Targeted intra-operative radiotherapy

Targeted intra-operative radiotherapy
The equipment and process of TARGIT intra-operative radiotherapy
Other namesTARGIT
Specialtyoncology

Targeted intra-operative radiotherapy, also known as targeted IORT is a technique of giving radiotherapy to the tissues surrounding a cancer after its surgical removal, a form of intraoperative radiation therapy. The technique was designed in 1998 at the University College London.[1] In patients having lumpectomy for breast cancer, the TARGIT-A(lone) randomized controlled trial (recruitment from 2000–2012) tested whether TARGIT within a risk-adapted approach is non-inferior to conventional course of external beam postoperative radiotherapy given over several weeks.[2]

One IORT technique is known as TARGIT (TARGeted Intraoperative radioTherapy). TARGIT is a method where the radiation is applied during an operation and targeted to the peri-tumoural tissues. TARGIT technique was designed at University College London[3] by Jayant S. Vaidya (who coined the TARGIT acronym) and Michael Baum along with Jeffrey S Tobias in 1998. The term was first used when the technique was described,[4] and the protocol for a randomised trial was published by The Lancet.[5]

Medical uses

Breast cancer

The largest experience with IORT using the TARGIT technique and the best evidence for its potentials exists in breast cancer where a substantial number of patients have already been treated.[6]

Adoption

At the St Gallen Breast Cancer Conference (16–19 March 2011) the consensus amongst over 52 breast cancer expert panelists was that TARGIT alone could be used as the only radiation treatment in selected cases after breast conserving surgery (49% yes, 36% no), or as a tumour bed boost instead of external beam radiotherapy boost (62% yes, 23% no).[7]

On 25 July 2014 the UK National Institute for Health and Care Excellence (NICE) gave provisional recommendation for the use of TARGIT IORT with Intrabeam in the UK National Health Service.[8][9] In September 2014, NICE requested further information from the clinical trial investigators, citing several comments and concerns.[10] Concerns cited included the immaturity of the data with a median follow up of the entire population being only 2 years and 5 months as well as the noninferiority criterion used in the study.[11] This extra information was supplied by the authors, and has since been published as part of the comprehensive paper on TARGIT-A trial.[12] In 2017, NICE described it as an option for early breast cancer.[13]

The 2015 update of guidelines of the Association of Gynaecological Oncology (AGO) (an autonomous community of the German Society of Gynaecology and Obstetrics (DGGG) and the German Cancer Society) includes TARGIT IORT during lumpectomy as a recommended option for women with a T1, Grade 1 or 2, ER positive breast cancer.[14]

On 21 May 2015, the Australian Government Medical Services Advisory Committee (MSAC) announced that "After considering the available evidence in relation to safety, clinical effectiveness and cost-effectiveness, MSAC supported public funding of a new Medicare Benefits Schedule (MBS) item for treatment of pathologically documented invasive ductal breast cancer in eligible patients with TARGIT-IORT when used concurrently with breast-conserving surgery".[15] The Australian Government also approved budget item for the treatment of early stage breast cancer using targeted intraoperative radiotherapy[16] and patients can avail of this treatment from 1 September 2015.[17]

On 26 May 2015, in response to a query by the British Medical Journal, NICE clarified that while their appraisal is going on, TARGIT IORT with Intrabeam can continue to be offered to patients who need it.[18]

About 260 centres in over 35 countries including North America (about 80 centres), South America, Europe (e.g., 60 centres in Germany), Australia, Middle East (e.g., 9 centres in Israel), and the Far East are currently using TARGIT IORT for breast cancer treatment, and over 45,000 patients have so far been treated using TARGIT IORT.[19] Several independent studies from USA, South America, Denmark, Germany, France, Switzerland, Russia, South Korea, Singapore, South Africa, and China have found excellent results with the use of TARGIT IORT.[19][20][21]

Evaluation of the long-term outcomes in patients who were treated with TARGIT-IORT for breast cancer confirmed that it is as effective as whole breast external beam radiotherapy in controlling cancer, and also reduces deaths from other causes [22][23] as shown in a large international randomised clinical trial published in the British Medical Journal.[24]

According to a recent report, while deaths from breast cancer with more focussed radiation (TARGIT-IORT) were similar to whole breast radiation, deaths from other causes such as cardiovascular or lung problems or from other cancers were found to be substantially reduced from 9.85% to 5.41% over a 12-year follow up.[25] Compared with whole breast radiation, the risk-adapted TARGIT-IORT approach needs fewer hospital visits and has lower toxicity. Other benefits include reduced breast pain, a better quality of life and a cosmetically superior outcome.

