Pattern of Radiotherapy Treatment in Low-Risk, Intermediate-Risk, and High-Risk Prostate Cancer Patients: Analysis of National Cancer Database.

Background: In this study, the utilization rates and survival outcomes of different radiotherapy techniques are compared in prostate cancer (PCa) patients stratified by risk group. Methods: We analyzed an extensive data set of N0, M0, non-surgical PCa patients diagnosed between 2004 and 2015 from the National Cancer Database (NCDB). Patients were grouped into six categories based on RT modality: an intensity-modulated radiation therapy (IMRT) group with brachytherapy (BT) boost, IMRT with/without IMRT boost, proton therapy, stereotactic body radiation therapy (SBRT), low-dose-rate brachytherapy (BT LDR), and high-dose-rate brachytherapy (BT HDR). Patients were also stratified by the National Comprehensive Cancer Network (NCCN) guidelines: low-risk (clinical stage T1−T2a, Gleason Score (GS) ≤ 6, and Prostate-Specific Antigen (PSA) < 10), intermediate-risk (clinical stage T2b or T2c, GS of 7, or PSA of 10−20), and high-risk (clinical stage T3−T4, or GS of 8−10, or PSA > 20). Overall survival (OS) probability was determined using a Kaplan−Meier estimator. Univariate and multivariate analyses were performed by risk group for the six treatment modalities. Results: The most utilized treatment modality for all PCa patients was IMRT (53.1%). Over the years, a steady increase in SBRT utilization was observed, whereas BT HDR usage declined. IMRT-treated patient groups exhibited relatively lower survival probability in all risk categories. A slightly better survival probability was observed for the proton therapy group. Hormonal therapy was used for a large number of patients in all risk groups. Conclusion: This study revealed that IMRT was the most common treatment modality for PCa patients. Brachytherapy, SBRT, and IMRT+BT exhibited similar survival rates, whereas proton showed slightly better overall survival across the three risk groups. However, analysis of the demographics indicates that these differences are at least in part due to selection bias.

Dose uncertainty due to needle-tip localization error in prostate seed implantation.

Purpose: This study quantified the dosimetric uncertainty caused by needle-tip detection errors in ultrasound images due to bevel-tip orientation differences, with respect to the location on template grid. Material and methods: Trans-rectal ultrasound (TRUS) system with physical template grid and 18-gauge bevel-tip brachytherapy needles were used. TRUS was set at 6.5 MHz in water phantom, and measurements were taken with 50% and 100% B-mode TRUS gains. Needle-tip localization errors were then retrospectively applied back to 45 prostate seed implant plans to evaluate the important planning parameters for the prostate (D90, V100, V150, and V200), urethra (D10 and D30), and rectum (V100, D2cc, and D0.1cc), following the ABS and AAPM TG-137 guidelines. Results: The needle-tip detection errors for 50% and 100% TRUS gains were 3.7 mm (max) and 5.2 mm (max), respectively. The observed significant decrease in prostate coverage (mean D90 lower by 12.8%, and V100 lower by 3.9% for smaller prostates) after seed placements were corrected by compensating the needle-tip detection errors. Apex of the prostate was hotter, and the base was cooler. Dosimetric difference for urethral and rectal parameters were not statistically significant. Conclusions: This study revealed that the beveled needle-tip orientation could considerably impact the needle tips detection accuracy, based on which the seeds might be delivered. These errors can lead to significant dosimetric uncertainty in prostate seed implantation.

Roles of p53, NF-κB and the androgen receptor in controlling NGAL expression in prostate cancer cell lines.

Neutrophil gelatinase-associated lipocalin (NGAL a.k.a lipocalin 2, lnc2) is a secreted protein which can form a complex with matrix metalloproteinase-9 (MMP9). This MMP9/NGAL complex has been associated with metastasis. MMP9 and NGAL are detected in the urine of patients afflicted with many different types of cancer, including prostate cancer. The effects of p53, NF-κB and the androgen receptor (AR) on the expression of NGAL was examined in four prostate cancer cell lines. Prostate cancer cell lines that are AR negative and expressed either mutant or no p53 (DU145 and PC3) displayed higher levels of NGAL expression compared to the prostate cancer cell lines (LNCaP and 22Rv-1) which are AR positive and express wild type (WT) p53. Introduction of WT-p53 into the PC3 prostate cancer cell line, resulted in reduction of the levels of NGAL expression. Conversely, introduction of dominant negative (DN) p53 or a retroviral construct expressing NF-κB into LNCaP cells increased NGAL expression. NGAL expression had functional effects on the ability of the cells to form colonies in soft agar. Whereas suppression of WT-53 in LNCaP cells increased NGAL expression, the introduction of WT-p53 suppressed NGAL transcription activity in PC3 prostate cells which normally express high level of NGAL. NF-κB and p53 were determined to regulate NGAL expression by positive and negative mechanisms, respectively. Our data indicate that prostate cancer growth, progression and sensitivity to chemotherapeutic drugs are regulated in part by NGAL and may involve complex interactions between NGAL, MMP9, NF-κB and p53.

