among patients who haven’t personally been affected — at least, not yet.

“They may have access to the drug, but the concept that there is a shortage is having an emotional toll on many,” said Moore, who notes that the shortages are a common theme in the organization’s hundreds of support groups.

Grappling with the unknown

Evans still wonders if she feels the lingering side effects of the cisplatin, and recovering from the chemo sessions seems to take longer than usual even as she is back on carboplatin. She doesn’t know whether what she feels is a cisplatin hangover of sorts, or just her impression, but that’s precisely the problem: not knowing. “Psychologically it did a little number on me,” she said in July.

There is something else she doesn’t know: Her treatment isn’t as effective as usual this time around, and she may have to tack on some additional chemo sessions after her sixth, which would typically have been her last. Is it because she is older? Is her cancer becoming resistant to carboplatin? Or was it the one time she had to take cisplatin that made her treatment less effective? “I don’t really know how much that has to do with taking the cisplatin. Probably nothing, but it’s still in my mind,” said Evans. “You never can tell.”

Before a new chemo session, she often worries she’ll again receive a call to go in earlier to prepare for a cisplatin infusion, because there is no carboplatin available for her. She tries not to do too much speculating, which has been her approach to her treatment so far.

But days ahead of her most recent session, she was feeling lucky again. “This time they haven’t called me. So I’m just keeping my fingers crossed.”