Tolerability and toxicity of prophylactic cranial irradiation in patients with non-small cell lung cancer - Results of a phase II study (with estimation of hematological toxicity, pituitary function and magnetic resonance spectra changes).

AIM: To evaluate the tolerability and toxicity of PCI in patients with NSCLC. BACKGROUND: Prophylactic cranial irradiation (PCI) is a standard treatment for patients with small cell lung cancer. There are data showing a decreasing ratio of brain metastases after PCI for non-small cell lung cancer (NSCLC-non small cell lung cancer) patients but, so far, there is no evidence for increasing overall survival. The main concern in this setting is the tolerance and toxicity of the treatment. MATERIALS AND METHODS: From 1999 to 2007, 50 patients with NSCLC treated with radical intent underwent PCI (30 Gy in 15 fractions). Mean follow-up was 2.8 years. The tolerability and hematological toxicity were evaluated in all patients, a part of participants had done neuropsychological tests, magnetic resonance imaging with (1)H nuclear magnetic resonance spectra, and estimation of pituitary function. RESULTS: During follow-up, 20 patients developed distant metastases, 4-brain metastases. Fourteen (30%) patients had acute side effects: (headache, nausea, erythema of the skin). The symptoms did not require treatment breaks. Six patients complained of late side effects (vertigo, nausea, anxiety, lower extremity weakness, deterioration of hearing and olfactory hyperesthesia). Hematological complications were not observed. Testosterone levels tended to decrease (p = 0.062). Visual-motor function deteriorated after treatment (p < 0.059). Performance IQ decreased (p < 0.025) and the difference between performance IQ and verbal IQ increased (p < 0.011). Degenerative periventricular vascular changes were observed in two patients. Analysis of the spectroscopic data showed metabolic but reversible alterations after PCI. CONCLUSION: PCI in the current series was well tolerated and associated with a relatively low toxicity.

Sparing the Hippocampus in Prophylactic Cranial Irradiation Using Three Different Linear Accelerators: A Comparative Study.

Hippocampus protection, as an organ at risk in brain radiotherapy, might protect patients' quality of life. Prophylactic cranial irradiation (PCI) has been used traditionally in small cell lung cancer (SCLC) patients as it increases survival. This study aimed to discover the contributing parameters for a successful PCI with simultaneous protection of the hippocampus by using three different treatment machines. For this purpose, treatment plans were generated for 45 SCLC patients using three half-arcs in three linear accelerators (LINACs; Elekta Infinity, Synergy, and Axesse; Elekta Ltd, Stockholm, Sweden) with different radiation field sizes and multileaf collimator (MLC) leaf thickness characteristics. The prescribed dose was 25 Gy in 10 fractions. Thresholds for the hippocampus were calculated based on the Radiation Therapy Oncology Group 0933 dose constraints. The planning and treatment system templates were common to all three LINACs. Plan evaluation was based on the dosimetric target coverage by the 95% isodose, the maximum dose of the plan, the conformity index (CI), the degree of plan modulation (MOD), and the patient-specific quality assurance (QA) pass rate. The mean target coverage was highest for Infinity (97.3%), followed by Axesse (96.6%) and Synergy (95.5%). The mean maximum dose was higher for Synergy (27.5 Gy), followed by Infinity (27.0 Gy) and Axesse (26.9 Gy). Axesse plans had the highest CI (0.93), followed by Infinity (0.91) and Synergy (0.88). Plan MOD was lower for Synergy (2.88) compared with Infinity (3.07) and Axesse (3.69). Finally, patient-specific QA was successful in all Infinity plans, in all but one Synergy plan, and in 17/45 Axesse plans, as was expected from the field size in that treatment unit. Based on overall performance, the most favorable combination of target coverage, hippocampus sparing, and plan deliverability was obtained with the LINAC, which has the largest field opening and thinnest MLC leaves.

Prophylactic cranial irradiation-related lymphopenia affects survival in patients with limited-stage small cell lung cancer.