Induction chemotherapy for head and neck cancer: is there still a role?

Integration and optimization of active systemic agents and radiosensitizers into the therapeutic regimen for head and neck cancer remains a topic of active investigation. Recent trials have not consistently supported the use of induction chemotherapy. There are several clinical scenarios in which there is a strong rationale for induction chemotherapy, such as larynx preservation, unfavorable sites and bulky locally advanced disease. The increasing prevalence of HPV-positive malignancies, impacts both interpretation of clinical research and the design of future trials. In the broad spectrum of this disease the prognosis is often dismal, with substantial room for improvement over current therapy. In the face of conflicting clinical data, we address the question of whether there remains a role for induction chemotherapy.

Tolerance of Superficial Dose to Setup Error With Tomotherapy: Is a Skin Flash Tool Required?

BACKGROUND: In cancers of the head and neck, gross tumor or areas at risk of microscopic disease often lie close to the skin, while the skin itself may not be at risk. With intensity-modulated radiotherapy, setup errors can lead to underdosage of superficial structures because the collimator will not by default open beyond the skin surface to apply coverage in the air overlying the skin. Thus, small setup errors can move superficial structures out of field for some beams. Some planning systems allow for manually extrapolating fluence for beams tangential to superficial targets. It is unclear whether this problem is significant with tomotherapy. METHODS: A head and neck phantom was utilized. A 3-mm bolus was used to represent the skin and allow placement of dosimeters at 3 mm depth. Thermoluminescent dosimeters were placed at reproducible points on the skin surface and at 3 mm depth. The phantom was irradiated, with the target volume deep to the thermoluminescent dosimeters receiving a dose of 5 Gy. This process was repeated with the phantom displaced 2.5 mm and again with a displacement of 5 mm. These displacements simulated setup errors that in clinical practice would correspond to bending or twisting of the neck that could not be corrected with rotations or translations. RESULTS: When the phantom was displaced 2.5 mm, the dose measured at 3 mm depth was 99.2% (95.9%-102.5%) of the control. With a 5-mm displacement, the dose at 3 mm only dropped to 91.1% (88.8%-93.4%) of the control. Dose measured at skin surface decreased to a greater degree with such setup error. CONCLUSIONS: Dose at superficial depths degraded only slightly with 2.5-mm and even 5-mm displacements. With the tomotherapy system, superficial dose appears to be robust to clinically relevant setup errors. However, if the skin is at risk, bolus should be used to ensure adequate coverage.

Radiotherapy in the management of pancreatic neuroendocrine tumors (PNET): experience at three institutions.

AIM: Advanced pancreatic neuroendocrine tumor (PNET) presents a therapeutic challenge as many are unresectable and relatively resistant to systemic therapy with a high malignant potential. We share our experience using concurrent capecitabine or infusional 5-fluorouracil with radiation for patients with resected and locally advanced PNET. PATIENTS AND METHODS: Six patients (two females, four males) with PNET were treated with capecitabine or infusional 5-FU and concurrent radiation. RESULTS: The median age was 52 years (range: 38 to 63 years), with ECOG Performance Status (PS) 0-1, grade 0-1 weight loss, and grade 0-1 pain. One patient underwent resection with negative margins, two with positive margins, and three had unresectable locally advanced disease. All six patients demonstrated partial radiographic response and sustained local control. The treatment was tolerable with only grade 2 hand-foot syndrome and grade 1 mucositis observed. CONCLUSION: Prospective studies to further investigate the role of chemoradiation in this setting are warranted.

Variation of neck position with image-guided radiotherapy for head and neck cancer.

