Jian Z. Wang

Radiotherapeutic and surgical management for newly diagnosed brain metastasis(es): An American Society for Radiation Oncology evidence-based guideline

Purpose To systematically review the evidence for the radiotherapeutic and surgical management of patients newly diagnosed with intraparenchymal brain metastases. Methods and Materials Key clinical questions to be addressed in this evidence-based Guideline were identified. Fully published randomized controlled trials dealing with the management of newly diagnosed intraparenchymal brain metastases were searched systematically and reviewed. The U.S. Preventative Services Task Force levels of evidence were used to classify various options of management. Results The choice of management in patients with newly diagnosed single or multiple brain metastases depends on estimated prognosis and the aims of treatment (survival, local treated lesion control, distant brain control, neurocognitive preservation). Single brain metastasis and good prognosis (expected survival 3 months or more): For a single brain metastasis larger than 3 to 4 cm and amenable to safe complete resection, whole brain radiotherapy (WBRT) and surgery (level 1) should be considered. Another alternative is surgery and radiosurgery/radiation boost to the resection cavity (level 3). For single metastasis less than 3 to 4 cm, radiosurgery alone or WBRT and radiosurgery or WBRT and surgery (all based on level 1 evidence) should be considered. Another alternative is surgery and radiosurgery or radiation boost to the resection cavity (level 3). For single brain metastasis (less than 3 to 4 cm) that is not resectable or incompletely resected, WBRT and radiosurgery, or radiosurgery alone should be considered (level 1). For nonresectable single brain metastasis (larger than 3 to 4 cm), WBRT should be considered (level 3). Multiple brain metastases and good prognosis (expected survival 3 months or more): For selected patients with multiple brain metastases (all less than 3 to 4 cm), radiosurgery alone, WBRT and radiosurgery, or WBRT alone should be considered, based on level 1 evidence. Safe resection of a brain metastasis or metastases causing significant mass effect and postoperative WBRT may also be considered (level 3). Patients with poor prognosis (expected survival less than 3 months): Patients with either single or multiple brain metastases with poor prognosis should be considered for palliative care with or without WBRT (level 3). It should be recognized, however, that there are limitations in the ability of physicians to accurately predict patient survival. Prognostic systems such as recursive partitioning analysis, and diagnosis-specific graded prognostic assessment may be helpful. Conclusions Radiotherapeutic intervention (WBRT or radiosurgery) is associated with improved brain control. In selected patients with single brain metastasis, radiosurgery or surgery has been found to improve survival and locally treated metastasis control (compared with WBRT alone).

Stereotactic body radiation therapy: a novel treatment modality

Stereotactic body radiation therapy (SBRT) involves the delivery of a small number of ultra-high doses of radiation to a target volume using very advanced technology and has emerged as a novel treatment modality for cancer. The role of SBRT is most important at two cancer stages—in early primary cancer and in oligometastatic disease. This modality has been used in the treatment of early-stage non-small-cell lung cancer, prostate cancer, renal-cell carcinoma, and liver cancer, and in the treatment of oligometastases in the lung, liver, and spine. A large body of evidence on the use of SBRT for the treatment of primary and metastatic tumors in various sites has accumulated over the past 10–15 years, and efficacy and safety have been demonstrated. Several prospective clinical trials of SBRT for various sites have been conducted, and several other trials are currently being planned. The results of these clinical trials will better define the role of SBRT in cancer management. This article will review the radiobiologic, technical, and clinical aspects of SBRT.

How low is the α/β ratio for prostate cancer?

Purpose: It has been suggested recently that the / ratio for human prostate cancer is low (around 1.5 Gy), and much debate on the evidence for such a low value is ongoing. Analyses reported so far ignored the contribution of tumor repopulation. Extremely low values and unrealistic cell numbers of tumor clonogens are found in these studies. In this paper, we present a comprehensive analysis of the updated clinical data to derive a self-consistent set of parameters for the linear-quadratic (LQ) model. Methods and Materials: The generalized LQ model, considering the effects of dose rate, sublethal damage repair, and clonogenic proliferation, was used to analyze the recently reported clinical data for prostate cancer using either external-beam radiotherapy or brachytherapy. Three LQ parameters, , /, and the repair time, were determined based on the clinical finding that the external-beam radiotherapy and the 125 I and 103 Pd permanent implants are biologically equivalent. The tumor control probability model was used also to analyze the clinical data to obtain an independent relationship of / vs. and to estimate clonogenic cell numbers for patients in different risk groups. Results: Based on the analysis of clinical data and a consideration of repopulation effect, we have derived a self-consistent set of LQ parameters for prostate cancer: 0.15 0.04 Gy 1 , / 3.1 0.5 Gy. Our analysis indicates the half-time of sublethal damage repair to be in the range from 0 to 90 min with a best estimate of 16 min. The best estimate of clonogenic cell numbers in prostate tumors is found to range from 10 6 to 10 7 according to the patient risk level. These values are more realistic than those derived previously (only 10 ‐100). Conclusions: The effect of tumor repopulation is not negligible in determining the LQ parameters for prostate cancer, especially for the low-dose-rate permanent implants. Analysis of clinical data for prostate cancer with corrections for damage repair and repopulation effects results in a low / ratio of 3.1 Gy. Unrealistic clonogenic cell numbers and extremely small values of reported in the literature can be resolved by correcting for repopulation effect. The LQ parameters derived presently from the clinical data are consistent with reports of intrinsic radiosensitivity in vitro.

