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.     

Approaching clinical problems in prostate cancer radiotherapy using the number needed to treat (NNT) technique

The goals of this article are to review the application of the number needed to treat (NNT) concept to selected clinical problems in prostate cancer radiotherapy. Particular emphasis will be placed on (1) comparison of radiotherapy with other treatment options for early-stage disease, (2) the role of hormone therapy in addition to radiotherapy over a spectrum of disease presentation, and (3) systematic comparison of adjuvant versus salvage radiotherapy in the post-prostatectomy setting. Limitations of NNT calculations based on non-randomized comparisons also are discussed.     

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.     

Efficacy of 5-HT3 receptor antagonists in radiotherapy-induced nausea and vomiting: a quantitative systematic review

5-HT3 receptor antagonists are used to treat radiation-induced sickness. The purpose of this study was to define anti-emetic efficacy and potential for harm of these drugs in radiotherapy. A systematic search, critical appraisal and quantitative analysis of relevant data using the number-needed-to-treat or harm (NNT/H) were conducted. Acute (0 to 24h) and delayed (beyond 24 h) anti-emetic efficacy were analysed separately. Data from 1,404 patients were found in 40 trials published in 36 reports. Data from 197 patients receiving ondansetron or granisetron in five randomised trials were regarded as valid according to preset criteria. One placebo-controlled trial had 10 patients per group and in this ondansetron was not significantly different from placebo. In a larger (n = 105) placebo-controlled trial, ondansetron was significantly more efficacious than metoclopramide for complete control of acute vomiting (NNT 2.2, 95% confidence interval (CI) 1.7-3.3) and acute nausea (NNT 3.6, 95% CI 2.2-10.2). Three trials reported delayed outcomes with ondansetron or granisetron: there was no evidence of any difference compared with placebo or other anti-emetics. Two trials reported no acute or delayed but a 'worst day' outcome; in these ondansetron's antivomiting effect was significantly better than placebo (NNT 4.4, 95% CI 2.5-23) or prochlorperazine (NNT 3.8, 95% CI 2.4-10.3), but not its antinausea effect. Constipation and headache were associated significantly with 5-HT3 receptor antagonists compared with other anti-emetics or placebo (NNH 6.4 and 17.1, respectively). Only 14% of published data enabled valid estimation of the anti-emetic efficacy of 5-HT3 receptor antagonists in radiotherapy. There was some evidence that these drugs prevent acute vomiting: 40% of treated patients will benefit (NNT approximately 2.5). The evidence for nausea was less clear. There was no evidence that these drugs are of any benefit beyond 24 h. There was evidence that they produce specific adverse effects.     

Hormone therapy adjuvant to external beam radiotherapy for locally advanced prostate carcinoma: a complication-adjusted number-needed-to-treat analysis

BACKGROUND: Hormone therapy commonly is used to treat metastatic, locally advanced, and localized prostate carcinoma. The objective of the current investigation was to determine, using the number-needed-to-treat (NNT) method, the effect of using hormone therapy to treat locally advanced disease, with consideration given to both the complications and the known advantages associated with hormone therapy. METHODS: A literature review was performed to determine 1) the absolute benefit, based on available clinical endpoints, associated with the addition of hormone therapy to external beam radiotherapy for locally advanced prostate carcinoma; 2) the incidence of side effects of short-term and long-term hormone therapy; and 3) the stepwise progression from biochemical failure to death. A model was constructed to estimate the complication/utility-adjusted survival detriment resulting from the side effects of short-term ( 6 months) hormone therapy, and the absolute/unadjusted and complication-adjusted NNTs for the addition of short-term and long-term hormone therapy were computed. In all cases, the magnitudes and signs of the NNTs obtained were used to gauge the effect of hormone therapy. RESULTS: The unadjusted NNTs were positive and in most cases had relatively small magnitudes (the greater the NNT, the smaller the benefit) for both short-term and long-term hormone therapy; these results were expected, and they suggested that there is a strong benefit associated with the use of hormones adjuvant to radiotherapy for locally advanced disease. Adjusted NNTs remained positive and had relatively small magnitudes even after the introduction into the analysis of complications of short-term and long-term hormone therapy. This finding, although weak with respect to the effect of short-term hormone therapy on cause-specific survival, remained robust over the range of values for utility impairment expected from short-term and long-term hormone therapy. CONCLUSIONS: The benefits of short-term and long-term hormone therapy for locally advanced prostate carcinoma appear to be significant and to outweigh the associated side effects. Long-term therapy appears to be better than short-term therapy in terms of virtually all endpoints studied, even when the increased incidence of side effects is considered. The current investigation was successful in the use of the complication-adjusted NNT method for oncologic and radiotherapeutic scenarios in which the results of randomized trials could be summarized, adjusted for treatment toxicity, and individualized to a given patient.     

