Publications Update # 54
Non-Medical Article of the Week
Recently, in a conversation with an undisclosed individual, it became apparent that many physicians still struggle with financial literacy, particularly in understanding money and investments. In upcoming newsletters, I aim to shed light on crucial financial decisions. Step 1: Dive into this insightful book. With just 96 pages, it's a concise read that can be completed in two hours.
Surrogate Endpoints in Oncology and their role in regulatory approval
Are you wondering how drug approval works? And what is the role of surrogate endpoints, such as PFS/response rate, etc., used in this process?
I highly recommend watching this video, as it is a must-see!
After you watch the video, consider the following questions
- Is the use of Pembrolizumab in pMMR patients in endometrial cancer justified?
- Consider a patient receiving carboplatin, paclitaxel, and pembrolizumab for advanced endometrial cancer. She progresses on pembrolizumab maintenance. Is the use of Pembrolizumab along with Lenvatinib justified in a pMMR patient?
- Should all patients with ovarian cancer receive Bevacizumab (PFS benefit but no OS benefit)
Vulvar Cancer
Neil S Horowitz
Year of Publication
2024
Hypothesis
To assess the efficacy and toxicity of combined cisplatin (C), gemcitabine (G), and intensity-modulated radiation therapy (IMRT) in treating locally advanced vulvar cancer not amenable to surgery.
Inclusion Criteria
- Locally advanced, previously untreated primary SCC of the vulva (T2 or T3, N0-3, M0)
- Not amenable to surgical resection by standard radical vulvectomy
Exclusion Criteria
- Prior radiation or chemotherapy for vulvar cancer
- Non-squamous cell carcinoma histology
- Presence of septicemia, severe infection, or severe GI symptoms requiring intervention
- Evidence of other invasive malignancies within the past 5 years, excluding non-melanoma skin cancer
Primary Endpoint
Complete Pathologic Response (CPR)
Experimental Arm(s)
Chemotherapy:
- Gemcitabine 50 mg/m² and Cisplatin 40 mg/m², administered once per week throughout IMRT.
- Maximum of seven cycles, with chemotherapy potentially held up to 4 weeks for resolution of hematologic toxicity and up to 2 weeks for non-hematologic toxicity before removal from trial.
Radiation:
- IMRT with 64 Gy prescribed to the vulva and 50-64 Gy to the groins/low pelvis.
Control Arm
Not applicable - single arm study.
Results
| Metric | Value | 90% CI | Additional Info |
|---|---|---|---|
| CPR | 73% | 61% to 83% | Compared to 50% CPR in GOG 205 and 31% in GOG 101 |
| 12-month PFS | 74% | 62.2% to 82.7% | Improvement over 70% 12-month PFS in GOG 205 |
| 24-month OS | 70% | 57% to 79% | Stable compared to historical rates; suggests sustained benefit |
Conclusions
Weekly C and G concurrent with IMRT sufficiently improved CPR in women with locally advanced vulvar squamous cell carcinoma not amenable to surgical resection.
Limitations
- The study was single-arm without a comparative group, making it difficult to determine the efficacy relative to other therapies.
- Over 90% of participants were White, which may not generalize to all patient populations.
- HPV status of tumors was not collected, potentially influencing the responsiveness to the treatment based on underlying biological differences.
Top Grade 3 or Higher Toxicities
| Toxicity | Grade 3 or Greater | Total Patients | Percentage (%) |
|---|---|---|---|
| Hematologic Toxicity | 27 | 52 | 51.9% |
| Hypomagnesemia | 3 | 52 | 5.8% |
| Radiation Dermatitis | 18 | 52 | 34.6% |
| Infection | 5 | 52 | 9.6% |
| Thrombocytopenia | 20 | 52 | 38.5% |
This table summarizes the occurrence and percentage of each grade 3 or higher toxicity among the 52 patients evaluated in the study, highlighting that the study managed acceptable toxicity levels despite the intensive treatment regimen.
Comparison of GOG/NRG Preoperative Chemoradiation Outcomes in Women With Locally Advanced Vulvar Cancer
| Study | Radiation Dose | Chemotherapy | Complete Clinical Response | Complete Pathologic Response | PFS at 12 Months |
|---|---|---|---|---|---|
| GOG 101 | 4,760 cGy | Cisplatin + Fluorouracil | 48% | 31% | NA |
| GOG 205 | 5,670 cGy | Cisplatin | 64% | 50% | 70% |
| NRG/GOG 279 | 6,400 cGy | Cisplatin + Gemcitabine | 71.2% | 73.1% | 74% |
Observations:
- Radiation Dose: There's a progressive increase in the radiation dose across the studies, with NRG/GOG 279 utilizing the highest at 6,400 cGy.
- Chemotherapy Regimen: The addition of Gemcitabine to Cisplatin in NRG/GOG 279, compared to the single-agent Cisplatin in GOG 205 and the combination of Cisplatin with Fluorouracil in GOG 101.
- Clinical Responses: Both clinical and pathologic responses have improved in NRG/GOG 279 compared to earlier studies. This suggests a beneficial effect of the higher radiation dose and the modified chemotherapy regimen.
- Progression-Free Survival: There is a consistent improvement in PFS at 12 months across the studies, with the latest study showing the highest PFS.
Cervical Cancer
Recently, the KEYNOTE A18 showed that adding pembrolizumab to chemotherapy improved progression-free survival in patients with locally advanced cervical cancer.
Shitanshu Uppal
Here are some reasons to be skeptical that this approach is going to be a game-changer
- CALLA was a negative trial. Although A18 authors made a big point of differentiating the PD-L1 blockers (Durvalumab) from the PD-1 blockers (Pembro)
Shitanshu Uppal- KEYNOTE-412 trial is negative in head and neck
Jean-Pascal MachielsIf you watched the video above regarding surrogate markers, it should give you a significant pause before you prescribe pembrolizumab to a patient with locally advanced cervical cancer. Is the cost and inconvenience to patients justified without any benefit in OS?
Information regarding the enrollment in the GYOEDU Board Review Course for 2025
Shitanshu Uppal
That's it for now
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