Abstract: Stereotactic body radiation therapy (SBRT) is a novel treatment modality in radiation oncology that delivers a very high dose of radiation to the tumor target with high precision using single or a small number of fractions. SBRT is the result of technological advances in patient/tumor immobilization, image guidance, and treatment planning and delivery. This modality is safe and effective in both early stage primary cancer and oligometastases. Compared to the use of stereotactic radiosurgery for other tumor sites, SBRT is slow to be adopted in the management of genitourinary malignancies. There are now emerging data that show the safety and efficacy of this treatment modality in genitourinary (GU) malignancies especially in prostate cancer and renal cell carcinoma. Preclinical data, clinical experience, and challenges are reviewed and discussed.
In 1951, Leksell first reported stereotactic radiosurgery (SRS) by coupling radiation with a stereotactic guiding device (Leksell, 1951). SRS is now an established safe and effective treatment modality for benign and malignant intracranial tumors. Stereotactic body radiation therapy (SBRT), or “SRS applied to extracranial sites,” is defined by American Society for Radiation Oncology (ASTRO) and American College of Radiology (ACR) as a “treatment method to deliver a high dose of radiation to the target, utilizing either a single dose or a small number of fractions with a high degree of precision within the body” (Potters et al., 2004).
Important Aspects of SBRT
This novel modality is the result of advances in radiation oncology technology. The requirements include precise target localization (may involve fusion of various imaging modalities), patient/tumor immobilization or tracking, image guidance, as well as radiation treatment planning and delivery to produce a steep isodose gradient outside the target volume as shown in Figures 1 and 2. Because of the high dose delivery per fraction, it is very important to respect the radiation tolerance of surrounding critical normal tissues to avoid severe toxicity. It is important to take into consideration and account the organ or tumor motion in order to perform SBRT safely and effectively (Teh et al., 2007a; Teh et al., 2007b).
Currently, there are various modern linacs with integrated stereotactic delivery systems (Lo et al., 2010). Some of the important features of these machines include micro-multileaf collimator (to enhance conformality of the stereotactic plan), BrainLab (Munich, Germany) “ExacTrac X-ray 6D” system with robotic treatment couch (to allow near real-time image guidance with 6 degrees of freedom), Tomotherapy Hi-Art System (Madison, WI, USA) that utilizes on board megavoltage computed tomography (MVCT) for daily image-guidance, Cyberknife (Accuray, Sunnyvale, CA, USA) that has a compact 6MV X-band linac mounted on a six-joint robotic arm with corresponding robotic couch with six degrees of freedom and near real-time kilovoltage (KV) guidance, as well as Varian, Elekta, and Novalis TX that all have conebeam CT for volumetric image guidance. For linacs with only the capability of KV-X-Ray for image guidance, the placement of fiducial markers in soft tissues is important (Teh et al., 2007a; Teh et al., 2007b).
The dose fractionation schemes used in SBRT ranging from 6-34 Gy per fraction (compared to the conventional 1.8-2 Gy per fraction) are aimed to yield substantially more potent radiobiological dose leading to improved clinical outcomes, but not at the expense of normal tissue toxicities. Applying linear-quadratic formula, Fowler and colleagues have compared the relative biological effectiveness of various SBRT fractionation schemes with the conventional fractionation scheme for lung cancer (Fowler et al., 2005). Radiobiologically, the conventional 60 Gy in 30 fractions (2 Gy per fraction) and the SBRT 60 Gy in 3 fractions (20 Gy per fraction) have biological equivalent doses of 72 Gy and 180 Gy, respectively. These two different fractionation schemes can yield an estimated progression free survival at 30 months of 15% and > 99%, respectively.
Radiobiologically, SBRT approach therefore is especially beneficial for treating more radio-resistant tumors such as non-small cell lung cancer, renal cell carcinoma, melanoma, sarcoma, and high grade malignancies including prostate cancer. However, one very important aspect of consideration of SBRT is the surrounding normal tissues and their radiation tolerance. A practitioner needs to keep a very tight constraint on the critical normal tissues, e.g., spinal cord when planning to deliver SBRT to spine, in order to avoid serious treatment related sequelae (Jhaveri et al., 2008).
