Colchicine Shows Potential in Malignant Pericardial Effusion

 

(UPDATED) Cancer patients who experience pericardial effusion, either due to their malignancy or in reaction to chemotherapy or radiotherapy, may have better long-term outcomes if they receive adjunctive colchicine, according to a single-center, observational study.

After successful pericardiocentesis with extended catheter drainage, the anti-inflammatory was given orally at a dose of 0.6 mg twice daily for 2 months.

Pericardiocentesis is “relatively safe” when performed under echocardiographic guidance, say So Ree Kim, MD (Anam Hospital, Seoul, South Korea), and colleagues. It also “can be helpful to patients with malignancy, in that rapid return to anticancer therapy is possible compared with surgical methods, which are more invasive,” they explain. But little is known about its long-term outcomes and many patients develop pericardial adhesion or constriction, leading to “worse prognosis by delaying further anticancer therapy and decreasing performance status due to systemic congestion or tachyarrhythmic events.”

Study co-author Eun Kyoung Kim, MD, PhD (Samsung Medical Center, Seoul), told TCTMD how their hospital arrived at this approach. Many patients with malignant PE were found to have signs of both inflammation and diffuse adhesion after pericardiocentesis; thus, taking steps to reduce local inflammation resulting from the procedure might address “pathological changes of cardiac pericardial physiology,” she explained via email. “Colchicine was relatively safe [and] could be well tolerated even in advanced-stage cancer patients.”

Colchicine is more broadly a common treatment for pericarditis, so its use in the context of cancer to target constrictive pericarditis makes sense, Salim S. Hayek, MD (University of Michigan Frankel Cardiovascular Center, Ann Arbor, MI), told TCTMD. Hayek, who didn’t take part in the study, says he uses the anti-inflammatory when treating cancer patients and therefore is happy to see these results.

“I was pretty excited about this study, mainly because it validates what I personally have been practicing and what others have been doing in the field of cardio-oncology for some time,” Hayek said. “Metastatic pericardial effusions and their consequences can be truly devastating. There have been really very limited studies out there about this. This is the first large, albeit single center and observational, study, . . . but it’s not definitive evidence.” The condition, he said, “is not uncommon and definitely warrants a randomized trial.”

It validates what I personally have been practicing and what others have been doing in the field of cardio-oncology for some time. Salim S. Hayek

Daniel Lenihan, MD (Washington University School of Medicine in St. Louis, MO), on the other hand, said the results were interesting but not entirely convincing.

“This is a nice data set that raises the possibility [of benefit]. In my practice, I don’t usually use colchicine in this setting. For the most part, I think in somebody who has pericardial effusion associated with a malignancy, most of the time if you just drain it and get it completely dry, then it won’t come back,” he commented to TCTMD.

Massimo Imazio, MD (AOU Città della Salute e della Scienza di Torino, Italy), in an accompanying editorial, writes that colchicine appears “promising” for malignant pericardial effusion. The condition’s manifestations can range from asymptomatic to hemodynamic instability. “Despite its clinical impact, little progress has been made in the diagnosis and treatment of this condition,” he points out. “Especially for treatment, there is a great need for new, more efficacious therapies and interventions, to decrease the recurrences of disease, improve the quality of life of patients, and [improve] the prognosis, whenever possible.”

Colchicine, Steroids, NSAIDs

The researchers analyzed results for 445 patients (median age 57 years; 56% men) with malignant pericardial effusion who underwent echocardiography-guided pericardiocentesis, which was successful in 97%, between May 2007 and December 2018. Cancer type varied, with the most common being lung (63.4%), breast (11.0%), and gastrointestinal (7.4%). Patients who had pericardial adhesion or constriction after catheter removal were given colchicine, nonsteroidal anti-inflammatory drugs (NSAIDs), and/or steroids at physician discretion.

Full follow-up data were available for 376 patients. Among the colchicine-treated patients in this group, 28.6% received steroids and 31.9% took NSAIDs. For patients not on colchicine, rates of steroid and NSAID use were 9.1% and 21.4%, respectively. Another reason for colchicine’s appeal, said Kim, is that some patients’ chemotherapy regimens involved “intermittent steroids and a large amount of hydration. In these situations, the administration of NSAIDs or steroids was burdensome.”

