The decrease of biologic effect if delivery of dose fractions takes more than a few minutes has been occasionally recognized in the literature but has been insufficiently studied. It has been ...recognized as a problem in the long exposures necessary for stereotactic radiotherapy and is also a potential problem in some applications of IMRT. Modeling repair rates is a complex function of dose per fraction, dose rate, half-times of repair, and nature of the tissue of interest (the α/β ratio of intrinsic radiosensitivity to repair capacity). In this article, we model repair rates for a range of doses per fraction and draw conclusions.
We review the data on half-times of repair in tissues
in situ in animals and human patients and conclude that a single first-order (exponential) repair rate is no longer an appropriate assumption for most tissues. At least 2 half-times of repair, and perhaps a distribution of half-times, are required. The faster components have a median half-time of 0.3 h (range, 0.08–1.2 h), and the longer components have a median of 4 h (range, 2.4–>6 h). Modeling repair rates by a two-component model is the simplest approach. We have used two models of repair to represent these ranges, one with equal proportions of 0.2 h + 4.0 h half-times, the other with 0.4 h + 4.0 h half-times of repair. Data are also reviewed on the few experiments that have been reported with cell culture that investigate this problem.
Computations indicate that any fraction delivery that lasts more than half an hour might experience a clinically significant loss of cell-sterilizing effect. We suggest that a loss of more than 10% in biologically effective dose should be compensated for and show modeled doses and fraction durations for which this situation seems to be likely. It will be dose, tissue, and system dependent and will require more investigation at the clinical level.
It is suggested that any radiotherapy schedule that requires more than half an hour for the delivery of 1 fraction should have careful records made and reported, to look for a possible decrease of biologic effect with fraction duration.
When I came into radiotherapy in 1950, I was puzzled that some patients were treated to 3000 rads (cGy) in 3 weeks but others received 4000 in 5 or 6000 in 6 weeks. When I asked why, there were no ...convincing answers given, except 'this is what we usually do'. It wasn't until I went to a course on 'Radiobiology for Radiotherapy' in Cambridge that I learnt about the basic theories of Douglas Lea and the very considerable history of research into radiobiology and clinical radiotherapy. And there were still some questions outstanding, such as the relative importance of intracellular repair between 'daily' fractions, whether a 2 day gap each week was a good or a bad idea, and the role of proliferation, if any, during irradiation. I thought that a few simple animal experiments might help to give answers! That led me to a continuing interest in these questions and answers, which has taken me more than 50 years to pursue. This is the very personal story of what I saw happening in the subject, decade by decade. I was happy to experience all this together with scientists in many other countries, and our own, along the way.
To correct several elementary radiobiologic errors in the otherwise admirable article by Kasibhatla, Kirkpatrick, and Brizel (2007) on estimating the equivalent radiation effect of the concomitant ...chemotherapy in head-and-neck chemoradiotherapy.
(1) Their equation was wrong because it omitted the lag or onset time of repopulation in tumors, Tk. Instead of zero days this should be 18-35 days. (2) Instead of a doubling time of 5 days, at most 3 days should be used for head-and-neck tumors. (3) Their slope "S" (the gamma-50 slope) for head-and-neck tumors should be 1.7, not 1.1. The same percentages of increased locoregional control as quoted by Kasibhatla et al. are used.
The average time-corrected biologically effective dose for the 16 schedules listed should be 72.4 instead of 63.1 Gy(10). The average gains in locoregional tumor control are the equivalent of 8.8 Gy(10), not 10.6 Gy(10) (p = 0.05).
The equivalent number of 2-Gy fractions of concomitant chemotherapy as used in the 16 listed schedules is 3.6 (95% confidence interval, 2.7-4.1), not 5 as claimed by Kasibhatla et al. The difference is statistically significant (p < 0.001).
Phase I of Radiation Therapy Oncology Group (RTOG) 0117 determined that 74 Gy was the maximum-tolerated dose with concurrent weekly carboplatin/paclitaxel chemotherapy for inoperable non-small-cell ...lung cancer (NSCLC). Phase II results are reported here. PATIENTS AND METHODS Patients with unresectable stages I-III NSCLC were eligible. Chemotherapy consisted of weekly paclitaxel at 50 mg/m(2) and carboplatin at area under the curve 2 mg/m(2). The radiation dose was 74 Gy given in 37 fractions. Radiation therapy volumes included those of the gross tumor and involved nodes. The volume of lung at or exceeding 20 Gy (V20) was mandated to be <or= 30%.
Of the combined phase I/II enrollment, a total of 55 patients received 74 Gy, of whom 53 were evaluable. The median follow-up was 19.3 months (range, 0.9 to 57.9 months) for all patients and 25.4 months (range, 13.1 to 57.9 months) for those still alive. The median survival for all patients was 25.9 months. The percentage surviving at least 12 months was 75.5% (95% CI, 65.7% to 85.2%). The median overall survival (OS) and progression-free survival (PFS) times for stage III patients (n = 44) were 21.6 months and 10.8 months, respectively. OS and PFS rates at 12 months were 72.7% and 50.0%, respectively. Twelve patients experienced grade >or= 3 lung toxicity (two patients had grade 5 lung toxicity).
