Risk assessment of radio-chemotherapy in pediatric soft tissue sarcomas

J o u r n a l o f R a d i a t i o n R e s e a r c h a n d A p p l i e d S c i e n c e s 8 ( 2 0 1 5 ) 1 1 0 e1 1 9

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Risk assessment of radio-chemotherapy in pediatric soft tissue sarcomas A. Abaza a,b,*, H. El-Shanshoury c,d a

Radiation protection Department, Nuclear and Radiological Regulatory Authority, Cairo, Egypt Institute of Postgraduate Childhood Studies, Medical Studies Department, Cairo, Egypt c Radiation Safety Department, Nuclear and Radiological Regulatory Authority, Cairo, Egypt d Department of Medical Applications of Laser, National Institute of Laser Sciences, Cairo University, Cairo, Egypt b

article info

abstract

Article history:

Soft tissue sarcomas (STS) are a group of rare and heterogenous cancers, that diverse a

Received 8 October 2014

wide spectrum of histology and varied clinical behavior. The aim was to study, retro-

Accepted 17 December 2014

spectively and prospectively the adverse effects of therapy in STS patients attending the

Available online 27 December 2014

Pediatric Oncology Clinic, National Cancer Institute (NCI), Cairo University during the last 10 years. Files of 106 STS patients were revised for history, staging, investigations, treat-

Keywords:

ment modalities and side effects of therapy. Radiotherapy (RTH) and surgery remains the

Soft tissue sarcoma

backbone of the multi-modality treatment plan. Chemo-radiotherapy (CRTH) induces acute

Hazards

and delayed toxicity in the form of hematological & gastrointestinal (GIT) toxicity and al-

Treatment effects

opecia that occur in all patients. However, hepatic & genitourinary toxicity, cardiotoxicity,

Risk assessment

neurotoxicity and skin complications can be seen in 13.2%, 11.3%, 1.9% and 4.7% and 28.3% of patients respectively. Mucositis was noticed in 42.5% of patients, 15.1% of them were due to RTH, which can also cause dysphagia & dysphonia, impaired taste sensation and transient conjunctivitis in 4.7%, 1.9% and 6.6% of patients respectively. Additionally, 46.7% of post-pubertal patients were found to be azoospermic >5 years of end of treatments. However, 3.8% and 6.6% of patients developed ototoxicity and skin fibroses due to local irradiations. Furthermore, hypo- or hyperthyroidism and growth retardation was encountered in 7.5% and 6.6% of patients respectively. However, 5.7% of patients developed secondary malignancy, 7 years after the end of CRTH. Finally, the current study concluded that STS multidisciplinary management may cause early and late toxicity. Future approaches including radiation dose and volume reduction or application of new radiation technologies are needed. New strategies with reduction or elimination of chemotherapy (CTH) dose are also recommended for dealing with pediatric STS patients. Copyright © 2015, The Egyptian Society of Radiation Sciences and Applications. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

* Corresponding author. E-mail addresses: [email protected] (A. Abaza), [email protected] (H. El-Shanshoury). Peer review under responsibility of The Egyptian Society of Radiation Sciences and Applications. http://dx.doi.org/10.1016/j.jrras.2014.12.005 1687-8507/Copyright © 2015, The Egyptian Society of Radiation Sciences and Applications. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

J o u r n a l o f R a d i a t i o n R e s e a r c h a n d A p p l i e d S c i e n c e s 8 ( 2 0 1 5 ) 1 1 0 e1 1 9

1.

