Six-Dimensional Correction of Intra-Fractional Prostate Motion with CyberKnife Stereotactic Body Radiation Therapy

A randomized radiotherapy dose escalation trial was undertaken between 1993 and 1998 to compare the efficacy of 70 vs. 78 Gy in controlling prostate cancer. A total of 305 Stage T1-T3 patients were entered into the trial and, of these, 301 with a median follow-up of 60 months, were assessable. Of the 301 patients, 150 were in the 70 Gy arm and 151 were in the 78 Gy arm. The primary end point was freedom from failure (FFF), including biochemical failure, which was defined as 3 rises in the prostate-specific antigen (PSA) level. Kaplan-Meier survival analyses were calculated from the completion of radiotherapy. The log-rank test was used to compare the groups. Cox proportional hazard regression analysis was used to examine the independence of study randomization in multivariate analysis. There was an even distribution of patients by randomization arm and stage, Gleason score, and pretreatment PSA level. The FFF rates for the 70- and 78 Gy arms at 6 years were 64% and 70%, respectively (p = 0.03). Dose escalation to 78 Gy preferentially benefited those with a pretreatment PSA >10 ng/mL; the FFF rate was 62% for the 78 Gy arm vs. 43% for those who received 70 Gy (p = 0.01). For patients with a pretreatment PSA 10 ng/mL who were treated to 78 Gy (98% vs. 88% at 6 years, p = 0.056). Rectal side effects were also significantly greater in the 78 Gy group. Grade 2 or higher toxicity rates at 6 years were 12% and 26% for the 70 Gy and 78 Gy arms, respectively (p = 0.001). Grade 2 or higher bladder complications were similar at 10%. For patients in the 78 Gy arm, Grade 2 or higher rectal toxicity correlated highly with the proportion of the rectum treated to >70 Gy. An increase of 8 Gy resulted in a highly significant improvement in FFF for patients at intermediate-to-high risk, although the rectal reactions were also increased. Dose escalation techniques that limit the rectal volume that receives >or=70 Gy to <25% should be used.

Volumetric modulated arc therapy (VMAT), a complex treatment strategy for intensity-modulated radiation therapy, may increase treatment efficiency and has recently been established clinically. This analysis compares VMAT against established IMRT and 3D-conformal radiation therapy (3D-CRT) delivery techniques. Based on CT datasets of 9 patients treated for prostate cancer step-and-shoot IMRT, serial tomotherapy (MIMiC), 3D-CRT and VMAT were compared with regard to plan quality and treatment efficiency. Two VMAT approaches (one rotation (VMAT1x) and one rotation plus a second 200 degrees rotation (VMAT2x)) were calculated for the plan comparison. Plan quality was assessed by calculating homogeneity and conformity index (HI and CI), dose to normal tissue (non-target) and D(95%) (dose encompassing 95% of the target volume). For plan efficiency evaluation, treatment time and number of monitor units (MU) were considered. For MIMiC/IMRT(MLC)/VMAT2x/VMAT1x/3D-CRT, mean CI was 1.5/1.23/1.45/1.51/1.46 and HI was 1.19/1.1/1.09/1.11/1.04. For a prescribed dose of 76 Gy, mean doses to organs-at-risk (OAR) were 50.69 Gy/53.99 Gy/60.29 Gy/61.59 Gy/66.33 Gy for the anterior half of the rectum and 31.85 Gy/34.89 Gy/38.75 Gy/38.57 Gy/55.43 Gy for the posterior rectum. Volumes of non-target normal tissue receiving > or =70% of prescribed dose (53 Gy) were 337 ml/284 ml/482 ml/505 ml/414 ml, for > or =50% (38 Gy) 869 ml/933 ml/1155 ml/1231 ml/1993 ml and for > or =30% (23 Gy) 2819 ml/3414 ml/3340 ml/3438 ml /3061 ml. D(95%) was 69.79 Gy/70.51 Gy/71,7 Gy/71.59 Gy/73.42 Gy. Mean treatment time was 12 min/6 min/3.7 min/1.8 min/2.5 min. All approaches yield treatment plans of improved quality when compared to 3D-conformal treatments, with serial tomotherapy providing best OAR sparing and VMAT being the most efficient treatment option in our comparison. Plans which were calculated with 3D-CRT provided good target coverage but resulted in higher dose to the rectum.

Total radiation dose is not a reliable measure of biological effect when dose-per-fraction or dose-rate is changed. Large differences in biological effectiveness (per gray) are seen between the 2 Gy doses of external beam radiotherapy and the large boost doses given at high dose-rate from afterloading sources. The effects are profoundly different in rapidly or slowly proliferating tissues, that is for most tumors versus late complications. These differences work the opposite way round for prostate tumors versus late complications compared with most other types of tumor. Using the Linear-Quadratic formula it is aimed to explain these differences, especially for treatments of prostate cancer. The unusually slow growth rate of prostate cancers is associated with their high sensitivity to increased fraction size, so a large number of small fractions, such as 35 or 40 "daily" doses of 2 Gy, is not an optimum treatment. Theoretical modeling shows a stronger enhancement of tumor effect than of late complications for larger (and fewer) fractions, in prostate tumors uniquely. Biologically Effective Doses and Normalized Total Doses (in 2 Gy fraction equivalents) are given for prostate tumor, late rectal reactions, and--a new development--acute rectal mucosa. Tables showing the change of fraction-size sensitivity (the alpha/beta ratio) with proliferation rates of tissues lead to the association of slow cell doubling times in prostate tumors with small alpha/beta ratios. Clinical evidence to confirm this biological expectation is reviewed. The alpha/beta ratios of prostate tumors appear to be as low as 1.5 Gy (95% confidence interval 1.3-1.8 Gy), in contrast with the value of about 10 Gy for most other types of tumor. The important point is that alpha/beta =1.5 Gy appears to be significantly less than the alpha/beta =3 Gy for late complications in rectal tissues. Such differences are also emerging from recent clinical results. From this important difference stems the superior schedules of, for example, 20 fractions of 3 Gy, or 10 fractions of 4.7 Gy, or 5 fractions of 7 Gy, which can all give tumor results equivalent to 80-90 Gy in 2 Gy fractions, while keeping late complications equivalent to only 72 Gy in 2 Gy fractions. Combination treatments of external beam (EBRT) and brachytherapy boost doses (25F x 2 Gy plus 2 x 10 Gy) can give higher biological tumor effects than any EBRT using daily 2 Gy doses, and with acceptable late complications. Monotherapy by brachytherapy for low-risk cancer prostate using two to four fractions in a few days can give even higher biological effects on the tumors.