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CASE REPORT
Year : 2020  |  Volume : 16  |  Issue : 6  |  Page : 1524-1527

Re-irradiation using proton therapy for radiation-induced secondary cancer with Li-Fraumeni syndrome: A case report and review of literature


1 Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital; Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
2 Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital, Tsukuba, Ibaraki, Japan
3 Department of Radiation Oncology, Proton Medical Research Center, University of Tsukuba Hospital; Department of Radiation Oncology, Tsukuba Medical Center Hospital, Tsukuba, Ibaraki, Japan
4 Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan
5 Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan

Date of Submission25-Jun-2019
Date of Decision08-Jan-2020
Date of Acceptance22-Jan-2020
Date of Web Publication26-Nov-2020

Correspondence Address:
Masashi Mizumoto
Department of Radiation Oncology, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki, 305-8575
Japan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_449_19

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 > Abstract 


Li-Fraumeni syndrome (LFS) is a genetic disease that is hypersensitive to radiotherapy. Proton therapy (PT) was strongly recommended for pediatric and radiation-sensitive tumors. However, there is little information on PT for LFS. The patient was a 7-year-old girl with LFS who was diagnosed with radiation-induced right shoulder blade osteosarcoma and left chest wall malignant fibrous histiocytoma. Both tumors were in the area that had previously been irradiated (36–45 Gy by photon radiotherapy). Sixty-six GyE in 30 fractions was planned for both tumors. We set the clinical target to the minimum gross tumor volume. To comprehensively assess any adverse events, PT was conducted under hospital administration. Cisplatin was used as simultaneous combination chemotherapy. Although administration of granulocyte-colony stimulating factor was necessary for myelosuppression by chemotherapy, PT was completed without interruption. Acute radiation toxicity was observed as Grade 1 dermatitis. The dermatitis became exacerbated 2 weeks after PT but subsequently improved with conservation treatment alone. Twenty-three months after PT, magnetic resonance imaging showed an increase in the tumor on the right shoulder. A histological examination was not conducted as the family declined, but secondary cancer was suggested rather than recurrent osteosarcoma, as the tumor developed mainly from the soft tissue. Additional surgical treatment and radiotherapy were not indicated, and the patient died of tumor progression and sepsis caused by myelosuppression 27 months after undergoing PT. Up to 23 months after PT, there were no signs of Grade 2 or more late toxicities. This represents the first reported case of PT for a patient with LF to treat radiation-induced secondary cancer.

Keywords: Li-Fraumeni syndrome, pediatric, proton radiotherapy, proton therapy, secondary cancer


How to cite this article:
Iwasaki T, Mizumoto M, Numajiri H, Oshiro Y, Suzuki R, Moritani K, Eguchi M, Ishii E, Sakurai H. Re-irradiation using proton therapy for radiation-induced secondary cancer with Li-Fraumeni syndrome: A case report and review of literature. J Can Res Ther 2020;16:1524-7

How to cite this URL:
Iwasaki T, Mizumoto M, Numajiri H, Oshiro Y, Suzuki R, Moritani K, Eguchi M, Ishii E, Sakurai H. Re-irradiation using proton therapy for radiation-induced secondary cancer with Li-Fraumeni syndrome: A case report and review of literature. J Can Res Ther [serial online] 2020 [cited 2021 Nov 27];16:1524-7. Available from: https://www.cancerjournal.net/text.asp?2020/16/6/1524/300998




 > Background Top


Li-Fraumeni syndrome (LFS) is a genetic disease that is caused by the mutation of tumor-suppressor gene TP53. Patients with this syndrome may develop multiple malignant neoplasms, and since they are more radiosensitive, they also have greater risk of radiotherapy-induced secondary malignancies.[1] Proton therapy (PT) can reduce the radiation dose for normal tissue around the tumor, and the lower dose area was smaller than photon radiotherapy, including intensity-modulated radiotherapy, due to its dose localization. Therefore, PT is expected to reduce the risk of radiation-induced late toxicity and secondary cancer[2],[3],[4] for pediatric patients. We previously showed that PT could be performed safely for a patient with DNA repair disorder (Bloom syndrome).[5] Herein, we describe the first case of the use of PT in a patient with LFS to treat radiation-induced secondary cancer. This study was approved by institutional Review Board.