Proposition de délinéation des volumes cibles anatomocliniques postopératoires de la tumeur primitive des cancers de l’ethmoïde

It is proposed to delineate the anatomo-clinical target volumes of primary tumor (CTV-P) in ethmoid cancers treated with post-operative radiotherapy. This concept is based on the use of radioanatomy and the natural history of cancer. It is supported by the repositioning of the planning scanner with preoperative imaging for the replacement of the initial GTV and the creation of margins around it extended to the microscopic risk zones according to the anatomical concept. This article does not discuss the indications of external radiotherapy but specifies the volumes to be delineated if radiotherapy is considered.     

Does hormone treatment added to radiotherapy improve outcome in locally advanced prostate cancer?

BACKGROUND:

To quantify the magnitude of benefit of the addition of hormone treatment (HT) to exclusive radiotherapy for locally advanced prostate cancer, a literature‐based meta‐analysis was conducted.

METHODS:

Event‐based relative risks (RR) with 95% confidence intervals (CIs) were derived through a random‐effect model. Differences in primary (biochemical failure and clinical progression‐free survival) and secondary outcomes (cancer‐specific survival, overall survival [OS], recurrence patterns, and toxicity) were explored. Absolute differences and numbers of patients needed to treat (NNT) were calculated. A heterogeneity test, a metaregression analysis with clinical predictors of outcome, and a correlation analysis for surrogate endpoints were also performed.

RESULTS:

Seven trials (4387 patients) were gathered. Hormone suppression significantly decreased both biochemical failure (RR, 0.76; 95% CI, 0.70‐0.82; P < .0001) and clinical progression‐free survival (RR, 0.81; 95% CI 0.71‐0.93; P = .002), with absolute differences of 10% and 7.7%, respectively, which translates into 10 and 13 NNT. cancer‐specific survival (RR, 0.76; 95% CI, 0.69‐0.83; P < .0001) and OS (RR, 0.86; 95% CI, 0.80‐0.93; P < .0001) were also significantly improved by the addition of HT, without significant heterogeneity, with absolute differences of 5.5% and 4.9%, respectively, which translates into 18 and 20 NNT. Local and distant relapse were significantly decreased by HT, by 36% and 28%, respectively, and no significant differences in toxicity were found. Primary and secondary efficacy outcomes were significantly correlated.

CONCLUSIONS:

Hormone suppression plus radiotherapy significantly decreases recurrence and mortality of patients with localized prostate cancer, without affecting toxicity. Cancer 2009. © 2009 American Cancer Society.     

Incertitudes inhérentes au concept actuel de volume cible prévisionnel en radiothérapie

The planning target volume is an essential notion in radiotherapy, that requires a new conceptualization. Indeed, the variability and diversity of the uncertainties involved or improved with the development of the new modern technologies and devices in radiotherapy suggest that random and systematic errors cannot be currently generalized. This article attempts to discuss these various uncertainties and tries to demonstrate that a redefinition of the concept of planning target volume toward its personalization for each patient and the robustness notion are likely an improvement basis to take into account the radiotherapy uncertainties.     

A simple measure of reliability in clinical trials of surgical adjuvant radiotherapy.

AIMS: The 'number needed to treat' (NNT) is a measure of therapeutic effect and is defined as the number of patients needed to be treated, so that the treatment of one of them is successful. Since many patients or physicians find this way to describe therapeutic potency very intuitive, I calculated the NNTs for the surgical adjuvant radiotherapy of different malignant neoplasias. METHODS: This computation was applied to selected, prospective, randomized trials or meta-analyses on adjuvant or adjunctive radiotherapy of epithelial or glial malignancies. RESULTS: Among 17 NNTs calculated for trials reporting improvements in local relapse rates 2 are smaller than 5, 8 are in the range from 5 to 10 and 7 are larger than 10 (median follow-up 5 years; range 3-20). In contrast, only 2 NNTs from 10 trials reporting survival advantages are smaller than 10 (median follow-up 4 years; range 1-20). CONCLUSIONS: NNTs correctly reflect that adjuvant radiotherapy has a far more pronounced impact on the probability of local recurrence of a malignancy as opposed to patient's survival.     

