Health economics of targeted intraoperative radiotherapy (TARGIT-IORT) for early breast cancer: a cost-effectiveness analysis in the United Kingdom

Objective: The clinical effectiveness of targeted intraoperative radiotherapy (TARGIT-IORT) has been confirmed in the randomised TARGIT-A (targeted intraoperative radiotherapy-alone) trial to be similar to a several weeks’ course of whole-breast external-beam radiation therapy (EBRT) in patients with early breast cancer. This study aims to determine the cost effectiveness of TARGIT-IORT to inform policy decisions about its wider implementation. Setting TARGIT-A randomised clinical trial (ISRCTN34086741) which compared TARGIT with traditional EBRT and found similar breast cancer control, particularly when TARGIT was given simultaneously with lumpectomy. Methods: Cost-utility analysis using decision analytic modelling by a Markov model. A cost-effectiveness Markov model was developed using TreeAge Pro V.2015. The decision analytic model compared two strategies of radiotherapy for breast cancer in a hypothetical cohort of patients with early breast cancer based on the published health state transition probability data from the TARGIT-A trial. Analysis was performed for UK setting and National Health Service (NHS) healthcare payer’s perspective using NHS cost data and treatment outcomes were simulated for both strategies for a time horizon of 10 years. Model health state utilities were drawn from the published literature. Future costs and effects were discounted at the rate of 3.5%. To address uncertainty, one-way and probabilistic sensitivity analyses were performed. Main outcome measures: Quality-adjusted life-years (QALYs). Results: In the base case analysis, TARGIT-IORT was a highly cost-effective strategy yielding health gain at a lower cost than its comparator EBRT. Discounted TARGITIORT and EBRT costs for the time horizon of 10 years were £12 455 and £13 280, respectively. TARGIT-IORT gained 0.18 incremental QALY as the discounted QALYs gained by TARGIT-IORT were 8.15 and by EBRT were 7.97 showing TARGIT-IORT as a dominant strategy over EBRT. Model outputs were robust to one-way and probabilistic sensitivity analyses. Conclusions: TARGIT-IORT is a dominant strategy over EBRT, being less costly and producing higher QALY gain

Fraction of normal remaining life span: a new method for expressing survival in cancer

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Single-dose intraoperative radiotherapy during lumpectomy for breast cancer:an innovative patient-centred treatment

In the randomised TARGIT-A trial, risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy was non-inferior to whole-breast external beam radiotherapy, for local recurrence. In the long-term, no difference was found in any breast cancer outcome, whereas there were fewer deaths from non-breast-cancer causes. TARGIT-IORT should be included in pre-operative consultations with eligible patients

Breast cancer and the black swan

Publication costs for this article were supported by ecancer (UK Charity number 1176307).Peer reviewedPublisher PD

Breast Conserving Surgery in Combination With Targeted Intraoperative Radiotherapy Compared to Mastectomy for In-breast-tumor-recurrence

BACKGROUND/AIM: Mastectomy is the standard treatment of in-breast-recurrence of breast cancer after breast conserving surgery (BCS) and external beam radiation therapy (EBRT). In selected cases, it is possible to preserve the breast if targeted intraoperative radiotherapy (TARGIT-IORT) can be given during the second lumpectomy. This is a comparative analysis of overall survival and quality of life (QoL). PATIENTS AND METHODS: Patients in our database with in-breast-recurrence and either mastectomy or BCS and TARGIT-IORT were included. Identified patients were offered participation in a prospective QoL-analysis using the BREAST-Q questionnaire. The cohorts were compared for confounding parameters, overall survival, and QoL. RESULTS: Thirty-six patients treated for in-breast-recurrence were included, 21 had received a mastectomy and 16 patients had received BCS with TARGIT-IORT. Mean follow-up was 12.8 years since primary diagnosis and 4.2 years since recurrence. Both groups were balanced regarding prognostic parameters. Overall survival was numerically longer for BCS and TARGIT-IORT, but the numbers were too small for formal statistical analysis. No patient had further in-breast-recurrence. Psychosocial and sexual wellbeing did not differ between both groups. Physical wellbeing was significantly superior for those whose breast could be preserved (p-value=0.021). Patient-reported incidence and severity of lymphedema of the arm was significantly worse in the mastectomy group (p=0.007). CONCLUSION: Preserving the breast by use of TARGIT-IORT was safe with no re-recurrence and no detriment to overall survival in our analysis and led to a statistically significant improvement in physical wellbeing and incidence of lymphedema. These data should increase the confidence in offering breast preservation after in-breast-recurrence of breast cancer

Promising development from translational or perhaps anti-translational research in breast cancer