Background: The study aimed to identify the relations of the absolute lymphocyte count (ALC) nadir during prophylactic cranial irradiation (PCI) and patient outcomes in limited-stage small cell lung cancer (LS-SCLC). Methods: We analyzed 268 L S-SCLC patients who underwent PCI from 2012 to 2019. ALC values were collected prior, during, and 3 months post PCI. Kaplan-Meier and Cox regression analyses were performed to assess the relation of ALC to patient prognosis. Two nomograms were developed on the basis of clinical variables for survival prediction. Results: Compared with the ALC before PCI (1.13 × 109 cells/L), the ALC nadir during PCI was significantly reduced by 0.68 × 109 cells/L (P < 0.001) and raised to 1.02 × 109 cells/L 3 months post PCI. Patients with a low ALC nadir during PCI (<0.68 × 109 cells/L) had inferior progression free survival (PFS) (median PFS: 17.2 m vs. 43.7 m, P = 0.019) and overall survival (OS) (median OS: 29.0 m vs 39.1 m, P = 0.012). Multivariate Cox analysis revealed that age, smoking history, clinical stage, and ALC nadir were independent OS (P = 0.006, P = 0.005, P < 0.001 and P = 0.027, respectively), as well as independent PFS predictors (P = 0.032, P = 0.012, P = 0.012 and P = 0.018, respectively). After internal cross-validation, the corrected concordance indices of the predictive nomograms for PFS and OS were 0.637 and 0.663, respectively. Conclusion: LS-SCLC patients with a low ALC nadir during PCI likely have worse survival outcomes. Dynamic evaluation of the ALC during PCI is recommended for LS-SCLC patients.

Development and validation of a nomogram for the prediction of brain metastases in small cell lung cancer.

INTRODUCTION: The aim was to develop and validate a nomogram for the prediction of brain metastases (BM) in small cell lung cancer (SCLC), to explore the risk factors and assist clinical decision-making. METHODS: We reviewed the clinical data of SCLC patients between 2015 and 2021. Patients between 2015 and 2019 were included to develop, whereas patients between 2020 and 2021 were used for external validation. Clinical indices were analysed by using the least absolute shrinkage and selection operator (LASSO) logistic regression analyses. The final nomogram was constructed and validated by bootstrap resampling. RESULTS: A total of 631 SCLC patients between 2015 and 2019 were included to construct model. Gender, T stage, N stage, Eastern Cooperative Oncology Group (ECOG), haemoglobin (HGB), the absolute value of lymphocyte (LYMPH #), platelet (PLT), retinol-binding protein (RBP), carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE) were identified as risk factors and included into the model. The C-indices were 0.830 and 0.788 in the internal validation by 1000 bootstrap resamples. The calibration plot revealed excellent agreement between the predicted and the actual probability. Decision curve analysis (DCA) showed better net benefits with a wider range of threshold probability (net clinical benefit was 1%-58%). The model was further externally validated in patients between 2020 and 2021 with a C-index of 0.818. CONCLUSIONS: We developed and validated a nomogram to predict the risk of BM in SCLC patients, which could help clinicians to rationally schedule follow-ups and promptly implement interventions.

The incorporation of cognitive-sparing techniques into prophylactic cranial irradiation in the management of small cell lung cancer.

The use of prophylactic cranial irradiation (PCI) remains an important component in the management of small cell lung cancer (SCLC). This is due to the high rates of subclinical brain metastases at the time of diagnosis. Following a response to initial treatment, PCI historically has been associated with improvements in overall survival and decreased development of brain metastases in patients with limited stage (LS-SCLC) and extensive stage (ES-SCLC) SCLC. However, PCI is commonly withheld in these settings in favor of observation, largely due to its association with cognitive sequelae following treatment. While randomized data has demonstrated that in patients with ES-SCLC, PCI may be withheld in favor of close MRI surveillance without a detriment in overall survival or cognitive functioning, these patients did not undergo formal neuropsychological assessments. In recent years, cognitive sparing techniques incorporated into whole brain radiation therapy and PCI, such as the addition of memantine and hippocampal avoidance, have demonstrated significant improvements in cognitive outcomes. As the overall survival in patients with SCLC continues to improve due to the incorporation of novel systemic therapies (e.g., immune checkpoint inhibitors), the role of PCI and maximizing quality of life remains a highly relevant topic. This article reviews the role of PCI and cognitive-sparing techniques in the management of SCLC.

Usefulness of pro-gastrin-releasing peptide as a predictor of the incidence of brain metastasis and effect of prophylactic cranial irradiation in patients with limited-stage small-cell lung cancer.

