Chemotherapy for LGSOC: Why Response Rates Are Low and What You Need to Know

Chemotherapy for LGSOC (low-grade serous ovarian cancer) has consistently shown  lower response rates than other ovarian cancers, yet it remains part of standard treatment protocols. If you or someone you love has been diagnosed with this rare form of ovarian cancer, understanding the actual effectiveness of chemotherapy could significantly impact your treatment decisions.

Let’s dig into the hard truth about chemo and LGSOC, backed by recent research.

The Reality Check: How Effective Is Chemotherapy for LGSOC?

The effectiveness of chemotherapy for low-grade serous ovarian cancer (LGSOC) differs significantly from its efficacy in other ovarian cancer subtypes. Current clinical evidence indicates that chemotherapy has limited efficacy in treating LGSOC compared to high-grade serous ovarian cancer (HGSOC).

One study examined 50 patients with LGSOC between 1998 and 2021. The researchers found that when chemotherapy was administered after suboptimal debulking surgery (where some visible tumor remained), 58% of patients demonstrated a verifiable reduction in tumor size. 

This “objective response” included both partial responses (at least a 30% decrease in tumor size) and complete responses (all tumors disappeared). However, when administered as neoadjuvant therapy (given before surgery with the intent to shrink the cancer and make the subsequent debulking surgery more effective), the response rate decreased significantly to just 9%.

This substantial difference in response rates depending on treatment timing is noteworthy for clinical decision-making. The data suggests that only approximately 10% of LGSOC patients responded to chemotherapy when it was administered before surgical intervention.

These findings collectively indicate that LGSOC demonstrates different biological behavior and treatment response patterns compared to other ovarian cancer subtypes when treated with conventional chemotherapy regimens. Understanding these differences is essential for developing more effective treatment strategies for patients with this specific ovarian cancer subtype.

Why is LGSOC Resistant to Chemotherapy?

LGSOC responds poorly to chemotherapy for specific biological reasons that make it different from other ovarian cancers.

The main reason is the growth rate. LGSOC tumors grow much more slowly than high-grade tumors. Since chemotherapy works by attacking rapidly dividing cells, it’s less effective against the slower-growing LGSOC cells. This is why fast-growing cancers like high-grade serous ovarian cancer (HGSOC) typically respond better to standard chemotherapy drugs for ovarian cancer.

LGSOC also has a different genetic profile. These tumors frequently have gene mutations in KRAS, BRAF, or NRAS. These mutations cause abnormal activation of what scientists call the MAPK pathway (mitogen-activated protein kinase), a cellular communication system that normally regulates cell growth and proliferation. When mutations cause this pathway to be constantly active, it helps cancer cells survive despite chemotherapy treatment. In contrast, high-grade serous ovarian cancers usually have mutations in a different gene called TP53.

These fundamental biological differences explain why standard chemotherapy regimens often show limited effectiveness against LGSOC. Most traditional ovarian cancer treatments were developed primarily for high-grade serous ovarian cancer (HGSOC), which affects a much larger number of women and has historically received more research attention and funding. Additionally, LGSOC was only recognized as a distinct form of ovarian cancer about 20 years ago. Understanding these biological and historical differences has led researchers to explore more targeted treatment approaches specifically designed for the unique biology of LGSOC.

The Platinum Problem: Does “Platinum-Sensitive” Even Apply to LGSOC?

When ovarian cancer returns after treatment, doctors typically classify it as either “platinum-sensitive” or “platinum-resistant.” This simply means whether the cancer is likely to respond to platinum-based chemotherapy drugs like carboplatin.

If a patient’s cancer returns 6 or more months after finishing platinum chemotherapy, doctors call it “platinum-sensitive” and often recommend trying platinum drugs again. 

Some experts further classify these patients as “partially platinum-sensitive” (if recurrence happens between 6 and 12 months) or “fully platinum-sensitive” (if recurrence happens after 12 months). 