PURPOSE: An understanding of the setup variation of the low neck in relation to the upper neck is necessary to define appropriate planning margins, while treating the full neck with intensity-modulated radiotherapy (IMRT) technique. MATERIALS AND METHODS: The setup of 20 sequential head and neck cancer patients was studied. Daily position verification was performed with a computed tomography (CT) on rails. An upper neck point was defined as the anterior-most portion of the cervical spine on the lowest CT cut on which both styloid processes are visible. A low neck point was defined as the anterior-most portion of the cervical spine on the lowest CT cut on which the thyroid gland was visible bilaterally. This procedure was carried out on the planning CT and on each daily treatment CT. The variation of the low neck was analyzed, assuming perfect alignment of the upper neck anatomy. RESULTS: Daily treatment CT of upper neck anterior cervical spine points were normalized to the planning CT. Relative to this coordinate system, the low neck cervical spine point was displaced an average of 3.08 mm anteriorly, ±0.17 mm. There was no systematic lateral or craniocaudal displacement. Random setup errors resulted in low neck standard deviations of 3.9 mm (anteroposterior), 3.3 mm (lateral), and 2.6 mm (craniocaudal). CONCLUSIONS: Position variation in the low neck varied in excess of the planning margins. There was a systematic anterior displacement. Random setup error was greater than expected. The results suggest that the neck volumes located distant from the region of fusion should be drawn with larger planning margins.

Identification of prognostic and predictive markers in pancreatic adenocarcinoma. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011.

Pancreatic cancer remains a significant cause of morbidity and mortality. While increasing treatment options have improved outcomes for many patients, they have also complicated decision-making for treatment. Unfortunately, most patients with pancreatic cancer die from their disease. Prognostic and predictive markers could play a role to improve treatment by identifying patients who may or may not require a given therapy, and determining those most likely to benefit from a therapy. At the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium held in San Francisco, January 2011, several interesting abstracts were presented that focused on prognostic and predictive markers associated with pancreatic adenocarcinomas. These abstracts discuss progress made in identifying molecular subtypes of pancreatic cancers that may provide insight into selection of patients likely to benefit from certain therapies.

Emerging MEK inhibitors.

IMPORTANCE OF THE FIELD: The Ras/Raf/MEK/ERK pathway is often activated by genetic alterations in upstream signaling molecules. Integral components of this pathway such as Ras and B-Raf are also activated by mutation. The Ras/Raf/MEK/ERK pathway has profound effects on proliferative, apoptotic and differentiation pathways. This pathway can often be effectively silenced by MEK inhibitors. AREAS COVERED BY THIS REVIEW: This review will discuss targeting of MEK which could lead to novel methods to control abnormal proliferation which arises in cancer and other proliferative diseases. This review will cover the scientific literature from 1980 to present and is a follow on from a review which focused on Emerging Raf Inhibitors published in this same review series. WHAT THE READER WILL GAIN: By reading this review the reader will understand the important roles that genetics play in the response of patients to MEK inhibitors, the potential of combining MEK inhibitors with other types of therapy, the prevention of cellular aging and the development of cancer stem cells. TAKE HOME MESSAGE: Targeting MEK has been shown to be effective in suppressing many important pathways involved in cell growth and the prevention of apoptosis. MEK inhibitors have many potential therapeutic uses in the suppression of cancer, proliferative diseases and aging.

Emerging Raf inhibitors.

BACKGROUND: The Raf/MAPK kinase/extracellular-signal-regulated kinase pathway is often activated by genetic alterations in upstream signaling molecules. An integral component of this pathway, BRAF, is also activated by mutation, especially in melanoma and thyroid cancers. The Raf/MAPK kinase/extracellular-signal-regulated kinase pathway has profound effects on proliferative, apoptotic and differentiation pathways as well as the sensitivity and resistance to chemotherapeutic drugs. OBJECTIVES/METHODS: This review discusses targeting of Raf which could control abnormal proliferation in cancer and other proliferative diseases. The important roles that genetics plays in the response of patients to Raf inhibitors is also evaluated. We also discuss the rationales for approaches combining Raf inhibitors and chemotherapeutic drugs. RESULTS/CONCLUSIONS: Various Raf inhibitors have been developed and are being clinically used to treat patients with melanoma, thyroid, hepatocellular and renal cell cancers. Some 'Raf-kinase inhibitors' affect other kinases which are also expressed on malignant cells; yet, these inhibitors have proven useful in the therapy of certain cancer patients. Other more recently developed Raf specific inhibitors have shown success in the treatment of tumors bearing Raf mutations. The development of Raf inhibitors has significantly advanced cancer therapy in the past decade.

