The Application of Number Needed to Treat (NNT) to Clinical Problems in Radiotherapy

The goals of this report are: 1) to review the number needed to treat (NNT) concept, which, although well established in many sectors of medicine, is still relatively new to the radiotherapy community; 2) to discuss several clinical radiotherapy examples illustrating the inherent advantages of the NNT approach; and 3) to discuss potential future roles of the NNT concept within radiotherapy.     

The application of number needed to treat (NNT) to clinical problems in radiotherapy

The goals of this report are: 1) to review the number needed to treat (NNT) concept, which, although well established in many sectors of medicine, is still relatively new to the radiotherapy community; 2) to discuss several clinical radiotherapy examples illustrating the inherent advantages of the NNT approach; and 3) to discuss potential future roles of the NNT concept within radiotherapy.     

Hormone therapy and radiotherapy for early prostate cancer: a utility-adjusted number needed to treat (NNT) analysis

PURPOSE: To quantify, using the number needed to treat (NNT) methodology, the benefit of short-term (< or =6 months) hormone therapy adjuvant to radiotherapy in the group of patients with early (clinical stage T1-T2c) prostate cancer. METHODS AND MATERIALS: The absolute biochemical control benefit for the use of hormones adjuvant to radiotherapy in early-stage disease was determined by literature review. A model was developed to estimate the utility-adjusted survival detriment due to the side effects of hormone therapy. The NNTs before and after the incorporation of hormone sequelae were computed; the sign and magnitude of the NNTs were used to gauge the effect of the hormones. RESULTS: The absolute NNT analysis, based on summarizing the results of 8 reports including a total of 3652 patients, demonstrated an advantage to the addition of hormones for the general early-stage prostate cancer population as well as for all prognostic groups. After adjustment for hormone-induced functional loss, the advantage of hormones remained considerable in the high- and intermediate-risk groups, with the utility-adjusted NNT becoming weakened in the low-risk group when the utility compromise from complications of hormones was assumed to be considerable. CONCLUSIONS: Short-term hormone therapy seems to be beneficial for selected early-stage prostate cancer patients. The advantage seems to be greatest in the intermediate- and high-risk groups; with current follow-up, the side effects of hormones may outweigh their benefit in certain clinical situations in the favorable group. The present investigation demonstrates the significant role of the NNT technique for oncologic and radiotherapeutic management decisions when treatment complications need to be considered and balanced with the beneficial effects of the treatment.     

Early prostate cancer: hedonic prices model of provider-patient interactions and decisions

PURPOSE: To determine the relative influence of treatment features and treatment availabilities on final treatment decisions in early prostate cancer. METHODS AND MATERIALS: We describe and apply a model, based on hedonic prices, to understand provider-patient interactions in prostate cancer. This model included four treatments (observation, external beam radiotherapy, brachytherapy, and prostatectomy) and five treatment features (one efficacy and four treatment complication features). We performed a literature search to estimate (1) the intersections of the "bid" functions and "offer" functions with the price function along different treatment feature axes, and (2) the treatments actually rendered in different patient subgroups based on age. We performed regressions to determine the relative weight of each feature in the overall interaction and the relative availability of each treatment modality to explain differences between observed vs. predicted use of different modalities in different patient subpopulations. RESULTS: Treatment efficacy and potency preservation are the major factors influencing decisions for young patients, whereas preservation of urinary and rectal function is much more important for very elderly patients. Referral patterns seem to be responsible for most of the deviations of observed use of different treatments from those predicted by idealized provider-patient interactions. Specifically, prostatectomy is used far more commonly in young patients and radiotherapy and observation used far more commonly in elderly patients than predicted by a uniform referral pattern. CONCLUSIONS: The hedonic prices approach facilitated identifying the relative importance of treatment features and quantification of the impact of the prevailing referral pattern on prostate cancer treatment decisions.     