If cancer returns within 6 months, it’s considered “platinum-resistant.” This category can be further divided: cancer that progresses during treatment or returns within 0 to 3 months is sometimes called “platinum-refractory,” while recurrence between 3 to 6 months is “platinum-resistant.” 

However, some researchers view platinum sensitivity as a continuum rather than having strict time cutoffs. Ultimately, the duration of time without platinum treatment — the platinum-free interval — is what defines these classifications.

But here’s the problem: this classification was created based on how high-grade serous ovarian cancer behaves. New research suggests it doesn’t work well for low-grade serous ovarian cancer.

One study found that when LGSOC returns, platinum drugs don’t work very well regardless of when the cancer comes back. Only 22% of patients responded when platinum drugs were used as a second treatment, and this dropped to just 10% when used as a third treatment.

The researchers concluded that platinum-based chemotherapy has moderate activity in LGSOC when the cancer is first diagnosed, but minimal activity when it returns. This means the traditional way of deciding treatment based on “platinum-sensitivity” may not be helpful for LGSOC patients.

Why is Chemotherapy Still Used for LGSOC Despite Poor Response Rates?

Given these dismal response rates, you might wonder why chemotherapy is still commonly used to treat LGSOC. There are several reasons:

• Limited research data: Since LGSOC is relatively rare, there aren’t enough large-scale studies to definitively change standard treatment protocols. Much of our understanding comes from retrospective data rather than large clinical trials. Additionally, LGSOC was only recognized as a distinct type of ovarian cancer in 2004, giving researchers just 21 years to study it specifically — a relatively short time in medical research.
• Limited alternatives: Until recently, few effective targeted therapies existed specifically for LGSOC.
• Disease stabilization: Even when chemotherapy doesn’t shrink tumors, it can sometimes help prevent them from growing further. This “stable disease” can be valuable for patients, as stopping cancer growth is still beneficial. Studies show that while LGSOC rarely shrinks with chemotherapy, some patients experience periods where their cancer stops growing during treatment.
• Individual variability: Some patients do respond to chemotherapy. A study shows that the timing of chemotherapy matters significantly. The response rate is much higher (58%) when given after surgery compared to when given before surgery (9%). The response rate also tends to be lower when treating cancer that has returned.
• Historical precedent: Treatment protocols developed for the more common high-grade serous ovarian cancer have traditionally been applied to all types of ovarian cancer.
• Lack of predictive biomarkers: Currently, there’s no reliable way to predict which LGSOC patients will respond to chemotherapy. This is changing, though: STAAR Ovarian Cancer Foundation recently funded research at Memorial Sloan Kettering to develop biomarker tools to predict chemotherapy response in LGSOC patients.

Are Some Chemotherapy Regimens Better Than Others for LGSOC?

While overall response rates to chemotherapy remain low in low-grade serous ovarian cancer (LGSOC), emerging research suggests some treatment approaches may offer more hope than others.

A few studies have explored various treatment combinations for LGSOC. While some approaches appeared promising, the research is often limited by very small sample sizes — a common challenge when studying rare cancers like LGSOC. Despite these limitations, researchers have observed that certain combinations of non-platinum chemotherapy with bevacizumab (a drug that targets blood vessel formation critical to tumor growth) may show activity in some patients with recurrent disease. However, larger studies are needed before definitive treatment recommendations can be made.

A study uncovered nuanced findings about treatment effectiveness. In the second and third lines of treatment, researchers observed the highest response rates when combining non-platinum chemotherapy with bevacizumab, a drug that targets blood vessel formation, which is critical to tumor growth. The results were intriguing: a 100% response rate (2 of 2 patients) in second-line treatment and a 30% response rate (3 of 10 patients) in third-line treatment.

Another study of LGSOC patients treated with pegylated liposomal doxorubicin (PLD) revealed a modest objective response rate of 14.3%. Notably, nearly 79% of patients achieved stable disease, suggesting the treatment’s potential to slow cancer progression.