 > Case Report Top


A 2-year-old girl experienced right shoulder pain when she carried a satchel on her back and was diagnosed as having right neck to right shoulder blade rhabdomyosarcoma (RMS) at a previous hospital. Initially, surgical resection followed by chemotherapy and photon radiotherapy (45 Gy in 25 fractions) was performed, and the tumor disappeared completely. However, 2 years after the initial treatment, RMS appeared in the right anterior chest, and the tumor was again well controlled by surgery, chemotherapy, and radiotherapy (36 Gy in 20 fractions). Five years after the initial treatment (at 7 years old), secondary tumors were observed in the right shoulder blade (osteosarcoma) and in the left chest wall (malignant fibrous histiocytoma). Details of clinical course and genetic analysis are described elsewhere.

The tumor in the right shoulder was within the previous irradiation field, and the tumor size was 65 mm × 44 mm × 53 mm and highly enhanced on magnetic resonance imaging (MRI). FDG positron emission tomography (FDG-PET) showed abnormal uptake with a slightly increased maximal standardized uptake value (SUVmax) of 1.7 [Figure 1]. This tumor was diagnosed as osteosarcoma and considered as a secondary cancer by previous irradiation. The tumor in the left chest wall was 17 mm in diameter located outside of the previous irradiation field. This tumor was not enhanced on MRI, but FDG-PET showed abnormally high uptake with a SUVmax of 9.4 [Figure 2]. The tumor was diagnosed as malignant fibrous histiocytoma. According to Chompret criteria and genetic testing, she was diagnosed as having LFS. As these secondary tumors were unresectable, chemotherapy was administered. However, the tumors were resistant to chemotherapy, and photon radiotherapy was considered. Thus, as there might be a great risk of radiation-induced cancer and radiation toxicities due to the previous radiotherapy, we selected PT to minimize the risk of radiation-induced toxicities. [Figure 3] shows the irradiated dose before PT. We considered that prognosis was poor if these tumors were not controlled. Therefore, we selected 66 GyE in 30 fractions for both tumors to achieve local control.
Figure 1: FDG positron emission tomography image of the right shoulder osteosarcoma before proton therapy

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Figure 2: FDG positron emission tomography image of the left chest wall malignant fibrous histiocytoma before proton therapy

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Figure 3: Image of the total irradiated dose of photon therapy before proton therapy. At first, 45 Gy in 25 fractions was performed for right shoulder tumor (including left anterior chest). Next, 36 Gy in 20 fractions was performed for right chest tumor. Therefore, before proton therapy, total dose of right shoulder tumor was 81 Gy (45 Gy + 36 Gy) and left anterior chest tumor was 45 Gy, respectively

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Due to the LFS and previous radiotherapy, the risk of radiation toxicities was expected to be very high. Therefore, we set the clinical target to the minimum gross tumor volume. To comprehensively assess any adverse events, PT was conducted under hospital administration. Considering the tolerable dose of normal organs, we revised the treatments plan after every ten cycles. [Figure 4]a and [Figure 4]b shows the actual treatment plan. Cisplatin was used as simultaneous combined chemotherapy (100 mg/m2). Although administration of granulocyte-colony stimulating factor was necessary for myelosuppression by chemotherapy, PT was completed without interruption. Acute radiation toxicity was only observed as Grade 1 dermatitis. The dermatitis was exacerbated 2 weeks after PT but subsequently improved with conservative treatment alone. After PT, both tumors were slightly shrunk and the uptake of FDG-PET was remarkably decreased. Twenty-three months after the PT, MRI showed an increase in the tumor on the right shoulder. MRI showed little enhancement of the lesion, but PET showed abnormally high uptake with an SUVmax of 5.1. There was no abnormal uptake for the left chest wall tumor. A histological examination was not conducted as the family declined. However, secondary cancer was suggested rather than osteosarcoma recurrence, because the tumor developed mainly from the soft tissue. Additional surgical treatment and radiotherapy were not indicated, and the patient died of tumor progression and sepsis caused by myelosuppression 27 months after PT. After PT, movement restriction of the right shoulder gradually progressed, and the right upper limb could not be raised above the shoulder. For up to 23 months after PT, there were no other signs of Grade 2 or more late toxicities.
Figure 4: The actual treatment plan (a). We changed the treatment plan after ten rounds, to accommodate changes in the tumor size during treatment (b). We further reduced the treatment margin gradually, to minimize the risk of proton-induced late toxicities

