Normalized Total Dose Research Articles

Radiobiology of re-irradiations

The treatment options for recurrent tumors are limited. Re irradiation is being increasingly considered as an option, in view of the advances in treatment techniques, particularly the ability to document doses, overlay plans, intensity modulation, and image guidance. preclinical and clinical studies has been to estimate the total cumulative doses (EQD2) also termed as normalized total dose (NTD) that can be delivered to various tissues. In this review article reirradiation radiobiology of different tissues and dose fractionation have been discussed.

Early volumetric change and treatment outcome of metastatic brain tumors after external beam radiotherapy: differential radiotherapy for brain metastasis

To evaluate the treatment outcomes of low-dose whole brain radiation therapy (WBRT)-based differential radiation therapy (RT) for metastatic brain tumors. A total of 242 targets (metastatic brain lesions) were analyzed in the present study. Median WBRT dose and number of fractions were 25 (range 25-35) Gy and 10 (range 8-15) fractions, respectively. A median normalized total dose (NTD) of 1.8 Gy (NTD(1.8Gy)) to the metastatic lesion was 45 (range 27-64.8) Gy. We numbered and contoured each metastatic lesion sequentially using computed tomography fused with serial magnetic resonance imaging to evaluate volumetric changes. The 6-month and 1-year freedom from remote intracranial failure rates were 87.7 and 58.5 %, respectively. The 6-month actuarial local control (LC) rate was 93.4 %. Tumor diameter was a major determinant for LC, and tumor histology was a significant parameter predicting the volume reduction rate. With overall complete response (CR) rate of 56.6 % after RT, CR rate, if the target was more than 1 cm in size, was 25 % with a median NTD(1.8Gy) of 45 Gy, requiring dose escalation to achieve better target regression. Low-dose WBRT with selective boost was feasible and effective. Our results pose the rationale of future trial of differential radiation therapy (RT), which prescribes different radiation dose according to the tumor density in metastatic brain tumors.

The energy margin strategy for reducing dose variation due to setup uncertainty in intensity modulated proton therapy (IMPT) delivered with distal edge tracking (DET)

Intensity‐modulated proton therapy (IMPT) can produce plans with similar target dose conformity but lower normal tissue dose than intensity‐modulated X‐ray therapy (IMXT). However, due to the finite range of proton beams in tissue, proton therapy treatment plans are usually more sensitive to setup uncertainties than X‐ray therapy plans. In this work, the energy margin (EM) concept, which was initially developed for passive scattering proton therapy, was generalized to apply to IMPT treatment planning. The effectiveness of the EM method was evaluated on five head‐and‐neck cancer patients with distal edge tracking (DET) treatment plans by comparing the original plans (ORG) without an EM to those with an EM. Three beam arrangements were considered: 24 beams delivered over a 360° arc, 12 beams delivered over a 180° arc, and 12 beams delivered over two 90° fan angles. Setup uncertainty was modeled by sampling rigid translational shifts from a Gaussian distribution with a mean of 0 mm and standard deviation of 2 mm in all directions. Delivered dose distributions for all 30 fractions were recalculated using the Geant4 Monte Carlo code. Normalized total dose (NTD) for both the CTV and a ring structure surrounding the PTV were recorded. The plan quality comparison revealed that EM plans had the same CTV coverage but higher dose to the normal tissue than ORG plans. After the simulated delivery, ORG plans resulted in more than 3% underdosage to 5% of the CTV volume in all three beam arrangements, whereas the EM plans did not. Both ORG and EM plans did not produce more than 5% overdose to D2% of the ring structure. The use of an EM for IMPT treatment planning can substantially reduce sensitivity of the resulting dose distributions to setup uncertainty.PACS number: 87.55.K‐

Equivalent normalized total dose estimates in cyberknife radiotherapy dose delivery in prostate cancer hypofractionation regimens