SBRT is used most commonly for small non-metastatic primary cancer and oligometastases (Lo et al., 2010; Timmerman and Kavanagh, 2005; Timmerman et al, 2007; Teh et al., 2007). One of the advantages of SBRT is to provide ablative treatment in a non-invasive manner. In addition, for the oligometastases, SBRT is targeted against gross metastatic disease (which may not be very responsive to systemic therapy) while systemic therapy is targeted against micrometastases. According to Norton-Simon hypothesis, SBRT, by reducing the gross tumor mass, can also potentially render tumor cells more sensitive to systemic therapy (Norton and Simon, 1986). Clinical experience with SBRT is most abundant in three extracranial sites namely lung, liver, and spine.
Small (designated T1 and T2) non-small cell lung cancers in either operable or medically inoperable patients as well as pulmonary oligometastases have been treated successfully with SBRT without significant side effects (Fritz et al., 2006; Nagata et al., 2005; Onishi et al., 2004; Ren et al., 2010; Rusthoven et al., 2009a; Teh et al., 2007a; Teh et al., 2007b; Wulf et al., 2004). In a recent phase II Radiation Therapy and Oncology Group (RTOG) multi-institutional trial, 55 medically inoperable patients with biopsy proven T1 and T2 non-small cell lung cancers were treated with SBRT to 54 Gy (18 Gy in 3 fractions). The 3-year tumor control, disease-free survival, and overall survival rates were 97.6%, 48.3%, and 55.8%, respectively (Timmerman et al., 2010). A larger multi-institutional retrospective Japanese study involving 245 patients showed that patients treated with SBRT have a similar survival rate when compared to surgical series, but with less treatment-related morbidity. Promising results in local control were also seen in pulmonary oligometastases (Fritz et al., 2006; Ren et al., 2010; Rusthoven et al., 2009a). For patients with primary hepatocellular carcinoma and liver oligometastases, SBRT can produce good local control and favorable toxicity profiles (Choi et al., 2008; Katz et al., 2007; Lo et al., 2009; Rusthoven et al., 2009b; Schefter et al., 2005; Teh et al., 2007b; Tse et al., 2008). Similar excellent results in pain relief and local control without significant toxicity with spine SBRT were reported (Jhaveri et al., 2008; Nguyen et al., 2010).
SBRT for GU Malignancies
SBRT is slow to be adopted in the management of genitourinary malignancies including kidney and other parts of upper urinary tract, bladder, prostate, testes, penis, and other parts of lower urinary tract. The reasons for the above include the following:
• Other effective competing local therapies, e.g., total/partial nephrectomy, cryoablation, and radiofrequency ablation for renal cell carcinoma (RCC), partial/total cystectomy for bladder cancers, prostatectomy, standard fractionated intensity modulated radiotherapy (IMRT) and brachytherapy for prostate cancers, orchiectomy for testicular cancer and partial/total peniectomy for penile cancer. These standard of care treatment options, e.g., IMRT/brachytherapy/prostatectomy for prostate cancer yield excellent outcome with long-term follow-up. It is difficult to introduce a new treatment option.
• Effective systemic therapies, e.g., novel targeted therapy (sunitinib, sorafenib, temsirolimus, and everolimus) for metastatic RCC, chemotherapy for bladder cancer, hormonal therapy and chemotherapy for metastatic prostate cancer, as well as chemotherapy for testicular cancers.
• Normal tissues tolerance in GU system is not well known especially in the SBRT dose range.
• Clinical trials data are scarce.
However, there are good rationales and benefits for integrating SBRT in the management of GU malignancies. They include:
• A recent review of 17 studies estimated an average alpha/beta ratio of prostate cancer of 1.85 Gy suggesting that the slow proliferating prostate cancer cells have high sensitivity to dose per fraction (Brenner et al., 2002; Dasu, 2007). Thus, radiobiologically, SBRT regimens with a larger radiation dose per fraction delivered in a smaller number of fractions may be more effective.