Dose optimization of breast balloon brachytherapy using a stepping 192Ir HDR source.

There is a considerable underdosage (11%-13%) of PTV due to anisotropy of a stationary source in breast balloon brachytherapy. We improved the PTV coverage by varying multiple dwell positions and weights. We assumed that the diameter of spherical balloons varied from 4.0 cm to 5.0 cm, that the PTV was a 1-cm thick spherical shell over the balloon (reduced by the small portion occupied by the catheter path), and that the number of dwell positions varied from 2 to 13 with 0.25-cm steps, oriented symmetrically with respect to the balloon center. By assuming that the perfect PTV coverage can be achieved by spherical dose distributions from an isotropic source, we developed an optimization program to minimize two objective functions defined as: (1) the number of PTV-voxels having more than 10% difference between optimized doses and spherical doses, and (2) the difference between optimized doses and spherical doses per PTV-voxel. The optimal PTV coverage occurred when applying 8-11 dwell positions with weights determined by the optimization scheme. Since the optimization yields ellipsoidal isodose distributions along the catheter, there is relative skin sparing for cases with source movement approximately tangent to the skin. We also verified the optimization in CT-based treatment planning systems. Our volumetric dose optimization for PTV coverage showed close agreement to linear or multiple-points optimization results from the literature. The optimization scheme provides a simple and practical solution applicable to the clinic.

Locally advanced pancreatic cancer: a review.

It is anticipated that there will be 37,170 new cases of pancreatic cancer diagnosed in the United States this year, resulting in approximately 33,370 deaths from the disease. Approximately 40% of these patients will present with locally advanced, non-metastatic disease. Treatment regimens that incorporate conventional radiation therapy for local tumor control, and chemotherapy to prevent distant failure in this metastasis-prone malignancy, are the current standard of care. A number of clinical studies have been undertaken to establish the optimal definitive chemoradiation treatment in this setting. Other potential treatment strategies include chemoradiation incorporating novel chemotherapeutic agents, intraoperative radiation therapy, brachytherapy, and the integration of combined therapies that utilize targeted molecular agents. This review summarizes the current status, controversies, and future prospects for the treatment of locally advanced pancreatic cancer.

Intensity modulation with respiratory gating for radiotherapy of the pleural space.

We wanted to describe a technique for the implementation of intensity-modulated radiotherapy (IMRT) with a real-time position monitor (RPM) respiratory gating system for the treatment of pleural space with intact lung. The technique is illustrated by a case of pediatric osteosarcoma, metastatic to the pleura of the right lung. The patient was simulated in the supine position where a breathing tracer and computed tomography (CT) scans synchronized at end expiration were acquired using the RPM system. The gated CT images were used to define target volumes and critical structures. Right pleural gated IMRT delivered at end expiration was prescribed to a dose of 44 Gy, with 55 Gy delivered to areas of higher risk via simultaneous integrated boost (SIB) technique. IMRT was necessary to avoid exceeding the tolerance of intact lung. Although very good coverage of the target volume was achieved with a shell-shaped dose distribution, dose over the targets was relatively inhomogeneous. Portions of target volumes necessarily intruded into the right lung, the liver, and right kidney, limiting the degree of normal tissue sparing that could be achieved. The radiation doses to critical structures were acceptable and well tolerated. With intact lung, delivering a relatively high dose to the pleura with acceptable doses to surrounding normal tissues using respiratory gated pleural IMRT is feasible. Treatment delivery during a limited part of the respiratory cycle allows for reduced CT target volume motion errors, with reduction in the portion of the planning margin that accounts for respiratory motion, and subsequent increase in the therapeutic ratio.

Doppler broadening effect on low-energy photon dose calculations using MCNP5 and PENELOPE.