小靶区调强放疗治疗前列腺癌的临床疗效观察

目的 探讨小靶区调强放疗治疗期前列腺癌的疗效及安全性。方法 收集2006年1月至2010年6月间78例前列腺癌患者接受自定义小靶区调强放疗,DT 72.6 Gy,2.2 Gy／f,共33次。观察患者急性和慢性放射性反应、总生存时间（OS）、无生化复发率、无进展生存时间（PFS）、无远处转移率,Cox比例风险回归模型评价影响预后的危险因素。结果 小靶区定义和RTOG定义的肿瘤体积分别为（274.21±92.64）cm3和（600.68±113.72）cm³,差异有统计学意义（P＜0.05）。所有患者均能完成放疗计划,骨髓抑制以1级为主,急性泌尿系统损伤大多为1～2级,放射性肠道损伤以1级为主。随访截止于2014年12月31日,随访率为91.0％,患者的5年生存率、无进展生存率、无生化复发率和无远处转移率分别为82.1％、79.4％、84.6％和94.9％。年龄、PSA水平、ECOG评分、Gleason评分是影响患者OS和PFS的独立危险因素。结论 前列腺癌患者小靶区外照射生存率高,亦可减轻急慢性放射性反应,同时能保护患者的造血功能。     

Hypofractionated accelerated radiotherapy using concomitant intensity-modulated radiotherapy boost technique for localized high-risk prostate cancer: acute toxicity results

PURPOSE: To evaluate the acute toxicities of hypofractionated accelerated radiotherapy (RT) using a concomitant intensity-modulated RT boost in conjunction with elective pelvic nodal irradiation for high-risk prostate cancer. METHODS AND MATERIALS: This report focused on 66 patients entered into this prospective Phase I study. The eligible patients had clinically localized prostate cancer with at least one of the following high-risk features (Stage T3, Gleason score >/=8, or prostate-specific antigen level >20 ng/mL). Patients were treated with 45 Gy in 25 fractions to the pelvic lymph nodes using a conventional four-field technique. A concomitant intensity-modulated radiotherapy boost of 22.5 Gy in 25 fractions was delivered to the prostate. Thus, the prostate received 67.5 Gy in 25 fractions within 5 weeks. Next, the patients underwent 3 years of adjuvant androgen ablative therapy. Acute toxicities were assessed using the Common Terminology Criteria for Adverse Events, version 3.0, weekly during treatment and at 3 months after RT. RESULTS: The median patient age was 71 years. The median pretreatment prostate-specific antigen level and Gleason score was 18.7 ng/L and 8, respectively. Grade 1-2 genitourinary and gastrointestinal toxicities were common during RT but most had settled at 3 months after treatment. Only 5 patients had acute Grade 3 genitourinary toxicity, in the form of urinary incontinence (n = 1), urinary frequency/urgency (n = 3), and urinary retention (n = 1). None of the patients developed Grade 3 or greater gastrointestinal or Grade 4 or greater genitourinary toxicity. CONCLUSION: The results of the present study have indicated that hypofractionated accelerated RT with a concomitant intensity-modulated RT boost and pelvic nodal irradiation is feasible with acceptable acute toxicity.     

Five-year prospective patient evaluation of bladder and bowel symptoms after dose-escalated radiotherapy for prostate cancer with the BeamCath technique

PURPOSE: Late side effects were prospectively evaluated up to 5 years after dose-escalated external beam radiotherapy (EBRT) and were compared with a previously treated series with conventional conformal technique. METHODS AND MATERIALS: Bladder and bowel symptoms were prospectively evaluated with the Prostate Cancer Symptom Scale (PCSS) questionnaire up to 5 years posttreatment. In all, 257 patients completed the questionnaire 5 years posttreatment. A total of 168 patients were treated with the conformal technique at doses<71 Gy, and 195 were treated with the dose-escalated stereotactic BeamCath technique comprising three dose levels: 74 Gy (n=68), 76 Gy (n=74), and 78 Gy (n=53). RESULTS: For all dose groups analyzed together, 5 years after treatment, urinary starting problems decreased and urinary incontinence increased in comparison to baseline values. No increase in other bladder symptoms or frequency was detected. When comparing dose groups after 5 years, both the 74-Gy and 78-Gy groups reported increased urinary starting problems compared with patients given the conventional dose (<71 Gy). No increased incontinence was seen in the 76-Gy or the 78-Gy groups. Bowel symptoms were slightly increased during the follow-up period in comparison to baseline. Dose escalation with stereotactic EBRT (74-78 Gy) did not increase gastrointestinal late side effects after 5 years in comparison to doses<71 Gy. CONCLUSION: Dose-escalated EBRT with the BeamCath technique with doses up to 78 Gy is tolerable, and the toxicity profile is similar to that observed with conventional doses<71 Gy.     