Background: A great deal of the public’s money has been spent on cancer research but demonstrable benefits to patients have not been proportionate. We are a group of scientists and physicians who several decades ago were confronted with bimodal relapse patterns among early stage breast cancer patients who were treated by mastectomy. Since the bimodal pattern was not explainable with the then well-accepted continuous growth model, we proposed that metastatic disease was mostly inactive before surgery but was driven into growth somehow by surgery. Most relapses in breast cancer would fall into the surgery-induced growth category thus it was highly important to understand the ramifications of this process and how it may be curtailed. With this hypothesis, we have been able to explain a wide variety of clinical observations including why mammography is less effective for women age 40–49 than it is for women age 50–59, why adjuvant chemotherapy is most effective for premenopausal women with positive lymph nodes, and why there is a racial disparity in outcome. Methods: We have been diligently looking for new clinical or laboratory information that could provide a connection or correlation between the bimodal relapse pattern and some clinical factor or interventional action and perhaps lead us towards methods to prevent surgery-initiated tumor activity. Results: A recent development occurred when a retrospective study appeared in an anesthesiology journal that suggested the perioperative NSAID analgesic ketorolac seems to reduce early relapses following mastectomy. Collaborating with these anesthesiologists to understand this effect, we independently re-examined and updated their data and, in search of a mechanism, focused in on the transient systemic inflammation that follows surgery to remove a primary tumor. We have arrived at several possible explanations ranging from mechanical to biological that suggest the relapses avoided in the early years do not show up later. Conclusions: We present the possibility that a nontoxic and low cost intervention could prevent early relapses. It may be that preventing systemic inflammation post surgery will prevent early relapses. This could be controlled by the surgical anesthesiologist’s choice of analgesic drugs. This development needs to be confirmed in a randomized controlled clinical trial and we have identified triple negative breast cancer as the ideal subset with which to test this. If successful, this would be relatively easy to implement in developing as well as developed countries and would be an important translational result

Cosmetic outcome as rated by patients, doctors, nurses and BCCT.core software assessed over 5 years in a subset of patients in the TARGIT-A trial

Background: The purpose of this research was to assess agreement between four rating systems of cosmetic outcome measured in a subset of patients with early breast cancer participating in the randomised TARGIT-A trial. TARGIT-A compared risk-adapted single-dose intra-operative radiotherapy (TARGIT-IORT) to whole breast external beam radiotherapy (EBRT). Methods: Patients, their Radiation Oncologist and Research Nurse completed a subjective cosmetic assessment questionnaire before radiotherapy and annually thereafter for five years. Objective data previously calculated by the validated BCCT.core software which utilizes digital photographs to score symmetry, colour and scar was also used. Agreement was assessed by the Kappa statistic and longitudinal changes were assessed by generalized estimating equations. Results: Overall, an Excellent-Good (EG) cosmetic result was scored more often than a Fair-Poor (FP) result for both treatment groups across all time points, with patients who received TARGIT-IORT scoring EG more often than those who received EBRT however this was statistically significant at Year 5 only. There was modest agreement between the four rating systems with the highest Kappa score being moderate agreement which was between nurse and doctor scores at Year 1 with Kappa = 0.46 (p \u3c 0.001), 95% CI (0.24, 0.68). Conclusion: Despite similar overall findings between treatment groups and rating systems, the inter-rater agreement was only modest. This suggests that the four rating systems utilized may not necessarily be used interchangeably and it is arguable that for an outcome such as cosmetic appearance, the patient’s point of view is the most important. Trial Registration: TARGIT-A ISRCTN34086741, Registered 21 July 2004, retrospectively registered

NSAID analgesic ketorolac used perioperatively may suppress early breast cancer relapse: particular relevance to triple negative subgroup

To explain a bimodal relapse hazard among early stage breast cancer patients treated by mastectomy we postulated that relapses within 4 years of surgery resulted from something that happened at about the time of surgery to provoke sudden exits from dormant phases to active growth. Relapses at 10 months appeared to be surgery-induced angiogenesis of dormant avascular micrometastases. Another relapse mode with peak about 30 months corresponded to sudden growth from a single cell. Late relapses were not synchronized to surgery. This hypothesis could explain a wide variety of breast cancer observations. We have been looking for new data that might provide more insight concerning the various relapse modes. Retrospective data reported in June 2010 study of 327 consecutive patients compared various perioperative analgesics and anesthetics in one Belgian hospital and one surgeon. Patients were treated with mastectomy and conventional adjuvant therapy. Follow-up was average 27.3 months with range 13–44 months. Updated hazard as of September 2011 for this series is now presented. NSAID ketorolac, a common analgesic used in surgery, is associated with far superior disease-free survival in the first few years after surgery. The expected prominent early relapse events are all but absent. In the 9–18 month period, there is fivefold reduction in relapses. If this observation holds up to further scrutiny, it could mean that the simple use of this safe and effective anti-inflammatory agent at surgery might eliminate most early relapses. Transient systemic inflammation accompanying surgery could be part of the metastatic tumor seeding process and could have been effectively blocked by perioperative anti-inflammatory agents. In addition, antiangiogenic properties of NSAIDs could also play a role. Triple negative breast cancer may be the ideal group with which to test perioperative ketorolac to prevent early relapses