The role of radiotherapy in the management of squamous cell cancer of the penis.

PURPOSE: To review the evidence for radiotherapy in the management of primary penile cancer, either as brachytherapy or external beam radiation, and the role of external beam radiotherapy in node positive penile cancer. METHODS: English language literature was reviewed for the past 3 decades. As penile cancer is uncommon in developed nations, high quality evidence to guide management is limited. Single institution reports often span decades during which time staging systems and treatments have evolved, reducing their relevance to current practice. Successful clinical trials require collaboration not only among disciplines but also among multiple institutions and nations. RESULTS: Radiotherapy is a definitive organ-preserving option for T1-T2 penile cancers. Interstitial brachytherapy is associated with penile preservation in 85% of men at 5 years, maintained in 70% by 10 years. Results of external radiotherapy are not quite as promising but nonetheless 60% of men will have an intact penis at 5 years. Inguino-pelvic external radiotherapy has been reported to increase overall survival when delivered as adjuvant treatment for men with pN3 groin but pN0 pelvic nodes, and improve disease specific survival for those with involved pelvic nodes. InPACT (ECOG-ACRIN_8134) is investigating the role of inguino-pelvic chemo-radiotherapy for men with pN3 inguinal nodes but imaging negative pelvic nodes. CONCLUSIONS: Radiotherapy has a well-defined role to play in treatment of squamous cell cancers of other sites, such as vulva, anal canal, uterine cervix and head and neck malignancies. Emerging data support the incorporation of radiotherapy into treatment paradigms for penile cancer.

Interpreting Testosterone and Concomitant Prostate Specific Antigen Values during Androgen Deprivation Therapy for Recurrent Prostate Cancer.

PURPOSE: Measurement of testosterone levels during androgen deprivation therapy (ADT) is broadly recommended, but how therapy should be altered in response to testosterone values during ADT remains controversial. Our objective was therefore to evaluate the relation between testosterone and concomitant prostate specific antigen (PSA) levels during ADT on clinical outcomes. MATERIALS AND METHODS: Patients from the continuous androgen deprivation arm of the PR.7 trial of intermittent ADT for biochemically recurrent prostate cancer following radiotherapy were included. Statistical analyses evaluated the prognostic importance of testosterone levels during ADT relative to concomitant PSA levels. We similarly evaluated whether the number of testosterone breakthroughs >1.7 nmol/l predicted the time to castrate-resistant prostate cancer (CRPC), cancer specific survival (CSS) or overall survival (OS) with Kaplan-Meier and Cox regression analyses. RESULTS: Overall, the prognostic importance of testosterone on outcomes was eclipsed by the prognostic value of concomitant PSA values. The occurrence of testosterone values >0.7 nmol/l in the first year of therapy was associated with subsequent rises >1.7 nmol/l, but the number of testosterone breakthroughs per patient had no relationship to the risk of CRPC, CSS or OS. A time-dependent adjusted analysis indicated as expected that PSA values were prognostic, but there was no association of relative cumulative testosterone exposure with outcomes. CONCLUSIONS: In this large-scale trial with long followup, breakthrough testosterone was unrelated to time to CRPC, CSS or OS. Castrate testosterone values during ADT for recurrent prostate cancer provides prognostic information that must be considered alongside the time since ADT initiation and concomitant PSA values.

Long-Term Prostate Specific Antigen Stability and Predictive Factors of Failure after Permanent Seed Prostate Brachytherapy.

