The influence of RBE variations in a clinical proton treatment plan for a hypopharynx cancer.

Currently, most clinical range-modulated proton beams are assumed to have a fixed overall relative biological effectiveness (RBE) of 1.1. However, it is well known that the RBE increases with depth in the spread-out Bragg peak (SOBP) and becomes about 10% higher than mid-SOBP RBE at 2 mm from the distal edge (Paganetti 2003 Technol. Cancer Res. Treat. 2 413-26) and can reach values of 1.3-1.4 in vitro at the distal edge (Robertson et al 1975 Cancer 35 1664-77, Courdi et al 1994 Br. J. Radiol. 67 800-4). We present a fast method for applying a variable RBE correction with linear energy transfer (LET) dependent tissue-specific parameters based on the alpharef/betaref ratios suitable for implementation in a treatment planning system. The influence of applying this variable RBE correction on a clinical multiple beam proton dose plan is presented here. The treatment plan is evaluated by RBE weighted dose volume histograms (DVHs) and the calculation of tumour control probability (TCP) and normal tissue complication probability (NTCP) values. The variable RBE correction yields DVHs for the clinical target volumes (CTVs), a primary advanced hypopharynx cancer and subclinical disease in the lymph nodes, that are slightly higher than those achieved by multiplying the absorbed dose with RBE=1.1. Although, more importantly, the RBE weighted DVH for an organ at risk, the spinal cord is considerably increased for the variable RBE. As the spinal cord in this particular case is located 8 mm behind the planning target volume (PTV) and hence receives only low total doses, the NTCP values are zero in spite of the significant increase in the RBE weighted DVHs for the variable RBE. However, high NTCP values for the non-target normal tissue were obtained when applying the variable RBE correction. As RBE variations tend to be smaller for in vivo systems, this study-based on in vitro data since human tissue RBE values are scarce and have large uncertainties-can be interpreted as showing the upper limits of the possible effects of utilizing a variable RBE correction. In conclusion, the results obtained here still indicate a significant difference in introducing a variable RBE compared to applying a generic RBE of 1.1, suggesting it is worth considering such a correction in clinical proton therapy planning, especially when risk organs are located immediately behind the target volume.

Fractionated, stereotactic proton beam treatment of cerebral arteriovenous malformations.

OBJECTIVES: To evaluate the therapeutic efficiency and adverse effects of stereotactic proton beam treatment of cerebral arteriovenous malformations (AVM). MATERIAL AND METHODS: Twenty-six patients treated in Uppsala during 1991-97 were included (men = 14, women = 12; mean age = 39, range = 23-64). The nidus volumes ranged from 0.3 to 102 ml (mean = 24, median = 13). The follow-up included clinical evaluation, magnetic resonance imaging (and/or computed tomography) every 6-12 months for 3 years and final angiography. RESULTS: The volume changes at final follow-up in AVMs >25 ml were -89, -85, -44, -29, -7, 0, 0, +5 and +18 (%); in AVMs 11-24 ml, -100, -100, -97, -92 and 0 (%); and in AVMs <10 ml, -100, -100, -100, -100, -100, -99, -98, -50, -0 and +40 (%). Two patients were lost to follow-up due to cerebral haemorrhage and myocardial infarction. Radiology displayed significant perifocal oedema in one patient and slight oedema in four patients. Of nine patients with epilepsy, seven became seizure-free after therapy while two continued to suffer from seizures. CONCLUSION: Proton beam irradiation is successful in a relatively high proportion of intermediate and large-sized cerebral AVMs. The adverse effects are acceptable. The advantage of proton treatment compared with gamma knife and LINAC stereotactic irradiation is that protons can irradiate even large volumes with a very sharp dose profile against normal surroundings. Thus, proton beam irradiation is a valuable option in the treatment of AVMs larger than 10 ml.

Preoperative radiotherapy for rectal cancer--is 5 x 5 Gy a good or a bad schedule?

Preoperative radiotherapy substantially lowers local failure rates after rectal cancer surgery, an effect that is seen whether surgery is optimized, total mesorectal excision (TME), or not. Preoperative radiotherapy also slightly improves survival. Postoperative radiotherapy also decreases local recurrence rates, but the relative reduction is less pronounced even when higher doses are used. Preoperatively, a high-dose, short-term schedule, 5 x 5 Gy in one week, has been used in several randomised trials. This is a convenient schedule and has low toxicity if properly conducted. In trials where the radiation technique has been simplified, resulting in large irradiated volumes, unacceptable acute and late toxicities have been seen. It has not yet been possible to detect any late toxicity in trials where the treatment was given using techniques avoiding the irradiation of unnecessarily large tissue volumes outside the target volume. The relative advantages of using this short-term schedule relative to a conventional irradiation for about 5 weeks are discussed.