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 > Discussion and Review of Literature Top


LFS is a genetic disease that is caused by the mutation of tumor-suppression gene TP53.[6] These patients have a very high risk of developing multiple and early-onset malignancies. These patients also have a very high risk of secondary malignancies after radiation therapy[7],[8],[9] although radiation therapy plays an important role in cancer treatment, especially for pediatric malignancies. American Society for Radiation Oncology (ASTRO) classified pediatric tumor, radiation hypersensitive disease and re-irradiation as medically necessary (good indication) for proton therapy. However, there is very limited information on these conditions. Searching in PubMed (keywords; Li-Fraumeni and radiotherapy), 66 reports were detected. Moreover, seven of 66 reports include clinical results of radiotherapy for LFS. Hosoya et al. showed that a 7-year-old boy received focal irradiation with 50 Gy for anaplastic ependymoma.[1] Local recurrence was occurred only 1 month after radiotherapy, so evaluating late toxicities was difficult. Barbosa et al. showed that a 38-year-old woman received adjuvant radiotherapy for right breast cancer. Four years after radiotherapy, she was diagnosed with left breast carcinoma.[10] Adverse effect of radiotherapy was not mentioned. Wong and Han showed that a 61-year-old woman received pelvic radiotherapy using four-field box technique (45 Gy in 25 fractions) and palliative radiotherapy for right proximal humerus (35.25 Gy in 15 fractions). This patient did not develop any Grade 1 or greater toxicities during whole pelvic radiotherapy and palliative radiotherapy for right proximal humerus.[11] Limacher et al. showed that a 25-year-old woman received locoregional radiotherapy for breast cancer (46 Gy on chest wall and supraclavicular and internal mammary nodes). She also received radiotherapy for ovaries (20 Gy). There were no severe radiation-induced toxicities, but secondary cancers arose within the internal mammary radiotherapy field and within the field irradiated for ovaries.[12] Kappel et al. showed that three patients received radiotherapy for breast cancer (age 17, 23, and 32). They had multiple tumors after radiotherapy inside and outside the irradiated field. Moreover, radiation-induced toxicities (acute and late) were not so severe.[13] Bahar et al. analyzed choroid plexus carcinoma with LFS. Eleven patients received 22.5–23.4 Gy craniospinal irradiation and 54 Gy locoregional irradiation to primary tumors or to metastatic nodules. Compared to 17 patients who did not receive radiotherapy, irradiated patients were poor prognosis and the risk of secondary malignancy was increased.[14] Nandikolla et al. showed that a 21-year-old female (breast cancer) received PT to the left chest wall and a 28-year-old female (breast cancer) also received radiotherapy for chest wall.[15] After 35 and 110 months of follow-up, they had no severe radiation-induce toxicities. Above seven reports indicate that radiation-induced toxicities were not specific for the patients with LFS, but the risk of secondary malignancy probably increases after radiotherapy. Hence, if the therapeutic effect of radiotherapy is expected to outweigh the risk of secondary malignancy, we can use radiotherapy as a standard treatment. Some reports showed that PT can reduce the lower dose area. Therefore, secondary cancer risk from the lower dose area should probably be reduced.[16],[17] In our case, chemotherapy was indicated for the secondary cancer after photon radiotherapy as this patient had been diagnosed as having LFS. However, the disease could not be controlled by chemotherapy and surgery, and radiotherapy was considered necessary. Due to overlapping with the previous field, photon radiotherapy was difficult and PT was selected. Unfortunately, secondary malignancies subsequently developed within the proton treatment field. However, these were well controlled for 2 years without severe toxicities. Therefore, we considered that PT yields a survival benefit for these patients.


 > Conclusion Top


This represents the first reported case of PT for a patient with radiation-induced secondary cancer. PT may be more useful than photon radiotherapy among these susceptible patients.

Ethics approval and consent to participate

Patient's signed consent before treatment was initiated and data were collected.

Consent for publication

Patient's signed consent before treatment was initiated and data were collected.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the parents have given consent for images and other clinical information to be reported in the journal. The parents understand that the names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This study was supported by Mitsui Life Social Welfare Foundation.

Conflicts of interest

There are no conflicts of interest.



 
 > References Top

1.
Hosoya T, Kambe A, Nishimura Y, Sakamoto M, Maegaki Y, Kurosaki M. Pediatric case of Li-Fraumeni syndrome complicated with supratentorial anaplastic ependymoma. World Neurosurg 2018;120:125-8.  Back to cited text no. 1
    
2.
Mizumoto M, Murayama S, Akimoto T, Demizu Y, Fukushima T, Ishida Y, et al. Long-term follow-up after proton beam therapy for pediatric tumors: A Japanese National Survey. Cancer Sci 2017;108:444-7.  Back to cited text no. 2
    
3.
Mizumoto M, Murayama S, Akimoto T, Demizu Y, Fukushima T, Ishida Y, et al. Proton beam therapy for pediatric malignancies: A retrospective observational multicenter study in Japan. Cancer Med 2016;5:1519-25.  Back to cited text no. 3
    
4.
Mizumoto M, Oshiro Y, Yamamoto T, Kohzuki H, Sakurai H. Proton beam therapy for pediatric brain tumor. Neurol Med Chir (Tokyo) 2017;57:343-55.  Back to cited text no. 4
    
5.
Mizumoto M, Hashii H, Senarita M, Sakai S, Wada T, Okumura T, et al. Proton beam therapy for malignancy in Bloom syndrome. Strahlenther Onkol 2013;189:335-8.  Back to cited text no. 5
    
6.
Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 1969;71:747-52.  Back to cited text no. 6
    
7.
Hisada M, Garber JE, Fung CY, Fraumeni JF Jr., Li FP. Multiple primary cancers in families with Li-Fraumeni syndrome. J Natl Cancer Inst 1998;90:606-11.  Back to cited text no. 7
    
8.
Strong LC, Williams WR. The genetic implications of long-term survival of childhood cancer. A conceptual framework. Am J Pediatr Hematol Oncol 1987;9:99-103.  Back to cited text no. 8
    
9.
Heyn R, Haeberlen V, Newton WA, Ragab AH, Raney RB, Tefft M, et al. Second malignant neoplasms in children treated for rhabdomyosarcoma. Intergroup rhabdomyosarcoma study committee. J Clin Oncol 1993;11:262-70.  Back to cited text no. 9
    
10.
Barbosa OV, Reiriz AB, Boff RA, Oliveira WP, Rossi L. Angiosarcoma in previously irradiated breast in patient with Li-Fraumeni syndrome. A case report. Sao Paulo Med J 2015;133:151-3.  Back to cited text no. 10
    
11.
Wong P, Han K. Lack of toxicity in a patient with germline TP53 mutation treated with radiotherapy. Curr Oncol 2014;21:e349-53.  Back to cited text no. 11
    
12.
Limacher JM, Frebourg T, Natarajan-Ame S, Bergerat JP. Two metachronous tumors in the radiotherapy fields of a patient with Li-Fraumeni syndrome. Int J Cancer 2001;96:238-42.  Back to cited text no. 12
    
13.
Kappel S, Janschek E, Wolf B, Rudas M, Teleky B, Jakesz R, et al. TP53 germline mutation may affect response to anticancer treatments: Analysis of an intensively treated Li-Fraumeni family. Breast Cancer Res Treat 2015;151:671-8.  Back to cited text no. 13
    
14.
Bahar M, Kordes U, Tekautz T, Wolff J. Radiation therapy for choroid plexus carcinoma patients with Li-Fraumeni syndrome: Advantageous or detrimental? Anticancer Res 2015;35:3013-7.  Back to cited text no. 14
    
15.
Nandikolla AG, Venugopal S, Anampa J. Breast cancer in patients with Li-Fraumeni syndrome a case-series study and review of literature. Breast Cancer (Dove Med Press) 2017;9:207-15.  Back to cited text no. 15
    
16.
Sethi RV, Shih HA, Yeap BY, Mouw KW, Petersen R, Kim DY, et al. Second nonocular tumors among survivors of retinoblastoma treated with contemporary photon and proton radiotherapy. Cancer 2014;120:126-33.  Back to cited text no. 16
    
17.
Cotter SE, Herrup DA, Friedmann A, Macdonald SM, Pieretti RV, Robinson G, et al. Proton radiotherapy for pediatric bladder/prostate rhabdomyosarcoma: Clinical outcomes and dosimetry compared to intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys 2011;81:1367-73.  Back to cited text no. 17
    


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