4 Discussion
Desmoid tumor is a rare intermediate tumor characterized by infiltrative growth and a tendency to local recurrence6, with an annual incidence of approximately 2 to 4 per million per year, and two peaks of age 6-15 years and age 40 years1. Infiltrative growth is a threat to the vital structure around the tumor, especially in the HN, which accounts for 7-15% of all the DT, and higher in the pediatric population (26-33%) than the adult (7-9%)2-4. The treatment was challenging in the pediatric DT in HN, for the stronger demand of organ and tissue preservation than those of adults and limit of treatment modality 9. Although the treatment varied, in recent years, the strategy of the treatment changed in the trend from surgery and radiotherapy to conservative methods, with the development of targeted therapy and knowledge to the nature of DT6. But for DT in HN of pediatric population, the treatment modalities used now are not satisfactory.
Observation, also described as “wait and see” approach, was proved reasonable for the indolent nature of DT, with evidence of stabilization and even regression in the absence of therapy 15. Since 2020, observation had been listed as first-line management, while both NCCN guideline and Desmoid Tumor Working Group stressed that initial observation was only recommended for cases not causing morbid even if progressed 5-7. With the threat to functional or cosmetic preservation from progression, observation was only suitable for small DT in HN, which would often be managed by surgeons with complete resection at first. The condition for choosing observation is strict in HN, as all cases in this study underwent intervention and none took observation for organ preservation.
Complete resection with clear margin used to be regarded as mainstay treatment before 2000, and the 5-years local control rate were up to 80% according to several retrospective study16. While in the region of HN, the local control rate declined to between 24 and 70%17. And for pediatric patient involved HN, a systematic review demonstrated a 27.2% recurrence rate of 125 patients treated with surgery in reports from 1982 to 2015. However, the pursue of complete resection or at least R1 margin, which was regarded acceptable18, at price of excessive long-term functional or cosmetic sequelae was not recommended in tumors located at HN of pediatric population9. Therefore, sole surgery have been abandoned as a choice for most DT in the HN5. And in this study, patient with R2 margin after surgery were treated supplementarily with brachytherapy for local control.
External beam radiotherapy was considered to be either sole modality for inoperative cases of DT or complementary therapy for resectable ones, and the latter was regarded as better solution than sole surgery by a review of 22 articles19. However, while considering on pediatric population, the long-term sequelae and adverse effects of external beam radiation exposure in children, such as secondary malignancy and inhibition of the cranial-facial bone, caused the limited use of radiotherapy on pediatric DT20-22. Besides, efficacy of radiotherapy on pediatric DT was uncertain according to a study reporting 10 out of 13 children recurrent and 3 out of 13 dead23.
Medical therapy including anti-hormonal therapies, non-steroidal anti-inflammatory drugs (NSAIDs), chemotherapy and tyrosine kinase inhibitors (TKIs) was another way the clinicians turned to6. Anti-hormonal agents such as tamoxifen or toremifene, along with or without NSAIDs were reported retrospectively effective24. However, a phase II study in pediatric population using tamoxifen25 showed limit activity for an progression free rate of 36%, and notable safety problem with 40% females developing ovarian cysts. Chemotherapy including a “low-dose” regimen with methotrexate plus vinblastine or vinorelbine, was evaluated and proved well efficacy and acceptable toxicity 6. Tyrosine kinase inhibitors seemed hopeful with progression-free survival ranging from 59% to 89% and low toxicity according to several phase II and III studies 26. Therefore, chemotherapy and Tyrosine kinase inhibitors were advocated as active treatments5,6. But meanwhile, there was still a need for a back-up therapy since the effectiveness of tyrosine kinase inhibitors might related to certain genome type 27, and also a solution for relapse from medical therapy.
Brachytherapy is a minimally invasive radiotherapy modality with high local dose while sparing surrounding normal tissues28. Late radiation induced toxicity complications like growth retardation and second primary malignancies, with a strong relation to a dose-volume effect, can be kept to a minimum by the brachytherapy for its smaller target volume than external beam radiotherapy11. Previous studies in our department had reported the application of brachytherapy on pediatric population in HN, and showed good effectiveness and safety29-31. Besides, the study on pediatric survivors with parotid gland carcinoma after brachytherapy showed mild affection on the mandible growth32. The use of brachytherapy on DT in adult had also been reported with well local control33,34. However, the application of brachytherapy on pediatric DT in HN remained unclear, with long term effectiveness and safety needing to be reported.
In this study, during the long-term follow-up time, it was inspiring that no recurrence was observed. In spite of the limit of the amount of cases, we could still concluded that brachytherapy as an effective method for pediatric DT in HN for many other evidence we collected. There were several methods the Desmoid Tumor Working Group recommended for assessment of treatment effect6. And we adopted the dimensional criteria, MR signal, and the gold standard, core-needle aspiration.
All the lesions in this study reach partial regression six month visit after brachytherapy, with dimensional change evaluated using CT or MR. Although CT examination was advised for measurement on dimensional change according to the Desmoid Tumor Working Group6 and NCCN guideline5, the125I seeds would affect the observation on the tumor outline on CT with radiological artifact. As an alternative, clinicians will measure the cluster volume of 125I seeds and a general volumetric shrinkage tendency indirectly showed the shrinkage of tumor volume 35. However, that was not a common parameter to use for comparison with other studies. Another alternative was measurement using MR, with artifact still but would not affect the measurement, because the125I seeds showed as small black area. But as for children, the time consuming on MR examination was a problem for their weak obedience ability and often needed sleeping pill. Therefore, in this study, we still used CT as an assessment on tumor diameter change, and accomplished with other methods.
Changes in T2 weighed intensity signal of MR image is useful for evaluation on activity of DT, because low T2 weighed signal corresponds to relatively lower cellularity and higher collagen content6,36. In this study, all cases with preoperative and postoperative MR showed clearly reduction in T2 weighed intensity signal. The change in T2 weighed signal can be evaluated even though artifact existed after brachytherapy, and therefore can be added as an ancillary criteria for treatment evaluation, following the diameter change. However, the acquisition of MR from children still remained difficult. And to ensure the treatment effect, some cases in this study underwent core-needle aspiration for pathological examination, and no tumor cell was found, which further confirmed the result concluded from change of T2 weighed signal and diameters.
All children in this study experienced mild acute side effects after brachytherapy (RTOG1-2), and no late or severe toxicity (RTOG 3–4) or second primary cancer were observed. Besides, except for cases already had massive bone defect before therapy, no growth retardation was observed. Based on the long-term follow-up, the safety of brachytherapy could be shown as only mild and short-term toxicity was observed and no severe or late radiation induced toxicity complications occurred.
However, as discussed above, since the relatively indolent nature of DT, more conservative method should be considered firstly, such as TKIs or observation if suitable, and then aggressive method like surgery and brachytherapy if needed and possible. Brachytherapy could be turned to for unresectable lesion with looming unacceptable destruction, or as a salvage after failure of the former treatments, or a combination with them as an potential alternative for external-beam radiation in pediatric DT in HN.
Even though DT is rare, the number of cases in this study is still obviously limited, while more cases reported was expected. Besides, the data of toxicity evaluation is limited also because of the small sample size.