Resection Should be Considered for Residual Non-Retroperitoneal Disease in Post-Chemo NSGCTs

Jennifer M. King, MD

Although patients with metastatic nonseminomatous germ-cell tumors (NSGCTs) who had teratoma in the primary tumor were found to have a higher rate of teratoma in residual non-retroperitoneal disease following chemotherapy, those without teratoma in the primary tumor could have teratoma or active testicular germ-cell tumors (GCTs) in residual disease post-chemotherapy and should be considered for resection, according to findings from a retrospective study published in the Journal of Clinical Oncology.

Among the 75 patients with teratoma in the primary tumor, 55% had at least 1 post-chemotherapy non-retroperitoneal surgical specimen with teratomatous elements vs 17% of those who did not have teratoma in the primary tumor (n = 54; P < .001).

Moreover, 31% of patients with teratoma in the primary tumor had at least 1 post-chemotherapy non-retroperitoneal surgical specimen with active GCT vs 56% of patients without teratoma in the primary tumor (P = .0046).

“Notably, 72% of patients with teratoma in the primary [tumor] and 63% of patients without teratoma in the primary [tumor] had either teratoma or active GCT in the resected disease; thus, we found no clear criteria for observation for patients with non-retroperitoneal residual disease,” lead study author Jennifer M. King, MD, and colleagues, wrote. King is an assistant professor of Clinical Medicine in the Division of Hematology-Oncology of the Department of Medicine at Indiana University School of Medicine.

Cisplatin-based chemotherapy can lead to cure in most patients with testicular GCTs; however, approximately 30% of patients with advanced NSGCT have residual disease on imaging following first-line chemotherapy. Surgical resection is recommended for patients with normal tumor markers and residual retroperitoneal disease measuring more than 1 cm in long axis. For patients with residual non-retroperitoneal disease in the absence of residual retroperitoneal disease, limited data are available to drive disease management.

To investigate whether the presence of teratoma in the primary tumor of patients with metastatic NSGCT was associated with a higher rate of teratoma in residual non-retroperitoneal resected disease following first-line or salvage chemotherapy, King and colleagues gathered data on patients treated at Indiana University between 1990 and 2021.

The prospectively maintained Indiana University Testicular Cancer Database provided information on patient demographics, primary tumor site, stage at diagnosis, tumor marker levels, orchiectomy pathology, International Germ Cell Cancer Group (IGCCCG) risk classification, initial treatment, date of last follow-up, and status at last follow-up.

Patients who initially had retroperitoneal metastasis at the time of diagnosis that later normalized to less than 1 cm in long axis after chemotherapy were included, along with patients who were initially observed following chemotherapy before undergoing surgical resection of non-retroperitoneal disease in the salvage setting. Investigators excluded those with post-chemotherapy residual retroperitoneal and non-retroperitoneal disease. All patients underwent post-chemotherapy surgical resection of non-retroperitoneal disease.

The primary objective of the study was to evaluate whether the presence of teratoma in the primary tumor was associated with a higher rate of teratoma in post-chemotherapy residual non-retroperitoneal disease. Investigators also examined rates of histology found at the time of residual non-retroperitoneal resection.

The median age was 29 years (range, 16-52), and testis was the primary tumor site for 99% of patients. One patient had retroperitoneum as the primary tumor site. Orchiectomy predominant histology included embryonal carcinoma (35%), mixed (26%), choriocarcinoma (15%), teratoma (12%), yolk sac tumor (10%), seminoma (2%), and necrosis (1%).

Patients’ IGCCCG risk classification included good (43%), intermediate (16%), and poor (40%). Observed metastatic sites were retroperitoneum (15%), pulmonary (28%), mediastinal lymph nodes (8%), liver (9%), bone (7%), brain (20%), retrocrural lymph nodes (6%), supraclavicular/cervical lymph nodes (1%), and pelvic lymph nodes (2%).