• SBRT, with higher than standard dose per fraction, may be effective for more radio-resistant tumors such as renal cell carcinoma, and high grade and metastatic GU malignancies (Teh et al., 2007a).
• SBRT may be used in conjunction with systemic therapy targeting gross and micrometastatic disease, eliciting synergistic effects and accomplishing Norton-Simon phenomenon.
• SBRT allows shorter course of treatment. Provided clinical outcome is not inferior or toxicity increased, patients will experience convenience and possibly improved quality of life.
There are only reported series on SBRT for prostate and renal cell carcinoma but not other GU malignancies. Clinical experience of SBRT for oligometastases from various primaries including metastatic RCC have been well reported (Lo et al., 2009; Teh et al., 2007a).
There are at least two randomized trials showing that dose escalation for localized prostate cancer resulted in improvement in biochemical progression-free survival but at the expense of an increased risk of late rectal toxicity (Dearnaley et al., 2007; Pollack et al., 2002). One of the ways to decrease rectal toxicity while keeping the escalated dose is to utilize intensity-modulated radiation therapy (IMRT) or image-guided radiation therapy (IGRT) in more recent years (Cahlon et al., 2008; Teh et al., 2004). On the other hand, various studies including a recent review reported the low alpha/beta ratio of prostate cancers (Brenner et al., 2002; Dasu, 2007). If this is correct and using the linear/quadratic model, SBRT should improve the therapeutic ratio in radiotherapy for prostate cancer.
Using a subcutaneous model in nude mice by injecting C4-2 human prostate cancer cells, Lotan et al. (2006) showed that SBRT dose level treatments were able to decrease tumor volume and prostate-specific antigen (PSA) as well as there was a dose response relationship in this dose range. Similarly, utilizing human prostate cancer cell line CWR22RV1, the Methodist/Baylor group demonstrated the efficacy of high-dosage hypofractionation irradiation resulting in a sustained anti-tumor control both in vitro and in vivo, when compared to standard fractionation and control groups (Teh et al., 2008).
There are several clinical studies of SBRT reported in recent years. In these published series, SBRT is mainly used for low risk localized prostate cancer. However, based on some of the theoretical advantages mentioned above, SBRT can be considered as boost after more standard fractionation approaches. The most important factor in delivering SBRT for prostate cancer is the careful consideration of surrounding critical structures including ano-rectum, bladder, urethra, femoral neck, and testicles as well as their corresponding dose volume histogram (DVH). Figure 1 shows an SBRT plan for low risk organ confined prostate cancer. Endorectal balloon is used to further decrease rectal volume receiving high dose radiation.
