For decades, the reflexive response to an advanced ovarian cancer diagnosis was straightforward: operate first, remove as much tumor as possible, then follow with chemotherapy. But a new review co-authored by Houston Methodist gynecologic oncologist Dr. Pedro Ramirez reinforces a more nuanced reality for patients with rare ovarian cancer subtypes: the right sequence of treatment depends on the biology of the tumor — and in most cases, chemotherapy first is not a compromise, but an evidence-based strategy.

Published in the International Journal of Gynecological Cancer, the review examined two decades of published evidence comparing primary cytoreductive surgery followed by chemotherapy versus upfront neoadjuvant chemotherapy followed by interval surgery for rare epithelial and non-epithelial ovarian cancers. The analysis included low-grade serous, endometrioid, clear-cell and mucinous ovarian cancers, as well as several uncommon non-epithelial tumor types.

The headline finding is remarkably clear: Among the rare ovarian cancers studied, low-grade serous ovarian cancer stands alone as the only subtype requiring surgery first.

“Because low-grade serous ovarian tumors respond poorly to chemotherapy, surgery should remain the preferred first treatment whenever possible."

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Pedro Ramirez, MD

For nearly every other rare histological subtype, however, patients experienced comparable outcomes whether they underwent surgery first or received chemotherapy before surgery, particularly when extensive disease made complete tumor removal unlikely.

"For most of those rare tumors, when the patient has advanced disease, there is no difference if you do primary surgery followed by chemotherapy, or if you do chemotherapy first, interval surgery and then additional chemotherapy," explains Dr. Ramirez. "If it looks like you're not going to be able to resect all of the disease, give chemotherapy first because it is effective and often makes the eventual resection significantly less invasive."

That distinction reflects an important shift in gynecologic oncology. Modern treatment planning is driven primarily by the likelihood of achieving complete tumor removal safely.

Rather than operating immediately on every patient with bulky disease, physicians now carefully evaluate imaging to determine whether chemotherapy can shrink tumors enough to make surgery both safer and more effective. In many cases, what might have required a six- or seven-hour operation can become a routine two-hour procedure after several cycles of systemic therapy.

One goal of the study, Dr. Ramirez says, is to help dispel a common misconception among patients.

"Anytime you say we're not going to do surgery first, many patients think they're at a disadvantage," says Dr. Ramirez. "But having data like this can help explain why it's actually better to get the chemotherapy first and then do the surgery afterward."

In other words, chemotherapy-first treatment should not be viewed as a consolation prize. For many patients, it represents the optimal approach based on the biology and extent of their disease.

The review also highlights how rapidly treatment options have expanded for these uncommon cancers. Historically, chemotherapy was often the only systemic therapy available. Today, molecular profiling increasingly guides treatment decisions, opening the door to targeted therapies, immunotherapies and antibody-drug conjugates tailored to specific tumor characteristics.

"For many of these rare tumors, it's no longer just chemotherapy," says Dr. Ramirez. "Now, because of targeted therapy, there are so many options. We're treating these tumors as personalized medicine."

That evolution is especially meaningful for patients with rare cancers, who historically have had fewer evidence-based treatment options and fewer clinical trials available. In fact, Dr. Ramirez notes that many targeted therapies are now standard treatments outside of research studies, while additional clinical trials continue expanding opportunities for carefully selected patients.

Because rare ovarian cancers remain underrepresented in prospective clinical trials, Dr. Ramirez and his co-authors emphasize that additional research and international registries will be essential to refining treatment recommendations. Still, the review provides one of the most comprehensive syntheses to date of the available evidence, offering clinicians practical guidance when confronting these uncommon and often challenging diagnoses.