Prophylactic cranial irradiation (PCI) is recommended for patients with limited-stage small-cell lung cancer (LS-SCLC) who respond well to initial treatment. However, PCI is often omitted because of its potential neurotoxicity in the era of modern diagnostic imaging devices. In the present study, we aimed to investigate the risk factors for brain metastasis (BM) in patients eligible for PCI and who may benefit more from it. Patients with LS-SCLC who responded well to definitive thoracic chemoradiotherapy were included in the present study. Competing risk regression was used to identify factors associated with BM, and the Kaplan-Meier method was used to assess overall survival (OS). Between 2004 and 2017, 62 patients were eligible for PCI and were analyzed. Of these, 38 (61.3%) underwent PCI. Overall, 17 patients (27.4%) developed BM, with a 2-year cumulative incidence of 22.8%. Multivariate analysis (MVA) revealed that pretreatment elevated pro-gastrin-releasing peptide (ProGRP) levels were associated with an increased risk for BM (HR, 7.96, P = 0.0091). PCI tended to reduce the risk of BM (HR, 0.33; P = 0.051). The use of PCI was associated with improved OS in patients with ProGRP levels > 410 pg/mL (P = 0.008), but not in those with ProGRP ≤ 410 pg/mL (P = 0.9). Pretreatment ProGRP levels may be useful in predicting the development of BM in patients with LS-SCLC who achieved a good response to initial therapy and to determine which patients should undergo PCI.

Hippocampal avoidance in prophylactic cranial irradiation for small cell lung cancer: benefits and pitfalls.

Small cell lung cancers (SCLC) are a group of cancers that are clinically and pathologically different from other lung cancers. They are associated with high recurrence rates and mortality, and many patients present with metastatic disease. Approximately ten percent of SCLC patients have brain metastases at time of diagnosis, and the cumulative incidence of brain metastases increases to more than fifty percent at two years, even with optimal treatment. Hence, in patients without brain metastases at presentation, prophylactic cranial irradiation (PCI) is an important component of treatment along with systemic chemotherapy and radiotherapy. The goal of PCI is to decrease the incidence of subsequent symptomatic brain metastases in patients who show an initial response to the systemic treatment. Various clinical trials have evaluated the utility of PCI and found substantial benefit. Unfortunately, the long-term toxicity associated with PCI, namely the neuro-cognitive impairment that may develop in patients as a result of the radiation toxicity to the hippocampal areas of the brain, has raised concern both for patients and their treating physicians. Various techniques have been tried to ameliorate the neuro-cognitive impairment associated with PCI, including pharmacological agents and highly conformal hippocampal avoidance radiation. All of these have shown promise, but there is a lack of clarity about the optimal way forward. Hippocampal avoidance PCI appears to be an excellent option and a number of groups are currently evaluating this technique. Although there is clear benefit with this specialized radiation treatment, there are also concerns about the risk of disease recurrence in the undertreated hippocampal areas. This review attempts to compile the available data regarding the benefits and pitfalls associated with hippocampal avoidance PCI in the setting of SCLC.

Shared decision-making for prophylactic cranial irradiation in extensive-stage small-cell lung cancer: an exploratory study.

BACKGROUND: Prophylactic cranial irradiation (PCI) offers extensive-stage small-cell lung cancer (ES-SCLC) patients a lower chance of brain metastasis and slightly longer survival but is associated with a short-term decline in quality of life due to side-effects. This tradeoff between survival and quality of life makes PCI suitable for shared decision-making (SDM), where patients and clinicians make treatment decisions together based on clinical evidence and patient preferences. Despite recent clinical practice guidelines recommending SDM for PCI in ES-SCLC, as well as the heavy disease burden, research into SDM for lung cancer has been scarce. This exploratory study presents patients' experiences of the SDM process and decisional conflict for PCI. METHODS: Radiation oncologists (n=7) trained in SDM applied it in making the PCI decision with ES-SCLC patients (n=25). We measured patients' preferred level of participation (Control Preferences Scale), the level of SDM according to both groups (SDM-Q-9 and SDM-Q-Doc), and patients' decisional conflict [decisional conflict scale (DCS)]. RESULTS: Seventy-nine percent of patients preferred a collaborative role in decision-making, and median SDM scores given by patients and clinicians were 80 (IQR: 75.6-91.1) and 85.2 (IQR: 78.7-88.9) respectively, indicating satisfaction with the process. However, patients experienced considerable decisional conflict. Over 50% lacked clarity about which choice was suitable for them and were unsure what to choose. Sixty-four percent felt they did not know enough about the harms and benefits of PCI, and 60% felt unable to judge the importance of the harms/benefits in their life. CONCLUSIONS: ES-SCLC patients prefer to be involved in their treatment choice for PCI but a substantial portion experiences decisional conflict. Better information provision and values clarification may support patients in making a choice that reflects their preferences.