Application of deep learning to auto-delineation of target volumes and organs at risk in radiotherapy

The technological advancement heralded the arrival of precision radiotherapy (RT), thereby increasing the therapeutic ratio and decreasing the side effects from treatment. Contour of target volumes (TV) and organs at risk (OARs) in RT is a complicated process. In recent years, automatic contouring of TV and OARs has rapidly developed due to the advances in deep learning (DL). This technology has the potential to save time and to reduce intra- or inter-observer variability. In this paper, the authors provide an overview of RT, introduce the concept of DL, summarize the data characteristics of the included literature, summarize the possible challenges for DL in the future, and discuss the possible research directions.     

Antiviral prophylaxis in haematological patients: Systematic review and meta-analysis

PurposeAntiviral prophylaxis is commonly prescribed to haematological cancer patients. We conducted a systematic review and meta-analysis to quantify its overall benefit in specific clinical scenarios.MethodsRandomised controlled trials assessing antiviral prophylaxis versus placebo, no treatment, pre-emptive treatment or another antiviral drug were included. Patients undergoing haematopoietic stem cell transplantation (HSCT) or intensive chemotherapy for acute leukaemia or high-grade lymphoma were included. No restrictions on language, year or publication status were applied. Overall mortality, herpes simplex virus (HSV) and cytomegalovirus (CMV) diseases were assessed as primary outcomes. Pooled relative risks (RRs) and numbers needed to treat (NNT) with 95% confidence intervals (CI) are reported.ResultsHSCT was the condition assessed in 22 trials and intensive chemotherapy in 5 trials. In the pre-engraftment setting of autologous or allogeneic HSCT, antiviral prophylaxis (mainly acyclovir for HSV seropositive recipients) significantly reduced HSV (NNT 2, 2–2, control event rate (CER) 61.9%) and CMV disease, with no effect on overall mortality. In the allogeneic post-engraftment setting (mainly CMV-seropositive recipients/donors), antiviral prophylaxis resulted in a significant reduction in overall mortality, RR 0.79 (0.65–0.95), NNT 12 (7–50, CER 39.4%) and all viral-related outcomes. In this setting, acyclovir significantly reduced overall mortality (RR 0.71, 0.53–0.96, 4 trials) and ganciclovir/maribavir significantly reduced CMV disease (RR 0.26, 0.14–0.48, 5 trials). During chemotherapy, acyclovir significantly decreased HSV disease (NNT 3, 2–4, CER 37.4%) and infection rates, with no effect on mortality.ConclusionsAntiviral prophylaxis reduced mortality with a small NNT in the post-engraftment setting of allogeneic HSCT. In the pre-engraftment phase and during chemotherapy only viral-related morbidity was reduced.     

Routine perioperative chemotherapy instillation with initial bladder tumor resection

BACKGROUND:

Level‐1 evidence has demonstrated decreased recurrence of low‐grade bladder tumors when initial transurethral resection (TUR) is followed by perioperative instillation (PI) of chemotherapy. A meta‐analysis determined that the number needed to treat (NNT) was 8.5 patients to prevent 1 recurrence. No benefit was demonstrated for tumors classified as T0, tumor in situ, or T2; thus, patients with those tumors were excluded from the analysis, which potentially may have resulted in underestimating the true NNT. Economic benefits were suggested, but cost calculations were not presented. The objectives of the current analysis were to recalculate the NNT considering patients who previously were excluded and to examine the economic implications based on various management alternatives for tumor recurrence.

METHODS:

For each study that was included in the current meta‐analysis, the number of patients excluded because of ‘inappropriate’ pathology results was determined. A potentially more accurate NNT was calculated, and pertinent Medicare reimbursements were obtained to estimate costs.

RESULTS:

The added cost for 8.5 patients who underwent inpatient TUR to receive PI was $1711. Inpatient TUR ($7025) was extremely costly compared with hospital outpatient TUR ($2666), ambulatory surgery center TUR ($2113), and physician office fulguration ($1167). Although the inclusion of patients who previously were excluded resulted in a recalculated NNT of 9.6 patients, the authors used a more conservative NNT if 8.5 patients to estimate the economic impact of the ‘best‐case scenario.’