As the α/β value of prostate is very small and lower than the surrounding critical organs, hypofractionated radiotherapy became a vital mode of treatment of prostate cancer. Cyberknife (Accuray Inc., Sunnyvale, CA, USA) treatment for localized prostate cancer is performed in hypofractionated dose regimen alone. Effective dose escalation in the hypofractionated regimen can be estimated if the corresponding conventional 2 Gy per fraction equivalent normalized total dose (NTD) distribution is known. The present study aims to analyze the hypofractionated dose distribution of localized prostate cancer in terms of equivalent NTD. Randomly selected 12 localized prostate cases treated in cyberknife with a dose regimen of 36.25 Gy in 5 fractions were considered. The 2 Gy per fraction equivalent NTDs were calculated using the formula derived from the linear quadratic (LQ) model. Dose distributions were analyzed with the corresponding NTDs. The conformity index for the prescribed target dose of 36.25 Gy equivalent to the NTD dose of 90.63 Gy (α/β = 1.5) or 74.31 Gy (α/β = 3) was ranging between 1.15 and 1.73 with a mean value of 1.32 ± 0.15. The D5% of the target was 111.41 ± 8.66 Gy for α/β = 1.5 and 90.15 ± 6.57 Gy for α/β = 3. Similarly, the D95% was 91.98 ± 3.77 Gy for α/β = 1.5 and 75.35 ± 2.88 Gy for α/β = 3. The mean values of bladder and rectal volume receiving the prescribed dose of 36.25 Gy were 0.83 cm3 and 0.086 cm3, respectively. NTD dose analysis shows an escalated dose distribution within the target for low α/β (1.5 Gy) with reasonable sparing of organs at risk. However, the higher α/β of prostate (3 Gy) is not encouraging the fact of dose escalation in cyberknife hypofractionated dose regimen of localized prostate cancer.

Analysis of Radiation Pneumonitis (RP) Incidence in a Phase I Stereotactic Body Radiotherapy (SBRT) Dose Escalation Study for Multiple Metastases

Analysis of Radiation Pneumonitis (RP) Incidence in a Phase I Stereotactic Body Radiotherapy (SBRT) Dose Escalation Study for Multiple Metastases

Proton Radiotherapy: The Biological Effect of Treating Alternating Subsets of Fields for Different Treatment Fractions

Common practice in proton radiotherapy is to deliver a subset of all fields in the treatment plan on any given treatment day. We investigate using biological modeling if the resulting variation in daily dose to normal tissues has a relevant detrimental biological effect. For four patient groups, the cumulative normalized total dose (NTD) was determined for normal tissues (OARs) of each patient using the clinically delivered fractionation schedule (FS(clin)), and for hypothetical fractionation schedules delivering all fields every day (FS(all)) or only a single field each day (FS(single)). Cumulative three-dimensional NTD distributions were summarized using the generalized equivalent uniform dose (gEUD) model. For the skull base/cervical spine chordoma group, the largest effect is a 4-Gy increase in gEUD of the chiasm when treating only a subset of fields on any day. For lung cancer and pancreatic cancer patients, the variation in the gEUD of normal tissues is <0.2 Gy. For the prostate group, FS(clin) increases the gEUD of the femoral heads by 9 Gy compared with FS(all). Use of FS(single) resulted in the highest NTD to normal tissues for any patient. FS(all) resulted in an integral NTD to the patient that is on average 5% lower than FS(clin) and 10% lower than FS(single). The effects of field set of the day treatment delivery depend on the tumor site and number of fields treated each day. Modeling these effects may be important for accurate risk assessment.

Dosimetric Comparison of Helical Tomotherapy and Linac-IMRT Treatment Plans for Head and Neck Cancer Patients

The rapid development and clinical implementation of external beam radiation treatment technologies continues. The existence of various commercially available technologies for intensity-modulated radiation therapy (IMRT) has stimulated interest in exploring the differential potential advantage one may have compared with another. Two such technologies, Hi-Art Helical Tomotherapy (HT) and conventional medical linear accelerator–based IMRT (LIMRT) have been shown to be particularly suitable for the treatment of head and neck cancers. In this study, 23 patients who were diagnosed with stages 3 or 4 head and neck cancers, without evidence of distance metastatic disease, were treated in our clinic. Treatment plans were developed for all patients simultaneously on the HT planning station and on the Pinnacle treatment planning system for step-and-shoot IMRT. Patients were treated only on the HT unit, with the LIMRT plan serving as a backup in case the HT system might not be available. All plans were approved for clinical use by a physician. The prescription was that patients receive at least 95% of the planning target volume (PTV), which is 66 Gy at 2.2 Gy per fraction. Several dosimetric parameters were computed: PTV dose coverage; PTV volume conformity index; the normalized total dose (NTD), where doses were converted to 2 Gy per fraction to organs at risk (OAR); and PTV dose homogeneity. Both planning systems satisfied our clinic's PTV prescription requirements. The results suggest that HT plans had, in general, slightly better dosimetric characteristics, especially regarding PTV dose homogeneity and normal tissue sparing. However, for both techniques, doses to OAR were well below the currently accepted normal tissue tolerances. Consequently, factors other than the dosimetric parameters studied here may have to be considered when making a choice between IMRT techniques.