Over 2-year follow-up, 26.1% of patients saw their pericardial effusion recur and 46.0% developed constrictive pericarditis.

Kim et al performed multivariable adjustment that accounted for age, sex, cancer type, cancer status/stage, current chemotherapy, effusion amount, duration of indwelling catheter, presence of malignant cells in the infusion, anti-inflammatory/steroid use, and early timing of diffuse adhesion and constriction.

With colchicine, there was a lower risk of the primary composite endpoint—all-cause death, repeat pericardiocentesis, or pericardial window operation due to recurrent pericardial effusion—as compared to no colchicine (adjusted HR 0.65; 95% CI 0.49-0.87). Propensity-score matching magnified the association (adjusted HR 0.55; 95% CI 0.37-0.82). All-cause death also was reduced in the colchicine group, both with multivariate analysis (adjusted HR 0.60; 95% CI 0.45-0.81) and propensity-score matching (adjusted HR 0.50; 95% CI 0.33-0.75).

NSAID and steroid use were not associated with a reduction in risk, which Kim said came as a surprise. “This result can be explained by patients with more severe clinical features having been treated with steroid or NSAIDs. Considering the retrospective feature of the present study, it is too early to conclude that steroid or NSAIDs had no benefit on the management of malignant PE,” she advised.

“Besides colchicine treatment, age, gender, cancer status, ongoing chemotherapy, and effusion amount were associated with adverse clinical outcomes in patients with malignant pericardial effusion,” the investigators write, noting that the link between colchicine and outcomes was consistent across subgroups. Although there were some slight differences, the P values for interaction didn’t reach statistical significance. Patients below the age of 57, women, and those with malignant cells detected in their pericardial effusion didn’t see any difference in the primary composite with colchicine.

The researchers point out that shortly after pericardiocentesis more than two-thirds of the patients they studied had elevated levels of serum inflammatory markers and diffuse adhesion. “This suggests that the inflammatory reaction after pericardiocentesis plays a role in some portion, even though its causative mechanism was due to the malignancy itself,” they say. Emphasizing that their study is from a single center, Kim et al call for prospective investigation on the best timing, dose, and duration for an anti-inflammatory agent in this setting.

The ‘Nitty Gritty’

Lenihan observed that the current report is a mix of cases where pericardial effusion simply occurred in a patient with cancer and those where the pericardial fluid itself contained cancer cells. This, he said, complicates its interpretation, especially given data showing no positive effect from colchicine when there were malignant cells (HR 0.85; 95% CI 0.61-1.17).

Kim countered that colchicine use shouldn’t be discouraged here, since the relationship between malignant cells and outcome here did not reach statistical significance (P for interaction = 0.81).

When treating his own patients, Lenihan first drains the fluid then confirms whether it does or doesn’t contain cancer. “If you have actual positive cytology . . . then we know that is a higher-risk population. It’s also one [for which] you’re more likely to need to do surgical drainage, so you’ll have to do a window,” he said. “Whether or not colchicine is helpful in somebody who has a malignancy-related effusion is a question.”

Also injecting a word of caution, Hayek said that with cancer patients in general, extra care must be taken to ensure safety. Many have other comorbidities, especially kidney dysfunction and pancytopenia, that could be exacerbated by colchicine and require the drug therapy to stop, he commented.

Whether or not colchicine is helpful in somebody who has a malignancy-related effusion is a question. Daniel Lenihan

Lenihan similarly said he would be “very careful” when it comes to colchicine in certain populations: people with a hematologic malignancy or significant renal insufficiency. This is because a rare complication of colchicine can be aplastic anemia, he explained.

Especially in people already on several therapies, “I would not really want to add another drug to their medicines unless I was pretty sure that it was going to be helpful. Whether there are actual malignant cells in the pericardial fluid I think would be an important decision point,” said Lenihan, calling for clinicians to “get down to the nitty gritty” of the new study’s results.

That said, “it’s good that people are trying to report on their clinical experience in a disciplined way, especially in cardio-oncology, because sometimes we have small populations with impressive findings. We really need to share data among ourselves, so that we ultimately are improving practice.”