Laboratory studies have provided additional insights into LGSOC’s drug responsiveness. The research indicates strong resistance to several standard chemotherapy drugs, including paclitaxel, carboplatin, cisplatin, cyclophosphamide, and gemcitabine. Some studies have examined alternative chemotherapy agents, but results remain modest. For example, one study found only a 14% objective response rate with doxorubicin, highlighting the continued challenge of finding effective chemotherapy options for this cancer type.

These findings also underscore a critical point in LGSOC treatment: the need for personalized, targeted approaches that go beyond traditional chemotherapy protocols.

Emerging Alternatives to Chemotherapy for LGSOC

Thankfully, the treatment landscape for LGSOC is evolving. Several alternatives to traditional chemotherapy are showing promise:

MEK Inhibitors

Researchers have discovered a promising new treatment for LGSOC by targeting the MAPK pathway. Trametinib, a drug that interrupts this critical cancer-driving pathway, has shown remarkable results in clinical trials.

In one study, trametinib dramatically improved outcomes for patients with recurrent LGSOC. The clinical trial found that:

• 26% of patients taking trametinib saw their tumors respond to treatment, compared to just 6% of patients receiving standard treatments
• Patients on trametinib went almost twice as long without their cancer progressing (13.0 months versus 7.2 months)
• The drug reduced the risk of disease progression by 52%

Interestingly, the drug worked well across different patient groups. Even patients without specific gene mutations saw benefits, suggesting the treatment could help a wide range of LGSOC patients.

Trametinib is now being considered a new standard treatment for women with recurrent low-grade serous ovarian cancer. This represents a significant step forward in a cancer type that has historically had limited treatment options.

Endocrine (Hormone) Therapy

Since approximately 80 to 90% of LGSOC tumors express estrogen receptors, hormone therapies like letrozole (an aromatase inhibitor) and tamoxifen have shown promising benefits.

A study of patients with recurrent LGSOC showed a response rate of 9% to hormone therapy for ovarian cancer, with 62% achieving stable disease. When used as maintenance therapy, hormone treatment has been associated with improved survival rates: one paper reported a 75% 60-month survival rate compared to 65% without it.

A smaller retrospective study examining hormone therapy alone (without chemotherapy) after surgery showed encouraging results. At a median follow-up of 41 months, only 22.2% of patients developed tumor recurrence. The median progression-free survival and overall survival had not yet been reached at the time of analysis, with 3-year rates of 79% and 92.6%, respectively. Among the 27 patients in this study, letrozole was given to 55.5%.

Currently, an important clinical trial (NRG-GY-019) is comparing chemotherapy followed by letrozole versus letrozole alone as initial treatment. When completed, this study will provide the most definitive evidence to date on whether chemotherapy can be safely omitted from initial LGSOC treatment, a promising development for patients seeking more effective treatment options.

Related: Learn more about hormone therapy for ovarian cancer. 

Questions to Ask Your Doctor About Chemotherapy for LGSOC

If you’re facing treatment decisions for LGSOC, consider asking your doctor these questions:

• Given the low response rates, what’s the specific goal of chemotherapy in my case? Tumor shrinkage, disease stabilization, or something else?
• What’s my expected response rate based on my specific situation (newly diagnosed vs. recurrent, stage, previous treatments)?
• Are there alternatives to chemotherapy that might be more effective for LGSOC?
• Am I eligible for any clinical trials testing newer treatments?
• Can genetic testing of my tumor help predict whether I’m likely to respond to chemotherapy or other treatments?
• What’s the expected impact on my quality of life with chemotherapy versus other options?

The Future: Personalized Treatment for LGSOC

The future of low-grade serous ovarian cancer treatment is all about personalization. Researchers are developing tools to predict which patients will respond to specific treatments, potentially preventing unnecessary interventions and reducing patient exposure to ineffective therapies.

If you or someone you love has LGSOC, open and frank discussions with your medical team are crucial. Your individual situation, values, and preferences should guide treatment decisions, working hand-in-hand with the latest medical evidence. You are more than a statistic: you are a unique individual deserving of a targeted, thoughtful approach to treatment.