Chemotherapy for uterine cancer: treatment regimens

Chemotherapy achieves three major goals: reducing the risk of disease recurrence after surgery (adjuvant); helping to make the tumor resectable or increasing the chance of organ preservation before surgery (neoadjuvant, often as part of chemoradiation or total neoadjuvant therapy); and, in advanced disease, prolonging life, reducing symptoms, and sometimes compressing metastases to a point where they can be removed. The basic "skeleton" of almost all regimens is platinum plus a taxane: carboplatin plus paclitaxel. This combination is comparable in effectiveness to more "rigorous" regimens and is better tolerated. [1]

The role of chemotherapy in endometrial cancer is changing today due to advances in immunotherapy. For tumors with high microsatellite instability or defects in the DNA error correction system, it is often preferable to begin treatment with immune checkpoint inhibitors, with chemotherapy being added later or in combination. However, for most patients with advanced or recurrent disease, carboplatin plus paclitaxel remains the standard, supplemented with a targeted or immune component tailored to the tumor's biology. [2]

A separate category is uterine carcinosarcoma (a tumor of mixed structure). Previously, ifosfamide was considered the "gold standard," but a large randomized trial demonstrated that the combination of carboplatin and paclitaxel was no worse in terms of survival, less toxic, and therefore became the preferred first-line treatment. This simplified practice and allowed more patients to complete the full course of treatment. [3]

Finally, for a small proportion of patients with highly differentiated, hormonally sensitive tumors and low tumor burden, chemotherapy is not the first option: hormonal regimens (progestins, aromatase inhibitors, and sometimes combinations with mTOR inhibitors) are appropriate, with chemotherapy reserved for later. This step-by-step approach does not reduce chances, but improves tolerability and quality of life. [4]

When is it appointed and how is it included in the overall plan?

In postoperative treatment, chemotherapy is indicated for most patients with stage III endometrial cancer and selected patients with high-risk stage II. In practice, carboplatin with paclitaxel is most often chosen, sometimes in combination with radiation therapy using the strategy of "first radiation with a low dose of cisplatin as a radiosensitizer, then systemic platinum-taxane." This reduces the risk of both local and distant recurrence. [5]

In metastatic and recurrent disease, the initial strategy depends on biomarkers. For tumors without DNA repair defects, treatment often begins with carboplatin and paclitaxel plus antiangiogenic therapy or with the addition of immunotherapy as indicated by studies. In cases of repair deficiency or high microsatellite instability, the benefit of adding a PD-1 inhibitor to chemotherapy has already been demonstrated in the first lines. After a response, the intensity is reduced, switching to maintenance regimens to reduce cumulative toxicity. [6]

For serous cancers with HER2 receptor overexpression, trastuzumab is added to carboplatin and paclitaxel; this improves disease control and is included in current guidelines. In real-world practice, it is important to remember to test HER2 in all serous and "serous-like" tumors with unfavorable biology to avoid missing an addition to the regimen. [7]

If the disease progresses after a platinum-containing regimen, the next steps are determined by biology: for tumors without MSI-H/repair deficiency, a combination of lenvatinib and pembrolizumab is effective; for MSI-H/repair deficiency, monotherapy with PD-1 inhibitors or their combination with chemotherapy is effective. These strategies have already received regulatory approval and are available in routine clinical practice. [8]

What modes are used and how have they evolved?

The "classic" regimen consists of carboplatin plus paclitaxel every three weeks. This regimen has proven effective with lower toxicity compared to alternatives, and is therefore firmly established in recommendations. In fragile patients, lower-dose or weekly regimens are often used to maintain tolerability and avoid treatment interruptions. [9]

Key news in recent years includes the emergence of immunochemotherapy as a frontline treatment. The US Food and Drug Administration approved pembrolizumab in combination with carboplatin and paclitaxel, with subsequent pembrolizumab maintenance, for patients with primary or recurrent disease. Similar data were obtained with dostarlimab in the RUBY trial, demonstrating a significant improvement in overall survival. This also changes the standard for patients with intact DNA repair function. [10]

For HER2-positive serous endometrial cancer, trastuzumab is added to platinum and paclitaxel. Antibody-conjugates (e.g., trastuzumab deruxtecan) are on the horizon as part of personalized approaches in pretreated patients, although more data are currently available from observational series and tumor-specific subanalyses. Standardization of HER2 testing is important to ensure reproducible decisions. [11]

For uterine carcinosarcoma, the standard first-line treatment is also carboplatin with paclitaxel: in a randomized trial, it was found to be as good as ifosfamide with paclitaxel in terms of survival and better in terms of tolerability. This is particularly important, as tolerability determines how many cycles a patient can complete without delays or dose reductions. [12]