Early results of a Canadian phase I/II study (pHART3) using a five-fraction hypofractionated accelerated radiotherapy treatment (35 Gy in five daily fractions) for low risk localized prostate cancer were reported (Tang et al., 2008). At 6 months follow-up, there was no grade 3 toxicity. However, longer term follow-up is needed to evaluate both efficacy and toxicity. Madsen et al. (2007) reported the clinical experience with SBRT in 40 patients with low risk prostate cancer. They were all treated with 33.5 Gy in five fractions, which is equivalent to 78 Gy in 2 Gy fractions based on alpha/beta ratio of 1.5. The actuarial 4-year biochemical progression-free survival was 90% with a median follow-up of 41 months. There were only two cases of grade 3 acute urinary toxicity. There was no late toxicity > grade 3 was reported. King et al. recently reported a phase II trial in two separate publications (King et al., 2009; Wiegner and King, 2010). Forty-one patients with low risk prostate cancer with minimum 6 months follow-up received 36.25 Gy in five fractions of 7.25 Gy with SBRT alone. With a median follow-up of 33 months, there was no biochemical failure. Toxicity profile was also very encouraging with no Grade 4 or higher toxicity; two patients had grade 3 late urinary toxicity but no grade 3 late rectal toxicity. Using the Expanded Prostate Cancer Index Composite (EPIC)-validated quality of life questionnaire, they reported results on 32 consecutive patients treated with SBRT. The mean EPIC sexual domain summary score, sexual function score, and sexual bother score decreased by 45%, 49% ,and 25% respectively at 50 months follow-up. The penile bulb dose was not associated with erectile dysfunction. The investigators concluded that the rates of erectile dysfunction appeared comparable to those reported for other modalities of radiotherapy. In a phase I dose escalation trial from University of Texas Southwestern Medical Center (presented in the American Society of Clinical Oncology 2010 Genitourinary Cancers Symposium), 45 patients with low to intermediate risk prostate cancer were treated with a 5 fraction regimen. Treatment was delivered using image guidance, intensity modulation, and a rectal balloon with pretreatment enema. The starting radiation dose was 45 Gy in 5 fractions, and it was subsequently escalated to 47.5 Gy and 50 Gy. Patients were followed for toxicity using CTCAE (Common Terminology Criteria for Adverse Events) v3 scoring and AUA (American Urological Association) and EPIC questionnaires. At an median follow-up of 12 months, no grade 3 gastrointestinal toxicities and only one grade 3 genitourinary toxicity were observed. Mean AUA score before SBRT was 5 and rose to 8-9 during follow-up. EPIC rectal mean scores fell from baseline at 6 weeks to 12 months but returned to baseline at 18 months. PSA control is 95% by nadir +2 definition and 100% by 3 consecutive rises definition. Currently, the phase II study utilizing 50 Gy in 5 fractions is being conducted.
Similar results were reported by two other institutions (Friedland et al., 2009; Katz et al., 2010). Friedland et al. (2009) reported 112 patients with early stage organ confined prostate cancer treated with SBRT 35-36 Gy administered in 5 consecutive fractions. At a median follow-up of 24 months, the mean PSA value was 0.78 ng/ml with two patients having developed biopsy-proven local recurrence and one with distant metastases; a single case of grade 3 rectal toxicity was reported, otherwise no other significant toxicity was seen. A larger study done by Katz et al. (2010) involving 304 patients, treated either with 35 Gy or 36.25 Gy in 5 fractions. Similar findings of low toxicity with only one grade 3 late urinary toxicity were reported and quality of life was maintained at a short follow-up of 17 months. However, they observed biochemical failures in two low-risk and two high-risk patients.
Longer term follow-up is warranted to evaluate the efficacy and late toxicity especially in patients with low risk prostate cancer. This is especially true because we have long term data of other very effective treatment modalities.
Renal Cell Carcinoma
Renal cell carcinoma is traditionally thought to be a radio-resistant malignancy. It is believed that conventional radiotherapy does not have a role in the definitive management of RCC as there is no survival benefit of adding radiotherapy to the nephrectomy bed. Conventional radiotherapy has, however, been shown to be effective in palliating most sites of metastatic RCC including lung, bone, and soft tissues in approximately 50% of patients (DiBiase et al., 1997). On the other hand, stereotactic radiosurgery has been shown to provide a very high local control rate of up to 95% in various clinical series involving RCC brain metastases (Doh et al., 2006b; Hoshi et al., 2002; Noel et al., 2004; Sheehan et al., 2003). This suggests that RCC may not be truly “radio-resistant” but more likely to be “radio-resistant” to lower fraction sizes. As in the case of stereotactic radiosurgery, SBRT is ideal to be utilized in patients with “radio-resistant” RCC. SBRT with the capability to deliver high dose per fraction is made feasible by the recent refinement in precise IGRT and stereotaxis technology. In contrast to other local therapeutic modalities such as radio-frequency ablation, surgery, and cryotherapy, SBRT offers the only non-invasive, highly efficient means of eradicating discrete tumor foci either at a primary or metastatic site.
