Outliers in Testicular Cancer Management

Although the successful multidisciplinary management of testicular cancer is the solid tumor treatment paradigm, challenging cases require detailed knowledge of the disease and therapy options to achieve a successful outcome. Examples of these challenges include primary cisplatin resistance, late relapse, and the growing teratoma syndrome (GTS). Primary cisplatin-refractory disease calls for new therapeutic alternatives, while GTS, if unappreciated, may easily lead to excessive treatment and delayed use of curative surgery. Given the rarity of these events, establishing a "standard of care" is a challenge. However, the skilled clinician with knowledge of the underlying disease and the pathology will be able to successfully manage such patients.

Moore et al use clinical examples of these "difficult" germ-cell tumors to review the complexities encountered in the management of select germ-cell tumors. They thus make a case for surgery as salvage in cisplatin-refractory disease as well as "salvage" from excessive unnecessary chemotherapy in GTS and cystic mature teratoma with moderate marker expression.

Platinum Resistance

The first case presentation is an example of primary platinum resistance. The extent of the recurring disease is limited, making the patient a well suited candidate for a surgical approach. However, the consensus is that a rising serum human chorionic gonadotropin (HCG) level predicts for recurrence and has been considered a contraindication to surgery in this setting.[1]

Experience in platinum-resistant and refractory disease following salvage surgery is suggestive of benefit in roughly one of three patients. Complete resection is the most favorable predictive factor. Unfortunately most patients with primary platinum-refractory disease also have unresectable cancer due to the extent of spread.

It would be of value to the practicing physician to be informed about the more recently introduced chemotherapeutic combinations with potential to overcome cisplatin resistance. It appears that these combinations may lead to an increase in the frequency of successful salvage surgery as part of an integrated treatment algorithm. Promising combinations, such as paclitaxel/gemcitabine (Gemzar), gemcitabine/oxaliplatin (Eloxatin), or paclitaxel/gemcitabine/cisplatin, achieved response rates exceeding 30% in these patients.[2]

In the Murphy et al report, reviewed by the authors in support of the role of salvage surgery in properly selected patients, the occurrence of late relapse was identified as a favorable presurgical characteristic.[3] This finding is in keeping with the widely held view that the mainstay of late relapse therapy is complete surgical removal.[4,5] Late relapse has a unique biology that accounts for the clinical observation. These tumors are slow-growing with a low potential for metastasis to additional anatomic sites and do not respond to chemotherapy with cytoreduction.

Diagnostic Awareness

The second and third case presentations are ideal tests for the level of diagnostic awareness required by the practicing physician. The implementation of guidelines in disease management is driven by the need to establish a minimum standard of care, and is not meant to establish a strict medical manual. Admittedly, a growing mass in the case of an underlying malignancy should be first considered cancer until proven otherwise. This increased sensitivity, however, should not come at the cost of specificity, leading to subsequent overtreatment and toxicity.

The growing teratoma syndrome described in the second case presentation is a characteristic example. The normalization of markers followed by the increase of tumor size during chemotherapy should lead the clinician to consider surgery.

The third case presented-residual mass with moderate marker expression following chemotherapy exemplifies a clinical presentation that if unappreciated often leads to overtreatment. This conclusion is supported by a report from Beck et al, summarizing an experience with testicular cancer patients who had elevated serum tumor markers at postchemotherapy retroperitoneal lymph node dissection (RPLND).[6] Despite elevated serum tumor markers and presumed active disease, surgical pathology revealed teratoma in 34.2% of patients and

fibrosis in 12.3% of patients, with 5-year overall survival rates of 77.5% and 85.7%, respectively. Other series have also reported an incidence of teratoma or fibrosis ranging from 20% to 40%, despite elevated serum tumor markers at the time of postchemotherapy RPLND.

Other Prognostic Issues

Clinical parameters predictive of teratoma or fibrosis include declining serum tumor markers, low serum HCG (< 100 ng/mL), and first-line chemotherapy only. ¹⁸F-fluorodeoxyglucose-positron-emission tomography (FDG-PET) in this setting is unable to distinguish necrosis from mature teratoma. Thus FDG-PET does not spare mixed germ-cell tumor patients with postchemotherapy residual masses the need for resection, at least by current evidence, and is therefore not indicated in this setting. Of interest, an FDG-PET within the first 2 weeks after chemotherapy may be associated with a decline in sensitivity due to reduced metabolic activity of the remaining tumor. It can be safely recommended that, in such a case, resection of residual masses should be performed within 4 to 6 weeks after a low-level marker plateau is achieved.

Interpretation of serum markers can also be misleading; false-positive HCG measurements may result from cross-reactivity of HCG with luteinizing hormone (LH), marijuana use (as noted by the authors), or the existence of heterophilic antibodies. Cross-reactivity may originate from multiple sources, including autoimmune diseases, vaccination, and influenza infection, and they may occur in healthy individuals with a frequency of ~3%. Measuring urinary HCG by a highly specific carboxyl-terminal assay, as well as simultaneous measurements of serum HCG and LH and validation of serum HCG by a different laboratory assay, may detect false-positive increases of serum HCG in patients with testicular cancer more rapidly than testosterone administration, given the relative urgency of surgical intervention.

Conclusions

Therefore, patients with late relapse, those meeting the two initial GTS criteria, and those with resectable residual lesions and elevated tumor markers postchemotherapy should immediately undergo surgery. In resectable but cisplatin-refractory disease, salvage surgery can be considered, although its benefit to patients is not as clear in alpha- fetoprotein (AFP)-persistent cases. Clinicians should be even more reluctant to recommend surgery in the presence of a rapidly rising HCG. In patients with extensive disease and a rapidly rising HCG, an alternative chemotherapy combination designed to overcome cisplatin resistance, followed by surgery, is the recommended approach. Thus, in patients with resectable cancer in the presence of a rising HCG or with unresectable disease, the preferred strategy is further chemotherapy followed by surgical consolidation.

—Eleni Efstathiou, MD
—Christopher J. Logothetis, MD

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Schmoll HJ, Souchon R, Krege S, et al: European consensus on diagnosis and treatment of germ cell cancer: A report of the European Germ Cell Cancer Consensus Group (EGCCCG). Ann Oncol 15:1377-1399, 2004.

2. Farmakis D, Pectasides M, Pectasides D: Recent advances in conventional-dose salvage chemotherapy in patients with cisplatin-resistant or refractory testicular germ cell tumors. Eur Urol 48:400-407, 2005.

3. Murphy BR, Breeden ES, Donohue JP, et al: Surgical salvage of chemorefractory germ cell tumors. J Clin Oncol 11:324-329, 1993.

4. Shahidi M, Norman AR, Dearnaley DP, et al: Late recurrence in 1263 men with testicular germ cell tumors. Multivariate analysis of risk factors and implications for management. Cancer 95:520-530, 2002.

5. Oldenburg J, Alfsen GC, Waehre H, et al: Late recurrences of germ cell malignancies: A population-based experience over three decades. Br J Cancer 94:820-827, 2006.

6. Beck SD, Foster RS, Bihrle R, et al: Outcome analysis for patients with elevated serum tumor markers at postchemotherapy retroperitoneal lymph node dissection. J Clin Oncol 23:6149-6156, 2005.

7. Stenman UH, Alfthan H, Hotakainen K: Human chorionic gonadotropin in cancer. Clin Biochem 37:549-561, 2004.