First-line chemotherapy regimens included 4 cycles of bleomycin/etoposide/cisplatin (52%), 3 cycles of bleomycin/etoposide/cisplatin (22%), 4 cycles of etoposide/cisplatin (8%), 4 cycles of etoposide/ifosfamide/cisplatin (5%), or other (13%). Eighty-one percent of patients underwent surgical resection after first-line chemotherapy, 16% had surgery after salvage chemotherapy, and 4% of patients received surgery after first-line chemotherapy and again after salvage chemotherapy.

Sixty-five percent of patients underwent lung node resection, 16% had brain metastasis resection, 12% had mediastinal lymph node dissection, 6% had cervical lymph node dissection, 5% underwent bone metastasis resection, and 2% had liver resection.

Additional data showed that 31% of patients with teratoma in the primary tumor had non-teratoma GCT in resected non-retroperitoneal disease, and 28% had necrosis. Notably, 13% of patients had both teratoma and non-teratoma GCT in resected non-retroperitoneal disease.

In the non-retroperitoneal surgical resection specimens for patients without teratoma in the primary tumor, 56% had non-teratoma GCT, 37% had necrosis, and 9% had both teratoma and non-teratoma GCT.

Twenty-seven patients in both groups underwent resection of non-retroperitoneal disease in the salvage surgical setting, due to either growing disease or rising markers. In these patients from the group without teratoma in the primary tumor, 6 were negative for tumor markers, 14 were positive for tumor markers, and tumor marker status was unknown for 7. In those with teratoma in the primary tumor who underwent surgical resection of non-retroperitoneal disease after salvage chemotherapy, 13 were tumor marker negative, 6 were tumor marker positive, and 8 patients had unknown tumor marker status. In the tumor marker–positive patients, 5 had rising tumor markers and 1 patient had persistently elevated tumor markers after finishing chemotherapy and was referred for possible salvage surgery.

“Even when trying to evaluate the role of positive tumor markers at the time of surgery, no clear pattern emerged, as many patients with negative tumor markers still had active GCT present at the time of surgical resection,” the study authors wrote.

Additionally, 12 patients who had teratoma in the primary tumor and 2 patients without teratoma in the primary tumor had teratoma resected from more than 1 non-retroperitoneal site. One patient in both groups had non-teratoma GCT in non-retroperitoneal resected disease in more than 1 site.

Twenty patients, including 9 who had teratoma in orchiectomy and 11 without teratoma in orchiectomy, required resection of residual disease in the brain. Three of these patients had necrosis, 17 had active GCT, and 3 had both active GCT and teratoma. No patients had only teratoma at the time of residual brain resection, irrespective of primary tumor pathology.

In the 11 patients without teratoma in the primary tumor who underwent a brain resection, 10 had a primary orchiectomy specimen that was predominantly embryonal carcinoma, and the other patient had a primary orchiectomy specimen that was predominantly choriocarcinoma with elements of embryonal carcinoma. Among those patients with teratoma in the primary tumor, the primary orchiectomy pathology was predominantly embryonal carcinoma in 4 patients, and other pathologies included mixed embryonal carcinoma, yolk sac, and choriocarcinoma.

King and colleagues noted that selection bias was a limitation of the study. Although investigators included all patients in the established time frame who met the inclusion criteria, they had no ability to identify patients with residual non-retroperitoneal disease who did not undergo surgical resection.

“To our knowledge, this is the largest dataset of patients with residual non-retroperitoneal disease in the setting of no residual retroperitoneal disease. Similarly to residual retroperitoneal disease, teratoma in the primary [tumor] is associated with higher rates of teratoma in residual non-retroperitoneal disease,” the study authors concluded. “However, patients without teratoma in the primary [tumor] still have high rates of active GCT in residual non-retroperitoneal disease, and thus, the absence of teratoma in the primary [tumor] should not dissuade surgical resection.”

Reference

King JM, Cheng M, Kesler K, et al. Management of residual nonretroperitoneal disease in postchemotherapy nonseminomatous germ-cell tumors. J Clin Oncol. Published online February 9, 2023. doi:10.1200/JCO.22.02205