Impact of Fraction Size on Lung Radiation Toxicity: Hypofractionation may be Beneficial in Dose Escalation of Radiotherapy for Lung Cancers

To assess how fraction size impacts lung radiation toxicity and therapeutic ratio in treatment of lung cancers. The relative damaged volume (RDV) of lung was used as the endpoint in the comparison of various fractionation schemes with the same normalized total dose (NTD) to the tumor. The RDV was computed from the biologically corrected lung dose-volume histogram (DVH), with an alpha/beta ratio of 3 and 10 for lung and tumor, respectively. Two different (linear and S-shaped) local dose-effect models that incorporated the concept of a threshold dose effect with a single parameter D(L50) (dose at 50% local dose effect) were used to convert the DVH into the RDV. The comparison was conducted using four representative DVHs at different NTD and D(L50) values. The RDV decreased with increasing dose/fraction when the NTD was larger than a critical dose (D(CR)) and increased when the NTD was less than D(CR). The D(CR) was 32-50 Gy and 58-87 Gy for a small tumor (11 cm(3)) for the linear and S-shaped local dose-effect models, respectively, when D(L50) was 20-30 Gy. The D(CR) was 66-97 Gy and 66-99 Gy, respectively, for a large tumor (266 cm(3)). Hypofractionation was preferred for small tumors and higher NTDs, and conventional fractionation was better for large tumors and lower NTDs. Hypofractionation might be beneficial for intermediate-sized tumors when NTD = 80-90 Gy, especially if the D(L50) is small (20 Gy). This computational study demonstrated that hypofractionated stereotactic body radiotherapy is a better regimen than conventional fractionation in lung cancer patients with small tumors and high doses, because it generates lower RDV when the tumor NTD is kept unchanged.

Comparison of PDR brachytherapy and external beam radiation therapy in the case of breast cancer

Pulsed dose rate brachytherapy (PDR) was compared to external beam radiation therapy (EBRT) in the case of breast cancer. The benefits were figured out by evaluation of dosimetric parameters and calculating the normal tissue complication probability (NTCP). PDR plans were set up for five randomly chosen left-sided breast cancer patients delivering a total dose of 50.4 Gy to the target (dose rate 0.8 Gy h−1). For EBRT five left-sided breast cancer patients were planned using 3D-conformal tangential photon beams with a prescribed total dose of 50 Gy (2 Gy/fraction) to the total breast volume. For plan ranking and NTCP calculation the physical dose was first converted into the biologically effective dose (BED) and then into the normalized total dose (NTD) using the linear quadratic model with an α/β ratio of 3 Gy. In PDR the relative effectiveness (RE) was calculated for each dose bin of the differential dose volume histogram to get the BED. NTCPs were calculated for the ipsilateral lung and the heart as contoured on CT slices based on the Lyman model and the Kutcher reduction scheme. Dosimetric parameters as Vth (percentage of the total volume exceeding a threshold dose) and Jackson's fdam (fraction of the organ damaged) were also used to figure out the benefits. The comparison of calculated NTCPs in PDR and EBRT showed no difference between these two modalities. All values were below 0.01%. fdam derived from EBRT was always higher (mean value 8.95% versus 1.21% for the lung). The mean V10 and V20 of the lung related to BED were 6.32% and 1.72% for PDR versus 11.72% and 9.59% for EBRT. When using dosimetric parameters as Vth and fdam, PDR was mostly superior to EBRT in respect of sparing normal tissues. NTCP calculation as a single method of modality ranking showed a lack of information, especially when normal tissue was exposed to low radiation doses.

Radiation pneumonitis in patients treated for malignant pulmonary lesions with hypofractionated radiation therapy

Purpose We evaluated the relationship between the mean lung dose (MLD) and the incidence of radiation pneumonitis (RP) after stereotactic body radiation therapy (SBRT), and compared this with conventional fractionated radiation therapy (CFRT). Materials and methods For both SBRT ( n = 128) and CFRT ( n = 142) patients, RP grade ⩾2 was scored. Toxicity models predicting the probability of RP as a function of the MLD were fitted using maximum log likelihood analysis. The MLD was NTD (Normalized Total Dose) corrected using an α/ β ratio of 3 Gy. Results SBRT patients were treated with 6–12 Gy per fraction with a median MLD of 6.4 Gy (range: 1.5–26.5 Gy). CFRT patients were treated with 2 Gy or 2.25 Gy per fraction, the median MLD was 13.2 Gy (range: 3.0–23.0 Gy). The crude incidence rates of RP were 10.9% and 17.6% for the SBRT and CFRT patients, respectively. A significant dose–response relationship for RP was found after SBRT, which was not significantly different from the dose–response relationship for CFRT ( p = 0.18). Conclusion We derived a significant dose–response relationship between the risk of RP and the MLD for SBRT from the clinical data. This relation was not significantly different from the dose–response relation for CFRT, although statistical analysis was hampered by the low number of patients in the high dose range.

