Studies about brachytherapy PBI or intraoperative PBI more than EB PBI. Our meta-analysis compared EB PBI and WBI which systemic proved that EB PBI has similar LRR, regional node recurrence, contralateral breast cancer, distant recurrence, non-breast second cancer, and mortality with WBI for early breast patients. Besides, EB PBI has less acute skin toxicity (˃ 1 grade), similar late skin toxicity, and worse cosmetic score than WBI. The protection for subcutaneous tissue during radiotherapy plans delivery and limited the dose in EB PBI will contribute to better cosmetic outcomes. In the study we included, the dose of EB PBI was from 30 Gy/5f to 40 Gy/15 f. In the current report, the dose of EB PBI was 30-50Gy/5-10f, QD/BID3,25,26,28,29. The best optimal dose of EB PBI radiation has not been determined, National Comprehensive Cancer Network(NCCN) recommend EB PBI deliver in the dose of 34 or 38.5 Gy/10f, BID and 40-42.5 Gy/15-16f, QD for WBI-accelerated. Dose of 4 studies is different which might the source of heterogeneity for LRR, cosmetic score, and acute skin toxicity (˃ 1 grade). TJ W23’s study has a maximum proportion of patients. It was the main reason for heterogeneity for LRR and cosmetic score. It compared WBI-accelerated vs APBI, and the dose of it was the highest than other studies. Although its dose of WBI-accelerated and APBI was accepted by NCCN, Highest does and the different delivery fraction of irradiation might induce worst cosmetic score, LRR, local recurrence rates, mortality, and distant recurrence.
Yasmin Korzets et al16 fond that EB PBI may have the best control of local recurrence than brachytherapy PBI and IORT. EB PBI has similar local recurrence rate(LRR) with WBI. But they didn’t include outcomes of RAPID23 and didn’t evaluate regional recurrence, cosmetic score, acute, and late skin toxicity. Our study is the systematic meta-analysis of EB PBI versus WBI. We found that EB PBI had no significant difference in LRR, regional node recurrence, contralateral breast cancer, distant recurrence and mortality compared with WBI. These conclusions were similar to Yasmin Korzets’s30 and Liu’s18 study. But we found that EB PBI tends to increase the risk of LRR, decrease the risk of regional node recurrence, contralateral breast cancer, distant recurrence, and mortality, although all of them had no statistical difference between EB PBI and WBI groups.
The selection of PBI patients was controversial. NCCN, GEC-ESTRO, and UK guidelines recommend the patients suitable for PBI were as follows (Table 2). Different guidelines have different Selection criteria for low-risk early breast cancer patients. The patients that could deliver PBI were early breast stages with low recurrence risk. More studies were exploring the application and outcomes of PBI. NCCN guidelines recommend PBI was considered in patients as follows. (1) Older than 50 years old, T1, Negative margin ≥ 2 mm, no LVI, ER-positive, and BRCA negative. (2) Low/medium nuclear grading. The measured size of DCIS detected by screening is less than 2.5 cm and the margin of the negative cutting edge is more than or equal to 3 mm. GEC-ESTRO is similar to NCCN guidelines. In addition to the above inclusion criteria, UK consensus statements recommend that tumor size ≦ 3 cm and negative her-2 could also be considered for PBI. The inclusion criteria of PBI are still under discussion.