Impact of prolonged fraction delivery times on tumor control: a note of caution for intensity-modulated radiation therapy (IMRT).

PURPOSE Intensity-modulated radiation therapy (IMRT) allows greater dose conformity to the tumor target. However, IMRT, especially static delivery, usually requires more time to deliver a dose fraction than conventional external beam radiotherapy (EBRT). The purpose of this work is to explore the potential impact of such prolonged fraction delivery times on treatment outcome. METHODS AND MATERIALS The generalized linear-quadratic (LQ) model, which accounts for sublethal damage repair and clonogen proliferation, was used to calculate the cell-killing efficiency of various simulated and clinical IMRT plans. LQ parameters derived from compiled clinical data for prostate cancer (alpha = 0.15 Gy(-1), alpha/beta = 3.1 Gy, and a 16-min repair half-time) were used to compute changes in the equivalent uniform dose (EUD) and tumor control probability (TCP) due to prolonged delivery time of IMRT as compared with conventional EBRT. EUD and TCP calculations were also evaluated for a wide range of radiosensitivity parameters. The effects of fraction delivery times ranging from 0 to 45 min on cell killing were studied. RESULTS Our calculations indicate that fraction delivery times in the range of 15-45 min may significantly decrease cell killing. For a prescription dose of 81 Gy in 1.8 Gy fractions, the EUD for prostate cancer decreases from 78 Gy for a conventional EBRT to 69 Gy for an IMRT with a fraction delivery time of 30 min. The values of EUD are sensitive to the alpha/beta ratio, the repair half-time, and the fraction delivery time. The instantaneous dose-rate, beam-on time, number of leaf shapes (segments), and leaf-sequencing patterns given the same overall fraction delivery time were found to have negligible effect on cell killing. CONCLUSIONS The total time to deliver a single fraction may have a significant impact on IMRT treatment outcome for tumors with a low alpha/beta ratio and a short repair half-time, such as prostate cancer. These effects, if confirmed by clinical studies, should be considered in designing IMRT treatments.

A Generalized Linear-Quadratic Model for Radiosurgery, Stereotactic Body Radiation Therapy, and High–Dose Rate Brachytherapy

