Effects of Neoadjuvant Chemotherapy on Image-Directed Planning of Surgical Resection for Distal Femoral Osteosarcoma

The standard of care for isolated extremity osteosarcoma in adolescents and young adults has changed very little in the last twenty years1. Chemotherapeutic regimens including doxorubicin, cisplatin, and high-dose methotrexate have predominated, and the timing of treatments has also changed very little. Most patients receive some portion of their chemotherapy prior to surgical local control (termed neoadjuvant chemotherapy) and then additional adjuvant chemotherapy following surgical resection. As so much of this care standard has been subjected to repeated evaluation in randomized controlled clinical trials1, it may be assumed that the timing of treatments is similarly evidence-based. It is not. The timing of treatments is instead rational, based on the following four considerations that led to its development and incorporation into common practice. First, early in the days of limb salvage surgery, neoadjuvant chemotherapy was undertaken to delay definitive surgery to permit the fabrication of the custom endoprosthetic implants then used for limb salvage reconstructions. Second, neoadjuvant chemotherapy permitted measurement of the treatment effect on the primary tumor2 in the form of preoperative chemotherapy-induced tumor necrosis, thereby providing a surrogate measure of chemotherapeutic response and eradication of clinically undetectable microscopic metastatic disease. Third, treating physicians thought that initiating systemic treatments quickly put priorities in proper philosophical order, with an upfront attack on the deadly presumed systemic disease, rather than an initial focus on the primary tumor and local control. Fourth, surgeons preferred performing close-margin resections around tumors that had been largely treated already. Often-touted potentially advantageous treatment effects of neoadjuvant chemotherapy included tumor size reduction, clearing of peritumoral edema on magnetic resonance imaging (MRI) scans, development of a rind or pseudocapsule, and increased palpable firmness of the tumor. The first rationale has largely disappeared now that modular implants and large regional and national allograft tissue repositories are available. The second rationale remains, but provides only prognostic information rather than treatment guidance, as changing protocols following a poor histological response (limited tumor necrosis) to preoperative chemotherapy does not improve prognosis3. In a Pediatric Oncology Group study beginning in the late 1980s, investigators attempted to provide evidence for the third rationale, but the study was closed after years of insufficient patient accrual4. The reason suspected for the poor enrollment was that many surgeons already believed too firmly in the fourth rationale to enroll their patients for possible randomization to the immediate-surgery arm when limb salvage was planned. Although they failed to reach significance, the published results trended toward improved survival in the immediate-surgery group4. This study’s underpowered results did not slow the acceptance of neoadjuvant chemotherapy as the standard of care for patients with osteosarcoma. Thus, even the lack of data for the third rationale is the result of the yet unstudied fourth rationale, that neoadjuvant chemotherapy makes local control surgery easier or safer. While a number of modalities have been tested with regard to their value in noninvasively measuring the treatment effect of neoadjuvant chemotherapy on the primary tumor prior to local control surgery, no modality has been sufficiently successful at predicting the treatment effect to be widely adopted by sarcoma treatment centers5-14. While evaluation of changes between pre-chemotherapy and post-chemotherapy MRIs has not proven to accurately predict histologically confirmed treatment effects, these MRIs are still almost universally used by surgeons to plan local control resections15. Furthermore, MRI is the most accurate noninvasive means of staging the local bone and soft-tissue extent of sarcomas, including compartmental spread, neurovascular involvement, and intra-articular spread16-22. We investigated the effect of neoadjuvant chemotherapy on MRI-based surgical planning for osteosarcoma. Even a tumor that has responded well to preoperative chemotherapy in terms of histological necrosis may have progressed with regard to surgically critical anatomy. This study was undertaken to evaluate the surgically important anatomic effects of neoadjuvant chemotherapy. Because the practice standard of neoadjuvant chemotherapy was deeply entrenched and we had no reason to believe that it was erroneous, we thought that it was both impractical and unethical to randomize patients to immediate surgery or neoadjuvant chemotherapy followed by surgery. Instead we chose to evaluate the practice in a pilot study using available data from existent MRIs. In order to measure surgically important anatomic changes on these MRIs, we developed a surgical planning questionnaire focused on the distal part of the femur, assessed its reliability across different surgeons, and tested it against a separate validation in the form of radiologists assessing the same MRIs with their own anatomic details questionnaire. With this tool, we could then safely ask our question: does neoadjuvant chemotherapy change the surgical resections planned by surgeons for distal femoral osteosarcomas?