The median survival time and OS rate at 12 months for this regimen are encouraging. These results serve as projection expectations for the high-dose radiation arms of the current RTOG 0617 phase III intergroup trial.
Now that the follow-up time has exceeded 5 years, an estimate of the α/β ratio can be presented. The additional late outcomes in patients treated with three-dimensional conformal external beam ...radiotherapy for localized prostate cancer using a hypofractionated vs. a standard fractionation regimen are reported from this prospective nonrandomized contemporary comparison.
A total of 114 nonrandomized patients chose hypofractionation delivered in 20 fractions of 3 Gy or 3.15 Gy (mean 3.06 Gy) for localized prostate cancer within a median overall time of 32 days (range, 29-49) using four fractions weekly. A total of 160 comparable patients were contemporarily treated within a median of 55 days (range 49-66). The median follow-up was 66 months (range, 24-95) for the hypofractionated arm and 63 months (range, 36-92) for the standard arm. The percentage of patients in the low-, medium-, and high-risk groups was 36%, 46%, and 18% in the hypofractionated arm and 44%, 50%, and 6% in standard arm (2 Gy), respectively.
The 5-year actuarial biochemical absence of disease (prostate-specific antigen nadir + 2 ng/mL) and disease-free survival rate was the same at 89% in both arms, making the α/β calculation unambiguous. The point ratio of α/β was 1.86 (95% confidence interval, 0.7-5.1 Gy). The 95% confidence interval was determined entirely by the binomial confidence limits in the numbers of patients. Rectal reactions of grade 3 and 4 occurred in 1 of 114 (hypofractionated) and 2 of 160 (standard) patients.
The presented three-dimensional conformal regimen was acceptable, and the α/β value was 1.8, in agreement with other very recent low meta-analyses (reviewed in the "Discussion" section).
Recent analyses of clinical results have suggested that the fractionation sensitivity of prostate tumors is remarkably high; corresponding point estimates of the α/β ratio for prostate cancer are ...around 1.5 Gy, much lower than the typical value of 10 Gy for many other tumors. This low α/β value is comparable to, and possibly even lower than, that of the surrounding late-responding normal tissue in rectal mucosa (α/β nominally 3 Gy, but also likely to be in the 4–5 Gy range). This lower α/β ratio for prostate cancer than for the surrounding late-responding normal tissue creates the potential for therapeutic gain. We analyze here possible high-gain/low-risk hypofractionated protocols for prostate cancer to test this suggestion.
Using standard linear-quadratic (LQ) modeling, a set of hypofractionated protocols can be designed in which a series of dose steps is given, each step of which keeps the late complications constant in rectal tissues. This is done by adjusting the dose per fraction and total dose to maintain a constant level of late effects. The effect on tumor control is then investigated. The resulting estimates are theoretical, although based on the best current modeling with α/β parameters, which are discussed thoroughly.
If the α/β value for prostate is less than that for the surrounding late-responding normal tissue, the clinical gains can be rather large. Appropriately designed schedules using around ten large fractions can result in absolute increases of 15% to 20% in biochemical control with no evidence of disease (bNED), with no increase in late sequelae. Early sequelae are predicted to be decreased, provided that overall times are not shortened drastically because of a possible risk of acute or consequential late reactions in the rectum. An overall time not shorter than 5 weeks appears advisable for the hypofractionation schedules considered, pending further clinical trial results. Even if the prostate tumor α/β ratio turns out to be the same (or even slightly larger than) the surrounding late-responding normal tissue, these hypofractionated regimens are estimated to be very unlikely to result in significantly increased late effects.
The hypofractionated regimens that we suggest be tested for prostate-cancer radiotherapy show high potential therapeutic gain as well as economic and logistic advantages. They appear to have little potential risk as long as excessively short overall times (<5 weeks) and very small fraction numbers (<5) are avoided. The values of bNED and rectal complications presented are entirely theoretical, being related by LQ modeling to existing clinical data for approximately intermediate-risk prostate cancer patients as discussed in detail.
In preparation for a Phase III comparison of high-dose versus standard-dose radiation therapy, this Phase I/II study was initiated to establish the maximum tolerated dose of radiation therapy in the ...setting of concurrent chemotherapy, using three-dimensional conformal radiation therapy for non-small-cell lung cancer.
Eligibility included patients with histologically proven, unresectable Stages I to III non-small-cell lung cancer. Concurrent chemotherapy consisted of paclitaxel, 50 mg/m(2), and carboplatin, AUC of 2, given weekly. The radiation dose was to be sequentially intensified by increasing the daily fraction size, starting from 75.25 Gy/35 fractions.