The TARGIT-A trial included a large number of higher-risk patients: 1898 (83%) were younger than 70 years, 366 (16%) had tumours >2 cm in size, 443 (20%) patients had grade 3 cancers, 488 (22%) patients had involved nodes, and 426 (19%) had ER- or PgR-negative tumours. Therefore, the TARGIT-IORT approach is suitable for patients with much wider selection criteria compared with other partial breast radiation techniques The eligibility criteria are age >=45 years with breast cancer (invasive ductal carcinoma) suitable for breast preservation, with tumour size less than 3.5 cm in size.[25]

Rationale

When breast cancer is surgically excised, it can come back (local recurrence) in the remaining breast or on the chest wall in a small proportion of women. Adjuvant radiotherapy is necessary if breast cancer is treated by removing only the cancerous lump with a rim of surrounding normal tissue, as it reduces the chance of local recurrence.[26][27][28][29] When cancer does come back, it most commonly occurs in the tissues surrounding the original cancer (the tumour bed), even though there are multicentric cancers in remote areas of the breast. This suggests that it is most important to treat the tumour bed.[30]

The rationale for TARGIT is to deliver a high dose of radiation precisely to the tumour bed. Conventional radiation techniques such as external beam radiotherapy (EBRT) following surgical removal of the tumour have been time tested and proven to be effective. EBRT is usually given as a course of whole breast radiotherapy and an additional tumour bed boost, or partial breast irradiation of a smaller area.[31][32] However, it has a few drawbacks; for example, the tumour bed where the boost dose should be applied can be missed due to the difficulties in localization of the complex wound cavity ("geographical miss"), even when modern radiotherapy planning is used. Additionally, the usual delay between the surgical removal of the tumour and EBRT may allow a repopulation of the tumour cells ("temporal miss"). These potentially harmful effects may be avoided by delivering the radiation more precisely to the targeted tissues leading to immediate sterilization of residual tumour cells.[33] The use in TARGIT of a small treatment device which can be positioned in close physical proximity to the treatment site aims to avoid some of these practical issues. TARGIT irradiation has also been shown to affect the properties of wound fluid, which may be linked to cancer cell proliferation and possibly local recurrence.[34][35] Based on results from the TARGIT-A trial it has been hypothesised that TARGIT may have an abscopal effect reducing the risk of non-cancer death, although this is not proven.[36][37]

Technique

The Intrabeam system, manufactured by Carl Zeiss AG, is used for TARGIT.[38] It is a miniature and mobile X-ray source which emits low energy X-ray radiation (max. 50 kV) in isotropic distribution. Due to the higher ionisation density caused by soft X-ray radiation in the tissue, the relative biological effectiveness (RBE) of low-energy X-rays on tumour cells is higher when compared to high-energy X-rays or gamma rays which are delivered by linear accelerators.[39] Lower energy radiation such as this has a limited range, and therefore conventional walls may be sufficient to stop the radiation scatter produced in the operating room without extra measures for radiation protection.[40][41]

Professional Society for Intraoperative Radiation Therapy

In 1998, the International Society of IORT (ISIORT) was formed to foster the scientific and clinical development of IORT. The ISIORT has more than 1000 members worldwide and meets every two years.[42]