Extrapolation of Normal Tissue Complication Probability for Different Fractionations in Liver Irradiation

The ability to predict normal tissue complication probability (NTCP) is essential for NTCP-based treatment planning. The purpose of this work is to estimate the Lyman NTCP model parameters for liver irradiation from published clinical data of different fractionation regimens. A new expression of normalized total dose (NTD) is proposed to convert NTCP data between different treatment schemes. The NTCP data of radiation- induced liver disease (RILD) from external beam radiation therapy for primary liver cancer patients were selected for analysis. The data were collected from 4 institutions for tumor sizes in the range of of 8-10 cm. The dose per fraction ranged from 1.5 Gy to 6 Gy. A modified linear-quadratic model with two components corresponding to radiosensitive and radioresistant cells in the normal liver tissue was proposed to understand the new NTD formalism. There are five parameters in the model: TD(50), m, n, alpha/beta and f. With two parameters n and alpha/beta fixed to be 1.0 and 2.0 Gy, respectively, the extracted parameters from the fitting are TD(50)(1) = 40.3 +/- 8.4Gy, m =0.36 +/- 0.09, f = 0.156 +/- 0.074 Gy and TD(50)(1) = 23.9 +/- 5.3Gy, m = 0.41 +/- 0.15, f = 0.0 +/- 0.04 Gy for patients with liver cirrhosis scores of Child-Pugh A and Child-Pugh B, respectively. The fitting results showed that the liver cirrhosis score significantly affects fractional dose dependence of NTD. The Lyman parameters generated presently and the new form of NTD may be used to predict NTCP for treatment planning of innovative liver irradiation with different fractionations, such as hypofractioned stereotactic body radiation therapy.

Dose Coverage Beyond the Gross Tumor Volume for Various Stereotactic Body Radiotherapy Planning Techniques Reporting Similar Control Rates for Stage I Non–Small-Cell Lung Cancer

To investigate the dose falloff region for various stereotactic body radiotherapy (SBRT) planning techniques used in the treatment of Stage I non-small-cell lung cancer reporting similar control rates. The SBRT plans were constructed on five patient data sets using seven different planning regimens. These regimens varied in the number of beams, number of fractions, prescription target, and prescribed dose used. For each case all regimens were planned using a common gross tumor volume (GTV). To compare dose falloff for the various regimens, resulting physical dose grids were converted into normalized total dose (NTD) grids. Furthermore, to determine the potential coverage of microscopic extension of the various regimens minimal peripheral NTD (NTD-MP(100)) were calculated and plotted as a function of incremental volume expansions of the GTV. Average values for NTD-MP(100) varied over a range of 174 Gy at the GTV periphery, but this range fell to 10 Gy at a distance of 14 mm from the GTV. Of 35 plans, 23 resulted in potential microscopic extension coverage of 78% to 95%. Averages for five of seven regimens fell within the range of 80% to 85%. Results were negligibly affected when intrafraction motion effects were accounted for. Although average NTD-MP(100) varied dramatically at the GTV, periphery values became similar at a distance of 14 mm from the GTV. With the exception of two, potential coverage of microscopic extension was similar for all planning techniques, with averages falling within a 5% range.

Acute radiation esophagitis in a phase I dose-escalation trial evaluating helical tomotherapy for inoperable non-small cell lung cancer (NSCLC)