Table 2
NCCN, GEC-ESTRO, and UK guidelines recommend the patients suitable for PBI
Risk factors | NCCN(ASTRO) | GEC-ESTRO | UK |
Lymph nodes | positive | positive | negative |
Margin | ≥ 2 mm | ≥ 2 mm | ༞1–2 mm |
Tumor size | ≤ 2 cm, Single center, single tumor, no vascular invasion。 | ≤ 2cm,Non-central, single tumor | ≤ 3 cm |
Garde | 1–2 grade | - | 1–2 grade |
Hormonal state | ER positive,BRACA negative | - | ER positive,HER-2 negative |
Age | ≥ 50 years | ≥ 50 years | ≥ 50 years |
Dose | 38.5 Gy/10f,BID | 32 Gy/8f,bid | 40GY/15f |
[1] Rodriguez N, Sanz X, Dengra J, et al. Five-year outcomes, cosmesis, and toxicity with 3-dimensional conformal external beam radiation therapy to deliver accelerated partial breast irradiation[J]. Int J Radiat Oncol Biol Phys, 2013, 87(5): 1051-7. |
[2] Livi L, Meattini I, Marrazzo L, et al. Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial[J]. Eur J Cancer, 2015, 51(4): 451 − 63. |
[3] Coles C E, Griffin C L, Kirby A M, et al. Partial-breast radiotherapy after breast conservation surgery for patients with early breast cancer (UK IMPORT LOW trial): 5-year results from a multicentre, randomised, controlled, phase 3, non-inferiority trial[J]. Lancet, 2017, 390(10099): 1048–1060. |
[4] Tj W, Ja J, Ts B, et al. External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial[J]. Lancet (London, England), 2019, 394(10215): 2165–2172. |
Table 2 NCCN, GEC-ESTRO, and UK guidelines recommend the patients suitable for PBI
Radiation can damage DNA, massive DNA damage and accumulation of unrepaired chromosome breaks induce cell death. Recurrence and metastasis were associated with tumor cells that did not die after radiotherapy. DNA damaged to activate not only p16/Rb but also p53/p21 pathway, all of them take importance of cellular senescence by cellular arrest and oncogene-induced senescence31. Irradiation induced the ATM kinase activated and p38 mitogen-activated protein kinase (MAPK) through reactive oxygen species (ROS), H2AX, and other DNA repair protein repair DNA damage by NHEJ, HR. Then, activating transcription factor nuclear factor kappa-B activates pRb by p16INK4A ultimately induces durable cell-cycle arrest. Upregulation of inflammatory and fibrotic mediating, epigenetic changes, and disruption of normal oxygen metabolism will increase cytotoxicity reactive oxygen species (ROS) that occur within hours to years of exposure to ionizing radiation32. Apoptosis and senescence in cells trigger fibrosis through signaling pathways33. The key stages in the metastatic are the appearance of circulating tumor cells (CTCs) seeding and colonizing distant tissues and organs. EMT helps the tumor cells deform into a more metastasizing form. EMT is highly correlated with TGF-β34. TGF-β takes an important role in the process of preserving normal tissues, sensitizing tumor, pro-oxidant, and pro-fibrosis 32,33.
EB PBI has less acute skin toxicity (˃ 1 grade), similar late skin toxicity, and worse cosmetic score than WBI which similar to Hickey BE20 et al ’s study. Breast induration or fibrosis, atrophy, appearance changed, edema, the color of skin, fatty necrosis might affect the cosmetic score of EB PBI. The 4 studies we included in our meta-analysis were EB APBI vs WBI/WBI-accelerated. The dose of fraction of APBI mostly higher than WBI/WBI-accelerated which might induce worse toxicity in breast tissue. Patients in EB APBI groups got less irradiation exposure to normal tissue lead to less acute skin toxicity (˃ 1 grade). A higher dose of fraction and less irradiation exposure tissue affected cosmetic score and late skin toxicity. Livi L25 et al’s study was the source of heterogeneity for acute skin toxicity because it has a minimum proportion of patients with acute skin toxicity in the EB PBI group. Moreover, all 3 studies show EB PBI would cause less acute skin toxicity (˃ 1 grade) than WBI.
The position of tumor bed will atrophy after surgery35–37. The accuracy of tumor bed in EB PBI was not similar to branch therapy and IORT. Moreover, incomplete coverage of potential tumor targets and increased exposure to normal tissues in EB PBI also needs to solve. The recommended PBI exposure range is 1-3cm around the tumor bed23, it might incomplete coverage of potential target areas38. The different center has a different target area delineation standard. Different medical personnel had different delineation target area. But EB PBI has the largest irradiation range than beachy PBI and IORT which bring EB PBI better prognoses than PBI and IORT23. IMRT/VMRT can better fit the tumors than other technologies, the way of delivering irradiation will affect the results. Most PBI studies were about beachy PBI and IORT. But EB PBI was More economical, noninvasive, beautiful, easy to popularize.
In fact, increased irradiation exposure can kill potential cancer cells, but increased exposure to normal tissues such as heart, lung, and contralateral breast not necessarily lead to better outcomes. For PBI, the accurate selection of the population, the expansion of irradiation exposure range, and the adjustment of exposure mode still need to be further explored. There needs more study on EB PBI to help more and more early breast patients benefit from PBI.