See also

References

  1. ↑ "TARGIT: transforming the breast cancer treatment paradigm". University College London. 2014-12-14. Retrieved 26 July 2016.
  2. ↑ Vaidya JS, Wenz F, Bulsara M, Tobias JS, Joseph DJ, Keshtgar M, et al. (February 2014). "Risk-adapted targeted intraoperative radiotherapy versus whole-breast radiotherapy for breast cancer: 5-year results for local control and overall survival from the TARGIT-A randomised trial". Lancet. 383 (9917): 603–13. doi:10.1016/S0140-6736(13)61950-9. PMID 24224997.
  3. ↑ Vaidya JS (2002). A Novel Approach to local treatment of breast cancer (PhD thesis). University of London.
  4. ↑ Vaidya JS, Baum M, Tobias JS, D'Souza DP, Naidu SV, Morgan S, et al. (August 2001). "Targeted intra-operative radiotherapy (Targit): an innovative method of treatment for early breast cancer". Annals of Oncology. 12 (8): 1075–80. doi:10.1023/A:1011609401132. PMID 11583188.
  5. ↑ Vaidya JS, Baum M, Tobias JS, Houghton J. "Targeted Intraoperative Radiotherapy (TARGIT)-trial protocol". The Lancet.
  6. ↑ Vaidya JS, Baum M, Tobias JS, Massarut S, Wenz F, Murphy O, et al. (December 2006). "Targeted intraoperative radiotherapy (TARGIT) yields very low recurrence rates when given as a boost". International Journal of Radiation Oncology, Biology, Physics. 66 (5): 1335–8. doi:10.1016/j.ijrobp.2006.07.1378. PMID 17084562.
  7. ↑ Gnant M, Harbeck N, Thomssen C (2011). "St. Gallen 2011: Summary of the Consensus Discussion". Breast Care. 6 (2): 136–141. doi:10.1159/000328054. PMC 3100376. PMID 21633630.
  8. ↑ "NICE to recommend new breast cancer radiotherapy treatment alongside further research | Press and media | News". NICE. 2014-07-24. Retrieved 2016-05-18.
  9. ↑ Smyth C (2014). "Single-dose radiotherapy eases breast cancer stress". The Times. Retrieved 26 July 2016.
  10. ↑ "Breast cancer (early) - intrabeam radiotherapy system [ID618]". NICE. Retrieved 26 July 2016.
  11. ↑ NICE concerns and requested actions for TARGIT Trialists
  12. ↑ Vaidya JS, Wenz F, Bulsara M, Tobias JS, Joseph DJ, Saunders C, et al. (September 2016). "An international randomised controlled trial to compare TARGeted Intraoperative radioTherapy (TARGIT) with conventional postoperative radiotherapy after breast-conserving surgery for women with early-stage breast cancer (the TARGIT-A trial)". Health Technology Assessment. 20 (73): 1–188. doi:10.3310/hta20730. PMC 5056335. PMID 27689969.
  13. ↑ Wise J (February 2017). "NICE recommends controlled intrabeam use for breast cancer after three year delay". BMJ. 356: j725. doi:10.1136/bmj.j725. PMID 28188126. S2CID 27304777.
  14. ↑ "Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer" (PDF). AGO. Retrieved 26 July 2016.
  15. ↑ "Application 1189 - Targeted intraoperative radiotherapy (T-IORT) for early breast cancer" (PDF). Medical Services Advisory Committee. Australian Government. Retrieved 26 July 2016.
  16. ↑ Health. "Budget Paper No. 2: Budget Measures - Part 2: Expense Measures - Health". Budget.gov.au. Retrieved 2016-05-18.
  17. ↑ "Revolution in Radiotherapy". The West Australian. 31 August 2015. Archived from the original on 5 March 2016. Retrieved 26 July 2016.
  18. ↑ Hawkes N (May 2015). "Start of cheaper technique for breast cancer is delayed in UK despite adoption elsewhere". BMJ. 350 (may26 14): h2874. doi:10.1136/bmj.h2874. PMID 26013648. S2CID 34424227.