7694 Background: In an attempt to improve the poor local control in patients with locally advanced and medically inoperable lung cancer we investigated helical tomotherapy as a means to decrease radiation dose to critical normal structures while escalating tumor dose. Methods: Thirty-six patients with Stage I-IV NSCLC requiring definitive radiotherapy and judged not to be surgical candidates due to medical comorbidities or advanced tumor stage were enrolled in this phase I trial. Chemotherapy was given sequentially but not allowed concurrently. Pts were placed in 1 of 4 dose-per-fraction bins, all treated for 25 fractions, with dose per fraction ranging from 2.28 to 3.22 Gy. Bins were calculated to yield normalized total dose (NTD) equivalents in 2 Gy fractions of 60–100 Gy. Dose escalation limiting constraints included esophageal maximum NTD, lung NTD mean, and esophageal effective volume (Veff). Radiotherapy was limited to the primary site and clinically proven or suspicious nodal regions. Elective nodal irradiation (ENI) was not performed. A graded-response logistic regression analysis was performed to identify dosimetric and clinical factors associated with esophagitis. Results: No grade 3 (CTCAE v3.0 and RTOG) acute esophageal toxicities were observed. Only 6 patients (16.7%) required narcotic analgesia (RTOG gr. 2 toxicity). Average mean NTD dose to the esophagus (Dmean)=15.3 Gy. Average volume of the esophagus receiving NTD 55 Gy (V55)=3.65%. Both Dmean and V55 were significantly associated with the grade of esophagitis, with P- values of 0.018 and 0.010, respectively. In this limited series, there was no significant effect of sequential chemotherapy, in agreement with previous studies. Conclusions: 1) Acute esophageal toxicity was minimal despite dose escalation via helical tomotherapy for inoperable NSCLC cancer. 2) The observed significant associations between V55, Dmean, and grade of esophagitis validate improved dose distribution as a strategy to permit radiation dose escalation. Pending acceptable rates of radiation pneumonitis the addition of concurrent chemotherapy is anticipated. Supported by NIH Grant CA-88960. No significant financial relationships to disclose.

High-dose simultaneously integrated breast boost using intensity-modulated radiotherapy and inverse optimization

Recently a Phase III randomized trial has started comparing a boost of 16 Gy as part of whole-breast irradiation to a high boost of 26 Gy in young women. Our main aim was to develop an efficient simultaneously integrated boost (SIB) technique for the high-dose arm of the trial. Treatment planning was performed for 5 left-sided and 5 right-sided tumors. A tangential field intensity-modulated radiotherapy technique added to a sequentially planned 3-field boost (SEQ) was compared with a simultaneously planned technique (SIB) using inverse optimization. Normalized total dose (NTD)-corrected dose volume histogram parameters were calculated and compared. The intended NTD was produced by 31 fractions of 1.66 Gy to the whole breast and 2.38 Gy to the boost volume. The average volume of the PTV-breast and PTV-boost receiving more than 95% of the prescribed dose was 97% or more for both techniques. Also, the mean lung dose and mean heart dose did not differ much between the techniques, with on average 3.5 Gy and 2.6 Gy for the SEQ and 3.8 Gy and 2.6 Gy for the SIB, respectively. However, the SIB resulted in a significantly more conformal irradiation of the PTV-boost. The volume of the PTV-breast, excluding the PTV-boost, receiving a dose higher than 95% of the boost dose could be reduced considerably using the SIB as compared with the SEQ from 129 cc (range, 48-262 cc) to 58 cc (range, 30-102 cc). A high-dose simultaneously integrated breast boost technique has been developed. The unwanted excessive dose to the breast was significantly reduced.

Feasibility report of stereotactic body radiotherapy with tomotherapy for early stage medically inoperable lung cancer using extreme hypofractionation

17097 Background: This is a report on the technical feasibility, dosimetric aspects, and daily image-guidance capability with megavoltage computed tomography (MvCT) imaging of stereotactic body radiotherapy (SBRT) using tomotherapy for patients with medically inoperable early stage non-small cell lung cancer (NSCLC). Methods: Treatment planning was performed using 4D PET-CT in a BodyFix device. A pilot group of 4 patients with &lt;5 cm T1/2, N0 tumors, was treated using IMRT (tomotherapy), utilizing daily image guidance with MvCT. Patients received 60 Gy within 10 days, delivered in five 12Gy fractions. The primary endpoint of this study was evaluation of acute and sub-acute treatment related toxicities. The secondary endpoint was radiographic evaluation for objective tumor response. Results: All 20 fractions were successfully delivered. MvCT provided excellent tumor visualization for daily image guidance. No significant tumor regression was observed in any patient during the 2 weeks of therapy, using volumetric contouring on MvCT images. The relevant dosimetric aspects, measured as median normalized total dose (NTD) were as follows: tumor = 116.5 Gy10; whole lung = 6.8 Gy3. Maximum fraction-size equivalent dose (FED) demonstrated median values as follows: esophagus = 4.04 Gy3; spinal cord = 6.53 Gy3. All patients are alive at a median follow-up of 6 months, with no grade 2 or higher acute pulmonary toxicities. Early radiographic follow-up demonstrates all 4 patients experienced a partial response. The mean tumor regression is 79% (range 64–85%). Conclusions: 4D PET-CT permits precise target delineation. In this, the first reported clinical experience, IMRT delivery of SBRT using tomotherapy is feasible, safe and free of major acute toxicities. The conformality which is obtained by helical delivery of the therapeutic dose makes it well-suited for dose escalation through extreme hypofractionation, with extremely low mean NTD to normal tissue. The ability to obtain on-treatment megavoltage CT scans to confirm tumor localization is a substantial advantage. Further studies and longer follow-up are warranted to evaluate the efficacy of this treatment modality. [Table: see text]