Recent releases of the MCNP5 and PENELOPE Monte Carlo codes include the transport algorithm and momentum profiles that are necessary for accounting for Doppler broadening in Compton scattering processes. Such improvements might be particularly important in low-energy photon dose calculations. MCPLIB04 and PENDBASE (PENELOPE photon dataset) are based on the EPDL97 library with Compton momentum profiles, while MCPLIB03 and MCPLIB02 are based on the 1970's old library, with MCPLIB03 including the Compton momentum profiles. To isolate the dosimetric effects of Doppler broadening by the transport algorithm and Compton momentum profiles, we varied the choice of the above photon databases, in the same simulation geometry, using either version of MCNP5 or MCNP4 (no Doppler algorithm). We computed dose rate constants and dose distributions for r = 0.2-10 cm from a point source in a 50-cm-diameter sphere of water. Nine discrete energies for primary photon sources were chosen in the range of 10-150 keV. The results from both versions of MCNP with MCPLIB04 agreed with those of PENELOPE within statistical uncertainties (+/-1%) over the entire ranges of energies and radial distances investigated. MCNP5 with either MCPLIB03 or MCPLIB02 yielded almost identical data within statistical uncertainties (+/-1%) over the entire ranges of energies and radial distances investigated. This implies that in spite of the spectral broadening of scattered photons due to the orbital electron motion, the dosimetric effect of Doppler broadening for Compton interactions in water appears to be insignificant in the energy range investigated. The spectral dose analysis with and without the Doppler broadening supported this conclusion.

Intensity-modulated radiotherapy (IMRT) for carcinoma of the maxillary sinus: a comparison of IMRT planning systems.

The treatment of maxillary sinus carcinoma with forward planning can be technically difficult when the neck also requires radiotherapy. This difficulty arises because of the need to spare the contralateral face while treating the bilateral neck. There is considerable potential for error in clinical setup and treatment delivery. We evaluated intensity-modulated radiotherapy (IMRT) as an improvement on forward planning, and compared several inverse planning IMRT platforms. A composite dose-volume histogram (DVH) was generated from a complex forward planned case. We compared the results with those generated by sliding window fixed field dynamic multileaf collimator (MLC) IMRT, using sets of coplanar beams. All setups included an anterior posterior (AP) beam, and 3-, 5-, 7-, and 9-field configurations were evaluated. The dose prescription and objective function priorities were invariant. We also evaluated 2 commercial tomotherapy IMRT delivery platforms. DVH results from all of the IMRT approaches compared favorably with the forward plan. Results for the various inverse planning approaches varied considerably across platforms, despite an attempt to prescribe the therapy similarly. The improvement seen with the addition of beams in the fixed beam sliding window case was modest. IMRT is an effective means of delivering radiotherapy reliably in the complex setting of maxillary sinus carcinoma with neck irradiation. Differences in objective function definition and optimization algorithms can lead to unexpected differences in the final dose distribution, and our evaluation suggests that these factors are more significant than the beam arrangement or number of beams.

Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck.

BACKGROUND: We conducted a multinational, randomized study to compare radiotherapy alone with radiotherapy plus cetuximab, a monoclonal antibody against the epidermal growth factor receptor, in the treatment of locoregionally advanced squamous-cell carcinoma of the head and neck. METHODS: Patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy. The primary end point was the duration of control of locoregional disease; secondary end points were overall survival, progression-free survival, the response rate, and safety. RESULTS: The median duration of locoregional control was 24.4 months among patients treated with cetuximab plus radiotherapy and 14.9 months among those given radiotherapy alone (hazard ratio for locoregional progression or death, 0.68; P=0.005). With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone (hazard ratio for death, 0.74; P=0.03). Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P=0.006). With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups. CONCLUSIONS: Treatment of locoregionally advanced head and neck cancer with concomitant high-dose radiotherapy plus cetuximab improves locoregional control and reduces mortality without increasing the common toxic effects associated with radiotherapy to the head and neck. (ClinicalTrials.gov number, NCT00004227.)

Adenoviral vector-mediated augmentation of epidermal growth factor receptor (EGFr) enhances the radiosensitization properties of anti-EGFr treatment in prostate cancer cells.

