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In Reply

Indiana University Cancer Center, Indianapolis, IN

George J. Bosl

Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY

We thank Drs Gilligan et al and Drs Aparicio and Germa¹ for their thoughtful comments to our recent editorial² in the Journal of Clinical Oncology about the second Spanish Germ Cell Cancer Cooperative Group (SGCCCG) study. They correctly point out that the cancer-specific survival rate is virtually 100% following treatment of patients with clinical stage I seminoma with carboplatin. However, the cancer-specific survival rate following orchiectomy alone is also virtually 100%, as the vast majority of patients (80% to 85%) never experience disease recurrence, and for patients whose disease does recur, nearly all are cured with 3 to 4 cycles of cisplatin-based combination chemotherapy.

This point needs to be reiterated in another way. The fact that recurrence rates are low after carboplatin or radiation therapy (RT) for stage I seminoma in the phase II and III trials (Oliver et al³) as mentioned by these authors, does not mean that either one of these therapeutic endeavors benefited 96% to 98% of patients. It must be emphasized that approximately 85% of patients have no cancer at the time of the treatment. Thus, if 100 patients with unselected clinical stage I seminoma are treated, then only approximately 15 patients will potentially benefit from any therapy. The fact that the recurrence rates for radiation and for carboplatin are comparable does not negate the fact that recurrences still occur and that these patients still need surveillance. In fact, in the series report by Oliver et al,³ most of the relapses occurred in the abdomen. An advantage for those patients who receive adjuvant radiation therapy is that the need for computed tomography (CT) surveillance of the abdomen is abrogated as nearly all recurrences for these patients occur outside the radiotherapy portals.

Both Gilligan et al and Aparicio and Germa emphasize the apparent lack of long-term toxicity from carboplatin. However, both chemotherapy and radiation therapy are associated with long-term toxicities, which include cardiovascular events occurring after chemotherapy treatment.^4,5 We will agree that one or two cycles of carboplatin could have less long-term toxicity than four cycles of the current cisplatin-based chemotherapy regimen. In fairness, however, it is at least equally likely that current radiation therapy regimens with limited fields and with treatment planning by CT scans will have less long-term toxicity than orthovoltage or cobalt therapy without accurate radiographic imaging on which most RT late-toxicity reports are based.⁴ Data from trials studying limited chemotherapy will take several more years to mature. These studies certainly deserve our attention but they should not be taken as a priori proof that chemotherapy is harmless.

We believe that Drs Aparicio and Germa are correct with the goal that "...a risk-adapted therapeutic approach seems to be the next step to spare unnecessary toxicity in as many patients as possible." Unlike for clinical stage I nonseminomatous germ cell tumors, there are no prospective clinical trials that have established a reproducible set of criteria to predict relapse in stage I seminoma. Using the results of pooled data, primary tumors more than 4 cm in diameter without rate testis invasion and those less than 4 cm with rate testis invasion had 5-year relapse rates of 17% and 14%, respectively.⁶ In the study of Aparicio and Germa, all of these patients received adjuvant carboplatin, despite the fact that they were not likely to relapse. It remains that a substantial majority of patients who received carboplatin received it unnecessarily. While adjuvant carboplatin may decrease the incidence of recurrence, it does not eliminate this risk nor does it eliminate the need for surveillance with CT scans, chest radiographs, and markers.

Finally, Gilligan et al state that "surveillance represents the best option for most patients with stage I seminoma." Warde and Gospodarowicz would agree.⁶ We agree that it is an acceptable option. However, oncologists who recommend this approach must be prepared to observe these patients for a very long time and the patients must be very compliant. As Warde reported, approximately 30% of relapses occurred after 2 years and approximately 7% occurred after 5 years. We have seen several patients with relapsed seminoma on surveillance after 10 years (admittedly a small number skewed by referral bias). Nonetheless, late relapses are probably more common with surveillance for seminoma than nonseminoma germ cell tumors.

We applaud the efforts of the Spanish Germ Cell Cancer Cooperative Group for its attempt to address the difficult task of risk-adapted therapy for early-stage seminoma. The lack of reproducible data to predict relapse remains a continuing problem. Perhaps, more precise molecular markers might further this cause. In the interim, like Warde and Gospodarowicz in their editorial⁶ commenting on the Oliver trial, we caution the oncology community that the benefits and risks of alternative approaches for stage I seminoma should be explained fully to patients. We believe that adjuvant carboplatin remains an investigational option.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

REFERENCES

1. Aparicio J, Germa JR, del Muro XG, et al: Risk-adapted management for patients with clinical stage I seminoma: The Second Spanish Germ Cell Cancer Cooperative Group Study. J Clin Oncol 23:8717-8723, 2005[Abstract/Free Full Text]

2. Loehrer PJ, Bosl GJ: Carboplatin for stage I seminoma and the sword of Damocles. J Clin Oncol 23:8566-8569, 2005[Free Full Text]

3. Oliver RTD, Mason MD, Mead GM, et al: Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: A randomized trial. Lancet 366:293-300, 2005[CrossRef][Medline]

4. Travis LB, Curtis RE, Storm H, et al: Risk of second malignant neoplasms among long term survivors of testicular cancer. J Natl Cancer Inst 89:1429-1439, 1997[Abstract/Free Full Text]

5. Meinardi MT, Gietma JA, van der Graaf, et al: Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18:1725-1732, 2000[Abstract/Free Full Text]

6. Warde P, Specht L, Horwich A, et al: Prognostic factors for relapse in stage I seminoma managed by surveillance: A pooled analysis. J Clin Oncol 20:4448-4452, 2002[Abstract/Free Full Text]

7. Warde P, Gospodarowicz M: Adjuvant carboplatin in stage I seminoma. Lancet 366:267-268, 2005[CrossRef][Medline]

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Loehrer, P. J. Articles by Bosl, G. J. Search for Related Content PubMed Articles by Loehrer, P. J. Articles by Bosl, G. J. Social Bookmarking                            What's this?