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Management of Difficult Germ-Cell Tumors

Management of Difficult Germ-Cell Tumors

ABSTRACT: Although testicular cancer is a rare disease accounting for only 1% of all male neoplasms, it represents a paradigm for cancer curability. Overall, more than 95% of patients can expect to be cured of their disease with minimal long-term toxicity. Given these expectations, it is critical that cancer care providers are familiar with the diagnostic and therapeutic challenges encountered in these rare patients. In particular, clinicians managing these patients should be aware of some of the pitfalls encountered when determining relapse. In a series of case presentations, we review the evaluation and management of patients with persistent elevation of serum tumor markers and postchemotherapy residual radiographic abnormalities.

Although an uncommon malignancy, testicular cancer provides a paradigm for the treatment of disease with the intent to cure. Indeed, more than 95% of men with testicular cancer are cured, with little long-term toxicity. Most testicular tumors are of germ-cell origin. The following three cases illustrate key considerations in the evaluation and management of patients with difficult germ-cell tumors.

Case 1

A healthy 25-year-old male was diagnosed with right testicular nonseminomatous germ-cell tumor with small-volume retroperitoneal metastases. Retroperitoneal lymph node dissection (RPLND) revealed 2 out of 13 positive nodes. Post-RPLND, the patient was followed with close surveillance. Three months later, human chorionic gonadotropin (HCG) levels rose precipitously and two pulmonary nodules were seen on chest imaging. Three cycles of bleomycin, etoposide, and cisplatin were administered, resulting in normalization of serum markers and radiographic abnormalities. Within 3 months of chemotherapy, HCG again rose to 1,006 ng/mL and a new pulmonary nodule was observed. Brain magnetic resonance imaging and testicular ultrasound ruled out disease recurrence in sanctuary sites. Salvage chemotherapy with vinblastine, ifosfamide, and cisplatin was initiated. After one cycle, the pulmonary nodule had enlarged (see Figure 1) and HCG continued to rise.

What is the appropriate intervention in this patient?

Germ-cell tumors are unique in that they remain highly curable even in the metastatic setting and, to a lesser degree, even after primary chemotherapy has failed. Standard-dose cisplatin-based chemotherapy regimens such as BEP (bleomycin, etoposide, cisplatin [Platinol]) and VIP (etoposide [VePesid], ifosfamide, cisplatin) result in cure in approximately 70% to 80% of patients.[1] Salvage chemotherapy with vinblastine, ifosfamide, and cisplatin is associated with complete response (CR) in 50% of patients, but this remission is durable in only 25%.[2]

Patients who experience disease progression within 4 weeks after cisplatin-based chemotherapy are described as having platinum-refractory disease, whereas absolute platinum-refractory disease is used to describe those patients whose disease progresses during cisplatin-based treatment.[3] The prognosis for this group of patients is particularly poor and has prompted the investigation of surgical salvage (occasionally referred to as "desperation surgery"). In the majority of cases, patients with persistently elevated serum markers have systemic disease that is not amenable to surgical intervention. However, an increasing body of data points to a definite cure rate for surgical salvage in a highly select group of patients with surgically resectable chemorefractory germ-cell tumors.

Salvage Surgery in the Literature-Murphy et al[4] described 48 patients with chemorefractory disease who went on to surgical salvage. All patients had elevated serum markers at the time of surgery. Although 38 of 48 patients (79%) were rendered grossly disease-free after surgery, and 29 of 48 (60%) achieved serologic remission, only 10 of 48 (21%) remained continuously free of disease. Nineteen patients relapsed after obtaining remission with salvage surgery. Of these, four were rendered free of disease with further sugery, and two others obtained long-term remission after high-dose chemotherapy with autologous bone marrow transplant. Overall, 16 of 48 patients (33%) achieved long-term disease-free survival.