Expression of vascular endothelial growth factor (VEGF) in locally invasive prostate cancer is prognostic for radiotherapy outcome

PURPOSE: Vascular endothelial growth factor (VEGF) is an important hypoxia-inducible pro-angiogenic protein that has been linked with an adverse survival outcome after radiotherapy in other cancer types: we hypothesized that this may also occur in prostate cancer. A retrospective study was, therefore, carried out to evaluate the potential of tumor VEGF expression to predict radiotherapy outcome in patients with high-risk prostate cancer. METHODS AND MATERIALS: Fifty patients with locally advanced (T3 N0 M0) tumors of Gleason score > or =6, and who received radiotherapy alone as primary treatment for their disease, were studied. Vascular endothelial growth factor expression was assessed on pretreatment diagnostic tumor biopsies using a semiquantitative immunohistochemical scoring system. The results were analyzed in relation to clinicopathologic factors and patient outcome including biochemical failure and disease-specific mortality. RESULTS: High VEGF expression was associated with a poor prognosis: in univariate log rank analysis, VEGF was the only significant prognostic factor for disease-specific survival (p = 0.035). High VEGF expression also associated with increased Gleason score (p = 0.02), but not posttreatment biochemical failure. CONCLUSION: High tumor expression of VEGF identified patients at high risk of failure of treatment with radiotherapy. These patients might benefit from additional treatment approaches incorporating anti-angiogenic or hypoxia-specific agents.     

Sildenafil citrate (Viagra) and erectile dysfunction following external beam radiotherapy for prostate cancer: a randomized, double-blind, placebo-controlled, cross-over study

Purpose: To determine the efficacy of sildenafil citrate (Viagra) in patients with erectile dysfunction after three-dimensional conformal external beam radiotherapy (3D-CRT) for prostate cancer.

Methods and Materials: 406 patients with complaints of erectile dysfunction and who completed radiation at least 6 months before the study were approached by mail. 3D-CRT had been delivered (mean dose 68 Gy). Sixty patients were included and entered a double-blind, placebo-controlled, cross-over study lasting 12 weeks. They received during 2 weeks 50 mg of sildenafil or placebo; at Week 2 the dose was increased to 100 mg in case of unsatisfactory erectile response. At Week 6, patients crossed over to the alternative treatment. Data were collected using the International Index of Erectile Function (IIEF) questionnaire, and side effects were recorded.

Results: Mean age was 68 years. All patients completed the study. For most questions of the IIEF questionnaire there was a significant increase in mean scores from baseline with sildenafil, but not with placebo. Ninety percent of the patients needed a dose adjustment to 100 mg sildenafil. Side effects were mild or moderate.

Conclusion: Sildenafil is well tolerated and effective in improving erectile function of patients with ED after 3D-CRT for prostate cancer.     

Isoprostane levels in the urine of patients with prostate cancer receiving radiotherapy are not elevated

PURPOSE: Previous studies have demonstrated that urinary 8-iso-prostaglandin F (PGF)2alpha serves as a powerful biomarker of lipid peroxidation in diseases in which oxidative stress plays an important role in its pathophysiology. The goal of this study was to measure the urinary isoprostane levels in patients with prostate cancer treated with radiotherapy (RT) in an effort to determine whether isoprostane levels are elevated compared with in historical controls, whether the levels increase after RT, and whether such an increase would correlate positively with the degree of GU symptoms during treatment. METHODS AND MATERIALS: Urine samples were obtained before and during RT from patients enrolled on a recently reported Phase III trial examining the therapeutic efficacy of ibuprofen in decreasing the acute urinary symptoms of RT. Radioimmunoassays were performed on urine samples for 8-iso-PGF2alpha or 15-keto-dihydro-PGF2alpha. RESULTS: Fifteen patients provided samples both before and during RT. The levels of 8-iso-PGF(2alpha) and 15-keto-dihydro-PGF2alpha in the urine samples obtained before prostate RT (0.27 and 0.41 nmol/mmol creatinine) did not differ appreciably from the values observed in a normal cohort (0.27 and 0.46 nmol/mmol creatinine) and did not change after RT (0.23 and 0.37 nmol/mmol creatinine). CONCLUSION: We were unable to detect an increase in either 8-iso-PGF2alpha or 15-keto-dihydro-PGF2alpha in the urine of patients with prostate cancer compared with in historical normal controls. We were also unable to measure an increase in either of the eicosanoids during RT to the prostate gland.     