Implementation of pencil kernel and depth penetration algorithms for treatment planning of proton beams.

The implementation of two algorithms for calculating dose distributions for radiation therapy treatment planning of intermediate energy proton beams is described. A pencil kernel algorithm and a depth penetration algorithm have been incorporated into a commercial three dimensional treatment planning system (Helax-TMS, Helax AB, Sweden) to allow conformal planning techniques using irregularly shaped fields, proton range modulation, range modification and dose calculation for non-coplanar beams. The pencil kernel algorithm is developed from the Fermi Eyges formalism and Molière multiple-scattering theory with range straggling corrections applied. The depth penetration algorithm is based on the energy loss in the continuous slowing down approximation with simple correction factors applied to the beam penumbra region and has been implemented for fast, interactive treatment planning. Modelling of the effects of air gaps and range modifying device thickness and position are implicit to both algorithms. Measured and calculated dose values are compared for a therapeutic proton beam in both homogeneous and heterogeneous phantoms of varying complexity. Both algorithms model the beam penumbra as a function of depth in a homogeneous phantom with acceptable accuracy. Results show that the pencil kernel algorithm is required for modelling the dose perturbation effects from scattering in heterogeneous media.

Stereotactic irradiation of skull base meningiomas with high energy protons.

Nineteen patients with inextirpable skull base meningioma with involvement of neurovascular structures were given irradiation with a 180 MeV proton beam at the The Svedberg Laboratory, Uppsala, Sweden. The patients were treated seated in a fixed position with a stereotactic approach. Titanium-markers to the outer table served for identification and verification of the target positioning for dose planning and irradiation. The patients were given a total dose of 24 Gy in four consecutive daily 6 Gy fractions. All patients have been followed for at least 36 months. So far no meningiomas have progressed after treatment. Two patients have developed corticosteroid responsive oedema in the target area 6 moths after treatment. Late, but not serious, symptoms of side effects have been observed in one patient.

Potential gains using high-energy protons for therapy of malignant tumours.

High-energy protons have physical properties that virtually always will result in geometrically better dose distributions than can be achieved using photons or electrons. The clinical gains in terms of the probability of higher tumour control and/or the reduced probability of normal tissue complications are, however, not completely known. Comparative model dose planning studies using real patients offer the possibility of estimating the potential gains using a new technique. Several recently completed model studies, including clinically relevant endpoints, indicate that protons may have advantages, even when compared with the conventional treatment that is likely to be introduced at the most advanced hospitals world-wide within the next decade. These advantages can be seen not only in well-demarcated targets close to risk organs, but also when irradiating extended irregular tissue volumes at risk of containing tumour cells.

Comparative treatment planning between proton and x-ray therapy in esophageal cancer.

PURPOSE: Conformal treatment planning with megavoltage x-rays and protons for five patients with esophageal cancer has been studied in an attempt to determine if there are advantages of using protons instead of x-rays. METHODS AND MATERIALS: For each of the five patients, two different proton plans, one x-ray plan, and one mixed plan with x-rays and protons were made. A three-dimensional treatment planning system, TMS, was used. The evaluation of the different plans was made by applying the tumor control probability (TCP) model proposed by Nahum and Webb and the normal tissue complication (NTCP) model proposed by Lyman on the dose distributions in terms of dose-volume histograms (DVHs). RESULTS: The comparison shows advantages of using protons instead of x-rays for all five patients. The dose-limiting organs at risk are the spinal cord, the lungs, and the heart, but the proton plans also spare the kidneys better than the x-ray plan does. At 5% NTCP in any risk organ, the calculated mean TCP value for the five patients is increased by an average of 20%-units (from 2 to 23%-units) with the best proton plan compared with x-rays only. However, if we assume maximally a 1% risk in the spinal cord and a total NTCP for the two lungs of 100%, the mean TCP value for the five patients is increased from 6 to 49% with the best proton plan compared with x-rays only. The corresponding figure for the mixed plan is 27%. These gains are relatively insensitive to variations within reasonable limits in the biological parameters. CONCLUSIONS: Protons appear to have clear therapeutic advantages over conventional external radiotherapy when treating esophageal carcinoma.

Potential advantages of protons over conventional radiation beams for paraspinal tumours.