The Phase I portion of this study accrued 17 patients from 10 institutions and was closed in January 2004. After the initial 8 patients were accrued to cohort 1, the trial closed temporarily on September 26, 2002, due to reported toxicity. Two acute treatment-related dose-limiting toxicities (DLTs) were reported at the time: a case of grade 5 and grade 3 radiation pneumonitis. The protocol, therefore, was revised to de-escalate the radiation therapy dose (74 Gy/37 fractions). Patients in cohort 1 continued to develop toxicity, with 6/8 (75%) patients eventually developing grade >or=3 events. Cohort 2 accrued 9 patients. There was one DLT, a grade 3 esophagitis, in cohort 2 in the first 5 patients (1/5 patients) and no DLTs for the next 2 patients (0/2 patients).
The maximum tolerated dose was determined to be 74 Gy/37 fractions (2.0 Gy per fraction) using three-dimensional conformal radiation therapy with concurrent paclitaxel and carboplatin therapy. This dose level in the Phase II portion has been well tolerated, with low rates of acute and late lung toxicities.
To study retrospectively late complications and biochemical control in patients treated with three-dimensional conformal external-beam radiotherapy for localized prostate cancer administered using ...hypofractionation vs. a standard fractionation regimen. The hypofractionation regimen (Hypo) was designed to avoid more late rectal reactions and to be done in half as many treatment sessions.
Eighty-nine nonrandomized patients chose Hypo delivered in 20 fractions of 3 Gy (n = 52) or 3.15 Gy (n = 37) for a median overall treatment time of 33 days. One hundred thirty comparable patients were contemporaneously treated with standard fractionation to a median dose of 78 Gy delivered over 55 days. The median follow-up time was 49 months (range, 24-73 months).
The 5-year actuarial biochemical control rates were 96%, 84%, and 85% for low-, medium-, and high-risk disease in the Hypo group, respectively. The respective rates in the standard fractionation group were 98%, 84%, and 87%, with no statistical difference between the two groups. The rate of rectal Grade 2-4 complications was 5.5% in both treatment groups and of urinary Grade 2-4 complications was 5.6% in the Hypo and 3% in the standard group (p = 0.36). Similarly, there were no statistical differences in the rate of late complications between patients treated with 3 Gy/fraction vs. 3.15 Gy/fraction.
Our preliminary results showed that the Hypo regimen is feasible and does not reduce biochemical control compared with standard fractionation. The incidence of late complications was not increased when the tumor normalized total doses at 2Gy/fraction was increased from 77.1 to 83.7 Gy in patients treated with either 3 or 3.15 Gy/fraction in the Hypo group, respectively.
On cold spots in tumor subvolumes Tomé, Wolfgang A.; Fowler, Jack F.
Medical physics (Lancaster),
July 2002, Letnik:
29, Številka:
7
Journal Article
Recenzirano
Losses in tumor control are estimated for cold spots of various “sizes” and degrees of “cold dose.” This question is important in the context of intensity modulated radiotherapy where differential ...dose–volume histograms (DVHs) for targets that abut a critical structure often exhibit a cold dose tail. This can be detrimental to tumor control probability (TCP) for fractions of cold volumes even as small as 1%, if the cold dose is lower than the prescribed dose by substantially more than 10%. The Niemierko–Goitein linear-quadratic algorithm with
γ
50
slope 1–3 was used to study the effect of cold spots of various degrees (dose deficit below the prescription dose) and size (fractional volume of the cold dose). A two-bin model DVH has been constructed in which the cold dose bin is allowed to vary from a dose deficit of 1%–50% below prescription dose and to have volumes varying from 1% to 90%. In order to study and quantify the effect of a small volume of cold dose on TCP and effective uniform dose (EUD), a four-bin DVH model has been constructed in which the lowest dose bin, which has a fractional volume of 1%, is allowed to vary from 10% to 45% dose deficit below prescription dose. The highest dose bin represents a simultaneous boost. For fixed size of the cold spot the calculated values of TCP decreased rapidly with increasing degrees of cold dose for any size of the cold spot, even as small as 1% fractional volume. For the four-subvolume model, in which the highest dose bin has a fractional volume of 80% and is set at a boost dose of 10% above prescription dose, it is found that the loss in TCP and EUD is moderate as long as the cold 1% subvolume has a deficit less than approximately 20%. However, as the dose deficit in the 1% subvolume bin increases further it drives TCP and EUD rapidly down and can lead to a serious loss in TCP and EUD. Since a dose deficit to a 1% volume of the target that is larger than 20% of the prescription dose may lead to serious loss of TCP, even if 80% of the target receives a 10% boost, particular attention has to be paid to small-volume cold regions in the target. The effect of cold regions on TCP can be minimized if the EUD associated with the target DVH is constrained to be equal to or larger than the prescription dose.
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