  19. 1 2 "Vaidya, JS; Vaidya, UJ; Baum, M; Bulsara, M; Joseph, D; Tobias, JS; TARGIT-IORT Global Collaborators, ; (2021) Global adoption of single-shot targeted intraoperative radiotherapy (TARGIT-IORT) to improve breast cancer treatment – better for patients, better for health care systems". UCL Discovery. doi:10.14324/000.wp.10121050.
  20. ↑ Valente SA, Tendulkar RD, Cherian S, O'Rourke C, Greif JM, Bailey L, et al. (September 2016). "TARGIT-R (Retrospective): North American Experience with Intraoperative Radiation Using Low-Kilovoltage X-Rays for Breast Cancer". Annals of Surgical Oncology. 23 (9): 2809–15. doi:10.1245/s10434-016-5240-1. PMID 27160524. S2CID 23413489.
  21. ↑ "Indian-origin expert leads UK's major breast cancer radiotherapy study". The Economic Times. Retrieved 2021-03-01.
  22. ↑ Lay K. "New treatment heralds breakthrough for breast cancer patients". The Times. ISSN 0140-0460. Retrieved 2020-09-09.
  23. ↑ "New breast cancer treatment requires just one shot of radiotherapy". The Independent. 2020-08-20. Retrieved 2020-09-17.
  24. ↑ Vaidya JS, Bulsara M, Baum M, Wenz F, Massarut S, Pigorsch S, et al. (August 2020). "Long term survival and local control outcomes from single dose targeted intraoperative radiotherapy during lumpectomy (TARGIT-IORT) for early breast cancer: TARGIT-A randomised clinical trial". BMJ. 370: m2836. doi:10.1136/bmj.m2836. PMC 7500441. PMID 32816842.
  25. 1 2 Vaidya JS, Bulsara M, Baum M, Tobias JS (February 2021). "Single-dose intraoperative radiotherapy during lumpectomy for breast cancer: an innovative patient-centred treatment". British Journal of Cancer. 124 (9): 1469–1474. doi:10.1038/s41416-020-01233-5. PMC 7851812. PMID 33531693.
  26. ↑ Radiotherapy dose fractionation (3rd ed.). London: Royal College of Radiologists. 2019. p. 16.
  27. ↑ Early Breast Cancer Trialists' Collaborative Group (EBCTCG); Darby, S.; McGale, P.; Correa, C.; Taylor, C.; Arriagada, R.; Clarke, M.; Cutter, D.; Davies, C.; Ewertz, M.; Godwin, J.; Gray, R.; Pierce, L.; Whelan, T.; Wang, Y.; Peto, R. (November 2011). "Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10 801 women in 17 randomised trials". The Lancet. 378 (9804): 1707–1716. doi:10.1016/S0140-6736(11)61629-2. PMC 3254252. PMID 22019144.
  28. ↑ Ebctcg (Early Breast Cancer Trialists' Collaborative Group); McGale, P.; Taylor, C.; Correa, C.; Cutter, D.; Duane, F.; Ewertz, M.; Gray, R.; Mannu, G.; Peto, R.; Whelan, T.; Wang, Y.; Wang, Z.; Darby, S. (June 2014). "Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials". The Lancet. 383 (9935): 2127–2135. doi:10.1016/S0140-6736(14)60488-8. PMC 5015598. PMID 24656685.
  29. ↑ O’Rorke, M.A.; Murray, L.J.; Brand, J.S.; Bhoo-Pathy, N. (June 2016). "The value of adjuvant radiotherapy on survival and recurrence in triple-negative breast cancer: A systematic review and meta-analysis of 5507 patients". Cancer Treatment Reviews. 47: 12–21. doi:10.1016/j.ctrv.2016.05.001. PMID 27214603.
  30. ↑ Vaidya JS, Vyas JJ, Chinoy RF, Merchant N, Sharma OP, Mittra I (September 1996). "Multicentricity of breast cancer: whole-organ analysis and clinical implications". British Journal of Cancer. 74 (5): 820–4. doi:10.1038/bjc.1996.442. PMC 2074702. PMID 8795588.
  31. ↑ Haussmann, Jan; Budach, Wilfried; Corradini, Stefanie; Krug, David; Tamaskovics, Balint; Bölke, Edwin; Djiepmo-Njanang, Freddy-Joel; Simiantonakis, Ioannis; Kammers, Kai; Matuschek, Christiane (2020-08-17). "No Difference in Overall Survival and Non-Breast Cancer Deaths after Partial Breast Radiotherapy Compared to Whole Breast Radiotherapy—A Meta-Analysis of Randomized Trials". Cancers. 12 (8): 2309. doi:10.3390/cancers12082309. PMC 7464494. PMID 32824414.
