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Radiotherapy of Carcinoma-In-Situ of the Testis

University of Tuebingen, Tuebingen, Germany
Albertinen-Krankenhaus, Hamburg, Germany

To the Editor:We have read with interest the report of Petersen et al,¹ and we should like to congratulate the authors for their meticulous study on dose reduction of radiotherapy of testicular carcinoma-in-situ (CIS), including a detailed analysis of endocrinologic sequelae subsequent to treatment.

The report is, apart from a recently published Austrian trial² and an ongoing German CIS study,^3,4 the only published series for dose-reduction of radiotherapy of CIS aiming at amelioration of long-term detrimental effects of testicular irradiation. The study failed, however, to demonstrate a dose dependency of Leydig cell impairment for doses in the range of 14 to 20 Gy. This observation is in good accordance with our own yet premature data on 40 CIS patients treated with either 18 or 16 Gy. Decreasing the radiation dose below the current standard of 20 Gy⁴ was not associated with a higher rate of preserved hormone production. Thus, it seems that the rationale is only small for dose reduction below standard doses of 18 to 20 Gy for routine treatment of CIS.

Biopsies are the only way to verify eradication of CIS after radiotherapy. However, timing of biopsy taking may be a crucial denominator for the sensitivity of this intervention. CIS cells are known to proliferate only slowly. Thus, a few CIS cells resistant to radiotherapy may take long periods of time to proliferate within the testis until random biopsy may succeed to disclose recurrent disease. Therefore, timing the control biopsy late rather than early seems to be of particular importance for follow-up of CIS-patients. Furthermore, the dogma of diffuse distribution of CIS throughout the testicle probably does not apply to the postradiation situation. Relapse from the disease must be expected to develop focally, originating from only a few persisting cells after radiotherapy. Therefore, we advocate multiple-site biopsies, at least double biopsies, for postradiation control. It can thus be speculated that Petersen et al¹ might have detected more treatment failures if such double biopsies had been performed.

In Germany, we are currently performing a similar study to identify the lowest dose feasible for eradication of CIS. Although our experience is still incomplete, it is largely comparable with the Danish data. However, relapse was observed in one patient treated with 16 Gy (8 x 2 Gy). This observation indicates that this dose is as equally unsafe to control CIS as 14 Gy.

The reasons for the failure of low-dose radiotherapy need to be discussed in more detail. Basically, technical failure is conceivable, but this was ruled out in the case of Petersen et al¹ and in our own patient. Hence, it is most likely that some CIS cells were resistant to irradiation, subsequently giving rise to relapse from the disease. With respect to the dose-response curve, this dosage level would correspond to the bending top of the curve. At this point, the probability of cure is still high, but sporadic cases of relapse may occur. Furthermore, a recent report⁵ of invasive testicular malignancy despite previous radiotherapy of CIS with 18 Gy indicates that we may ultimately need to depart from our view of CIS being a lesion curable in 100% of cases.

We would like to draw attention to yet another problem of control biopsies taken after treatment. In our series, three patients showed persisting spermatogonia after radiotherapy. This observation has, to our knowledge, not been reported before. None of these patients has developed clinical relapse to date. We are, however, concerned that the presence of germ cells after treatment might herald the persistence of at least some CIS cells, too, that could ultimately proceed to invasive cancer. Thus, this unfavorable event again underscores the need for long-term follow-up of patients, including late control biopsies.

A new approach to radiotherapy of CIS has recently been suggested by Sedlmayer et al² by applying 13 Gy in 10 fractions to the CIS-bearing testis. Even though the number of patients was small, clearance of CIS was obtained in all patients, and no decline in basal testosterone production was observed during 2 years of follow-up. In fact, reducing the single dose of irradiation while maintaining a high number of fractions may increase the therapeutic ratio of irradiation due to the previously described inverse fractionation sensitivity of germ cells. Leydig cells which exhibit a conventional fractionation sensitivity may at the same time be less compromised, functionally, as a result of very small single fractions. Thus, reduced single doses of radiotherapy at an increased number of fractions may offer a new strategy to both complete eradication of CIS and hormone preservation.

REFERENCES

1. Petersen PM, Giwercman A, Daugaard G, et al: Effect of graded testicular doses of radiotherapy in patients treated for carcinoma-in-situ in the testis. J Clin Oncol 20: 1537-1543, 2002[Abstract/Free Full Text]

2. Sedlmayer F, Höltl W, Kozak W, et al: Radiotherapy of testicular intreaepithelial neoplasia (TIN): A novel treatment regimen for a rare disease. In J Radiat Oncol Biol Phys 50: 909-913, 2001

3. Classen J, Dieckmann K-P, Bamberg M: Can the total dose of radiotherapy (XRT) for testicular intraepithelial neoplasia (TIN) be safely reduced below 20 Gy? J Cancer Res Clin Oncol 126: R16, 2000 (abstr, suppl)

4. Dieckmann KP, Classen J, Souchon R, et al: Therapie der testikulären intraepithelialen Neoplasie (TIN) - eine Übersicht auf Grundlage der evidenzbasierten Medizin (EBM). Wien Klin Wochenschr 113: 7-14, 2001[Medline]

5. Dötsch M, Brauers A, Büttner R, et al: Malignant Germ cell tumor of the contralateral testis after radiotherapy for testicular intraepithelial neoplasia. J Urol 164: 452-453, 2000[CrossRef][Medline]

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