CONCLUSIONS:

Routine PI significantly lowered the overall cost if recurrences were managed in the inpatient setting, but these benefits were offset mostly or completely by outpatient management in the United States. Thus, the authors concluded that the decision to use routine PI of chemotherapy should be based on clinical effects and not on presumed economic benefits. Cancer 2009. © 2009 American Cancer Society.     

The Dandelion Dilemma Revisited for Oligoprogression: Treat the Whole Lawn or Weed Selectively?

Oligoprogressive disease is a relatively new clinical concept describing progression at only a few sites of metastasis in patients with otherwise controlled widespread disease. In the era of well-tolerated targeted treatments, resistance inevitably occurs and overcoming this is a challenge. Local ablative therapy for oligoprogressive disease may allow the continuation of systemic treatments by overcoming the few sub-clones that have developed resistance. Stereotactic body radiotherapy is now frequently used in treating oligometastatic disease using ablative doses with minimally invasive techniques and acceptable toxicity. We discuss the current retrospective clinical evidence base supporting the use of local ablative therapy for oligoprogression in metastatic patients on targeted treatments within multiple tumour sites. As there is currently a lack of published prospective data available, the best management for these patients remains unclear. We discuss current trials in recruitment and the potential advancements in treating this group of patients with stereotactic radiotherapy.     

Sentinel lymph node versus axillary lymph node dissection for early-stage breast carcinoma: a comparison using a utility-adjusted number needed to treat analysis

BACKGROUND: The current study was performed to compare the value of sentinel lymph node dissection (SND) and axillary lymph node dissection (AND) in improving the utility-adjusted survival for early-stage breast carcinoma patients. METHODS: A number needed to treat (NNT) analysis was used to compare SND with AND. In the NNT equation, 1/(S(SND) - S(AND)), S is the 5-year utility-adjusted survival. A literature review was performed to estimate 1) the prevalence of axillary lymph node disease for early-stage breast carcinoma, 2) the sensitivity and specificity of SND and AND, 3) the 5-year overall survival as a function of axillary lymph node involvement, 4) the risk of arm lymphedema as a function of the intervention performed, and 5) the utility correction (Uc; impairment of quality of life) for arm lymphedema. RESULTS: The NNT method of analysis favored SND over nearly the entire range of parameters with a sign change to a negative value occurring only as Uc becomes very close to unity. This suggests the superiority of the SND approach. Only when there is minimal loss of utility does AND become favored and then only minimally. CONCLUSIONS: Compared with AND, SND improves the utility-adjusted survival in patients with early-stage breast carcinoma. This finding is quite robust and was found to remain constant over a range of values for utility and lymph node prevalence.     

MR加速器在头颈部肿瘤自适应放疗中的临床应用北大核心CSCD

自适应放疗(ART)通过在放疗中适应肿瘤和正常组织轮廓变化从而提高了头颈部肿瘤治疗比。基于MR加速器的MR引导放疗(MRgRT)是目前创新性的头颈部肿瘤ART模式。MR加速器基于MR能实现每日ART, 同时也能在治疗中进行实时MR成像。通过每日ART能明显提高头颈部肿瘤治疗靶区准确性, 更好地避开周围重要危及器官。虽然目前发表的关于MRgRT在头颈部肿瘤ART的临床应用和实施技术的研究逐渐增加, 但总体上这个新型的放疗模式还处于初步发展阶段。本文将对基于MR加速器的MRgRT在头颈部肿瘤ART中的基本原理、临床应用及前景进行综述。     

Involved-Node-Radiotherapie in frühen Stadien des Hodgkin-Lymphoms

Radiotherapy of Hodgkin’s lymphoma has evolved from extended-field to involved-field (IF) radiotherapy which reduces toxicity whilst maintaining high rates of healing. Recent publications recommend further reduction of the radiation field to involved-node (IN) radiotherapy; however, this concept has never been tested in a randomized trial. The German Hodgkin Study Group (GHSG) aims to compare IN with standard IF radiotherapy in the future HD17 trial. The clinical target volume (CTV) encompasses the initial volume of the lymph node(s) before chemotherapy and incorporates the initial location and extent of the disease, taking into account the displacement of the normal tissues. The margin of the planning target volume (PTV) should be 2 cm in the axial and 3 cm in the craniocaudal direction. To minimize lung and cardiac toxicity the target definition in the mediastinum is different. The concept of IN radiotherapy has been proposed as a means to further improve the therapeutic ratio by reducing the risk of radiation-induced toxicity, including second malignancies. Field sizes will further decrease compared to IF radiotherapy.     