PURPOSE: Defining biochemical failure as nadir + 2 may overestimate cure after radiotherapy. We assessed long-term prostate specific antigen stability after low dose rate prostate brachytherapy and predictors of biochemical failure when prostate specific antigen was slowly rising below the nadir + 2 ng/ml threshold. MATERIALS AND METHODS: A total of 2,339 patients with low or intermediate risk prostate cancer received 125iodine brachytherapy from 1998 to 2010 with a minimum 3-year followup. In addition, 49.7% of the patients received 6 months of androgen deprivation. Clinical, dosimetric and prostate specific antigen data were retrieved from a prospective database. Biochemical results were classified as stable or rising prostate specific antigen (0.2 ng/ml or greater and increased 0.1 ng/ml or greater during the preceding 2 years), or biochemical failure (defined as nadir + 2). Multivariate analysis was done to identify predictors of failure used to create logistic regression models. RESULTS: At a median followup of 89 months (range 37 to 199) prostate specific antigen was stable (nadir 0.03 ng/ml and at 60 months 0.04 ng/ml) in 2,004 patients (86%) and rising (nadir 0.16 ng/ml and at 60 months 0.29 ng/ml) in 145 (6%) while biochemical failure (nadir 0.51 ng/ml, p <0.001) was noted in 190 (8%). When there was no prior androgen deprivation therapy, the prostate specific antigen nadir and prostate specific antigen at 60 months were the strongest predictors of failure (OR 20.6 and 18.3, respectively, each p <0.0001). The logistic regression model had 85% sensitivity and 98% specificity, and predicted failure in 8 of 82 men (9.8%). A second model was created for the group with androgen deprivation therapy and rising prostate specific antigen using the predictive factors prostate specific antigen at 60 months (OR 53.9, p <0.0001) and T stage (OR 0.25, p = 0.0008). This model predicted biochemical failure in 30 of 56 men (54%) with 85% sensitivity and 93% specificity. The 2 predictive models yield an anticipated 90% cure rate in the entire cohort. CONCLUSIONS: Brachytherapy is highly curative with stable prostate specific antigen at a surgical ablation level in 86% of patients. Rising prostate specific antigen is rare at a 6% incidence and often innocuous.

Radiotherapy approaches for locally advanced penile cancer: neoadjuvant and adjuvant.

PURPOSE OF REVIEW: As penile cancer is an uncommon malignancy in the Western society, randomized trials to address the controversies in management have not previously been undertaken. The incorporation of multidisciplinary approaches in the management of advanced penile carcinoma has largely borrowed evidence from analogous malignancies in the anogenital region. This review is being undertaken in preparation for the international launch of InPACT, the International Penile Advanced Cancer Trial, a collaborative effort from European and North American trialists. RECENT FINDINGS: The literature supporting the development of this trial is reviewed, along with the trial design, goals, and endpoints. Level one evidence of the benefits of combined chemo-radiotherapy in the management of squamous cell carcinoma of the cervix, oropharynx, vulva, and anal canal has led to the introduction of this approach for advanced penile cancer. InPACT will compare chemo-radiotherapy to the traditional surgical approach, with or without neoadjuvant chemotherapy. SUMMARY: InPACT will define the roles and optimal sequencing of surgery, chemotherapy, and radiotherapy in advanced penile cancer. In the meantime, this collaborative effort among the major research consortiums of Europe and North America lends credibility to the application of this evidence to the penile site.

Target volume definition for post prostatectomy radiotherapy: Do the consensus guidelines correctly define the inferior border of the CTV?

AIM: We compare urethrogram delineation of the caudal aspect of the anastomosis to the recommended guidelines of post prostatectomy radiotherapy. BACKGROUND: Level one evidence has established the indications for, and importance of, adjuvant radiotherapy following radical prostatectomy. Several guidelines have recently addressed delineation of the prostate bed target volume including identification of the vesico-urethral anastomosis, taken as the first CT slice caudal to visible urine in the bladder neck. The inferior border of clinical target volume is then variably defined 5-12 mm below this anastomosis or 15 mm cranial to the penile bulb. METHODS AND MATERIALS: Thirty-three patients who received adjuvant radiotherapy following radical prostatectomy were reviewed. All underwent planning CT with urethrogram. The authors (MM, JC) independently identified the CT slice caudal to the last slice showing urine in the bladder neck (called the CT Reference Slice), and measured the distance between this and the tip of the urethrogram cone. Five patients also had a diagnostic MRI at the time of CT planning to better visualize the anatomy. RESULTS: Sixty-six readings were obtained. The mean distance between the Bladder CT Reference Slice and the most cranial urethrogram contrast slice was 16.1 mm (MM 16.4 mm, JC 15.8 mm), range: 6.8-34.2 mm. The mean distance between the urethrogram tip and the ischial tuberosities was 19.9 mm (range 12.5-29.8 mm). The mean distance between the CT Reference Slice and the ischial tuberosities was 36.9 mm (range 28.3-52.4 mm). CONCLUSIONS: Guidelines for prostate bed radiation post prostatectomy have been developed after publication of the trials proving benefit of such treatment, and are thus untested. The anastomosis is a frequent site of local relapse but is variably defined by the existing guidelines, none of which take into account anatomic patient variation and all of which are at variance with urethrogram data. We recommend the use of planning urethrogram to better delineate the vesico-urethral junction and minimize the potential for geographic misses.

