TARGIT

This article is about the medical technique. For the business intelligence developer, see TARGIT Business Intelligence.

TARGIT (TARGeted Intra-operative radioTherapy) is a technique of giving radiotherapy to the tissues surrounding a cancer after its surgical removal. The technique was designed in 1998 at the University College London. 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. The ongoing TARGIT-B(oost) randomized controlled trial is testing whether TARGIT tumour bed boost given after lumpectomy for breast cancer in younger patients or those with a high risk of recurrence, is superior to conventional external beam radiotherapy boost for breast cancer.

Definition of TARGIT

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[1] 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,[2] and the protocol for a randomised trial was published by the Lancet.[3] One can say that TARGIT is a special method of intraoperative radiotherapy (IORT).

Rationale of TARGIT

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 significantly. 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.[4] 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 tumor 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. However, it has a few drawbacks; for example, the tumour bed where the boost dose should be applied can be missed ("geographical miss") due to the difficulties in localization of the complex wound cavity even when modern radiotherapy planning is used. Additionally, the usual delay ("temporal miss") between the surgical removal of the tumour and EBRT may allow a repopulation of the tumour cells. These potentially harmful effects can be avoided by delivering the radiation more precisely to the targeted tissues leading to immediate sterilization of residual tumour cells. Furthermore, TARGIT inhibits the stimulating effects of wound fluid on cancer cells, suggesting for the first time, a beneficial effect of intraoperative radiotherapy (IORT) on tumour microenvironment.[5][6]

The TARGIT technique

TARGeted Intraoperative radioTherapy (TARGIT) IORT for breast cancer

The machine used for TARGIT is Intrabeam (Carl Zeiss, Germany). 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 ionization 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. The radiation which is produced by mobile radiation systems has a limited range. For this reason, conventional walls are regarded sufficient to stop the radiation scatter produced in the operating room and no extra measures for radiation protection are necessary. This makes IORT for breast cancer by the TARGIT technique available in most operating rooms. The surgical technique[7] is relatively simple but needs to be meticulously followed.[8]

Clinical applications

TARGIT for 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.[9]

TARGIT-A (Alone)

The TARGIT-A Trial was an international multicenter prospective randomised phase 3 clinical trial designed to test whether a single dose of targeted intraoperative radiotherapy could replace the usual 3-6 week course of postoperative radiotherapy. The original trial original accrual goal of 2232 breast cancer patients was completed in 2010 and the results were announced at the American Society of Clinical Oncology meeting in Chicago (ASCO, June 4–8, 2010) and simultaneously published online on 5 June 2010 in the Lancet - Online First.[10] The local tumour control using single-dose targeted intraoperative radiotherapy was found to be equivalent to several weeks' of whole breast external beam radiotherapy. The difference in local recurrece rate between the two treatments at 4 years was 0.25% (95% CI -1.0% to +1.5%) which means that TARGIT could be at most 1.5% worse or 1% better than whole breast radiotherapy. TARGIT also caused less radiotherapy related toxicity than whole breast radiotherapy. A brief explanation of the results is at and in a short interview on eCancerTV.

In an invited lecture at the Churchill Hospital in Oxford in 2010, quoted in the Sydney Morning Herald, Professor John Boyages, author of Breast Cancer:Taking Control l expressed concern about the early release of the TARGIT trial. He noted that the average follow-up for all patients in the trial was only 2 years and that this was far too short to determine its routine efficacy . However, this criticism had already been addressed by the authors within the original paper PDF.

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, or as a tumour bed boost instead of external beam radiotherapy boost. At the Miami Breast Cancer conference (14–17 March 2012), 91% of the audience in the surgical oncology stream felt the same.

At the San Antonio Breast Cancer Symposium (3–8 December 2012), updated results of the IORT for breast cancer - TARGIT-A trial, which closed after recruiting 3451 patients, were presented and showed that giving TARGIT at the time of lumpectomy, gives results similar to whole breast radiotherapy in terms of breast cancer control (particularly in ER PR positive cases), with fewer non-breast cancer deaths[11] and a trend for lower overall mortality compared with conventional external beam whole breast radiotherapy. 2012 SABCS, Thursday 6 December, General Session 4.