Magnitude of benefit of the addition of bevacizumab to first-line chemotherapy for metastatic colorectal cancer: meta-analysis of randomized clinical trials

Background

Although the addition of bevacizumab to 1^st line chemotherapy provides a significant survival benefit for advanced colorectal cancer, the magnitudes of both advantages and toxicities have not been extensively investigated.

Methods

A literature-based meta-analysis was conducted; Hazard Ratios were extracted from randomized trials for primary end-points (Progression Free Survival, PFS, Overall Survival OS). The log of event-based risk ratio were derived for secondary endpoints (objective/partial response rate, ORR/PR; severe hypertension, bleeding and proteinuria). Absolute differences and the number needed to treat/harm (NNT/NNH) were calculated. A meta-regression analysis with clinical predictors and a sensitivity analysis according to the trial phase-design were conducted as well.

Results

Five trials (2,728 pts) were selected. The addition of bevacizumab to 1^st line chemotherapy significantly increased both PFS (although with significant heterogeneity) and OS over exclusive chemotherapy by 17.1% and 8.6% (NNT 6 and 12), regardless of the study setting (non significant interaction between phase II and III). The chance to improve PR was significantly increased by 6.5% (NNT 15), with a trend for ORR. The risk of hypertension was significantly increased by 6.2% (NNH 16). According to the meta-regression analysis, female gender and rectal primary site were significant predictors for PFS benefit.

Conclusions

Notwithstanding all the concerns related to costs and the significant HTN risk, the significant outcome improvement provided by bevacizumab in first-line treatment for unselected advanced colorectal cancer patients, should be considered when choosing the appropriate up-front therapy.     

Intensity-modulated radiation therapy leads to survival benefit only in patients with high-risk prostate cancer: a population-based study

BackgroundDuring the last years, there has been a rapid adoption of intensity-modulated radiation therapy (IMRT) in patients with prostate cancer (PCa), despite the lack of randomized trials evaluating its effectiveness. The aim of our study was to evaluate the survival benefit associated with IMRT in patients with PCa.Patients and methodsOverall, 42 483 patients with PCa treated with IMRT or initial observation between 2001 and 2007 within the Surveillance, Epidemiology, and End Results (SEER)-Medicare were evaluated. Patients in both treatment arms were matched using propensity-score methodology. After propensity-score matching, 19 064 patients remained in our analyses. Eight-year cancer-specific mortality (CSM) rates were estimated, and the number needed to treat (NNT) was calculated. Competing risks regression analyses tested the relationship between treatment type and CSM.ResultsOverall, the 8-year CSM rates were 3.4% and 4.1% for patients treated with IMRT versus initial observation, respectively (P < 0.001). The corresponding 8-year NNT was 142. In patients with low/intermediate-risk disease, IMRT was not associated with lower CSM rates compared with observation (P = 0.7). In patients with high-risk disease, the 8-year CSM rates for IMRT versus observation were 5.8% versus 10.5%, respectively (P < 0.001). The corresponding NNT was 21. When high-risk patients were stratified according to age (<73 versus ≥73), and Charlson comorbidity index (≤1 versus >1) the 8-year CSM rates for IMRT versus observation were 4.3% versus 9.4% and 6.9% versus 11.9% and 5.3% versus 11.4% and 6.1% versus 10.1%, respectively (all Ps < 0.001). The corresponding NNTs were 19, 21, 16, and 25, respectively. In multivariate analyses, the protective effect of IMRT was more evident in high-risk patients with younger age and lower comorbidities.ConclusionsIMRT leads to a survival advantage only in patients with high-risk disease. Conversely, patients with low/intermediate-risk disease did not benefit from IMRT at 8-year follow-up.     

Subclinical disease revisited

It has become commonplace to treat postoperative patients with adjuvant radiotherapy to increase local control. The reduction in local recurrences seen in patients with head and neck cancer following radiotherapy led to coining of the term "subclinical disease" to describe the presumed presence of small, clinically undetectable, nests of tumor cells which remain even after the most aggressive of surgeries. The basic assumption fundamental to the concept of subclinical disease is that any patient with residual disease will suffer a local failure if left untreated. For example, lymph node involvement, either clinically evident or pathologically proven, is considered an absolute indication for adjuvant therapy. A positive or "close" or "microscopically positive" margin is also considered grounds for further treatment. The purpose of this communication is to critically discuss recent reports that challenge this assumption.