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Summary In experimental mouse tumors, high-dose irradiation in a single fraction caused progressive increase in tumor cell death in 2 to 5 days. Such delayed tumor cell deaths appeared to be due to radiation-induced deterioration of intratumor microenvironment characterized by profound reduction of blood perfusion and increase in hypoxia. Similar secondary and indirect cell death may play an important role in clinical stereotactic body radiation therapy and stereotactic radiation surgery. Purpose The purpose of this study was to reveal the biological mechanisms underlying stereotactic body radiation therapy (SBRT) and stereotactic radiation surgery (SRS). Methods and Materials FSaII fibrosarcomas grown subcutaneously in the hind limbs of C3H mice were irradiated with 10 to 30 Gy of X rays in a single fraction, and the clonogenic cell survival was determined with in vivo—in vitro excision assay immediately or 2 to 5 days after irradiation. The effects of radiation on the intratumor microenvironment were studied using immunohistochemical methods. Results After cells were irradiated with 15 or 20 Gy, cell survival in FSaII tumors declined for 2 to 3 days and began to recover thereafter in some but not all tumors. After irradiation with 30 Gy, cell survival declined continuously for 5 days. Cell survival in some tumors 5 days after 20 to 30 Gy irradiation was 2 to 3 logs less than that immediately after irradiation. Irradiation with 20 Gy markedly reduced blood perfusion, upregulated HIF-1α, and increased carbonic anhydrase-9 expression, indicating that irradiation increased tumor hypoxia. In addition, expression of VEGF also increased in the tumor tissue after 20 Gy irradiation, probably due to the increase in HIF-1α activity. Conclusions Irradiation of FSaII tumors with 15 to 30 Gy in a single dose caused dose-dependent secondary cell death, most likely by causing vascular damage accompanied by deterioration of intratumor microenvironment. Such indirect tumor cell death may play a crucial role in the control of human tumors with SBRT and SRS.

Stereotactic body radiation therapy (SBRT) and stereotactic radiosurgery (SRS) have been demonstrated to be highly effective for a variety of tumors. However, the radiobiological principles of SBRT and SRS have not yet been clearly defined. It is well known that newly formed tumor blood vessels are fragile and extremely sensitive to ionizing radiation. Various lines of evidence indicate that irradiation of tumors with high dose per fraction, i.e. >10 Gy per fraction, not only kills tumor cells but also causes significant damage in tumor vasculatures. Such vascular damage and ensuing deterioration of the intratumor environment then cause ischemic or indirect/secondary tumor cell death within a few days after radiation exposure, indicating that vascular damage plays an important role in the response of tumors to SBRT and SRS. Indications are that the extensive tumor cell death due to the direct effect of radiation on tumor cells and the secondary effect through vascular damage may lead to massive release of tumor-associated antigens and various pro-inflammatory cytokines, thereby triggering an anti-tumor immune response. However, the precise role of immune assault on tumor cells in SBRT and SRS has not yet been clearly defined. The "4 Rs" for conventional fractionated radiotherapy do not include indirect cell death and thus 4 Rs cannot account for the effective tumor control by SBRT and SRS. The linear-quadratic model is for cell death caused by DNA breaks and thus the usefulness of this model for ablative high-dose SBRT and SRS is limited.

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There are radiobiological rationales supporting hypofractionated radiotherapy for prostate cancer. The recent advancements in treatment planning and delivery allow sophisticated radiation treatments to take advantage of the differences in radiobiology of prostate cancer and the surrounding normal tissues. The preliminary results from clinical studies indicate that abbreviated fractionation programs can result in successful treatment of localized prostate cancer without escalation of late toxicity.

Few cases of synchronous bilateral stage I seminomas have been reported in the world literature. We present a case of bilateral synchronous testicular seminoma, the current literature on the management of stage I seminoma, and the implications for radiotherapy. A forty-year-old man presented with synchronous bilateral classical seminomas, both stage IA. After undergoing bilateral inguinal orchiectomy, he received adjuvant external beam radiotherapy, with a standard paraaortic field. After 18 months of followup, he remains well, without evidence of recurrence. Bilateral germ cell tumors (BGCTs) are reported consistently at a low rate. Bilateral radical inguinal orchiectomy is standard of care, yet some groups have proposed an organ preservation approach. Of the reported cases of bilateral stage I synchronous GCT, with concordant seminoma histology, most of them were treated with bilateral orchiectomy and adjuvant radiotherapy. Although morbidity associated with radiotherapy directed at the abdomen is not negligible, adjuvant paraaortic radiotherapy remains safe and well-tolerated treatment regime. Bilateral synchronous stage I seminoma of the testes is rare. Organ preservation remains investigational. Chemotherapy is probably a reasonable option. We propose that patients with bilateral stage I synchronous GCT, with concordant seminoma histology, should be managed with bilateral orchiectomy, followed by paraaortic radiotherapy.