Introduction

Soft tissue sarcoma (STS) constitutes a heterogenous group of rare cancers, with heterogenous clinical presentation, histological subtypes and molecular alterations (Blay et al., 2013). Therefore, its management requires an experienced multi
choux, disciplinary team in an expert center (Faivre, & Le Pe 2013). They constitute about 1% of all solid tumors, (Shukla & Deo, 2011) and can occur in any part of the body (Umer, Umer, Qadir, Abbasi, and Masood, 2013). It present most commonly as an asymptomatic mass, and swelling was the presenting symptom in 96% patients (Shukla & Deo, 2011). Their biological behavior is characterized by local aggressiveness and tendency to hematogenous spreading. Almost 50% of STS patients develop metastatic disease, mainly within three years from initial diagnosis. The distribution of metastases from STS varies, depending on the primary site and histological subtype (Vincenzi et al., 2013). The prognosis of STS is determined by histological subtype, tumor size, localization, grade and the presence of metastases (Jakob, Rauch, Wenz, and Hohenberger, 2013). In pediatric oncology, most treatment concepts in the 21st century are of curative intent, aiming at long-term overall survival (OS) (Combs et al., 2012). The goals of sarcoma management include both a cure and functional preservation of involved tissues and adjacent critical structures (Kandel et al., 2013). With the advances made in the fields of imaging, surgical, medical and radiation oncology along with better understanding of tumor pathology and biology more effective management protocols are currently available (Shukla & Deo, 2011). Treatment are often multimodal and complex, and patients can experience significant morbidity and mortality as a consequence of treatment or the disease (Kandel et al., 2013). The standard treatment protocol involves wide surgical resection along with neoadjuvant or adjuvant RTH (Umer et al., 2013). The mainstay of therapy of non-metastasized STS is complete surgical resection combined with irradiation in large, high-grade tumors which are located deep to the superficial body fascia (Jakob et al., 2013). The application of brachytherapy (BRT) as a complementary therapy in STS has a history of 30-years. BRT seems to be a good method of adjuvant therapy in extremity STS, however its accessibility is limited. The number of complications was small. Further multicentre randomized studies should decide which method of adjuvant treatment (external beam radiation therapy (EBRT) vs. BRT) is better and what is the optimal sequence of therapies improving local control (Guzik, Lyczek, and Kowalik, 2012). The established standard of care for unresectable STS in first line is doxorubicin-based CTH, with typical response rates ranging from 10% to 30%. For patients who relapse or develop resistance, other therapeutic options were limited before the availability of trabectedin. For these patients, progression-free survival (PFS) and OS rarely exceed 6 months and 1 year respectively (Blay et al., 2013). With continuous increase in tumor control and cure, also side effects of the treatments, especially long-term side effects, have moved even more into focus (Combs et al., 2012). Examples are cardiac toxicity from anthracyclines, hearing loss or tinnitus from cisplatin, infertility from alkylator therapy or radiation to the pelvis, endocrine complications usually

111

from radiation to reproductive organs or the hypothalamicpituitary axis, bladder dysfunction from CTH and radiation, and second malignant neoplasms due to radiation and/or CTH (Arndt, Rose, Folpe, and Laack, 2012; Ginsberg, Goodman, and Leisenring, 2010; Nagarajan, Kamruzzaman, and Ness, 2011). Furthermore, thrombocytopenia (TCP) is a common side effect of CTH, and multiple studies have suggested that Chemotherapy-induced thrombocytopenia (CIT) is a doselimiting adverse event (AE) in the treatment of cancer, and can necessitate dose delays and/or dose reductions (Chawla et al., 2013). On the other hand, children receiving platinumcompound CTH for the treatment of malignancies may be at risk of an early- or delayed-onset hearing impairment that may affect learning, development, communication, school performance, social interaction and overall quality of life (Nitz et al., 2013; Orgel et al., 2012; PecoraLiberman et al., 2011; Skinner, 2004). However, port-associated complications (paravasation, irritation, infection) were more frequent (13%) than in continuous infusion protocols with other drugs (e.g., 5-FU) administered in the large outpatient center (Hoiczyk et al., 2013). With respect to RTH, sparing of normal tissue and reduction of integral dose is the most effective means to prevent treatment-related side effects. Over the last decades, advances in radiation oncology from conventional 2D-to 3Dradiation therapy, to the establishment of high-precision stereotactic RTH and subsequently intensity-modulated radiotherapy (IMRT) have continuously enabled the radiation oncologist to deliver higher local doses even to complex target volumes while sparing surrounding organs at risk (OAR). However, intermediate and low doses of radiation remain to be applied. One way of reducing integral dose and potentially reducing side effects is the use of particle therapy, due to the physical properties of ion beams (Combs et al., 2012). Although the introduction of multimodal treatment of STS improved local tumor control, local failure still occurs in a good number of patients. Therefore, further improvement of current treatment strategies is necessary (Jakob et al., 2013). The aim of the present work is to retrospectively and prospectively study the adverse effects of therapy in STS patients attending the Pediatric Oncology Clinic, National Cancer Institute (NCI), Cairo University during the last 10 years (from January 2004 till January 2014).

