Relapsed and Refractory germ cell tumors: finessing the rough end of a beautiful story

In this edition of Urological Oncology we have 4 invited review articles on the therapy of relapsed and refractory germ cell tumors (GCT) covering the potential role of high dose and novel chemotherapy regimens, targeted agents, and surgery. To many this may seem passé because since the advent of cisplatin combination chemotherapy, we cure almost all patients. Thus major challenges focused on not over treating, adequate surveillance and managing the sequelae of chemotherapy, surgery and radiation exposure have been emphasized ^1–6. While fewer than 400 patients die from germ cell tumors each year in the United States compared to an annual incidence of around 8000, the relative youth of those who die means that the productive life years lost is highly significant ⁷. One thing does need to be stated and that is that the incidence of relapsed and refractory, fatal germ cell tumor can be minimized by adhering to principles of therapy for the disease that include use of standard surveillance, chemotherapy and residual mass resection protocols across the population. This may be especially true for patients who present with poor risk metastatic germ cell tumor, who fail to obtain a complete radiological and marker response with first line therapy, have late relapse or are more than 50 years old at diagnosis ^8–12. These patients should be referred to a major center for assessment and therapy without delay. For most patients their journey to a cancer free life does not end after radical orchiectomy or chemotherapy or radiation therapy for their cancer. Every patient needs a multidisciplinary timetable of cancer assessment and therapy that leads to a well-crafted survivorship plan ³.

For refractory GCT patients many major therapeutic questions remain unanswered: At relapse after first line therapy should high dose chemotherapy with stem cell support (HDCSCT) be applied immediately, to everyone or to a select group, or should standard-dose salvage chemotherapy be used first, reserving HDSCT for those who fail to achieve complete remission? Does denser delivery of chemotherapy with growth factor support either in the first line or later increase the chance of response and decrease the chance of resistance? Can targeted agents be useful in defined populations of patients with refractory teratoma or other variants with malignant transformation? Does “heroic” surgery have any potential to cure the patient? The answers to these questions are important but interwoven because very few patients in the refractory group are cured by one modality alone. This means that a team that tailors therapy to the cancer and the person delivers optimal chance of cure.

Feldman and Powles review the use of high dose chemotherapy with stem cell rescue in relapsed patients ¹³. While such therapy can be curative in these patients, percentages would appear to favor use after first relapse. What is not clear is whether high dose therapy in the second line cures patients who would have been cured with standard chemotherapy with less toxicity and lower cost. This very issue is the major objective of the international phase III TIGER trial that will compare high dose and conventional chemotherapy regimens is this setting.

O’Carrigan and Grimison discuss the use of conventional regimens in the salvage setting as well as specifically discussing growing teratoma syndrome and the use of dose dense regimens for germ cell tumors as a whole ¹⁴. Dose dense therapy is being explored in a randomized trial as first line therapy where the administration of cisplatin and etoposide are accelerated to be given every 2 weeks with growth factor support, compared to conventional 3 week interval dosing of the platinum, etoposide and bleomycin (PEB) regimen that has been a standard for more than 20 years ¹⁵. It is possible that dose intensification may improve outcomes for refractory patients as well but the small numbers of patients available make clinical trials difficult to power and orchestrate. A further statement from O’Carrigan and Grimison needs emphasizing: in their flowchart they list “clinical trials” as their preferred salvage option. Some may not agree with this but its food for thought in an area where we do not have level 1 evidence for a specific mode of therapy.

Squillante and Vaughn discuss molecular targeted agents in germ cell tumors ¹⁶. While currently we have no targeted agents approved in this arena the advent of a targeted agent that produces disease stability with tolerable side effects, such as we have for renal cell carcinoma, would be welcome for germ cell tumor patients whose disease continues to progress. In that regard, molecular biology can be helpful. The discovery that virtually all teratomas have intact retinoblastoma gene and protein function was important. On that basis, a phase II study of a cyclin dependent kinase inhibitor has shown disease control in a major proportion of advanced teratoma patients treated and further studies are underway ¹⁷. Other therapeutic opportunities may become reality based on the molecular make up of individual refractory germ cells.

Daneshmand reviews the roles surgery can play in these patients ¹⁸. A rationale and detailed plan is important when planning what used to be called “desperation surgery”. A more tempered approach can lead to very significantly improved outcome in most patients with limited perioperative risk. A key point in this arena of residual germ cell tumor masses is that surgery has unique efficacy in treating chemotherapy-refractory cancer. This fact emphasizes the need for surgeon and oncologist to work closely together for optimal outcomes.

Treating refractory germ cell tumors is arduous and rarely straightforward. Hopefully the pearls from a panel of international experts in this edition of Urological Oncology will assist the reader in managing these challenging cases.