The biologic relevance of daily dose variations in adaptive treatment planning

To explore the biologic relevance of deviations from the intended uniform fractionation scheme. We study the effect of the variance of the dose per fraction on the normalized total dose (NTD), which incorporates the linear-quadratic model of radiation effects. In regions of steep dose gradients, we determine the shift between NTD isodose lines and physical isodose lines. We also look at ways to compensate for dose-variation effects through dose adjustments, without changing the number of fractions. Simple equations quantify effects of dose variation on the NTD. If the standard deviation of the dose is 10% of the daily dose fraction, the effects on the NTD for a given point in the irradiated area are always less than 1%, independent of the biologic parameters. In adaptive dose-correction schemes, the dose correction should be applied uniformly over the remaining fractions, to minimize the variance. Incomplete repair leads to a coupling of doses delivered on different days, which complicates the issue. Repopulation appears to be insignificant in the context of this study (constant overall treatment time). A variation of the dose between fractions always leads to a larger biologic effect than does the same total dose delivered with standard uniform fractionation. The increase in NTD is negligible if the standard deviation of the dose is less than 10% of the dose per fraction.

Pelvic nodal dose escalation with prostate hypofractionation using conformal avoidance defined (H-CAD) intensity modulated radiation therapy

The management of prostate cancer patients with a significant risk of pelvic lymph node involvement is controversial. Both whole pelvis radiotherapy and dose escalation to the prostate have been linked to improved outcome in such patients, but it is unclear whether conventional whole pelvis doses of only 45–50 Gy are optimal for ultimate nodal control. The purpose of this study is to examine the dosimetric and clinical feasibility of combining prostate dose escalation via hypofractionation with conformal avoidance-based IMRT (H-CAD) dose escalation to the pelvic lymph nodes. One conformal avoidance and one conventional plan were generated for each of eight patients. Conformal avoidance-based IMRT plans were generated that specifically excluded bowel, rectum, and bladder. The prostate and lower seminal vesicles (PTV 70) were planned to receive 70 Gy in 2.5 Gy/fraction while the pelvic lymph nodes (PTV 56) were to concurrently receive 56 Gy in 2 Gy/fraction. The volume of small bowel receiving ≥45 Gy was restricted to 300 ml or less. These conformal avoidance plans were delivered using helical tomotherapy or LINAC-based IMRT with daily imaging localization. All patients received neoadjuvant and concurrent androgen deprivation with a planned total of two years. The conventional, sequential plans created for comparison purposes for all patients consisted of a conventional 4-field pelvic box prescribed to 50.4 Gy (1.8 Gy/fraction) followed by an IMRT boost to the prostate of 25.2 Gy (1.8 Gy/fraction) yielding a final prostate dose of 75.6 Gy. For all plans, the prescription dose was to cover the target structure. Equivalent uniform dose (EUD) analyses were performed on all targets and dose-volume histograms (DVH) were displayed in terms of both physical and normalized total dose (NTD), i.e. dose in 2 Gy fraction equivalents. H-CAD IMRT plans were created for and delivered to all eight patients. Analysis of the H-CAD plans demonstrates prescription dose coverage of >95% of both the PTV 70 (prostate) and PTV 56 (nodes). The EUDs for PTV 70 and PTV 56 were greater than prescription dose for all eight plans. Analysis of bio-effective DVHs demonstrated similar amounts of small bowel receiving ≥45 Gy for H-CAD and sequential plans, in spite of the significantly higher dose to which H-CAD treated the pelvic nodes. The treatment was well tolerated in the eight treated patients in that no grade 2 or higher acute gastrointestinal toxicities were seen. Prostate hypofractionation with concurrent conformal avoidance-based pelvic IMRT for high risk prostate cancer represents an efficient and promising method for achieving dose escalation both of pelvic lymph nodes and the prostate with modest acute toxicity. Unlike a vascular-guided targeting approach, conformal avoidance has the potential advantage of also encompassing at-risk nodes that are not contained within major nodal chains. A phase II trial to more thoroughly examine this treatment approach is currently underway.

