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International journal of radiation oncology, biology, physics 10/2010; 78(2):640-1. · 4.59 Impact Factor
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Jack F Fowler
Journal of gastrointestinal and liver diseases: JGLD 03/2010; 19(1):7-8. · 1.81 Impact Factor
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Jack F Fowler
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ABSTRACT: Radiobiologic modeling is increasingly used to estimate the effects of altered treatment plans, especially for dose escalation. The present article shows how much the linear-quadratic (LQ) (calculated biologically equivalent dose [BED] varies when individual parameters of the LQ formula are varied by +/-20% and by 1%.
Equivalent total doses (EQD2 = normalized total doses (NTD) in 2-Gy fractions for tumor control, acute mucosal reactions, and late complications were calculated using the linear- quadratic formula with overall time: BED = nd (1 + d/ [alpha/beta]) - log(e)2 (T - Tk) / alphaTp, where BED is BED = total dose x relative effectiveness (RE = nd (1 + d/ [alpha/beta]). Each of the five biologic parameters in turn was altered by +/-10%, and the altered EQD2s tabulated; the difference was finally divided by 20. EQD2 or NTD is obtained by dividing BED by the RE for 2-Gy fractions, using the appropriate alpha/beta ratio.
Variations in tumor and acute mucosal EQD ranged from 0.1% to 0.45% per 1% change in each parameter for conventional schedules, the largest variation being caused by overall time. Variations in "late" EQD were 0.4% to 0.6% per 1% change in the only biologic parameter, the alpha/beta ratio. For stereotactic body radiotherapy schedules, variations were larger, up to 0.6 to 0.9 for tumor and 1.6% to 1.9% for late, per 1% change in parameter.
Robustness occurs similar to that of equivalent uniform dose (EUD), for the same reasons. Total dose, dose per fraction, and dose-rate cause their major effects, as well known.
International journal of radiation oncology, biology, physics 05/2009; 73(5):1532-7. · 4.59 Impact Factor
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Jack F Fowler
International Journal of Radiation OncologyBiologyPhysics 11/2008; 72(2):313-4. · 4.11 Impact Factor
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Jack F Fowler
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ABSTRACT: 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).
International Journal of Radiation OncologyBiologyPhysics 06/2008; 71(2):326-9. · 4.11 Impact Factor
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Jack F Fowler
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ABSTRACT: 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.
Physics in Medicine and Biology 08/2006; 51(13):R263-86. · 2.83 Impact Factor
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Physics in Medicine and Biology 04/2005; 50(6):L1-4; author reply L5-8. · 2.83 Impact Factor
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Daniel G Petereit,
Deborah Rogers,
Linda Burhansstipanov,
Judith Kaur,
Frank Govern,
Steve P Howard,
Christen H Osburn,
C Norman Coleman, Jack F Fowler,
Richard Chappell,
Minesh P Mehta
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ABSTRACT: The "Walking Forward" program is a scientific collaborative program between Rapid City Regional Hospital, the University of Wisconsin, the Mayo Clinic, and partnerships with the American Indian community in western South Dakota-3 reservations and 1 urban population. The purpose is to increase participation of health disparities populations on National Cancer Institute clinical trials as part of the Cancer Disparities Research Partnership program. Clinical practice suggests that Native American cancer patients present with more advanced stages of cancer and hence have lower cure rates and higher treatment-related morbidities. It is hypothesized that a conventional course of cancer treatment lasting 6 to 8 weeks may be a barrier.
Innovative clinical trials have been developed to shorten the course of treatment. A molecular predisposition to treatment side effects is also explored. These clinical endeavors will be performed in conjunction with a patient navigator research program.
Research metrics include analysis of process, clinical trials participation, treatment outcome, and assessment of access to cancer care at an early stage of disease.
Journal of Cancer Education 02/2005; 20(1 Suppl):65-70. · 0.76 Impact Factor
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Jack F Fowler
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ABSTRACT: 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.