The breast's normal tissue tolerance to radiation does not allow a second full-dose course of EBRT, even after several years. TARGIT and other forms of partial breast irradiation may be an option for selected patients with local recurrence of breast cancer after traditional radiation therapy.

Peer-reviewed publication of these main results in the Lancet from this updated analysis of mature data of TARGIT on 11 November 2013 showed

The authors concluded that TARGIT during lumpectomy should be offered as an alternative to whole breast radiotherapy in suitable patients.[12] The results of TARGIT TARGIT IORT for breast cancer are discussed in a podcast of the TARGIT-A and ELIOT trials on the Lancet website.. As the effect of radiotherapy on local recurrence of breast cancer is mostly in the first 2–3 years and almost none after the first 5 years, it is thought that sufficiently large number of patients in the TARGIT-A trial have an adequately long follow up . A robust response to scientifically weak criticisms for use of TARGIT IORT during lumpectomy breast cancer, including a decision aid (figure 4) is given in the Red Journal.[13] 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.[14] The 2015 update of guidelines of the Association of Gynecological Oncology (AGO), an autonomous community of the German Society of Gynecology 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 2015E_Updated_guidelines-see-page-633

TARGIT-B (Boost)

TARGIT as a tumour bed boost:' In conventional EBRT, the boost is delivered at the end of a complete course of EBRT. Clinical evidence suggests that boost radiation improves treatment outcome for breast cancer.[15] With TARGIT the boost can be delivered intraoperatively without any delay and more precisely as compared to conventional EBRT. A multicenter clinical trial has demonstrated that the boost administered with IORT resulted in a lower than expected rate of local recurrence (1.73%) as compared to an EORTC study which used external boost radiation.[16][17][18] As a tumour bed boost, TARGIT has been found to have a better than expected effectiveness[9][17][18] These results have prompted the inclusion of TARGIT boost as an option to EBRT boost in national clinical guidelines of many countries including Germany. Whether TARGIT is superior to an EBRT boost is being tested in a randomised trial IORT Boost TARGIT-B trial.

TARGIT for other organs

IORT was found to be useful and feasible in the multidisciplinary management of many solid tumours but further studies are needed to determine the benefit more precisely. Single-institution experiences have suggested a role of IORT e.g. in brain tumours and cerebral metastases, spinal metastasis,[19] locally advanced and recurrent rectal cancer, skin cancer, retroperitoneal sarcoma, pancreatic cancer and selected gynaecologic and genitourinary malignancies.[20]

' Other study groups using similar protocols and concepts have also demonstrated the effectiveness and safety of IORT in breast cancer patients.,[21][22]

Tolerability

IORT with the TARGIT technique has had a long clinical experience since 1998 and is found to be safe and well tolerated.

Pilot studies: In a study which examined acute side effects after boost radiation in patients with breast cancer, treatment was well tolerated with no grade 3/4 acute toxicity. Rare adverse effects following TARGIT included wound healing problems (2%), erythema grade I-II (3%), palpable seroma (6%) and mastitis (2–4%).[23][24]

Large prospective randomised study In the randomised TARGIT-A trial, the overall complications was equivalent between TARGIT and whole breast radiotherapy. There were more seroma needing aspiration in the TARGIT group. This was more than compensated for by the more troublesome radiotherapy related side effects that were less common with TARGIT than with whole breast radiotherapy.