Intermittent androgen suppression for rising PSA level after radiotherapy.

BACKGROUND: Intermittent androgen deprivation for prostate-specific antigen (PSA) elevation after radiotherapy may improve quality of life and delay hormone resistance. We assessed overall survival with intermittent versus continuous androgen deprivation in a noninferiority randomized trial. METHODS: We enrolled patients with a PSA level greater than 3 ng per milliliter more than 1 year after primary or salvage radiotherapy for localized prostate cancer. Intermittent treatment was provided in 8-month cycles, with nontreatment periods determined according to the PSA level. The primary end point was overall survival. Secondary end points included quality of life, time to castration-resistant disease, and duration of nontreatment intervals. RESULTS: Of 1386 enrolled patients, 690 were randomly assigned to intermittent therapy and 696 to continuous therapy. Median follow-up was 6.9 years. There were no significant between-group differences in adverse events. In the intermittent-therapy group, full testosterone recovery occurred in 35% of patients, and testosterone recovery to the trial-entry threshold occurred in 79%. Intermittent therapy provided potential benefits with respect to physical function, fatigue, urinary problems, hot flashes, libido, and erectile function. There were 268 deaths in the intermittent-therapy group and 256 in the continuous-therapy group. Median overall survival was 8.8 years in the intermittent-therapy group versus 9.1 years in the continuous-therapy group (hazard ratio for death, 1.02; 95% confidence interval, 0.86 to 1.21). The estimated 7-year cumulative rates of disease-related death were 18% and 15% in the two groups, respectively (P=0.24). CONCLUSIONS: Intermittent androgen deprivation was noninferior to continuous therapy with respect to overall survival. Some quality-of-life factors improved with intermittent therapy. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00003653.).

The role of intermittent androgen deprivation therapy in the management of biochemically recurrent or metastatic prostate cancer.

Androgen deprivation therapy (ADT) is a well-established treatment for locally advanced, biochemically recurrent and metastatic prostate cancer. However, it is associated with significant side effects including hot flashes, loss of libido and erectile function, muscular atrophy, metabolic abnormalities, and osteoporosis. In attempt to mitigate the side effects of ADT while retaining the oncological benefits, an approach of intermittent ADT (IAD) has been investigated. IAD involves alternating periods of treatment with intervals off treatment to allow hormone recovery. PSA thresholds are triggers for withdrawing and reinitiating therapy. Potential advantages of IAD include improved quality of life with fewer side effects and reduced cost. Delays in the development of hormone resistance have not been demonstrated clinically. The appropriate use of IAD requires patient selection and close monitoring of quality of life and disease status. This review presents the most recent evidence on the role of IAD in the management of prostate cancer.

The prostate cancer risk stratification project: database construction and risk stratification outcome analysis.

This investigation reports on the biochemical and clinical outcomes of a newly created pan-Canadian Prostate Cancer Risk Stratification (ProCaRS) database developed by the Genitourinary Radiation Oncologists of Canada (GUROC). GUROC ProCaRS template-compliant data on 7974 patients who underwent radiotherapy were received from 7 unique databases. Descriptive analysis, Cox proportional hazards, and Kaplan-Meier analyses were performed using American Society for Radiation Oncology (ASTRO) biochemical failure-free survival (BFFS), prostate cancer-specific survival, and overall survival. Multivariable modeling for the primary ASTRO BFFS end point showed that age, prostate-specific antigen, T stage, and Gleason score and components such as hormonal therapy, and radiation treatment (brachytherapy with better outcome than external-beam) were predictive of outcome. Kaplan-Meier analysis of the existing GUROC and new NCCN classification system both showed good separation of all clinical outcome curves. The construction of a pan-Canadian database has informed important prostate cancer radiotherapy outcomes and risk stratification.

A postimplant dosimetry simulation framework for robustness evaluation in permanent breast seed implant brachytherapy.