TGFB1 single nucleotide polymorphisms are associated with adverse quality of life in prostate cancer patients treated with radiotherapy

PURPOSE: To investigate whether the presence of single nucleotide polymorphisms (SNPs) located within TGFB1 might be predictive for the development of adverse quality-of-life outcomes in prostate cancer patients treated with radiotherapy. METHODS AND MATERIALS: A total of 141 prostate cancer patients treated with radiotherapy were screened for SNPs in TGFB1 using DNA sequencing. Three quality-of-life outcomes were investigated: (1) prospective decline in erectile function, (2) urinary quality of life, and (3) rectal bleeding. Median follow-up was 51.3 months (range, 12-138 months; SD, 24.4 months). RESULTS: Those patients who possessed either the T/T genotype at position -509, the C/C genotype at position 869 (pro/pro, codon 10) or the G/C genotype at position 915 (arg/pro, codon 25) were significantly associated with the development of a decline in erectile function compared with those who did not have these genotypes: 56% (9 of 16) vs. 24% (11 of 45) (p = 0.02). In addition, patients with the -509 T/T genotype had a significantly increased risk of developing late rectal bleeding compared with those who had either the C/T or C/C genotype at this position: 55% (6 of 11) vs. 26% (34 of 130) (p = 0.05). CONCLUSIONS: Possession of certain TGFB1 genotypes is associated with the development of both erectile dysfunction and late rectal bleeding in patients treated with radiotherapy for prostate cancer. Therefore, identification of patients harboring these genotypes may represent a means to predict which men are most likely to suffer from poor quality-of-life outcomes after radiotherapy for prostate cancer.     

A modelled comparison of prostate cancer control rates after high-dose-rate brachytherapy (3145 multicentre patients) combined with,or in contrast to,external-beam radiotherapy

Background and purpose

To analyse biochemical relapse-free-survival results for prostate cancer patients receiving combined external beam and high-dose-rate brachytherapy, in comparison with expected results using projections based on dose/fractionation/response parameter values deduced from a previous external-beam-alone 5969-patient multicentre dataset.

Material and methods

Results on a total of 3145 prostate cancer patients receiving brachytherapy (BT) as part or all of their treatment were collected from 10 institutions, and subjected to linear-quadratic (LQ) modelling of dose response and fractionation parameters.

Results

Treatments with BT components of less than 25 Gy, 3–4 BT fractions, doses per BT fraction up to 6 Gy, and treatment times of 3–7 weeks, all gave outcomes expected from LQ projections of the external-beam-alone data (α/β = 1.42 Gy). However, BT doses higher than 30 Gy, 1–2 fractions, 9 fractions (BT alone), doses per fraction of 9–15 Gy, and treatment in only 1 week (one example), gave local control levels lower than the expected levels by up to ∼35%.

Conclusions

There are various potential causes of the lower-than-projected control levels for some schedules of brachytherapy: it seems plausible that cold spots in the brachytherapy dose distribution may be contributory, and the applicability of the LQ model at high doses per fraction remains somewhat uncertain. The results of further trials may help elucidate the true benefit of hypofractionated high-dose-rate brachytherapy.     

Prostate-specific antigen kinetics following external-beam radiotherapy and temporary (Ir-192) or permanent (I-125) brachytherapy for prostate cancer

Background and purpose

The aim of the study was the evaluation of PSA kinetics after different radiotherapy methods.

Materials and methods

Two-hundred and ninety five patients received external-beam radiotherapy (EBRT; 70.2 Gy; n = 135), Ir-192 brachytherapy as a boost to EBRT (HDR-BT; 18 Gy + 50.4 Gy; n = 66) or I-125 brachytherapy (LDR-BT; 145 Gy; n = 94) as monotherapy. “PSA bounce” was defined as a PSA rise of ?0.2 ng/ml followed by spontaneous return to prebounce level or lower, biochemical failure as “nadir + 2 ng/ml”.