Ability to completely resect the disease was the factor most predictive of favorable outcome, and the authors emphasized that this group of patients made up only 8% of the 600 postchemotherapeutic resections performed at Indiana University over a 13-year period. Of 13 patients who had two or more sites of disease at the time of surgery, none were long-term survivors. Presurgical characteristics suggestive of favorable outcome included elevated alpha-fetoprotein (AFP) only at time of surgery, late relapse after chemotherapy, and presence of teratoma in the initial specimen.

This series confirmed many of the conclusions drawn by Wood et al[5] regarding the experience with surgical salvage at Memorial Hospital. Fifteen patients with chemorefractory disease and persistently elevated serum markers underwent surgical salvage. In each case, the entire residual mass or solitary metastasis was resected. Of these 15 patients, 12 were considered to have achieved CR with surgery as assessed by normalization of serum markers after resection. Seven of the patients who obtained CR with surgery alone remained without evidence of disease on follow-up 3 to 53 months after resection, but five relapsed within a median of 2 months after surgery. Two of the five relapsed patients achieved disease-free status with further chemotherapy. Of the three patients who did not achieve CR with surgery, two patients were rendered disease-free after postoperative salvage chemotherapy. Overall, 11 of the 15 patients (73%) were rendered disease-free after salvage surgery with or without additional therapy. Favorable prognostic factors in this cohort again included isolated AFP elevation and retroperitoneal site of disease.

Eastham and colleagues[6] reported their experience with surgical salvage in 16 patients with chemorefractory disease. Ten of these patients had a solitary metastasis in the retroperitoneum. Of this group, six patients had rising markers just prior to surgery, whereas the other four patients had elevated markers but had reached a plateau. The residual mass was successfully resected in all 10 patients. Viable tumor was found in eight patients; the remaining patients had only mature teratoma in the resected specimen. With an average follow-up of 64 months following resection, 5 of 10 patients were alive without evidence of disease. The remaining five patients all had recurrence of disease leading to death within 6 months of resection.

Six patients had more than one site of residual disease. Five patients had rising markers prior to surgery and one had elevated markers that had reached a plateau. The latter patient was the only long-term survivor of salvage surgery. The surgical specimen revealed only necrosis, but serum markers normalized postoperatively. All other patients died of relapsed disease.

Overall, a 37% (6/16) long-term disease-free survival was observed. This study did not confirm the prognostic significance of isolated AFP elevation. However, all five patients with elevated serum markers that had plateaued prior to surgery were long-term survivors. In contrast, only 1 of 11 patients with rising markers prior to surgery was a long-term survivor. A solitary retroperitoneal mass was again associated with a favorable outcome.

These results were confirmed by groups from the UK, Germany, and Japan. Ravi et al reported on 30 marker-positive patients, 17 of whom (57%) were rendered disease-free after salvage surgery.[7] Albers and colleagues achieved similar results in their cohort of 30 chemorefractory patients.[8] Habuchi et al describe 24 chemorefractory patients, 10 (42%) of whom achieved long-term disease-free survival after salvage surgery with or without adjuvant therapy.[9]

In the largest series of patients undergoing salvage surgery, investigators reviewed data from 64 patients with elevated serum markers after second-line chemotherapy. Active germ-cell cancer was detected in 75.8% of these patients. The 5-year overall survival rate was 33.3% with a median survival time for all 64 patients of 15 months (95% confidence interval [CI] = 9-21 months). Postoperative chemotherapy did not improve disease free recurrence in this cohort, as would be expected in patients with largely chemorefractory disease. Four variables were found to be negatively associated with survival: increasing preoperative beta-HCG, elevated AFP (continuous variable), repeat RPLND, and germ-cell cancer in the surgical specimen.[10]

Patients who develop chemorefractory disease represent a particularly challenging, and fortunately relatively small, subset of germ-cell tumor cases. Clinicians are obligated to recognize disease that is unlikely to respond to further chemotherapy and thoroughly evaluate these patients for potentially resectable disease. Cure rates with surgical salvage in this patient population range from 33% to 73%.

The patient underwent resection of the growing pulmonary nodule. Pathology revealed choriocarcinoma; serum markers normalized postoperatively (see Figure 2). The patient is alive without evidence of disease at 5 months postresection.

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