Personalization: Biomarkers that make a real difference

Every patient with advanced or recurrent disease should have their microsatellite instability/mismatch repair deficiency status determined. In the presence of MSI-H/mismatch repair deficiency, PD-1 inhibitors (pembrolizumab, dostarlimab) have demonstrated dramatic and durable responses as monotherapy and in combination with chemotherapy, quickly becoming front-runners. This is one of the best examples of how a molecular feature can change the norm. [13]

For HER2-positive serous tumors, the addition of trastuzumab to a platinum-taxane regimen improves outcomes and is already included in guidelines. In practice, it is important to establish appropriate immunohistochemical and, if necessary, confirmatory testing to avoid missing candidates for anti-HER2 therapy. [14]

If the tumor is microsatellite stable and progresses after platinum therapy, the combination of lenvatinib and pembrolizumab has proven survival and disease control benefits compared to chemotherapy alone—this is a high-evidence option. The downside is the specific toxicity of lenvatinib (hypertension, fatigue, diarrhea), which requires active monitoring and dose adjustment. [15]

Don't forget about hormonal sensitivity: in receptor-positive, slow-growing endometrioid tumors, progestins, aromatase inhibitors, and the combination of everolimus and letrozole in previously treated patients demonstrate good activity. These are not "competitors" to chemotherapy, but important components of an individualized regimen, allowing for the delay of cytotoxic lineages. [16]

Toxicity: What to Expect and How to Reduce Risks in Advance

Carboplatin most commonly causes myelosuppression (neutropenia, anemia), while paclitaxel causes peripheral neuropathy and alopecia. It is important to discuss the schedule, antiemetic support, the possibility of scalp freezing (if available), and criteria for temporary delays/dose reductions in advance to avoid disrupting the treatment plan at the first sign of toxicity. Regular blood tests and correction of iron/folate deficiencies increase the chances of completing the course without interruption. [17]

With the addition of PD-1 inhibitors, immune-related side effects are possible: thyroiditis, skin rash, colitis, and hepatitis. These are rare, but require the team's readiness to promptly recognize and treat with steroid courses according to the protocol. Patient education about "red flags" (diarrhea, severe weakness, scleral jaundice) is critical for safety. [18]

The combination of lenvatinib and pembrolizumab is effective but toxic: monitor blood pressure from the outset, keep lenvatinib dose tapering guidelines handy, discuss fluid intake, and early treatment of diarrhea. This toxicity is manageable, but requires careful monitoring. [19]

In everyday practice, the principle of "intensity as needed; toxicity as possible" applies. After achieving a response, doctors often remove the most "cumulatively toxic" component (for example, discontinuing paclitaxel while maintaining maintenance) to maintain control and avoid persistent neuropathy. This "step-down" has long been standard. [20]

Special situations: elderly, carcinosarcoma, rare histotypes

In elderly and fragile patients, the goal is a balance between efficacy and tolerability. Dose reductions and weekly schedules, early transition to maintenance regimens, and, in receptor-positive tumors, emphasis on hormonal options are acceptable. Key factors for success are control of comorbidities (anemia, hypertension, diabetes) and nutritional support. [21]

Carcinosarcoma is an aggressive disease, but even here, platinum-taxane has displaced ifosfamide-containing regimens from the first line. This simplifies treatment regimens and allows more patients to complete the planned number of cycles. In the case of HER2-positive carcinosarcoma, the addition of anti-HER2 therapy is being discussed in specialized centers, as reflected in observational series. [22]

For uterine sarcomas (leiomyosarcoma, poorly differentiated stromal sarcomas, etc.), the "rules of the game" are different: doxorubicin, gemcitabine with docetaxel, trabectedin, etc. are used; immunotherapy and targeted therapy options are limited. These cases require referral to a team specializing in sarcomas to avoid mixing strategies for epithelial and mesenchymal tumors. (Here, we deliberately separate the topic to avoid blurring the standards for endometrial cancer.)

Another important layer is molecular classification (POLE-ultramutant, MSI-H, "no specific molecular features," p53-aberrant). This helps to more accurately assess the risk of relapse and select chemotherapy supplements, especially in early, high-risk stages. In most centers, this profile has become routine. [23]

Short answers to frequently asked questions

Is chemotherapy always necessary after surgery? No. If the risk of recurrence is low, chemotherapy is not required. In stage III and some high-risk stage II cases, it reduces the likelihood of disease recurrence and is standard. [24]

What is currently considered the "best" first-line treatment for advanced disease? For many patients, it's carboplatin plus paclitaxel in combination with a PD-1 inhibitor, followed by immunotherapy support; for HER2-positive serous tumors, the addition of trastuzumab. The choice depends on biomarkers. [25]

If platinum doesn't work, is there an alternative other than more chemotherapy? Yes. For microsatellite-stable tumors, the combination of lenvatinib and pembrolizumab is effective; for MSI-H/repair deficiency, immunotherapy is a standalone option. [26]

Is it true that ifosfamide is better for carcinosarcoma? No longer. Carboplatin with paclitaxel has demonstrated similar results and lower toxicity and is now considered preferable. [27]