Resection of all residual disease after salvage chemotherapy offers the best chance for a cure for patients with refractory or relapsed advanced testicular cancer, according to the results of our recent retrospective study.
The data, published in the journal Urology, underscores the critical role of surgery in the management of advanced testicular cancer.
Together with our colleagues at Memorial Sloan Kettering Cancer Center, we analyzed clinical and pathological outcomes for 112 patients with cisplatin-refractory or relapsed germ cell tumors (GCT) who were treated with salvage chemotherapy followed by retroperitoneal lymph node dissection (RPLND) at MSK between 1994 and 2011. Patients received either conventional dose or high-dose chemotherapy as salvage chemotherapy, depending on prognostic factors related to the biology of their disease. (1)
Our results showed that approximately half of these patients had a viable GCT or teratoma at resection. Five-year disease-specific survival for the entire cohort was 73 percent (CI=95%; range 63–80%). Viable GCT histology at RPLND or extra-RPLND resection predicted worse disease-specific survival (hazard ratio 7.37, p=0.003). (1)
In general, five-year survival rates for metastatic testicular cancer have increased to about 95 percent from less than 30 percent in the 1950s, largely due to advances in multimodal treatment and the fact that GCTs are highly responsive to systemic therapy, especially the more recent taxane-based regimens. (2) Given the high survival rates, the focus has shifted to determining whether it is possible to maintain high survival rates while minimizing unnecessary treatments and help patients avoid the adverse effects associated with higher-dose chemotherapy.
In that regard, we are collaborating with colleagues at 95 centers in North America, Europe, and Australia on the prospective TIGER Trial, a randomized phase III trial of initial salvage chemotherapy for patients with germ cell tumors. Our objective is to determine whether there is a difference in two-year disease-free survival rates between patients receiving salvage chemotherapy as conventional dose chemotherapy versus high-dose chemotherapy with stem cell support. (3)
Advanced Testicular Cancer
GCT accounts for about 1 percent of male cancers and 5 percent of male genitourinary malignancies, and is the most common tumor diagnosed in young men between the ages of 14 and 44 years in Western countries. (4)We typically manage patients with advanced GCT with cisplatin-based induction chemotherapy. However, up to one-third of these patients relapse or experience disease progression, necessitating further treatment with salvage chemotherapy. (5)
While no widely accepted standard is recognized yet, at MSK, we use several prognostic factors to guide the selection for salvage chemotherapy. (6) Our experience has shown that carefully identifying the appropriate candidates for treatment with conventional dose chemotherapy — paclitaxel, ifosfamide, and cisplatin (TIP) — has resulted in a complete response in about 70 percent of patients who received the chemotherapy alone or in combination with surgery. (7) Prognostic factors for selecting these patients include those who have gonadal primary tumors with a partial, marker negative, or complete response to induction chemotherapy, and said response lasted more than six months.
For patients with unfavorable pathologic features, treatment with high-dose chemotherapy — paclitaxel and ifosfamide followed by high-dose carboplatin and etoposide with stem cell support (TICE) — has resulted in a complete response rate in about 50 percent of patients who received high-dose chemotherapy alone or in combination with surgery. (8)Unfavorable prognostic factors that guide treatment selection for this group include extra-gonadal primary tumors or disease progression following an incomplete response to first-line chemotherapy or following ifosfamide and cisplatin-based conventional dose chemotherapy.
Study Results: The Impact of Resecting Residual Disease
Given the lack of published data on clinical and pathological outcomes for patients who undergo RPLND following salvage chemotherapy, we analyzed the data for all 181 patients with advanced testicular cancer who were treated with either TIP or TICE at MSK between 1994 and 2011. (1) We currently perform more than 100 RPLND a year.
All eligible patients with evidence of retroperitoneal disease before salvage chemotherapy were offered surgical resection, and a total of 112 patients underwent postsalvage chemotherapy RPLND. The median follow-up period for the group was 7.3 years. Histology on resection showed viable GCT in 30 patients (27 percent), teratoma in 26 (23 percent), and fibrosis in 56 (50 percent). The five-year disease-specific survival rate was 74 percent (95% CI; range 63–80%). Multivariate analysis determined that patients with a viable GCT on histology at RPLND or extra-RPLND resection predicted a far worse disease-specific survival (hazard ratio 7.37, p=0.003). (1)
The results of this retrospective review of prospectively collected data from MSK highlight the vital role of surgery in these patients to remove residual disease. In addition, the data underscores that aggressive complete resection is critical in maximizing favorable outcomes.
Optimizing Salvage Chemotherapy: The TIGER Trial
Together with international colleagues, MSK is participating in the prospective TIGER Trial to determine if there is a difference in two-year progression-free survival rates between high-dose chemotherapy (TIP) or conventional dose therapy (TICE) plus autologous stem cell transplant.
We are seeking to recruit 420 participants across 95 study locations. Collaborating organizations include the National Cancer Institute, the European Organisation for Research of Cancer, and the Movember Foundation. The study opened in 2015 with an estimated primary completion date of June 2024.
Currently, there is no widely accepted standard for choosing between the two different options for salvage chemotherapy. We hope that the findings from the TIGER Trial will help guide the selection for optimal salvage chemotherapy regimens in the future. (9)
Advancing Understandings about Testicular Cancer
A recently published disease primer on testicular cancer with a focus on GCT - published in Nature Reviews - provides an overview of the biology, epidemiology, diagnosis, and current treatment guidelines for GCT, including the current classification system published by the World Health Organization (WHO) in 2016, which reflects the development potential of different cells of origin and their pathogenesis. (4)
Together with a panel of international colleagues, Dr. Feldman and Satish K. Tickoo, MD, also from MSK, recently co-authored two histopathology guides on neoplasia of the testis — one on orchidectomy and one on retroperitoneal lymphadenectomy — published by the International Collaboration on Cancer Reporting. The evidence-based recommendations are based on international data sets and present the required and recommended elements to be included in pathology reports. The guides include the updated 2016 WHO classification of urological tumors, the results of a consultation by the International Society of Urological Pathology, and the American Joint Committee on Cancer’s staging method, version eight. (2)
At MSK, we are committed to bringing all tools to bear to improve outcomes for patients with testicular cancer. Our multidisciplinary experts work together to determine the optimal treatment approach for each patient.