Re-evaluation of prophylactic cranial irradiation in limited-stage small cell lung cancer: a propensity score matched analysis.

We attempted to re-evaluate the efficacy of prophylactic cranial irradiation (PCI) in limited-stage small cell lung cancer (LS-SCLC) with more recent data. A total of 179 patients with LS-SCLC received radical thoracic radiotherapy and chemotherapy at our institution between 1998 and 2018. One hundred twenty-eight patients who achieved complete response (CR), good partial response (PR), and PR without progression for at least for one year after initial therapy were enrolled in this study. These patients were divided into a PCI group (group A, n = 43), and a non-PCI group (group B, n = 85). Survival outcomes were retrospectively evaluated. Because several background factors differed significantly between groups A and B, propensity score (PS) matching was performed as 1:1 match of the two groups. Finally, we analyzed 64 patients (group A/B = 32/32). Median follow-up periods were 53 and 31 months in groups A and B, respectively. There were no significant differences between the groups' backgrounds. Two-year overall survival (OS) rates were 77% in group A and 62% in group B (p = 0.224). Two-year brain metastasis free survival (BMFS) rates were 85% in group A and 57% in group B (p = 0.008). The number of patients who underwent a brain imaging test for confirmation of no brain metastasis (BM) after radical thoracic radiotherapy and chemotherapy (before PCI) was 84 (group A/B = 32/52). A PS matched analysis for cases of pre-PCI brain imaging group, two-year OS rates for group A/B were 73/59% (p = 0.446). Two-year BMFS rates for group A/B were 91/52% (p = 0.021). Retrospectively, PS matched analysis revealed that adding PCI to LS-SCLC patients who achieved good thoracic control significantly improved BMFS, but OS did not improve.

Prophylactic cranial irradiation or MRI surveillance for extensive stage small cell lung cancer.

The treatment paradigm for extensive stage small cell lung cancer (ES-SCLC) is evolving. Prophylactic cranial irradiation (PCI) has long been considered a component of standard treatment in patients with extensive stage disease who respond to chemotherapy. However, in the modern era of magnetic resonance imaging, the role of PCI has become an area of controversy following conflicting level I evidence. Due to conflicting data and toxicity concerns, the routine use of PCI has declined. Recent improvements in systemic disease control with the use of immunotherapy and reductions in the toxicity attributable to PCI with hippocampal avoidance and memantine have reignited the discussion. As such, we present here a narrative review of PCI with a focus on historical milestones, randomized data, risk mitigation and future directions.

Recent developments in limited stage small cell lung cancer.

Limited stage small cell lung cancer (LS-SCLC) remains a challenging disease, with 5-year overall survival ranging from 30-35% with current standard of care treatment consisting of thoracic radiation to 45 Gy in 30 fractions delivered twice daily, with concurrent platinum/etoposide chemotherapy, followed by prophylactic cranial irradiation (PCI). The randomized, phase III CONVERT study confirmed 45 Gy delivered twice daily to be the optimal radiation fractionation regimen, without significantly increased toxicity when compared to daily radiation to 66 Gy. Immunotherapy is now being studied in addition to chemoradiation, in both the concurrent and consolidative setting. These randomized trials are ongoing. Additionally, the role of PCI compared to MRI surveillance is being evaluated in patients with LS-SCLC in both the North America and Europe. Ideally these ongoing studies will continue to improve outcomes for LS-SCLC.

Prophylactic cranial irradiation is associated with improved survival following resection for limited stage small cell lung cancer.

