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A multimodal pattern of hazard of relapse among early stage breast cancer patients has been identified in multiple databases from US, Europe and Asia. What began as a simple investigation of these anomalous data has taken the authors on a path through a diverse variety of clinical topics involving a number of medical specialties and now proposing a clinical trial in Nigeria. We have been studying these data to determine if this can lead to new ideas on how to prevent relapse in breast cancer. Using computer simulation and access to a very high quality database from Milan for patients treated with mastectomy, we proposed that relapses within 3 years of surgery are stimulated somehow by the surgical procedure. Most relapses in breast cancer are in this early category. Retrospective data from a Brussels anesthesiology group suggests a plausible mechanism. Use of ketorolac, a common NSAID analgesic used in surgery was associated with far superior disease-free survival in the first 5 years after surgery. The expected prominent early relapse events in months 9-18 are reduced 5-fold. Transient systemic inflammation accompanying surgery (identified by IL-6 in serum) could facilitate angiogenesis of dormant micrometastases, proliferation of dormant single cells, and seeding of circulating cancer stem cells (perhaps in part released from bone marrow) resulting in early relapse and could have been effectively blocked by the perioperative anti-inflammatory agent. If this observation holds up to further scrutiny, it could mean that the simple use of this safe, inexpensive and effective anti-inflammatory agent at surgery might eliminate early relapses. We suggest this would be most effective for triple negative breast cancer and be especially valuable in low and middle income countries. Similar bimodal patterns have been identified in other cancers suggesting a general effect. Conclusions reached in this chapter: 1. We are proposing an answer to an unsolved two thousand year old problem in oncology. 2. Early relapses in breast cancer which comprise the majority of relapses consist of surges of angiogenesis and single cell activation from dormant states. These events are triggered by primary surgery. 3. Forget et al retrospective data suggest perioperative NSAID ketorolac reduces early relapses 5-fold. While we are cautiously optimistic, this still needs to be confirmed. If confirmed, this may reduce breast cancer mortality by 25 to 50% at low cost and toxicity. As the only possible adverse effects, there are the usual risks associated with NSAIDs 4. These data suggest transient systemic inflammation is the precipitating factor resulting in angiogenesis and single cell growth from dormancy. We do not claim to know all the relevant mechanisms but it does seem that systemic inflammation after primary surgery initiates the process. 5. Breast cancer runs its course in over a decade but relevant events leading to most relapses seem to occur in the week after surgery. 6. Based on computations using our simulation, this suggests metastatic progression is amplified by perhaps 100 fold during the week post primary surgery. 7. A small trial is underway in Belgium and we have identified India and especially sub-Saharan Africa as excellent places to conduct a clinical trial (high incidence of TNBC & early onset). Protocol is published (Demicheli et al 2016). Retsky visited Nigeria three times in the past few years. 8. As ketorolac is about $2, used at most a few times per patient and there are approximately 2 million new breast cancer cases discovered every year, an expenditure of $10 million could reduce the breast cancer problem by 25 to 50% in the world. (That is both the good news and the bad news.)

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Digital Access to Scholarship at Harvard  


Retsky, Michael W. -  Demicheli, Romano - 

Id.: 70835347

Idioma: inglés (Estados Unidos)  - 

Versión: 1.0

Estado: Final

Tipo de recurso: Monograph or Book  - 

Tipo de Interactividad: Expositivo

Nivel de Interactividad: muy bajo

Audiencia: Estudiante  -  Profesor  -  Autor  - 

Estructura: Atomic

Coste: no

Copyright: sí

: closed access

Requerimientos técnicos:  Browser: Any - 

Relación: [References] 10.1007/978-3-319-57943-6
[References] Perioperative Inflammation as Triggering Origin of Metastasis Development

Fecha de contribución: 07-ene-2018


* Retsky, Michael W., and Romano Demicheli. 2017. Perioperative Inflammation as Triggering Origin of Metastasis Development. In Perioperative Inflammation as Triggering Origin of Metastasis Development, eds. Michael W. Retsky and Romano Demicheli, 19-53. Houton, Netherlands: Springer International Publishing.
* 978-3-319-57943-6

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