Using a xenograft model involving A498 human RCC cells injected subcutaneously into nude mice, Walsh et al. (2006) demonstrated that SBRT treatment (48 Gy in 3 fractions) could result in a sustained decrease in tumor volume and marked cytologic changes when compared to the control group.
The safety and efficacy of SBRT have been reported in both primary and metastatic RCC (Teh et al., 2007a, Svedman et al., 2008; Svedman et al., 2006; Wersall et al., 2005). Beitler and colleagues first reported a series of nine patients with primary RCC treated with SBRT. There were four long-term survivors (minimum follow-up of 48 months) noted (Beitler et al., 2004). Svedman et al. (2008) later reported an interesting series involving seven patients who had initial nephrectomy and then developed metastases to the contralateral kidney. With SBRT, they were able to provide local control in six patients and maintaining stable renal function in five of them. In a retrospective study, Teh et al. (2007a) further confirmed the efficacy of SBRT in the treatment of primary and metastatic RCC. Pain relief and local control were observed in 93% and 87% of patients, respectively. The two patients with medically inoperable primary RCC also did well with pain relief and stable disease on imaging. The results compare favorably to those using conventional radiotherapy (DiBiase et al., 1997), but are consistent with the more recent findings utilizing SBRT for metastatic RCC. A local control rate of 90-98% was noted in a retrospective study involving 58 patients (50 patients with metastatic RCC and 8 patients with inoperable primary RCC) (Svedman et al., 2008; Svedman et al., 2006; Wersall et al., 2005).
The largest experience with SBRT in RCC was reported from the Karolinska group (Svedman et al., 2008; Svedman et al., 2006; Wersall et al., 2005). They have reported both their retrospective and prospective Phase II trials. Excellent local controls of 90 and 98% were achieved in 162 and 82 lesions, respectively. In the initial experience, they reported grade 3 side effects but only grade 1-2 in 90% of cases in the Phase II trial. These side effects included cough, fatigue, skin rash, and local pain. Bony and spinal metastases from RCC are common. There are now several reports confirming safety and efficacy of SBRT (Jhaveri et al., 2008; Nguyen et al., 2010; Teh et al., 2007a; Teh et al., 2007b). In another series of 48 patients with 60 RCC metastatic lesions involving various levels of spine, Gerszten and colleagues showed that pain was controlled in 89% of patients (Gerszten et al., 2005). In a series of 48 patients with 55 spinal metastases treated with SBRT of three different regimens, Nguyen et al. (2010) reported the actuarial 1-year spine tumor progression free survival of 82.1%.
SBRT for GU malignancies is an emerging treatment paradigm with a new promise in radiation oncology. The promise to produce biologically more potent dose in a shorter duration and a non-invasive manner is certainly very attractive. SBRT is certainly ideal for prostate cancer with low alpha/beta ratio, “radio-resistant” RCC, and high grade metastatic GU malignancies. SBRT can be applied to both primary and metastatic GU malignancies. Various aspects of SBRT still need further investigations and research. There is a need for more prospective clinical trials with a longer term follow-up to confirm the safety and efficacy. From the radiobiological point of view, more work is needed to look for an optimal radiobiological model for tumor and normal tissues as well as for investigating the mechanism of SBRT in overcoming radioresistance. Future research should look for most optimal SBRT regimens and associated factors such tumor types, location, tumor size, degree of hypoxia, and many others. Another area of interest is the combination use of SBRT and systemic therapy including the emerging targeted agents.
Robert Timmerman, M.D., has research grants from Varian Medical Systems and Accuray, Inc. His grant from Elekta Oncology has expired. Other authors have none to disclose.
(Corresponding author: Simon S. Lo, M.D., Associate Professor of Radiation Oncology and Neurosurgery, Director of Stereotactic Body Radiation Therapy, Department of Radiation Oncology, Arthur G. James Cancer Hospital, Ohio State University Medical Center, Columbus, Ohio 43210, USA.)
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[Discovery Medicine; ISSN: 1539-6509; Discov Med 10(52):255-262, September 2010.]