Results

Patients without biochemical failure reached a lower nadir after brachytherapy (median ?0.05 ng/ml after LDR- and HDR-BT without NHT) in comparison to EBRT (0.55 ng/ml without NHT; p < 0.01). Not a single patient without NHT and a nadir <0.1 ng/ml failed biochemically (0% vs. 45% with a nadir ?0.1 ng/ml; p < 0.01). PSA bounces were found predominantly in the LDR-BT group (42% vs. 23%/20% after HDR-BT/EBRT; p < 0.01). In a multivariate Cox regression analysis, LDR-BT and HDR-BT were associated with a significantly lower biochemical failure rate in comparison to EBRT.

Conclusions

PSA kinetics differ significantly following different radiotherapy methods. A lower nadir and a higher biochemical control rate suggest a higher radiobiological efficiency of brachytherapy in comparison to EBRT (with a dose of 70.2 Gy).     

Acute toxicity of curative radiotherapy for intermediate- and high-risk localised prostate cancer in the EORTC trial 22991

IntroductionThis trial randomly assessed short-term adjuvant hormonal therapy added to radiotherapy (RT) for intermediate- and high-risk (UICC 1997 cT2a or cT1b-c with high PSA or Gleason score) localised prostate cancer. We report acute toxicity (CTCAE v2) assessed weekly during RT in relation to radiation parameters.Patients and methodsCentres selected the RT dose (70, 74 or 78 Gy) and RT technique. Statistical significance is at 0.05.ResultsOf 791 patients, 652 received 3D-CRT (70 Gy: 195, 74 Gy: 376, 78 Gy: 81) and 139 received IMRT (74 Gy: 28, 78 Gy: 111). During RT, grade 3 gastrointestinal (GI) and genitourinary (GU) toxicities were reported by7 (0.8%) and 50 (6.3%) patients, respectively. No grade 4 was reported. The risk of grade ?2 GI toxicity increased significantly with increasing D50%-rectum (p = 0.004) and that of grade ?2 GU toxicity correlated only to Dmax-bladder (p = 0.051). 3D-RT technique, increasing total dose and V95% >400 cc increased D50% and Dmax. One month after RT, only 14 patients (1.8%) reported grade 3 toxicity. AST did not seem to influence the risk of GU or GI acute toxicity.ConclusionRT up to 78 Gy was well tolerated. Dmax-bladder and D50%-rectum influenced the risk of grade ?2 GU toxicity and GI toxicity, respectively. Both were lower with IMRT but remained high for an irradiated RT volume > 400 cc for 3D-RT and for a dose of 78 Gy. Hormonal treatment did not influence acute toxicity.     

Prognostic value of biochemical response to neoadjuvant androgen deprivation before external beam radiotherapy for prostate cancer: A systematic review of the literature

External beam radiation therapy (EBRT) in combination with androgen deprivation therapy (ADT) is considered a standard treatment option for patients with aggressive localized and locally-advanced prostate cancer. Randomized phase III trials have provided evidence for combining EBRT to short-term ADT for intermediate-risk disease and to long-term ADT for patients harboring high-risk tumors. Even if several improvements and developments have been made in the last years in terms of radiotherapy delivery techniques, image-guided radiotherapy, and better sparing of the organs at risk the current use of ADT remains still linked to a therapeutic algorithm based on the prostate cancer risk classification as proposed by clinical trials.Emerging literature has recently shown that the biochemical response to a course of neoadjuvant ADT before EBRT, called the “prostate-specific antigen (PSA) nadir” (lowest value after treatment), may influence the long-term biochemical tumor-control outcomes of prostate cancer patients. An individualized approach adapting the duration of hormonal treatment according to the PSA response during the neoadjuvant phase, as well using new generation hormonal agents, may represent a new therapeutic strategy and a future way to improve the therapeutic ratio for prostate cancer patients.In this systematic review of the literature we explored the prognostic value of the PSA response to the neoadjuvant ADT phase and the rationale to adjust the use of ADT and EBRT in patients with intermediate- and high-risk prostate cancer based on the biochemical response to the neoadjuvant androgen ablation phase.