  32. ↑ Vaidya, Jayant S.; Bulsara, Max; Wenz, Frederik; Coombs, Nathan; Singer, Julian; Ebbs, Stephen; Massarut, Samuele; Saunders, Christobel; Douek, Michael; Williams, Norman R.; Joseph, David; Tobias, Jeffrey S.; Baum, Michael (October 2016). "Reduced Mortality With Partial-Breast Irradiation for Early Breast Cancer: A Meta-Analysis of Randomized Trials". International Journal of Radiation Oncology, Biology, Physics. 96 (2): 259–265. doi:10.1016/j.ijrobp.2016.05.008. PMID 27478165.
  33. ↑ Vaidya, Jayant S; Benson, John R; Tobias, Jeffrey S (2013-01-03). "Targeted intraoperative radiotherapy for breast cancer: not all cancers in the breast will grow". In Benson, John R; Gui, Gerald P H; Tuttle, Todd (eds.). Early Breast Cancer: From Screening to Multidisciplinary Management (3rd ed.). Boca Raton: CRC Press. p. 455. ISBN 978-1-84184-886-0.
  34. ↑ Harris, Eleanor E. R.; Small, William (2017-12-22). "Intraoperative Radiotherapy for Breast Cancer". Frontiers in Oncology. 7: 317. doi:10.3389/fonc.2017.00317. PMC 5743678. PMID 29312887.
  35. ↑ Piotrowski, Igor; Kulcenty, Katarzyna; Wichtowski, Mateusz; Murawa, Dawid; Suchorska, Wiktoria (2017). "Intraoperative Radiotherapy of Breast Cancer and Its Biological Effects". Breast Care. 12 (2): 107–111. doi:10.1159/000454673. PMC 5447173. PMID 28559768.
  36. ↑ Kolberg, Hans‑Christian; Loevey, Gyoergy; Akpolat-Basci, Leyla; Stephanou, Miltiades; Fasching, Peter A.; Untch, Michael; Liedtke, Cornelia; Bulsara, Max; Vaidya, Jayant S. (2017-01-01). "Targeted intraoperative radiotherapy tumour bed boost during breast-conserving surgery after neoadjuvant chemotherapy". Strahlentherapie und Onkologie. 193 (1): 62–69. doi:10.1007/s00066-016-1072-y. ISSN 1439-099X. PMID 27858093. S2CID 27474061.
  37. ↑ Vaidya, Jayant S; Bulsara, Max; Baum, Michael; Wenz, Frederik; Massarut, Samuele; Pigorsch, Steffi; Alvarado, Michael; Douek, Michael; Saunders, Christobel; Flyger, Henrik; Eiermann, Wolfgang (2021-05-25). "New clinical and biological insights from the international TARGIT-A randomised trial of targeted intraoperative radiotherapy during lumpectomy for breast cancer". British Journal of Cancer: 1–10. doi:10.1038/s41416-021-01440-8. ISSN 1532-1827. PMC 8329051. PMID 34035435.
  38. ↑ Vaidya JS, Joseph DJ, Tobias JS, Bulsara M, Wenz F, Saunders C, et al. (July 2010). "Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial". Lancet. 376 (9735): 91–102. doi:10.1016/S0140-6736(10)60837-9. PMID 20570343. S2CID 2385098.
  39. ↑ Hill MA (15 December 2004). "The variation in biological effectiveness of X-rays and gamma rays with energy". Radiation Protection Dosimetry. 112 (4): 471–81. doi:10.1093/rpd/nch091. PMID 15623881.
  40. ↑ Holmes, Dennis R. (June 2017). "Early complications after intraoperative radiotherapy revisited". Journal of Surgical Oncology. 115 (7): 779–781. doi:10.1002/jso.24590. PMID 28230251. S2CID 30409236.
  41. ↑ Eaton, D J; Gonzalez, R; Duck, S; Keshtgar, M (November 2011). "Radiation protection for an intra-operative X-ray device". The British Journal of Radiology. 84 (1007): 1034–1039. doi:10.1259/bjr/29466902. PMC 3473704. PMID 21304003.
  42. ↑ "International Society of Intraoperative Radiation Therapy". Retrieved 26 July 2016.
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