BACKGROUND: Brain metastases are a major cause of mortality in patients with small cell lung cancer (SCLC). Prophylactic cranial irradiation (PCI) may improve survival among patients that respond to chemotherapy. Less is known about the outcomes of PCI following surgical resection of SCLC. The purpose of this study was to determine if patients who underwent initial surgical resection of SCLC benefit from PCI. METHODS: Adult patients in the National Cancer Database (NCDB) who underwent complete resection for primary, non-metastatic SCLC between 2004 and 2015 were identified. Patients that received preoperative chemotherapy or who did not receive appropriate adjuvant chemotherapy were excluded. Patients were grouped by treatment with or without cranial radiation within 8 months of resection. Survival was estimated using Kaplan-Meier and Cox multivariable analysis, adjusting for patient and tumor characteristics. RESULTS: A total of 859 patients met inclusion criteria (202 received PCI and 657 did not). Kaplan-Meier analysis demonstrated that patients treated with PCI had significantly improved survival compared to no PCI (5-year survival 59% vs. 50%, logrank P=0.0038). Multivariable cox models confirmed a significantly decreased hazard of death for patients receiving PCI (HR: 0.70, 95% CI: 0.55-0.89, P=0.003). In subset analyses, PCI was associated with significantly improved survival for node positive patients, but not node negative patients. CONCLUSIONS: PCI is associated with increased survival for patients following surgical resection of SCLC. Patients with positive lymph nodes appear to benefit the most, while it remains unclear if patients with negative lymph nodes derive a benefit. Further study is warranted to clarify which subsets of patients should be treated with PCI.

Radiotherapy in Lung Cancer: Current and Future Role.

Lung cancer is divided into two subgroups concerning its natural course and treatment strategies as follows: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). In this review, for NSCLC, the role of stereotactic body radiation therapy (SBRT) in early-stage, chemoradiation in the locally advanced stage, post-operative radiotherapy for patients with high risk after surgery and radiotherapy for metastatic disease will be discussed. Also, for SCLC, the role and timing of thoracic irradiation and prophylactic cranial irradiation (PCI) for the limited and extensive stages will be discussed.

Extracranial metastatic burden in extensive-stage small cell lung cancer: implications for prophylactic cranial irradiation.

BACKGROUND: Patients with extensive-stage small cell lung cancer (ES-SCLC) often develop brain metastases. There is significant controversy regarding the benefit of prophylactic cranial irradiation (PCI) for patients with ES-SCLC. Our objective is to identify ES-SCLC patients who might be most likely to benefit from PCI. METHODS: We retrospectively reviewed 173 patients with ES-SCLC treated between 2010-2015. Of these, 117 patients were initially diagnosed without brain metastases and received systemic chemotherapy. Following exclusion of patients who received PCI and less than 2 cycles of platinum doublet therapy, 93 patients remained. Patient records were reviewed for clinical and radiographic features previously identified as relevant risk factors. Primary outcome was brain metastasis-free survival (BMFS). Kaplan-Meier analysis, log-rank tests and Cox multivariate models were used to compare outcomes. RESULTS: Median follow-up was 10.7 months (range, 3-58 months). Thirty-eight (40.9%) patients developed brain metastases. Three or more metastatic sites was associated with inferior BMFS on univariable (1-year estimate 43.8% vs. 61.3%; P=0.020) and multivariable (MVA) analysis [hazard ratio (HR) 2.33, 95% CI: 1.08-5.01; P=0.03). CONCLUSIONS: Our results suggest that extracranial metastatic burden is associated with an increased risk for brain metastases in patients with ES-SCLC. As there is no clear standard regarding delivery of PCI in this patient population, utilizing the number of metastatic disease sites as a clinical indicator may help to improve selection of patients who benefit from PCI.

The evolving role of radiotherapy in the management of small cell lung cancer.

Small cell lung cancer (SCLC) represents a small but significant subset of newly diagnosed lung cancers. In spite of being both chemo- and radiation-sensitive, SCLC has a high-propensity for recurrence after treatment. Although systemic therapy plays a central role in the management of patients with SCLC, many of the advances in overall survival for patients with SCLC have directly related to the use of radiation therapy. The objective of this review is to discuss the key radiation therapy clinical trials that have defined the current standard-of-care treatment for SCLC, and to review ongoing advances in radiation therapy that may further advance outcomes for patients with SCLC.

The role of prophylactic cranial irradiation in surgically resected combined small cell lung cancer: a retrospective study.