PURPOSE: To determine whether an adenoviral vector approach to the augmentation of epidermal growth factor receptor (EGFr) expression results in increased antiproliferative and radiosensitization properties of anti-EGFr antibody therapy in prostate cancer cells. METHODS AND MATERIALS: DU145 and LNCaP human prostate cancer cells were used to test the above question in vitro. An adenoviral vector was utilized to transduce cells with an EGFr transgene (AdEGFr). Immunoblots were performed to measure EGFr expression and EGFr tyrosine phosphorylation. Radiolabeled ligand studies were employed to test binding of epidermal growth factor to EGFr. Scatchard analyses allowed for quantification of the number of EGFrs. Standard immunohistochemistry was performed to assess EGFr expression. Cellular proliferation was assessed after various combinations of treatment. RESULTS: Studies of prostate carcinoma cells infected with AdEGFr demonstrated an increase in EGFr expression. This increase in expression correlated with increased function of EGFr. Specifically, increased EGFr expression also resulted in increased ligand binding, ligand-induced internalization of EGFr, and ligand-induced EGFr tyrosine kinase activity that could be blocked with pre-exposure to IMC-C225 (an anti-EGFr monoclonal antibody). Transduction of the LNCaP cells with AdEGFr did not increase the antiproliferative effects of IMC-C225, but did significantly increase IMC-C225-induced radiosensitization as determined by cell proliferation. CONCLUSIONS: Augmentation of EGFr expression, through an adenoviral vector approach in prostate carcinoma cells, resulted in cells that demonstrated greater IMC-C225-induced radiosensitization compared to cells that were not treated with AdEGFr.

Sequential annealing-gradient Gamma-Knife radiosurgery optimization.

Simulated annealing and gradient methods are commonly employed for inverse planning of radiotherapy delivery schemes. Annealing is effective in finding an approximation of the global solution, suffering from slow late convergence and in some cases poor dose homogeneity. Gradient methods converge well but not necessarily to the global minimum. We explored simulated annealing followed by gradient optimization to improve on either method alone, using radiosurgery as the model system. Simulated annealing and gradient inverse planning programs using the same objective function were adapted for radiosurgical optimization. The objective function chosen is a least-squares dose-matching function, with differential weighting of tissues. A simple test target allowing local minima in the objective function was evaluated. Two hundred trials using the gradient method were done. The gradient method approximated the global solution only 12% of the time, commonly finding a local minimum. The annealing-gradient technique converged to the global minimum in 78 out of 80 trials, more efficiently than annealing alone. Dose homogeneity was improved. In conclusion, sequential annealing-gradient optimization can improve on either method alone. The technique may be extensible to radiotherapy inverse planning in general, with benefit expected for problems characterized by slow gradient method convergence and local minima.

Molecular targets as therapeutic strategies in the management of breast cancer.

Although the molecular and genetic determinants of most sporadic breast cancers remain unknown, increasing understanding of molecular and genetic events affecting breast carcinogenesis has provided information about the potential roles of specific biomarkers in tumour development and spread. It is now recognised that mutations of some tumour suppressor genes appear to play important early roles in the formation of some breast cancers. In addition, alterations in proto-oncogenes may contribute to the development of some breast cancers. The study of breast tumour biology at the molecular level has led to the development of targeted drug design, which provides a variety of agents targeted at specific molecules for the prevention, diagnosis and treatment of breast cancer. This review will describe the recognised molecular targets in breast cancer.

Tumor control probability for selective boosting of hypoxic subvolumes, including the effect of reoxygenation.

PURPOSE: To study the effect on tumor control probability of selectively boosting the dose to hypoxic subvolumes. METHODS AND MATERIALS: A Monte Carlo model was developed that separates the tumor into two compartments, one of which receives a primary dose, and one of which receives a higher boost dose. During radiation delivery, each compartment consists of three clonogen subpopulations: those that are well oxygenated, those that are temporarily hypoxic (geometrically transient hypoxia), and those that are permanently hypoxic (geometrically stable hypoxia). The spatial location of temporary hypoxia within the tumor volume varies over time, whereas, the spatial location of permanent hypoxia does not. The effect of reoxygenation was included. Clonogen proliferation was not included in the model. RESULTS: A modest boost dose (120%-150% of the primary dose) increases tumor control probability to that found in the absence of permanent hypoxia. The entire hypoxic subvolume need not be included to obtain a significant benefit. However, only tumors with a geometrically stable hypoxic volume will have an improved control rate. CONCLUSIONS: Tumors with an identifiable geometrically stable hypoxic volume will have an improved control rate if the dose to the hypoxic volume is escalated. Further work is required to determine the spatiotemporal evolution of the hypoxic volumes before and during the course of radiotherapy.