Pelvic Nodal Dose Escalation with Prostate Hypofractionation Using Conformal Avoidance Defined (H-CAD) Intensity Modulated Radiation Therapy

The management of prostate cancer patients with a significant risk of pelvic lymph node involvement is controversial. Both whole pelvis radiotherapy and dose escalation to the prostate have been linked to improved outcome in such patients, but it is unclear whether conventional whole pelvis doses of only 45-50 Gy are optimal for ultimate nodal control. The purpose of this study is to examine the dosimetric and clinical feasibility of combining prostate dose escalation via hypofractionation with conformal avoidance-based IMRT (H-CAD) dose escalation to the pelvic lymph nodes. One conformal avoidance and one conventional plan were generated for each of eight patients. Conformal avoidance-based IMRT plans were generated that specifically excluded bowel, rectum, and bladder. The prostate and lower seminal vesicles (PTV 70) were planned to receive 70 Gy in 2.5 Gy/fraction while the pelvic lymph nodes (PTV 56) were to concurrently receive 56 Gy in 2 Gy/fraction. The volume of small bowel receiving >or=45 Gy was restricted to 300 ml or less. These conformal avoidance plans were delivered using helical tomotherapy or LINAC-based IMRT with daily imaging localization. All patients received neoadjuvant and concurrent androgen deprivation with a planned total of two years. The conventional, sequential plans created for comparison purposes for all patients consisted of a conventional 4-field pelvic box prescribed to 50.4 Gy (1.8 Gy/fraction) followed by an IMRT boost to the prostate of 25.2 Gy (1.8 Gy/fraction) yielding a final prostate dose of 75.6 Gy. For all plans, the prescription dose was to cover the target structure. Equivalent uniform dose (EUD) analyses were performed on all targets and dose-volume histograms (DVH) were displayed in terms of both physical and normalized total dose (NTD), i.e. dose in 2 Gy fraction equivalents. H-CAD IMRT plans were created for and delivered to all eight patients. Analysis of the H-CAD plans demonstrates prescription dose coverage of >95% of both the PTV 70 (prostate) and PTV 56 (nodes). The EUDs for PTV 70 and PTV 56 were greater than prescription dose for all eight plans. Analysis of bio-effective DVHs demonstrated similar amounts of small bowel receiving >or=45 Gy for H-CAD and sequential plans, in spite of the significantly higher dose to which H-CAD treated the pelvic nodes. The treatment was well tolerated in the eight treated patients in that no grade 2 or higher acute gastrointestinal toxicities were seen. Prostate hypofractionation with concurrent conformal avoidance-based pelvic IMRT for high risk prostate cancer represents an efficient and promising method for achieving dose escalation both of pelvic lymph nodes and the prostate with modest acute toxicity. Unlike a vascular-guided targeting approach, conformal avoidance has the potential advantage of also encompassing at-risk nodes that are not contained within major nodal chains. A phase II trial to more thoroughly examine this treatment approach is currently underway.

Recurrent endometrial cancer after surgery alone: results of salvage radiotherapy