Acta Oncologica 02/2005; 44(3):265-76. · 3.33 Impact Factor
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ABSTRACT: To investigate and compare the biologically effective doses, equivalent doses in 2-Gy fractions, log tumor cells killed, and late effects that can be estimated for the large fractions in short overall times that are now being delivered in various clinically used schedules in several countries for the treatment of cancer in human lungs, liver, and kidney.
Linear quadratic (LQ) modeling is employed with only the standard assumptions that tumor alpha/beta ratio is 10 Gy, pneumonitis and late complication alpha/beta ratios are 3 Gy, that intrinsic radiosensitivity of tumor cells is 0.35 ln/Gy, that no tumor repopulation occurs within 2 weeks, and that LQ modeling is valid up to 23 Gy per fraction. As well as the planning target volume (PTV), we propose a practical term called the prescription isodose volume (PIV) to be used in this discussion. In the ideal case of 100% conformity, PIV equals PTV, but usually PIV is larger than the PTV. Biologically effective doses (BED) in Gy(10) for tumors or Gy(3) for normal lung are calculated and converted to equivalent doses in 2 Gy fractions (= normalized total doses [NTD]), and to estimated log cell kill. How such large biologic doses might be delivered to tissues is discussed.
Tumor cell kill varies between 16 and 27 logs to base 10 for schedules from 4F x 12 Gy to 3F x 23 Gy. The rationale for the high end of this scale is the possible presence of hypoxic or otherwise extraordinarily resistant cells, but how many tumors and which ones require such doses is not known. How can such large doses be tolerated? In "parallel type organs," it is shown to be theoretically possible, provided that suitably small volumes are irradiated, with rapid fall-off of dose outside the PTV, and a mean dose (excluding PTV and allowing for local fraction size) to both lungs of less than 19 Gy NTD. If suitably small PTVs were used, local late BEDs have been given which were as large as 600 Gy(3), equivalent to 2 Gy x 180F = 360 Gy in 2-Gy fractions, with remarkably few complications reported clinically. Questions of concurrent chemotherapy and microscopic extension of lung tumor cells are discussed briefly.
Such large doses can apparently be given, with suitable precautions and experience. Ongoing clinical trials from an increasing number of centers will be reporting the results of tumor control and complications from this new modality of biologically higher doses.
International Journal of Radiation OncologyBiologyPhysics 12/2004; 60(4):1241-56. · 4.11 Impact Factor
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Susanta K Hui,
Rupak K Das,
Jeff Kapatoes,
Gustavo Oliviera,
Stuart Becker,
Heath Odau,
John D Fenwick,
Rakesh Patel,
Robert Kuske,
Minesh Mehta,
Bhudatt Paliwal,
Thomas R Mackie, Jack F Fowler,
James S Welsh
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ABSTRACT: A novel treatment approach utilizing helical tomotherapy for partial breast irradiation for patients with early-stage breast cancer is described. This technique may serve as an alternative to high dose-rate (HDR) interstitial brachytherapy and standard linac-based approaches. Through helical tomotherapy, highly conformal irradiation of target volumes and avoidance of normal sensitive structures can be achieved. Unlike HDR brachytherapy, it is noninvasive. Unlike other linac-based techniques, it provides image-guided adaptive radiotherapy along with intensity modulation. A treatment planning CT scan was obtained as usual on a post-lumpectomy patient undergoing HDR interstitial breast brachytherapy. The patient underwent catheter placement for HDR treatment and was positioned prone on a specially designed position-supporting mattress during CT. The planning target volume (PTV) was defined as the lumpectomy bed plus a 20 mm margin. The prescription dose was 34 Gy (10 fx of 3.4 Gy) in both the CT based HDR and on the tomotherapy plan. Cumulative dose-volume histograms (DVHs) were generated and analyzed for the target, lung, heart, skin, pectoralis muscle, and chest wall for both HDR brachytherapy and helical tomotherapy. Dosimetric coverage of the target with helical tomotherapy was conformal and homogeneous. "Hot spots" (> or =150% isodose line) were present around implanted dwell positions in brachytherapy plan whereas no isodose lines higher than 109% were present in the helical tomotherapy plan. Similar dose coverage was achieved for lung, pectoralis muscle, heart, chest wall and breast skin with the two methods. We also compared our results to that obtained using conventional linac-based three dimensional (3D) conformal accelerated partial breast irradiation. Dose homogeneity is excellent with 3D conformal irradiation, and lung, heart and chest wall dose is less than for either HDR brachytherapy or helical tomotherapy but skin and pectoral muscle doses were higher than with the other techniques. Our results suggest that helical tomotherapy can serve as an effective means of delivering accelerated partial breast irradiation and may offer superior dose homogeneity compared to HDR brachytherapy.