BACKGROUND AND PURPOSE: Conformal treatment planning with megavoltage X-rays and protons was studied in an attempt to determine if there are advantage of boost therapy with protons instead of X-rays for a patient with a tumour growing around the cervical spinal cord. MATERIALS AND METHODS: A patient with a Ewing sarcoma was selected for the model study. The proton boost plan was realised with a six beam patched technique. Several X-ray boost techniques were planned, some not yet practically realisable. The techniques giving the best dose distributions and the best tumour control probabilities in the absence of significant late toxicity were looked for. The boost techniques were added to two large lateral X-ray beams covering the planning target volume (PTV) and the main risk organ, the spinal cord. The evaluation was made with two biological models, i.e. the tumour control probability (TCP) model, proposed by Webb and Nahum (Webb, S. and Nahum, A.E. A model for calculating tumour control probability in radiotherapy including the effect of inhomogeneous distributions of dose and clonogenic cell density. Phys. Med. Biol. 38: 653-666, 1993), and the normal tissue complication probability (NTCP) model, first derived by Lyman (Lyman, J.T. Complication probability as assessed from dose-volume histograms. Radiat. Res. 104: s13-s19, 1985). RESULTS: The comparison showed small but clear advantages of protons for the boost. At 1% NTCP in the spinal cord, the calculated TCP was on average 5% higher. However, depending on the values of the parameters chosen in the biological models, the gain for protons varied from 0-10%. The smallest gains were seen in radiosensitive tumours for which the TCP was close to 100% with any of the techniques and in radioresistant tumours for which neither technique resulted in any appreciable probability of local cure. CONCLUSION: Protons appear to have therapeutic advantages over conventional radiotherapy in tumours with relatively high radiosensitivity situated close to the spinal cord.

Radiotherapy in addition to radical surgery in rectal cancer: evidence for a dose-response effect favoring preoperative treatment.

PURPOSE: This study explored the relationship between radiation dose and reduction in local recurrence rate after preoperative and postoperative radiotherapy in rectal cancer. METHODS AND MATERIALS: All randomized trials initiated prior to 1988 comparing preoperative and postoperative radiotherapy with surgery alone or with each other were included. Local failure rates were available in 5626 randomized patients. The linear quadratic formula was used to compensate for different radiotherapy schedules. RESULTS: For preoperative radiotherapy, a clear dose-response relationship could be established. For postoperative radiotherapy, the range of doses was narrow, and a dose-response relationship could not be demonstrated. At similar doses, preoperative radiotherapy appeared to be more efficient in reducing local failure rate than postoperative. The only trial comparing preoperative with postoperative radiotherapy confirms this notion. A 15-20 Gy higher dose may be required postoperatively than preoperatively to reach similar efficacy. Neither approach alone significantly influences survival, although it is likely that a small survival benefit may be seen after preoperative radiotherapy. CONCLUSIONS: The information from the entire randomized experience suggests that preoperative radiotherapy may be more dose efficient than postoperative radiotherapy.

Comparative treatment planning between proton and X-ray therapy in locally advanced rectal cancer.

BACKGROUND AND PURPOSE: Conformal treatment planning with megavoltage X-rays and protons for medically inoperable patients with a large rectal cancer has been studied in an attempt to determine if there are advantages of using protons instead of X-rays. MATERIAL AND METHODS: Three dose plans were made for each of the six patients: one proton plan, including three beams covering the primary tumour and adjacent lymph nodes and three boost beams covering the primary tumour: one X-ray plan, eight beams including a boost with four beams and one mixed plan with four X-ray beams and a boost with three proton beams. A three dimensional treatment-planning systems, TMS, was used. The evaluation of the different plans was made by applying the biological models TCP and NTCP on the dose distributions in terms of dose-volume histograms. RESULTS: The comparison shows advantages of using protons instead of X-rays for all six patients, but in three of them, the advantage is only marginal. The dose-limiting organ at risk is the small bowel, but the proton plan and the mixed plan also spare the bladder and the femoral heads better. At 5% NTCP in any risk organ, the calculated mean TCP value for the six patients is increased by 14%-units with the proton plan and 8%-units with the mixed plan compared to X-rays only. CONCLUSIONS: Proton beam therapy has potential advantages when treating medically inoperable patients with a large rectal cancer over conventional X-ray therapy. Since the benefits are comparatively small, although clinically worthwhile, large randomised studies are needed.

Proton dosimetry intercomparison.