Purpose: Postoperative irradiation of endometrial cancer patients decreases the risk of local recurrence but is associated with a number of long-term sequelae. In a proportion of patients, no immediate postoperative radiotherapy is applied and this treatment is introduced only at relapse. The aim of our study was to assess the long-term results of salvage radiotherapy in previously nonirradiated endometrial cancer patients who developed local recurrence, and to evaluate the impact of patient- and treatment-related factors on treatment efficacy. Methods and Materials: We performed a detailed retrospective analysis of 73 endometrial cancer patients given radiotherapy for local recurrence after the initial surgery only. The mean age at diagnosis of the recurrence was 63 years (range, 39–78 years). Median time to recurrence was 11 months (range, 1–19 months). All recurrences were staged with the use of Perez modification of the International Federation of Gynecology and Obstetrics (FIGO) staging system for primary vaginal carcinoma. There were five (7%) Stage I patients, 43 (59%) Stage II patients, and 25 (34%) Stage III patients. Forty-four patients (60%) received both external beam irradiation (EBRT) and endovaginal brachytherapy (BRT), 17 (23%) received only BRT, and 12 (17%) received only EBRT. The mean total physical radiation dose was 75.9 Gy (range, 8–130 Gy), and the mean normalized total dose (NTD) calculated on the base of the linear-quadratic model was 86.6 Gy (range, 8.5–171.9 Gy). Median follow-up for alive patients was 8.8 years (range, 3–21 years). The impact of patient-, tumor-, and therapy-related factors on the treatment outcome was evaluated with the use of uni- and multivariate analyses. Results: Three- and 5-year overall survival rates were 33% and 25%, respectively. In the univariate analysis, lower stage of recurrent disease ( p < 0.0005), combined EBRT and BRT ( p = 0.027), higher total radiation dose ( p = 0.031), and higher NTD ( p = 0.006) were significantly correlated with better survival. In the multivariate analysis, only stage of recurrent disease ( p < 0.005) and high total dose ( p = 0.047) were independently correlated with better survival. Lower FIGO stage of recurrence ( p = 0.023) and higher total dose ( p = 0.005) were also independently correlated with longer time to progression, whereas higher radiotherapy dose was the only factor correlated with better local control ( p = 0.029). Conclusions: The efficacy of salvage radiotherapy in endometrial cancer patients with local failure after previous surgery is limited. Factors determining treatment outcome include advancement of the tumor at relapse and radiotherapy dose.

The potential for sparing of parotids and escalation of biologically effective dose with intensity-modulated radiation treatments of head and neck cancers: a treatment design study

Purpose: Conventional radiotherapy for cancers of the head and neck (HN) can yield acceptable locoregional tumor control rates, but toxicity of many normal tissues limits our ability to escalate dose. Xerostomia represents one of the most common complications. The purpose of this study is to investigate the potential of intensity-modulated radiotherapy (IMRT) to achieve adequate sparing of parotids and to escalate nominal and/or biologically-effective dose to achieve higher tumor control without exceeding normal tissue tolerances. Methods and Materials: An IMRT optimization system, developed at our institution for research and clinical purposes, and coupled to a commercial radiation treatment planning system, has been applied to a number of cases of HN carcinomas. IMRT plans were designed using dose- and dose-volume-based criteria for 4 and 6 MV coplanar but non-collinear beams ranging in number from 5 to 15 placed at equi-angular steps. Detailed analysis of one of the cases is presented, while the results of the other cases are summarized. For the first case, the IMRT plans are compared with the standard 3D conformal radiation treatment (3DCRT) plan actually used to treat the patient, and with each other. The aim of the 3DCRT plan for this particular case was to deliver 73 Gy to the tumor volume in 5 fractions of 2 Gy and 28 fractions of 2.25 Gy/fx; and 46 Gy to the nodes in 2 Gy/fx while maintaining critical normal tissues to below specified tolerances. The IMRT plans were designed to be delivered as a “simultaneous integrated boost” (SIB) using the “sweeping window” technique with a dynamic MLC. The simultaneous integrated boost strategy was chosen, partly for reasons of efficiency in planning and delivery of IMRT treatments, and partly with the assumption that dose distributions in such treatments are more conformal and spare normal tissues to a greater extent than those with sequential boost strategy. Biologically equivalent dose normalized to 2 Gy/fx, termed here as normalized total dose (NTD), for this strategy was calculated using published head and neck fractionation data. Results: IMRT plans were more conformal than the 3DCRT plans. For equivalent coverage of the tumor and the nodes, and for the dose to the spinal cord and the brainstem maintained within tolerance limits, the dose to parotids was greatly reduced. For the detailed example presented, it was shown that the tumor and the nodes in the 3DCRT plan receive NTDs of 78 and 46 Gy, respectively. For the IMRT plan, a nominal dose of 70 Gy could be delivered to the tumor in 28 fractions of 2.5 Gy each, simultaneously with 50.4 Gy to nodes with 1.8 Gy/fx. The two are biologically equivalent to 82 and 46 Gy, respectively, if delivered in 2 Gy/fx. Similar computations were carried out for other cases as well. The quality of IMRT plans was found to improve with increasing number of beams, up to 9 beams. Dose-volume-based criteria led to a modest improvement in IMRT plans and required less trial and error. Conclusion: IMRT has the potential to significantly improve radiotherapy of HN cancers by reducing normal tissue dose and simultaneously allowing escalation of dose. SIB strategy is not only more efficient and yields better dose distributions, but may also be biologically more effective. Dose-volume-based criteria is better than purely dose-based criteria. The quality of plans improves with number of beams, reaching a saturation level for a certain number of beams, which for the plans studied was found to be 9.