Technology in cancer research & treatment 12/2004; 3(6):639-46. · 2.02 Impact Factor
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ABSTRACT: 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 alpha/beta 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.
International Journal of Radiation OncologyBiologyPhysics 05/2004; 59(1):242-9. · 4.11 Impact Factor
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ABSTRACT: To investigate whether a predictive estimate can be obtained for a 'tolerance level' of acute oral and pharyngeal mucosal reactions in patients receiving head and neck radiotherapy, using an objective set of dose and time data.
Several dozen radiotherapy schedules for treating head and neck cancer have been reviewed, together with published estimates of whether they were tolerated or (in a number of schedules) not. Those closest to the borderline were given detailed analysis. Total doses and biologically effective doses (BED or ERD) were calculated for a range of starting times of cellular repopulation and rates of daily proliferation. Starting times of proliferation from 5 to 10 days and daily cellular doubling rates of 1-3 days were considered. The standard published form of BED with its linear overall time factor was used: BED=nd(1 + d/(alpha/beta) - Ln2(T - T(k))/alpha T(p) (see text for parameters).
A clear progression from acceptable to intolerable mucosal reactions was found, which correlated with total biologically effective dose (BED in our published modeling), for all the head and neck cancer radiotherapy schedules available for study, when ranked into categories of 'intolerable' or 'tolerable'. A review of published mechanisms for mucosal reactions suggested that practical schedules used for treatment caused stimulated compensatory proliferation to start at about 7 days. The starting time of compensatory proliferation had little predictive value in our listing, so we chose the starting time of 7 days. Very short and very long daily doubling rates also had little reliability, so we suggest choosing a doubling time of 2.5 days as a datum. With these parameters a 'tolerance zone of uncertainty' could be identified which predicted acute-reaction acceptability or not of a schedule within a range of about 2-10 Gy in total BED. If concurrent chemoradiotherapy is used, our provisional suggestion is that this zone should be reduced by up to roughly 3-5 Gy10 in BED, with a request for further evidence.
It is suggested that total BED should be used, as specified above. Parameters of alpha=0.35 Gy-(1), alpha/beta=10 Gy, Tk=7 days and Tp=2.5 days are suggested. The 'acute/ tolerance zone' then turns out to be 59-61 Gy10 for radiation-only treatments. Further information about the decrement caused by concurrent head-and-neck cancer chemoradiotherapy, possibly 3-5 Gy10, is required.
Radiotherapy and Oncology 12/2003; 69(2):161-8. · 5.58 Impact Factor
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International Journal of Radiation OncologyBiologyPhysics 11/2003; 57(2):593-5; author reply 595-6. · 4.11 Impact Factor
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ABSTRACT: In previous modelling of tumour control probability (TCP) for inhomogeneously irradiated tumours we used an expression that did not include a proliferation correction term, which should be lambda(T - Tk). We did not use that term in the specific examples in our previous work to model slowly growing tumours in order to avoid unnecessary mathematical complexity. We have now considered how to do so in more detail, and there are some variations, such as schedules that depart from a number of equal fractions over the entire course of treatment, if one wishes to compensate for proliferation in the remaining fractions by increasing the dose per fraction after the kick-off time has passed in order to achieve the same TCP when proliferation is neglected.