BACKGROUND: Permanent breast seed implant (PBSI) brachytherapy is a promising treatment that has the potential to be widely utilized with increased standardization, optimization, and robustness. Excellent early efficacy and very high patient acceptance were reported, however, to further evaluate and improve planning strategies, a framework to quantify plan robustness to implant uncertainties is necessary. PURPOSE: In this study, we aim to quantify clinical seed displacement using an automated algorithm and develop and validate a PBSI post-implant dosimetry simulation framework to evaluate PBSI plan robustness to implant uncertainties. METHODS AND MATERIALS: Clinical PBSI seed displacements were quantified for 63 consecutive patients. A PBSI simulator was developed in Matlab (2020) by resampling clinical seed displacements and computing a range of possible post-implant dosimetry outcomes under various seed displacement scenarios. Simulations were performed retrospectively on 63 previous clinical plans to evaluate plan robustness to seed displacement. RESULTS: Mean seed displacement for the whole cohort was 10 ± 6 mm. A clinical seed displacement database was established and a user interface was developed for the simulation framework. For all clinical plans, the median (range) value of simulated median ETV V90 in various seed displacement scenarios was 97.8% (87.5-100%). CONCLUSIONS: A PBSI postimplant dosimetry simulation framework was developed and validated. Simulation results showed that the current PTV planning margin is sufficient to provide adequate postimplant dose coverage of ETV. This simulator can be used to evaluate plan robustness to seed displacement and will facilitate future research in improving PBSI planning methods.

Seed distribution stability in permanent breast seed implant brachytherapy.

PURPOSES: In this study we aim to quantitatively evaluate the stability of implanted seeds in permanent breast seed implant (PBSI) brachytherapy and assess any impact on treatment quality. METHODS AND MATERIALS: Sixty-seven consecutive patients who received PBSI treatment at BC Cancer Kelowna from 2013 to 2021 with post-implant CT images available were included in this study. For each patient, two sets of post-implant CT scans were retrospectively analyzed: Day0, obtained immediately after implant, and Day30, obtained approximately one month following implant. Seed distributions were quantified using the 90% isodose contour, outlier seed maximum spread, and number of seeds located in the seroma as well as seroma quadrants. These were then compared between Day0 and Day30. Post-implant dosimetry of target volumes as well as critical structures were compared. RESULTS: The 90% isodose volume was found to decrease over time. All seeds remained in the breast region however the maximum spread of seeds increased in all directions from Day0 to Day30. All recorded target volume dosimetric parameters were, on average, lower on Day30 compared to Day0 but mean dosimetry levels still met clinical goals. Dose in critical structures was overall similar. CONCLUSIONS: In this study, we quantitatively described the changes in seed distributions as well as dosimetry from Day0 to Day30 post PBSI procedure. We addressed concerns related to seed stability in breast tissue and provided clinical evidence on dosimetric efficacy of the PBSI technique.

Mortality reduction and cumulative excess incidence (CEI) in the prostate-specific antigen (PSA) screening era.

The extent to which PSA screening is related to prostate cancer mortality reduction in the United States (US) is controversial. US Surveillance, Epidemiology, and End Results Program (SEER) data from 1980 to 2016 were examined to assess the relationship between prostate cancer mortality and cumulative excess incidence (CEI) in the PSA screening era and to clarify the impact of race on this relationship. CEI was considered as a surrogate for the intensity of prostate cancer screening with PSA testing and subsequent biopsy as appropriate. Data from 163,982,733 person-years diagnosed with 544,058 prostate cancers (9 registries, 9% of US population) were examined. Strong inverse linear relationships were noted between CEI and prostate cancer mortality, and 317,356 prostate cancer deaths were avoided. Eight regions of the US demonstrated prostate cancer mortality reduction of 46.0-63.7%. On a per population basis, the lives of more black men than white men were saved in three of four registries with sufficient black populations for comparison. Factor(s) independent of CEI (potential effects of treatment advances) explained 14.6% of the mortality benefit (p-value = 0.3357) while there was a significant main effect of CEI (effect = -0.0064; CI: [-0.0088, -0.0040]; p-value < 0.0001). Therefore, there is a strong relationship between CEI and prostate cancer mortality reduction that was not related to factors independent of screening utilization. Minority populations have experienced large mortality reductions in the context of PSA mass utilization.

A Randomized Trial Comparing Quality of Life After Low-Dose Rate or High-Dose Rate Prostate Brachytherapy Boost With Pelvic External Beam Radiation Therapy.