BACKGROUND AND PURPOSE: Methods for determining absorbed dose in clinical proton beams are based on dosimetry protocols provided by the AAPM and the ECHED. Both groups recommend the use of air-filled ionization chambers calibrated in terms of exposure or air kerma in a 60Co beam when a calorimeter or Faraday cup dosimeter is not available. The set of input data used in the AAPM and the ECHED protocols, especially proton stopping powers and w-value is different. In order to verify inter-institutional uniformity of proton beam calibration, the AAPM and the ECHED recommend periodic dosimetry intercomparisons. In this paper we report the results of an international proton dosimetry intercomparison which was held at Loma Linda University Medical Center. The goal of the intercomparison was two-fold: first, to estimate the consistency of absorbed dose delivered to patients among the participating facilities, and second, to evaluate the differences in absorbed dose determination due to differences in 60Co-based ionization chamber calibration protocols. MATERIALS AND METHODS: Thirteen institutions participated in an international proton dosimetry intercomparison. The measurements were performed in a 15-cm square field at a depth of 10 cm in both an unmodulated beam (nominal accelerator energy of 250 MeV) and a 6-cm modulated beam (nominal accelerator energy of 155 MeV), and also in a circular field of diameter 2.6 cm at a depth of 1.14 cm in a beam with 2.4 cm modulation (nominal accelerator energy of 100 MeV). RESULTS: The results of the intercomparison have shown that using ionization chambers with 60Co calibration factors traceable to standard laboratories, and institution-specific conversion factors and dose protocols, the absorbed dose specified to the patient would fall within 3% of the mean value. A single measurement using an ionization chamber with a proton chamber factor determined with a Faraday cup calibration differed from the mean by 8%. CONCLUSION: The adoption of a single ionization chamber dosimetry protocol and uniform conversion factors will establish agreement on proton absorbed dose to approximately 1.5%, consistent with that which has been observed in high-energy photon and electron dosimetry.

Preoperative radiotherapy in rectal carcinoma--aspects of acute adverse effects and radiation technique.

PURPOSE: To explain a possible association between treatment technique and postoperative mortality after preoperative radiotherapy of rectal carcinoma, the dose distributions were compared in model experiments. METHODS AND MATERIALS: Preoperative radiotherapy with a three-beam technique delivered in five fractions to 25 Gy (5 Gy/daily for 5 or 7 days) was given to patients with primary resectable rectal carcinoma. The adverse effects of this treatment, both acute and late, have been low. In a parallel trial using an identical fractionation schedule and total dose but with a two-beam technique, the postoperative mortality was higher. Two-, three-, and four-beam techniques were analyzed in 20 patients with computed tomography based, three-dimensional dose planning. Dose distributions and dose-volume histograms in the planning target volume (PTV) and in the organs at risk were considered. A numerical "biological" model was used to compare the techniques. RESULTS: The two-beam and the four-beam box techniques give the most homogeneous dose distributions in the PTV, although all techniques result in dose distributions that would be considered adequate, provided 16 MV or higher photon energies are used. Three- and four-beam techniques show advantages over the two-beam technique with respect to organs at risk, particularly the small bowel. With the two-beam technique and the upper beam limit at mid-L4, the volume of the bowel that receives > 95% of the prescribed dose, and hence, is included in the treated volume (TV), is more than twice as large as that with three- and four-beam techniques, and that of the total body between 1.5 and 2 times as large. The results of the analyses using the biological model indicate that the three- and four-beam techniques result in less small bowel complication rates than the two-beam technique. The integral energy to the total body is similar for all treatment modalities compared. CONCLUSIONS: The volume of bowel included in the TV, rather than the energy imparted to the body, influences postoperative mortality, and emphasizes the importance of precise radiotherapy planning to minimize normal tissue toxicity.

Faraday cup dosimetry in a proton therapy beam without collimation.

A Faraday cup in a proton beam can give an accurate measurement of the number of protons collected by the cup. It is shown that the collection efficiency with a proper design can be close to unity. To be able to calibrate an ionization chamber from such a measurement, as is recommended in some dosimetry protocols, the energy spectrum of the proton beam must be accurately known. This is normally not the case when the lateral beam extension is defined by collimators. Therefore a method for relating an ionization chamber measurement in an uncollimated beam to the total number of protons in the beam has been developed and is described together with experimental results from calibrating an ionization chamber using this method in the therapeutic beam in Uppsala. This method is applicable to ionization chambers of any shape and the accuracy is estimated to be 1.6% (1 SD).

Radiotherapy in addition to radical surgery in rectal cancer.

In order to lower unacceptably high local failure rates after surgery reported as curative for rectal cancer, perioperative radiotherapy has been extensively investigated. The collected information from a number of controlled trials indicates that the proportion of local recurrences is reduced to less than half when radiotherapy at moderately high doses is given preoperatively. This reduction in local failure rates is not seen after postoperative radiotherapy, even if higher doses have been used. Possibly, there is also a slight positive influence on survival from preoperative radiotherapy. Improved survival has been seen also in trials using postoperative radiotherapy, but then only when combined with chemotherapy. With proper dose planning, sufficiently high doses can be given preoperatively with little if any increase in postoperative mortality. Thus, although published knowledge is still rather limited, a properly planned preoperative radiotherapy seems to inflict small bowel and other complication rates, that are less than when radiotherapy of similar efficacy against the tumour is given postoperatively.