Physics in Medicine and Biology 10/2003; 48(18):N261-8. · 2.83 Impact Factor
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Urology 09/2003; 62(2):204-6. · 2.43 Impact Factor
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ABSTRACT: Recent analyses of clinical results have suggested that the fractionation sensitivity of prostate tumors is remarkably high; corresponding point estimates of the alpha/beta ratio for prostate cancer are around 1.5 Gy, much lower than the typical value of 10 Gy for many other tumors. This low alpha/beta value is comparable to, and possibly even lower than, that of the surrounding late-responding normal tissue in rectal mucosa (alpha/beta nominally 3 Gy, but also likely to be in the 4-5 Gy range). This lower alpha/beta 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 alpha/beta parameters, which are discussed thoroughly.
If the alpha/beta 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 alpha/beta 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.
International Journal of Radiation OncologyBiologyPhysics 08/2003; 56(4):1093-104. · 4.11 Impact Factor
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International Journal of Radiation OncologyBiologyPhysics 05/2003; 55(5):1159-61. · 4.11 Impact Factor
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ABSTRACT: Linear quadratic (LQ) modelling allows easy comparison of different fractionation schedules in radiotherapy. However, estimating the radiation effect of a single fractionated treatment introduces many questions with respect to the parameters to be used in the modelling process. Several studies have used tumour control probability (TCP) curves in order to derive the values for the LQ parameters that may be used further for the analysis and ranking of treatment plans. Unfortunately, little attention has been paid to the biological relevance of these derived parameters, either for the initial number of cells or their intrinsic radiosensitivity, or both. This paper investigates the relationship between single values for the TCP parameters and the resulting dose-response curve. The results of this modelling study show how clinical observations for the position and steepness of the TCP curve can be explained only by the choice of extreme values for the parameters, if they are single values. These extreme values are in contradiction with experimental observations. This contradiction suggests that single values for the parameters are not likely to explain reasonably the clinical observations and that some distributions of input parameters should be taken into consideration.
Physics in Medicine and Biology 03/2003; 48(3):387-97. · 2.83 Impact Factor
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ABSTRACT: The purpose of this study was to determine whether the use of tomotherapy in the treatment of non-small-cell lung cancer (NSCLC) has the potential to reduce radiation dose to normal tissues, in particular, the lungs, esophagus, and spinal cord, as compared with standard radiotherapy. Five patients with anatomically or physiologically inoperable stage III NSCLC were studied, representing a variety of tumor sizes and locations. For each patient, two treatment plans were generated. One was developed using conventional field arrangements (CFA), and the other for tomotherapy. Using dose-volume histogram reduction techniques, including mean normalized dose (NTDmean), V20, and effective uniform dose (EUD), the normal tissue doses for CFA and tomotherapy plans for a given fixed tumor dose were compared. In addition, the maximum tumor doses possible for a given level of mean normalized lung dose were computed and compared for the CFA and tomotherapy plans. The gross tumor volumes in the five patients studied ranged from 13.5 to 87.1 cm. The tumor dose distributions, determined by EUD and minimum dose, were similar for both CFA and tomotherapy plans, as intended. In all cases, the NTDmean of both lungs was significantly reduced using tomotherapy planning (range: 10-53% reduction, mean: 31%). The volume of lung receiving more than 20 Gy was also reduced in all cases using tomotherapy (range: 17-37% reduction, mean: 22%). For a constant lung NTDmean, it is shown that it should be possible to increase tumor dose to up to 160 Gy in certain patients with tomotherapy. The dose to the spinal cord and esophagus was also reduced in all cases with tomotherapy planning, compared with plans generated using conventional field arrangements. Both tomotherapy, and to a lesser extent conventional three-dimensional conformal radiotherapy, have the potential to significantly decrease radiation dose to lung and other normal structures in the treatment of NSCLC. This has important implications for dose escalation strategies in the future.
American Journal of Clinical Oncology 03/2003; 26(1):70-8. · 2.01 Impact Factor