PURPOSE: To compare health-related quality of life (QoL) in urinary, bowel, and sexual domains after combined external beam radiation therapy (EBRT) and either low-dose rate (LDR) or high-dose rate (HDR) prostate brachytherapy (BT). METHODS AND MATERIALS: Eligible men with intermediate or high-risk prostate cancer treated with combined pelvic EBRT and BT were randomly assigned to either HDR (15 Gy) or LDR (110 Gy) boost. International Prostate Symptom Score, Index of Erectile Function, and Expanded Prostate Cancer Composite were collected at baseline, 1, 3, 6, and 12 months, every 6 months to 3 years and then annually along with prostate-specific antigen/testosterone. Fisher's exact test compared categorical variables and the Mann-Whitney U test Expanded Prostate Cancer Index Composite (EPIC) domain scores. RESULTS: From January 2014 to December 2019, a random number generator assigned 195 men: 108 to HDR and 87 to LDR. Median age was 71 years. Risk group was high in 57% and unfavorable intermediate in 43%. Androgen deprivation (used in 74%) began with 3 months neoadjuvant and continued for median 12 months. Baseline EPIC scores were similar for the LDR/HDR cohorts: 89 and 88 respectively for Genito-urinary; 92 and 93 for Gastro-intestinal. EPIC urinary scores decreased at 1 month for HDR but recovered promptly to a steady state by 6 months. LDR scores reached a nadir at 3 months with slow recovery to 18 months, after which urinary QoL was similar for HDR and LDR. Bowel QOL scores fell in both cohorts reaching respective nadirs at 12 months. HDR patients recovered close to baseline and maintained higher scores than LDR patients to 5 years. The decline for LDR patients remained more than the minimum clinically important difference out to 5 years. CONCLUSIONS: The patient experience for combined EBRT and prostate BT is improved with HDR BT. Urinary QoL improves over time to be equivalent between the 2 modalities after 18 months, but LDR patients report lasting bowel symptoms.

Management of Lymph Node-positive Penile Cancer: A Systematic Review.

CONTEXT: Lymph node (LN) involvement in penile cancer is associated with poor survival. Early diagnosis and management significantly impact survival, with multimodal treatment approaches often considered in advanced disease. OBJECTIVE: To assess the clinical effectiveness of treatment options available for the management of inguinal and pelvic lymphadenopathy in men with penile cancer. EVIDENCE ACQUISITION: EMBASE, MEDLINE, the Cochrane Database of Systematic Reviews, and other databases were searched from 1990 to July 2022. Randomised controlled trials (RCTs), nonrandomised comparative studies (NRCSs), and case series (CSs) were included. EVIDENCE SYNTHESIS: We identified 107 studies, involving 9582 patients from two RCTs, 28 NRCSs, and 77 CSs. The quality of evidence is considered poor. Surgery is the mainstay of LN disease management, with early inguinal LN dissection (ILND) associated with better outcomes. Videoendoscopic ILND may offer comparable survival outcomes to open ILND with lower wound-related morbidity. Ipsilateral pelvic LN dissection (PLND) in N2-3 cases improves overall survival in comparison to no pelvic surgery. Neoadjuvant chemotherapy in N2-3 disease showed a pathological complete response rate of 13% and an objective response rate of 51%. Adjuvant radiotherapy may benefit pN2-3 but not pN1 disease. Adjuvant chemoradiotherapy may provide a small survival benefit in N3 disease. Adjuvant radiotherapy and chemotherapy improve outcomes after PLND for pelvic LN metastases. CONCLUSIONS: Early LND improves survival in nodal disease in penile cancer. Multimodal treatments may provide additional benefit in pN2-3 cases; however, data are limited. Therefore, individualised management of patients with nodal disease should be discussed in a multidisciplinary team setting. PATIENT SUMMARY: Spread of penile cancer to the lymph nodes is best managed with surgery, which improves survival and has curative potential. Supplementary treatment, including the use of chemotherapy and/or radiotherapy, may further improve survival in advanced disease. Patients with penile cancer with lymph node involvement should be treated by a multidisciplinary team.

Current concepts in penile cancer.

