Metastatic Testicular Cancer Stopped With High-Dose Regimen

INDIANAPOLIS, July 25 --When metastatic testicular cancer progresses despite initial chemotherapy, including a cisplatin-based combination, a high-dose salvage regimen with stem-cell rescue can lead to relapse-free complete responses.

So found Lawrence H. Einhorn, M.D., of Indiana University, and colleagues. In the July 26 issue of The New England Journal of Medicine, they reported that 116 of 184 (63%) consecutively treated patients, including 40 who failed cisplatin-based therapy, had complete remissions without relapse over a median 48-months follow-up.

The total number of relapse-free remissions included 94 of 135 patients (70%) who received the regimen as second-line therapy and 22 of 49 (45%) who received it as third-line or later therapy. There were three treatment-related deaths in the entire cohort.

"Testicular tumors are potentially curable by means of high-dose chemotherapy plus hematopoietic stem-cell rescue, even when this regimen is used as third-line or later therapy or in patients with platinum-refractory disease," Dr. Einhorn and colleagues concluded.

Most patients with germ-cell tumors do not have anatomically confined tumors that are amenable to surgery. Salvage options for metastatic disease include four courses of cisplatin-based combination chemotherapy or high-dose chemotherapy plus autologous stem-cell rescue.

In 1986 Dr. Einhorn and associates began treating patients with a carboplatin-based high-dose chemotherapy regimen. Initially, they used autologous bone-marrow cells for hematopoietic rescue but switched to stem-cell rescue in 1996. Stem cells engraft rapidly, reducing the recovery time before a second dose of high-dose chemotherapy, the investigators noted.

In the current report, Dr. Einhorn and coauthors reported findings from a retrospective review of data on the 184 consecutive patients they treated with the regimen from 1996 through 2004. The primary objective of the analysis was to examine the efficacy of the regimen for progressive, cisplatin-resistant testicular cancer.

The patients' median age was 31. Tumor histology was seminoma only in 35 patients and nonseminomatous germ cell tumors in 149. On the basis of the International Germ Cell Cancer Collaborative Group prognostic score, 71 patients were classified as low risk, 38 as intermediate risk, and 75 as high risk. Forty patients had platinum-refractory disease, defined as tumor progression within four weeks of the most recent cisplatin-based chemotherapy.

High-dose chemotherapy consisted of two cycles of carboplatin 700 mg/m² plus 750 mg/m² of etoposide, given intravenously five, four, and three days before infusion of autologous peripheral-blood stem cells. The second cycle of chemotherapy began after recovery of granulocyte and platelet counts, unless grade 4 nonhematologic toxicity occurred or the patient had no response to the first course. Most patients who responded to high-dose therapy received maintenance oral etoposide 50 mg/m² daily for 21 days, repeated every four weeks for three cycles.

Of the 116 patients who remained disease free during follow-up, 104 (90%) were disease free for more than two years. Additionally, 49 of 61 patients with favorable prognostic features remained disease free for a median of 46 months, and 18 of 40 platinum-refractory patients remained disease free for a median of 49 months.

Toxicity associated with high-dose chemotherapy consisted primarily of myelosuppression, mucositis, nausea, vomiting, dehydration, peripheral neuropathy, and otologic abnormalities. Three patients developed acute leukemia after high-dose therapy. All three had received high-dose chemotherapy as third line or later, and none had received etoposide maintenance therapy.

The authors noted that two randomized trials comparing high-dose and chemotherapy showed no advantage for high-dose therapy, leaving the role of high-dose therapy for metastatic testicular cancer unresolved. However, the authors said, the regimen has proven its mettle in platinum-refractory patients.

"There should be little or no debate on the use of high-dose chemotherapy for a patient with a germ-cell tumor that is refractory to platinum-based chemotherapy or that is not cured by a cisplatin-ifosfamide regimen as salvage chemotherapy," Dr. Einhorn and coauthors concluded.