A generalized mathematical model for the relation between radiation dose and tumor cell death enables better treatment planning and dose schedule designs for current targeted high-dose radiation therapies in cancer. Better Aim Through Better Math More like a laser-guided missile than a conventional bomb, current radiation therapy for cancer hits small targets and tries to minimize collateral damage. Better imaging and delivery, and new ways to keep patients immobilized, have improved our ability to irradiate small, defined areas. Because the doses can be higher when the radiation beams are highly focused (and normal tissue is less likely to suffer), new radiation therapies are given in fewer, larger doses than the long series of low-dose treatments used in the past. But the use of large doses has been problematic, because the calculations used historically to devise the dose and schedule for therapy do not work well with large shots of radiation. Wang et al. have now derived a general equation that applies to both low- and high-dose treatment situations, and so will improve further the effectiveness of current radiation treatments for cancer. When radiation oncologists develop a treatment plan for a cancer patient, they make assumptions about how much radiation is needed to kill the tumor cells. Guided by past experiments, the linear-quadratic equation has defined this dose-response relationship for decades. But this equation does not account for the fact that at high radiation doses there is less sublethal damage to DNA (and more lethal damage). The resulting error in the calculation grows as the doses get higher, causing the effectiveness of a given amount of radiation to be overestimated, potentially leading to inadequate treatment of patients. The general form of the linear-quadratic equation (gLQ) that is derived here by Wang et al. is valid at both low and high doses and accurately calculates the amount of sublethal damage to DNA. They show that the traditional LQ model is an instance of the general model, as is another model used for high radiation doses, called the target model. Experiments taken from the literature, which measure the effects of a wide dose range of radiation on cells grown in vitro and in animals, confirm that the gLQ model accurately predicts the killing effects of radiation through the whole dose range (up to 13 Gy, the highest amount given to animals). When used to predict high-dose responses, the standard LQ model does not conform to the actual data. The gLQ will be a boon to physicians for designing ever more sophisticated, specialized high-dose cancer therapies. With this approach, unusual treatment regimes that use one or a few large doses can be more accurately administered, and the abundant clinical experience in the low-dose range can be extrapolated to high doses. The gLQ, combined with newer image-guided radiation therapy, should markedly enable improvements in radiation ablation of solid cancers. Conventional radiation therapy for cancer usually consists of multiple treatments (called fractions) with low doses of radiation. These dose schemes are planned with the guidance of the linear-quadratic (LQ) model, which has been the most prevalent model for designing dose schemes in radiation therapy. The high-dose fractions used in newer advanced radiosurgery, stereotactic radiation therapy, and high–dose rate brachytherapy techniques, however, cannot be accurately calculated with the traditional LQ model. To address this problem, we developed a generalized LQ (gLQ) model that encompasses the entire range of possible dose delivery patterns and derived formulas for special radiotherapy schemes. We show that the gLQ model can naturally derive the traditional LQ model for low-dose and low–dose rate irradiation and the target model for high-dose irradiation as two special cases of gLQ. LQ and gLQ models were compared with published data obtained in vitro from Chinese hamster ovary cells across a wide dose range [0 to ~11.5 gray (Gy)] and from animals with dose fractions up to 13.5 Gy. The gLQ model provided consistent interpretation across the full dose range, whereas the LQ model generated parameters that depended on dose range, fitted only data with doses of 3.25 Gy or less, and failed to predict high-dose responses. Therefore, the gLQ model is useful for analyzing experimental radiation response data across wide dose ranges and translating common low-dose clinical experience into high-dose radiotherapy schemes for advanced radiation treatments.

The low α/β ratio for prostate cancer: what does the clinical outcome of HDR brachytherapy tell us?

Abstract Purpose Accumulating evidence demonstrates that prostate cancer has a low α/β ratio. However, several challenging issues have been raised from previous studies, including the biologic equivalence between external beam radiotherapy (EBRT) and brachytherapy, the effect of relative biologic effectiveness (RBE) for permanent implantation, and the systematic uncertainties of multi-institutional and multi-modality clinical data. The purpose of this study is to address these issues by reexamining a reported clinical outcome of high-dose-rate (HDR) brachytherapy and to confirm the low α/β ratio for prostate cancer. Methods and materials The generalized linear-quadratic (LQ) model with considerations of sublethal damage repair and clonogen repopulation was used to calculate the cell-killing efficiency of radiotherapy treatments for prostate cancer. Standard models of tumor cure based on Poisson statistics were used to bridge cell killing to treatment outcome. The data collected in a clinical trial using EBRT plus HDR brachytherapy boost for prostate cancer at William Beaumont Hospital (WBH) were reanalyzed. A 4-year post-treatment time endpoint was chosen as compared to the 3-year endpoint used in the previous study because of better maturity and stability of the data. The least chi-square method was employed to fit the clinical data to estimate the LQ parameters as well as their confidence intervals. The number of clonogens for prostate tumors derived in a separate study was used as a constraint for the data modeling to improve the confidence level. Results Our analysis demonstrates that only relationships among the LQ parameters, not their definitive and unique values, can be derived from the WBH data set alone. This is due to the large statistical uncertainties, i.e., the small numbers of sampled patients. By combining with the results obtained with the clinical data from Memorial Sloan-Kettering Cancer Center (MSKCC), a new set of LQ parameters (α = 0.14 ± 0.05 Gy −1 , α/β = 3.1 −1.6 +2.6 Gy) was obtained from the current analysis of the WBH data without dealing with data from permanent implants. The results are consistent with a previous study based on the biologic equivalence between EBRT and permanent implants with a consideration of tumor repopulation. This set of LQ parameters provides a consistent interpretation of clinical data currently available for prostate cancer. Conclusions This study provides further evidence to support that prostate cancer has a low α/β ratio of about 3.1 Gy. This study shows that the RBE effect in permanent implantation may not be clinically significant for prostate cancer. The consistency found between this analysis and the previous reported study supports the general biologic equivalence between EBRT and brachytherapy treatments for prostate cancer. The low α/β ratio opens the door to search for more effective radiotherapeutic approaches for prostate cancer, e.g., hypofractionation radiotherapy.