This review highlights the significant advances made in the diagnosis and management of penile cancer. This often-aggressive tumor phenotype has been characterized by its poor prognosis, mostly attributable to its late presentation and heterogeneity of surgical care because of the paucity of cases treated at most centers. Recent advances in understanding of the risk factors predisposing to penile cancer, including its association with the human papilloma virus (HPV), have brought forth the socioepidemiologic concept of HPV vaccination in certain high-risk populations and countries, which remains highly debated. The management of penile cancer has evolved in recent years with the adoption of penile-sparing and minimally invasive surgical approaches to the inguinal lymph nodes, which are a frequent site of regional spread for this malignancy. Lastly, this review highlights the importance of adopting a multimodal approach consisting of neoadjuvant systemic chemotherapy followed by consolidative surgical resection in patients presenting with bulky/locally advanced nodal metastases from penile cancer.

Interpreting a rising prostate-specific antigen after brachytherapy for prostate cancer.

The aim of the present study was to review the English language literature on the topic of prostate-specific antigen bounce after brachytherapy and present a summary of the current knowledge. Although ultimately prostate-specific antigen is a reliable measure of success after prostate brachytherapy, it can be very misleading in the first 3 years because of the frequency with which temporary benign rises in prostate-specific antigen occur. We have reviewed the English language literature on the topic of prostate-specific antigen bounce under the following headings: prostate neoplasms, brachytherapy, biochemical definition of prostate-specific antigen failure, "benign prostate-specific antigen bounce" and "prostate-specific antigen spike". We included brachytherapy delivered as either low dose rate or high dose rate, and either as monotherapy or as a boost combined with external beam radiotherapy. A benign self-limited rise in prostate-specific antigen after prostate brachytherapy is seen in an average of 35% of patients, but increases in frequency with younger age. In patients aged less than 55 years, it is observed in up to 68%. Other factors, such as sexual activity, dose, prostate volume and the use of high dose rate versus low dose rate have been implicated in affecting the frequency of the benign bounce. Benign increases in prostate-specific antigen are frequent after prostate brachytherapy. It is important to recognize and correctly diagnose this phenomenon in order to avoid unnecessary salvage treatment.

Treatment options for localized prostate cancer.

OBJECTIVE: To describe treatment options for clinically localized prostate cancer: radical prostatectomy, prostate brachytherapy, external beam radiation, and active surveillance. QUALITY OF EVIDENCE: Prostate-specific antigen (PSA) outcomes presented are from non-randomized, cohort, and other comparisons trials (level II evidence). We describe PSA outcomes from Canadian centres when they are available. One small randomized controlled trial (level I evidence) in localized prostate cancer is available to compare radical prostatectomy with brachytherapy. MAIN MESSAGE: Treatment choice in prostate cancer is based on initial PSA level, clinical stage of disease, and Gleason score, together with baseline urinary function, comorbidities, and patient age. In this article, we describe patients' eligibility for and the common side effects of all treatment options. Prostate brachytherapy and active surveillance have evolved as new standard treatments of localized prostate cancer. We give a brief overview of the brachytherapy procedure, side effects, and PSA outcomes across Canada, as well as active surveillance guidelines. CONCLUSION: Prostate cancer treatment requires a multidisciplinary approach, with input from both urology and radiation oncology. Input from family physicians is often as important in helping guide patients through the treatment decision process.

The role of intensity modulated radiotherapy in gynecological radiotherapy: Present and future.

AIM: This manuscript reviews the English language literature on the use of intensity modulated radiation therapy (IMRT) for gynecologic malignancies, focusing on the treatment cervical cancer. BACKGROUND: Radiation therapy plays a key role in both definitive and adjuvant treatment of these patients, although efforts continue to minimize acute and chronic toxicity. IMRT is an attractive option because of the potential to dose escalate to the target while sparing organs at risk. METHODS AND MATERIALS: The English language literature was reviewed for relevant studies. RESULTS: Multiple heterogeneous studies have showed dosimetric and clinical benefits with reduction in acute and late gastrointestinal, genitourinary and hematologic toxicity, especially in the post hysterectomy scenario and for dose escalation to para-aortic nodes. Consensus is evolving regarding necessary margins and target delineation in the context of organ movement and tumor shrinkage during the course of radiotherapy. Protocols with daily soft-tissue visualization are being investigated. CONCLUSIONS: Consistency in approach and reporting are vital in order to acquire the data to justify the considerable increased expense of IMRT.