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.[25]

See also

References

  1. ↑ Vaidya, Jayant S. A Novel Approach to local treatment of breast cancer (PhD thesis). University of London.
  2. ↑ Vaidya JS, Baum M, Tobias JS et al. (August 2001). "Targeted intra-operative radiotherapy (Targit): an innovative method of treatment for early breast cancer". Ann. Oncol. 12 (8): 1075–80. doi:10.1023/A:1011609401132. PMID 11583188.
  3. ↑ Vaidya JS, Baum M, Tobias JS, Houghton J. "Targeted Intraoperative Radiotherapy (TARGIT)-trial protocol". Lancet.
  4. ↑ Vaidya JS, Vyas JJ, Chinoy RF, Merchant N, Sharma OP, Mittra I (September 1996). "Multicentricity of breast cancer: whole-organ analysis and clinical implications". Br. J. Cancer 74 (5): 820–4. doi:10.1038/bjc.1996.442. PMC 2074702. PMID 8795588.
  5. ↑ Massarut S, Baldassare G, Belleti B, Reccanello S, D'Andrea S, Ezio C, Perin T, Roncadin M, Vaidya JS (2006). "Intraoperative radiotherapy impairs breast cancer cell motility induced by surgical wound fluid". J Clin Oncol 24 (18S): 10611.
  6. ↑ Belletti B, Vaidya JS, D'Andrea S et al. (March 2008). "Targeted intraoperative radiotherapy impairs the stimulation of breast cancer cell proliferation and invasion caused by surgical wounding". Clin. Cancer Res. 14 (5): 1325–32. doi:10.1158/1078-0432.CCR-07-4453. PMID 18316551.
  7. ↑ Vaidya JS, Baum M, Tobias JS, Morgan S, D'Souza D (June 2002). "The novel technique of delivering targeted intraoperative radiotherapy (Targit) for early breast cancer" ({). Eur J Surg Oncol 28 (4): 447–54. doi:10.1053/ejso.2002.1275. PMID 12099658.}
  8. ↑ The surgical technique of IORT for breast cancer
  9. ↑ 9.0 9.1 Vaidya JS, Baum M, Tobias JS et al. (December 2006). "Targeted intraoperative radiotherapy (TARGIT) yields very low recurrence rates when given as a boost". Int. J. Radiat. Oncol. Biol. Phys. 66 (5): 1335–8. doi:10.1016/j.ijrobp.2006.07.1378. PMID 17084562.
  10. ↑ Vaidya JS, Joseph DJ, Tobias JS, Bulsara M, Wenz F, Saunders C, Alvarado M, Flyger HL, Massarut S, Eiermann W, Keshtgar M, Dewar J, Kraus-Tiefenbacher U, Sutterlin M, Esserman L, Holtveg HM, Roncadin M, Pigorsch S, Metaxas M, Falzon M, Matthews A, Corica T, Williams NR, Baum M. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet. 2010;376(9735):91-102.
  11. ↑ Vaidya, Jayant S; Bulsara M, Wenz, F (27 June 2013). "Ischemic Heart Disease after Breast Cancer Radiotherapy". New England Journal of Medicine 368 (26): 2523–2527. doi:10.1056/NEJMc1304601.
  12. ↑ Vaidya, Jayant S; Wenz F, Bulsara M, Tobias JS, Joseph DD.... Baum M. (11 November 2013). "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". The Lancet. doi:10.1016/S0140-6736(13)61950-9.
  13. ↑ Vaidya, Jayant S; Bulsara, Max; Wenz, Frederik; Joseph, David; Saunders, Christobel; Massarut, Samuele; Flyger, Henrik; Eiermann, Wolfgang; Alvarado, Michael; Esserman, Laura; Falzon, Mary; Brew-Graves, Chris; Potyka, Ingrid; Tobias, Jeffrey S; Baum, Michael; On behalf of the TARGIT trialists' group (7 April 2015). "Pride, Prejudice, or Science – attitudes towards the results of the TARGIT-A trial of targeted intraoperative radiotherapy for breast cancer". International Journal of Radiation Oncology*Biology*Physics. doi:10.1016/j.ijrobp.2015.03.022.
