Localized or locally advanced (stage I-III per the staging system used in clear cell renal cell carcinoma) RMC is preferably treated with nephrectomy and retroperitoneal lymph node dissection followed by close surveillance. Radical nephrectomy is favored over partial nephrectomy even in very early stage tumors due to the infiltrative nature and medullary epicenter of RMC. Notably, up to 94% of patients with RMC present with nodal and/or visceral metastases. With few exceptions, even patients who initially present with localized disease will quickly develop distant metastases, often within weeks. Due to the aggressiveness of RMC, patients often develop early recurrence while still recovering from nephrectomy resulting in rapid deterioration of performance status which compromises the ability to safely administer systemic therapy. For this reason, upfront systemic therapy (platinum-based cytotoxic chemotherapy or clinical trial) is recommended for the majority of patients with newly diagnosed RMC, including those with localized disease at presentation. Upfront surgery can be considered in the very rare cases of isolated RMC tumors ≤4 cm in greatest dimension that are limited to the kidney. However, these patients are at high risk of recurrence and should therefore be very closely monitored postoperatively.In patients with metastatic disease, retrospective data suggest that cytoreductive nephrectomy, when feasible, results in improved overall survival (16.4 months vs 7.0 months) compared with systemic chemotherapy alone regardless of ECOG performance status (0-1 or 2-3) or whether systemic chemotherapy is first given pre-operatively or after nephrectomy. Based on these data, as well as expert opinion it is currently recommended that cytoreductive nephrectomy should be carefully considered for patients with metastatic RMC on the basis of response to upfront systemic therapy, performance status, and surgical evaluation. Due to the high risk for rapid recurrence, postoperative systemic therapy should be considered in all patients who undergo definitive or cytoreductive nephrectomy. Distant metastasectomy is generally not recommended. In cases where nephrectomy is not feasible, embolization can palliate symptomatic hematuria when necessary. RMC is resistant to targeted anti-angiogenic therapies, such as sorafenib, sunitinib, pazopanib, and bevacizumab, or mechanistic target of rapamycin (mTOR) inhibitors such as everolimus that are used against other renal cell carcinomas. It is also resistant to currently approved immune checkpoint therapies such as pembrolizumab. Therefore, these therapies should not be routinely used in patients with RMC. Cytotoxic combination chemotherapy (particularly platinum-based cytotoxic regimens) is the only systemic treatment approach that has consistently shown to produce partial or complete responses in approximately 29% of cases. Therefore, outside of clinical trials, platinum-based cytotoxic combination chemotherapy remains the mainstay of systemic treatment for RMC. Unfortunately, responses are not durable in most cases and there are no direct comparisons between the different chemotherapy regimens. Most series have used various combinations of platinum agents, taxanes, anthracyclines, or gemcitabine. High-dose-intensity combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), commonly used in patients with urothelial cell carcinomas, has shown efficacy against RMC. However, a retrospective analysis did not reveal a benefit of MVAC compared with a regimen containing cisplatin, paclitaxel, and gemcitabine (CPG). No particular cytotoxic chemotherapy combination has shown superiority over others and relatively low-intensity regimens can occasionally produce gratifying responses. For example, durable complete responses were noted in 2 of 22 patients (9%) with metastatic RMC treated with carboplatin and paclitaxel. Carboplatin may be preferred over cisplatin to minimize nephrotoxicity in anticipation of cytoreductive nephrectomy for those patients that will respond to the systemic treatment. Despite systemic chemotherapy, very few patients will live for >24 months and novel therapeutic strategies are therefore urgently needed.
A treatment algorithm for RMC and RCCU-MP (adapted from here) is shown below:
In the salvage setting, the following therapies have shown efficacy in platinum-resistant renal medullary carcinoma:
Additional information regarding our current recommendations on the diagnosis, management, and clinical trial eligibility criteria for patients with renal medullary carcinoma can be found in the following articles: