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Targeted intra-operative radiotherapy

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This article is about the medical technique. For the Danish 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. Ongoing randomized controlled trials are testing whether TARGIT is either equivalent or superior to conventional course of external beam postoperative radiotherapy for breast cancer.

Definition of TARGIT

TARGIT is a method where the radiation is applied during an operation and targeted to the peri-tumoural tisues. 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 on tumour microenvironment[5][6].

The TARGIT technique

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 TARGIT accessible 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 TARGIT and the best evidence for its potentials exists in breast cancer where a substantial number of patients have already been treated.[9].

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 trial original accrual goal of 2232 is completed 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 [1] and in a short interview on eCancerTV

In an invited lecture at the Churchill Hospital in Oxford, 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 [2].

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.[11]. 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.[12].[13][14]. As a tumour bed boost, TARGIT has been found to have a better than expected effectiveness[9][13][14]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 (TARGIT-B).

The normal tissue tolerance does not allow a second full-dose course of EBRT, even after several years. So, TARGIT is an option for patients with recurring cancer that already had traditional radiation therapy and are not suitable for a second radiation treatment.

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, locally advanced and recurrent rectal cancer, skin cancer, retroperitoneal sarcoma, pancreatic cancer and selected gynaecologic and genitourinary malignancies.[15].

' Other study groups using similar protocols and concepts have also demonstrated the effectiveness and safety of IORT in breast cancer patients.[16],[17]

Tolerability

TARGIT 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 %).[18][19]

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[20].

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. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Vaidya JS, Baum M, Tobias JS, Houghton J. "Targeted Intraoperative Radiothearpy (TARGIT)-trial protocol". Lancet.{{cite web}}: CS1 maint: multiple names: authors list (link)
  4. ^ Vaidya JS, Vyas JJ, Chinoy RF, Merchant N, Sharma OP, Mittra I (1996). "Multicentricity of breast cancer: whole-organ analysis and clinical implications". Br. J. Cancer. 74 (5): 820–4. PMC 2074702. PMID 8795588. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  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. {{cite journal}}: Unknown parameter |booktitle= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Belletti B, Vaidya JS, D'Andrea S; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Vaidya JS, Baum M, Tobias JS, Morgan S, D'Souza D (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)}
  8. ^ TARGIT Video
  9. ^ a b Vaidya JS, Baum M, Tobias JS; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  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. ^ Bartelink H, Horiot JC, Poortmans P; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Vaidya JS, Baum M, Tobias JS; et al. (2008). "Efficacy of Targeted Intraoperative Radiotherapy (TARGIT) boost after breast conserving surgery: Updated results". J Clin Oncol. 26 (20 Suppl): abstr 565. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ a b 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ a b Attention: This template ({{cite doi}}) is deprecated. To cite the publication identified by doi: 10.1016/j.ijrobp.2010.07.1996, please use {{cite journal}} (if it was published in a bona fide academic journal, otherwise {{cite report}} with |doi= 10.1016/j.ijrobp.2010.07.1996 instead.
  15. ^ Skandarajah AR, Lynch AC, Mackay JR, Ngan S, Heriot AG (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  16. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  17. ^ Ivaldi GB, Leonardi MC, Orecchia R; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  18. ^ Kraus-Tiefenbacher U, Bauer L, Kehrer T, Hermann B, Melchert F, Wenz F (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. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  19. ^ Kraus-Tiefenbacher U, Bauer L, Scheda A; et al. (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. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  20. ^ http://www.isiort.org/htm/index.shtm

External links


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