  14. ↑ The Times, London, UK
  15. ↑ Bartelink H, Horiot JC, Poortmans P et al. (November 2001). "Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation". N. Engl. J. Med. 345 (19): 1378–87. doi:10.1056/NEJMoa010874. PMID 11794170.
  16. ↑ Vaidya JS, Baum M, Tobias JS et al. (May 2008). "Efficacy of Targeted Intraoperative Radiotherapy (TARGIT) boost after breast conserving surgery: Updated results". J Clin Oncol 26 (20 Suppl): abstr 565.
  17. ↑ 17.0 17.1 Vaidya JS, Baum M, Tobias J, Massarut S, Wenz F, Hilaris B, Corica T, Roncadin M, Kraus-Tiefenbacher U, Keshtgar M, Williams N, Brew-Graves C, Bulsara M, Saunders C, Joseph D (2009). "Targeted Intraoperative Radiotherapy (Targit) Boost after Breast Conserving Surgery Results in a Remarkably Low Recurrence Rate in a Standard Risk Population: 5 Year Results". Cancer Res. 69 (24 Suppl): Abstract nr 4104. doi:10.1158/0008-5472.SABCS-09-4104.
  18. ↑ 18.0 18.1 Vaidya, J. S.; Baum, M.; Tobias, J. S.; Wenz, F.; Massarut, S.; Keshtgar, M.; Hilaris, B.; Saunders, C.; Williams, N. R.; Brew-Graves, C.; Corica, T.; Roncadin, M.; Kraus-Tiefenbacher, U.; Sütterlin, M.; Bulsara, M.; Joseph, D. (15 Nov 2011). "Long-term Results of Targeted Intraoperative Radiotherapy (Targit) Boost during Breast-conserving Surgery". International Journal of Radiation OncologyBiologyPhysics 81 (4): 1091–1097. doi:10.1016/j.ijrobp.2010.07.1996. PMID 20951505.
  19. ↑ Reis, T; Schneider, F; Welzel, G; Schmidt, R; Bludau, F; Obertacke, U; Wenz, F (Jul–Aug 2012). "Intraoperative radiotherapy during kyphoplasty for vertebral metastases (Kypho-IORT): first clinical results.". Tumori 98 (4): 434–40. doi:10.1700/1146.12636. PMID 23052158.
  20. ↑ Skandarajah AR, Lynch AC, Mackay JR, Ngan S, Heriot AG (March 2009). "The role of intraoperative radiotherapy in solid tumors". Ann. Surg. Oncol. 16 (3): 735–44. doi:10.1245/s10434-008-0287-2. PMID 19142683.
  21. ↑ Reitsamer R, Sedlmayer F, Kopp M et al. (2008). "Concepts and techniques of intraoperative radiotherapy (IORT) for breast cancer". Breast Cancer 15 (1): 40–6. doi:10.1007/s12282-007-0001-4. PMID 18224393.
  22. ↑ Ivaldi GB, Leonardi MC, Orecchia R et al. (October 2008). "Preliminary results of electron intraoperative therapy boost and hypofractionated external beam radiotherapy after breast-conserving surgery in premenopausal women". Int. J. Radiat. Oncol. Biol. Phys. 72 (2): 485–93. doi:10.1016/j.ijrobp.2007.12.038. PMID 18407434.
  23. ↑ Kraus-Tiefenbacher U, Bauer L, Kehrer T, Hermann B, Melchert F, Wenz F (March 2006). "Intraoperative radiotherapy (IORT) as a boost in patients with early-stage breast cancer -- acute toxicity". Onkologie 29 (3): 77–82. doi:10.1159/000091160. PMID 16514267.
  24. ↑ Kraus-Tiefenbacher U, Bauer L, Scheda A et al. (October 2006). "Long-term toxicity of an intraoperative radiotherapy boost using low energy X-rays during breast-conserving surgery". Int. J. Radiat. Oncol. Biol. Phys. 66 (2): 377–81. doi:10.1016/j.ijrobp.2006.05.042. PMID 16887294.
  25. ↑ http://www.isiort.org/htm/index.shtm

External links