Since 2013, MSK has offered primary retroperitoneal lymph node dissection (RPLND) to select patients with low-volume incident or relapsed seminoma metastatic only to the retroperitoneum, in lieu of the traditional standards of care which were previously chemotherapy or radiation. MSK surgeon-scientists recently published results from a series of patients who received open bilateral primary RPLND over a 10-year period.
“Our experience shows that primary RPLND provides patients with a safe and highly effective alternative to chemotherapy or radiation for low-volume pure seminoma that has metastasized to the retroperitoneum,” said urologic surgeon Richard Matulewicz, MD, MSCI, MS, lead author of a paper published in the Journal of Urology. (1) “Our real-world findings corroborate recent phase 2 study results in favor of this approach and the inclusion of primary RPLND as a management option in updated treatment guidelines from the American Urological Association and the National Comprehensive Cancer Network.”
In this Q&A with Dr. Matulewicz, we discuss MSK’s experience with RPLND for select patients with low-volume seminoma metastatic to the retroperitoneum. We also discuss MSK’s pioneering work developing the MSK microRNA assay for men with germ cell tumors.
Dr. Matulewicz is part of a team that was ranked #1 in the nation for Urology Cancer Care this year by U.S. News & World Report.
What has the standard treatment for this patient population been historically?
Patients with stage 2 or relapsed stage 1 pure seminoma metastatic to the retroperitoneum have typically received radiation or first-line chemotherapy. These treatments provide excellent recurrence-free survival (RFS) and overall survival, but they are associated with short-term toxicities and long-term adverse effects, including higher rates of cardiovascular disease, metabolic syndrome, and secondary cancers.
How are suitable candidates for primary RPLND after orchiectomy selected?
At MSK, all patients receive a contrast CT scan of the chest, abdomen, and pelvis and a standard serum tumor assessment at the time of their original diagnosis. For patients with Clinical Stage I pure seminoma (localized to the testicle only) we recommend surveillance following orchiectomy, which includes frequent tumor marker assessment and interval CT scans. For patients who relapse or those who had retroperitoneal adenopathy at the time of initial diagnosis, we consider multiple treatment options including chemotherapy, radiation, and now primary surgery.
Working closely with our multidisciplinary disease management team (DMT) members, we determine the best treatment plan for each patient. Our team includes genitourinary medical oncologists Samuel Funt, MD, and Darren Feldman, MD, Section Head of Germ Cell Cancer.
Patients with stage 2 or relapsed stage 1 pure seminoma with low-volume metastasis to the retroperitoneum are offered RPLND as a treatment option. Following surgery according to their disease pathology and personal preferences, they may also elect to receive two cycles of adjuvant chemotherapy or proceed with surveillance post-RPLND.
As a standard-of-care, all patients with evidence of metastasis outside of the retroperitoneum or those with “bulky” retroperitoneal disease receive chemotherapy.
What about seminoma that makes complete bilateral RPLND feasible as a curative-intent procedure?
Testicular seminoma has a predictable pattern of metastatic spread, making it one of the very few curable metastatic cancers. The normal template of dissection is basically from the kidney vessels down into the upper pelvis since the lymphatic drainage follows the pathway taken by the testes during descent from near the kidneys through the belly and into the scrotum during in-utero development.
What were the main findings of your patient series?
Among 45 patients treated with primary RPLND, 43 were treated for their first diagnosis of testicular germ cell tumors. Most (73%) had stage 1 pure seminoma at diagnosis that relapsed before RPLND, and 27% had stage 2 seminoma at the time of diagnosis.
Prior to RPLND, the median size of the largest measurable retroperitoneal node was 1.8 cm and most patients had 1 node enlarged, only.
For 29 patients treated with primary RPLND and managed with post-RPLND surveillance, the two-year RFS was 81%. There were no retroperitoneal relapses in this group, suggesting that bilateral template surgery was highly effective in preventing relapses due to incomplete surgery.
We also reported a two-year RFS rate of 92% for 16 patients who chose two cycles of chemotherapy (etoposide and cisplatin) after primary RPLND.
Regardless of the adjuvant management strategy, all patients were alive and disease-free at the time of their most recent follow up.
MSK sees a high volume of testicular cancer patients annually, between 400 and 500 new cases. How does the MSK approach differ from other institutions?
The mainstay of our approach is team-based multidisciplinary management. Surgically, some other centers will only perform a modified template RPLND for early stage testicular cancer. Given our operative volume, we are very experienced in performing nerve-sparing procedures which allows for a more complete resection while preserving ejaculatory function, the traditional justification for modified template operations.
Urologic surgeon Joel Sheinfeld, MD, Deputy Chief of the Urology Service and Florence and Theodore Baumritter/Endi Ancell Chair of Urologic Oncology at MSK, and colleagues pioneered nerve-sparing operations for patients with nonseminomatous germ cell tumors more than 20 to 25 years ago to help protect patients’ fertility and sexual function after surgery. (2)
Are there any other negative effects associated with primary RPLND after orchiectomy?
RPLND is a big operation, requiring a several day hospital stay and usually 6 to 8 weeks of recovery post operatively. However, the operation is generally quite safe with a low rate of significant surgical complications. The biggest post-operative complication we observe is chylous ascites, or lymphatic fluid buildup in the belly, which occurs about 5% of the time. It is easily managed with drainage, and any tiny vessel leaks typically heal up well on their own.
Our patients do not experience lymphedema as seen in patients who have lymph node removal for other types of cancers, such as breast cancer. The body has hundreds of lymph nodes and finds workaround routes for drainage. For the same reason, RPLND does not negatively affect the immune system.
Patients with testicular cancer are typically young, in their 20s and 30s, so fertility preservation counseling with members of our DMT is an essential part of their treatment plan. Patients interested in fertility preservation may elect to bank sperm before undergoing orchiectomy, and we offer nerve-sparing operations to all patients who wish to preserve their fertility or ejaculatory function.
How do the MSK study results compare to the findings from recent phase 2 clinical trials investigating this approach?
Our results corroborate findings from several recent studies, including the SEMS trial, PRIMETEST, and COTRIMS trials. Our results support experienced multidisciplinary patient selection for surgery and bilateral template RPLND, as we observed no retroperitoneal relapses with bilateral template resections, whereas other studies permitted some modified template operations and saw some relapses.
MSK developed the MSK microRNA assay (MMA) for testis cancer, the first CLIA and State Department of Health (New York) certified assay. When will it be ready for clinical use?
I lead the early-stage testicular cancer microRNA program on the surgery side in collaboration with Drs. Feldman and Funt on the medical oncology side and clinical laboratory scientist Fei Ye, PhD, Director of Assay Development at MSK.
The MMA detects two strains of microRNAs, which we believe can be more sensitive and specific for detecting seminoma than traditional serum tumor markers and potentially certain assays that detect only one microRNA strain. We also think it will add value to our traditional approach to staging and surveillance, which includes CT scans and HCG, AFP, and LDH tests. CT scans are pretty good, but lymph nodes can be enlarged for many reasons; AFP is never elevated in men with seminoma, and HCG only shows up in about 10% to 15% of patients, even among those with advanced disease.
The MMA certifications mean that our test is reliable and reproducible. We could use the MMA today in the clinic, but we’re still conducting research and want to ensure it’s ready for prime time before rolling it out.
Presently, we offer the MMA to newly diagnosed patients with testicular cancer as part of a prospective cohort study.
In our recent paper published in European Urology Open Science, (3) we reported that while the biomarkers miR-371a-3p and miR-372-3p reliably demonstrated high sensitivity and specificity for identifying localized germ cell tumors, both as a combined assay and separately, causes of variations in microRNA levels and time to normalization for individual patients after surgery were still unclear. With regard to it’s utility in detecting relapse, serum microRNA did not normalize within three weeks for all patients. However, no patient with normalized results within three weeks experienced a relapse at a median follow-up of 7.2 months.