Predicting Control of Primary Tumor and Survival by DCE MRI During Early Therapy in Cervical Cancer

Purpose:To assess the early predictive power of MRI perfusion and volume parameters, during early treatment of cervical cancer, for primary tumor control and disease-free-survival. Materials and Methods:Three MRI examinations were obtained in 101 patients before and during therapy (at 2–2.5 and 4–5 weeks) for serial dynamic contrast enhanced (DCE) perfusion MRI and 3-dimensional tumor volume measurement. Plateau Signal Intensity (SI) of the DCE curves for each tumor pixel of all 3 MRI examinations was generated, and pixel-SI distribution histograms were established to characterize the heterogeneous tumor. The degree and quantity of the poorly-perfused tumor subregions, which were represented by low-DCE pixels, was analyzed by using various lower percentiles of SI (SI%) from the pixel histogram. SI% ranged from SI2.5% to SI20% with increments of 2.5%. SI%, mean SI, and 3-dimensional volume of the tumor were correlated with primary tumor control and disease-free-survival, using Student t test, Kaplan-Meier analysis, and log-rank test. The mean post-therapy follow-up time for outcome assessment was 6.8 years (range: 0.2–9.4 years). Results:Tumor volume, mean SI, and SI% showed significant prediction of the long-term clinical outcome, and this prediction was provided as early as 2 to 2.5 weeks into treatment. An SI5% of <2.05 and residual tumor volume of ≥30 cm3 in the MRI obtained at 2 to 2.5 weeks of therapy provided the best prediction of unfavorable 8-year primary tumor control (73% vs. 100%, P = 0.006) and disease-free-survival rate (47% vs. 79%, P = 0.001), respectively. Conclusions:Our results show that MRI parameters quantifying perfusion status and residual tumor volume provide very early prediction of primary tumor control and disease-free-survival. This functional imaging based outcome predictor can be obtained in the very early phase of cytotoxic therapy within 2 to 2.5 weeks of therapy start. The predictive capacity of these MRI parameters, indirectly reflecting the heterogeneous delivery pattern of cytotoxic agents, tumor oxygenation, and the bulk of residual presumably therapy-resistant tumor, requires future study.

Comparison of in vitro and in vivo α/β ratios for prostate cancer

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Longitudinal Changes in Tumor Perfusion Pattern during the Radiation Therapy Course and its Clinical Impact in Cervical Cancer

PURPOSE To study the temporal changes of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns during the radiation therapy (RT) course and their influence on local control and survival in cervical cancer. METHODS AND MATERIALS DCE-MRI was performed in 98 patients with Stage IB(2)-IVA cervical cancer before RT (pre-RT) and during early RT (20-25 Gy) and mid-RT (45-50 Gy). Signal intensity (SI) from the DCE-MRI time-SI curve was derived for each tumor voxel. The poorly perfused low-DCE tumor subregions were quantified as lower 10th percentiles of SI (SI10). Local control, disease-specific survival, and overall survival were correlated with DCE parameters at pre-RT, early RT, and mid-RT. Median follow-up was 4.9 (range, 0.2-9.0) years. RESULTS Patients (16/98) with initial pre-RT high DCE (SI10 >or=2.1) had 100% 5-year local control, 81% disease-specific survival, and 81% overall survival, compared with only 79%, 61%, and 55%, respectively, in patients with pre-RT low DCE. Conversion from pre-RT low DCE to high DCE in early RT (28/82 patients) was associated with higher local control, disease-specific survival, and overall survival (93%, 74%, and 67%, respectively). In comparison with all other groups, outcome was worst in patients with persistently low DCE from pre-RT throughout the mid-RT phase (66%, 44%, and 43%; p = 0.003, 0.003, and 0.020; respectively). CONCLUSION Longitudinal tumor perfusion changes during RT correlate with treatment outcome. Persistently low perfusion in pre-RT, early RT, and mid-RT indicates a high risk of treatment failure, whereas outcome is favorable in patients with initially high perfusion or subsequent improvements of initially low perfusion. These findings likely reflect reoxygenation and may have potential for noninvasive monitoring of intra-treatment radio-responsiveness and for guiding adaptive therapy.

Ultra‐early predictive assay for treatment failure using functional magnetic resonance imaging and clinical prognostic parameters in cervical cancer

The authors prospectively evaluated magnetic resonance imaging (MRI) parameters quantifying heterogeneous perfusion pattern and residual tumor volume early during treatment in cervical cancer, and compared their predictive power for primary tumor recurrence and cancer death with the standard clinical prognostic factors. A novel approach of augmenting the predictive power of clinical prognostic factors with MRI parameters was assessed.