Patients with congenital achondroplasia present unique anatomical and physiological characteristics that may affect standard chemotherapy and immunotherapy dosing algorithms. The reviewed report emphasizes that currently no established dosing guidelines exist for cytotoxic or immune checkpoint therapies in this population, creating uncertainty about the accuracy of common dose calculations and the risk of under- or overexposure.
The report describes a 69-year-old female with lifelong congenital achondroplasia who was diagnosed with stage IV non-small cell lung carcinoma (adenocarcinoma). Tumor profiling demonstrated a high tumor mutational burden and programmed death-ligand 1 (PD-L1) expression of 20%.
The multidisciplinary team initiated combination therapy with carboplatin, pemetrexed, and pembrolizumab. Dosing choices were as follows:
Carboplatin: dose calculated using renal function via a measured creatinine clearance and the Calvert approach (area under the curve–based dosing).
Pemetrexed: dosed according to body surface area (BSA).
Pembrolizumab: administered at a fixed dose of 100 mg because the patient’s body weight was below 65 kg, per the dosing approach used in this case.
These initial decisions reflect pragmatic application of standard dosing methods while acknowledging potential limitations when applied to patients with disproportionate body composition and stature.
Given the uncertainty about whether conventional dosing formulas would achieve target exposure in congenital achondroplasia, therapeutic drug monitoring (TDM) was performed after the first treatment cycle. Results from TDM informed adjustments to the carboplatin and pemetrexed doses to better align systemic exposure with expected therapeutic ranges. Specific TDM values, pharmacokinetic targets, and the magnitude of dose changes were not reported in the abstract.
Overall the combined regimen was described as generally well tolerated in this patient. The notable treatment-related toxicity was grade 2 neutropenia, which prompted a one-week delay of the third cycle; the neutropenia resolved after this delay. Clinically, the patient achieved a favorable response after four cycles of therapy.
The core message of the report is that standard dosing algorithms—such as BSA-based dosing for cytotoxics, fixed dosing of immune checkpoint inhibitors for low body weight, and AUC-based carboplatin dosing using creatinine clearance—may have uncertain accuracy in congenital achondroplasia. Body composition, organ size, renal function estimation, and pharmacokinetic variability associated with skeletal dysplasia could all affect drug distribution and clearance.
In this context, the authors advocate consideration of TDM to support individualized dosing and to increase confidence that adequate drug exposure is achieved without undue toxicity. The use of measured creatinine clearance rather than estimated formulas was applied for carboplatin dosing in the presented case, reflecting an effort to improve accuracy in renal function assessment.
The case and literature review conclude that, because of the absence of established dosing guidelines for patients with congenital achondroplasia, individualized approaches including therapeutic drug monitoring may be valuable to optimize chemotherapy and immunotherapy exposure. TDM informed dose modifications in this case and was associated with a manageable toxicity profile and a favorable clinical response. The report highlights the need for further data to define best practices for dosing antineoplastic agents in this population.
Ethics approval was reported as not applicable. Informed consent was obtained from the patient. The authors declared no competing interests.
Note: The abstract and available PubMed record provide the clinical synopsis, dosing strategy, use of TDM, safety outcome (grade 2 neutropenia resolved after delay), and favorable response after four cycles. Detailed numeric TDM results, exact dose adjustments, pharmacokinetic parameters, and long-term outcomes were not reported in the abstract available on PubMed.