BACKGROUND: Combined small cell lung cancer (C-SCLC) is defined as small cell lung cancer (SCLC) combined with any of non-small cell lung cancer (NSCLC) histological types, such as large cell carcinoma, squamous cell carcinoma, or adenocarcinoma. Since C-SCLC is an increasingly recognized subtype of small cell carcinoma, we conducted a retrospective study in our institution to explore the value of prophylactic cranial irradiation (PCI) in patients with C-SCLC treated by surgery. METHODS: Between 2005 and 2014, the records of all consecutive patients with pathologically diagnosed C-SCLC after surgery in our institution were reviewed. Overall survival (OS), disease-free survival (DFS), and brain metastasis free survival (BMFS) were estimated by Kaplan-Meier method. Survival differences were evaluated by log-rank test, while multivariate analysis was performed by a Cox proportional hazards model. RESULTS: Of the total 91 patients included in this analysis, 11 patients (12.1%) were in PCI group and 80 (87.9%) in non-PCI group. The 5-year cumulative incidence of brain metastasis in the whole group was 22.2% (26.3% in non-PCI group vs. 0% in PCI group), and 5-year OS rate was 44.1%. Patients treated with PCI had significantly longer OS (P=0.011) and DFS (P=0.013), also had the trend to live a longer BMFS with marginal significance (P=0.092) than non-PCI-treated patients. The multivariate analysis showed that PCI [hazard ratio (HR) =0.102, P=0.024] was one of independent prognostic factors of the OS in surgery-treated C-SCLC patients. CONCLUSIONS: C-SCLC patients have a relative high risk of developing brain metastases based on our study. These data showed that PCI could improve OS and DFS, as well as tend to decrease brain metastases in surgically resected C-SCLC. However, whether PCI could be part of comprehensive treatment modalities in C-SCLC should be assessed in prospective studies.

Treatment outcomes of patients with small cell lung cancer without prophylactic cranial irradiation.

BACKGROUND: Prophylactic cranial irradiation (PCI) is indicated for limited disease (LD) in small cell lung cancer (SCLC) patients who achieve a complete or near-complete response; however, it is sometimes not administered because of possible adverse reactions or patient refusal. Here we assessed treatment outcomes among patients with SCLC who were not treated with PCI. METHODS: The medical records of 60 patients (45 men, 15 women; mean age, 68 years; age range, 51-82 years) with SCLC were retrospectively reviewed. The tumors were staged by TNM classification. Two, 2, 5, 4, 32, and 15 patients had stage IA, IB, IIA, IIB, IIIA, and IIIB tumors, respectively. The patients were treated with thoracic radiotherapy (TRT) and four courses of chemotherapy. RESULTS: Our subjects had a median survival of 25 months and 2- and 5-year survival rates of 52.6% and 25.3%, respectively. Univariate analysis revealed that the development of brain metastasis, performance status (PS), and T-stage were significant factors correlated with survival rate. Multivariate analysis identified only PS [hazard ratio (HR), 5.845, 95% confidence interval (CI), 2.333-14.63, P=0.002] and brain metastasis as independent prognostic variables (HR, 2.344, 95% CI, 1.071-5.128, P=0.033). CONCLUSIONS: The results of our study demonstrated that the outcomes of treatment without PCI were improved, as compared with those of previously published data. Our findings may be used as reference data when PCI cannot be performed.

Potential toxicities of prophylactic cranial irradiation.

Prophylactic cranial irradiation (PCI) with total doses of 20-30 Gy reduces the incidence of brain metastasis (BM) and increases survival of patients with limited and extensive-disease small-cell lung cancer (SCLC) that showed any response to chemotherapy. PCI is currently not applied in non-small-cell lung cancer (NSCLC) since it has not proven to significantly improve OS rates in stage IIIA/B, although novel data suggest that subgroups that could benefit may exist. Here we briefly review potential toxicities of PCI which have to be considered before prescribing PCI. They are mostly difficult to delineate from pre-existing risk factors which include preceding chemotherapy, patient age, paraneoplasia, as well as smoking or atherosclerosis. On the long run, this will force radiation oncologists to evaluate each patient separately and to estimate the individual risk. Where PCI is then considered to be of benefit, novel concepts, such as intensity-modulated radiotherapy and/or neuroprotective drugs with potential to lower the rates of side effects will eventually be superior to conventional therapy. This in turn will lead to a re-evaluation whether benefits might then outweigh the (lowered) risks.