2.

Patients and methods

One hundred and six STS patients were recorded among the total pediatric malignant cases registered during the period of study. Data were collected about age of the patients at presentation, sex, primary site (s), staging, histopathological subtype, site of metastases (if present) and dose & duration of therapy. Clinical examinations were done laying stress on site and clinical extent of tumor with assessment of nodal enlargement. Results of routine laboratory investigations; bone marrow aspiration and/or biopsy were also reviewed. The results of plain X-ray, CT scans or MRI, isotopic bone scan for evaluations of the primary site and metastasis. Scrotal sonography for paratesticular tumor was also identified. Urinalysis and assessment of bladder function by cystourethrogram in case of hemorrhagic cystitis. Follow-up was

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done one month after treatment completion, then every 3 months for first 2 years, every 6 months thereafter during 3 years, and then annually. Times of follow-up were measured from the date of diagnosis. The studied patients included 70 (66%) males and 36 (34%) females, with a male to female ratio of 1.94:1. Their ages ranged from 6 month to 21 years with a mean of 9 ± 5.8 years and median age of 9 years. 64 (60.4%) of the patients were below 10 years old. The follow-up time for all patients ranged from 5 to 80 months with median of 38 months. Staging was done according to IRS-TNM pretreatment clinical staging classification and IRS clinical grouping classification (Dalen et al., 2004; Wunder, Healey, Davis, and Brennan, 2000). CT guided or open surgery biopsy was done to confirm the diagnoses and to define the histological subtypes.

2.1.

Treatment modalities

2.1.1.

Surgery

Initially, a wide and complete resection of the primary tumor with a surrounding envelope of normal tissue was done, followed by second look operation according to need. Delayed resection of the primary tumor was performed at week 12 evaluation for local control. Delayed resection of the residual primary tumor after RTH is recommended to achieve complete remission and to improve the accuracy of clinical and radiological assessment of response.

2.1.2.

Radiotherapy

Patients received RTH according to their stage and clinical group. All patients received RTH at week 12e13 except node negative, completely resected patients, and patients who have had second look resection. Patients with parameningeal sites with criteria of meningeal extension and who require emergency RTH begin RTH at day zero. RTH was given for all microscopic and gross residual with entire lymph node involvements and to all sites of metastatic disease which can be localized and imaged (i.e. excluding the bone marrow). Treatment is directed to the initial tumor volume in all cases with 2e3 cm safety margins. Conformal 3D planning is performed to decrease the dose to normal tissue with minimal radiation dose to the ossific center in children. Oophropexy marked by metal clips was done in pelvic irradiation in girls, and external lead shield in boys. Megavoltage conventional daily fractionation was given in a dose of 45 GY in 25 daily fractions (1.8 GY/fraction, to be reduced to 1.5 GY for large sensitive volumes). A boost of 5 GY in 3 daily fractions was used according to the site, and increased to 10 GY in 6 daily fractions with residual microscopic disease. Furthermore, without skull base erosion and cranial nerve palsy, the brain, skull base and meninges are not routinely irradiated.

- Actinomycin D (A): 0.45 mg/kg (max 2.5 mg) IV push. In patient <1 year as 0.025 mg/kg IV push. Or can be given as1.35 mg/m2 IV push High risk patients. - Cyclophosphamide (C): 1.2 mg/m2 IV infusion over 60 mints with hydration and Mesna. In patient <1 year as 40 mg/kg. It can be given as 1.5e1.8 mg/m2 IV infusion over 2 h with hydration and Mesna in High risk patients.

2.1.4.

Statistical analysis

Statistical analysis was done using Statistical Package for Social Sciences (SPSS). Mean, standard deviation, percentage, and Chi-square was applied whenever indicated. Survival analysis; including OS, DFS were done. Differences between groups were tested for statistical significance using log rank test. P value was always two-tailed and is significant at p  0.05 (Winters, Winters, and Amedee, 2010).

3.

Results

The results of the present work are presented in Tables (1e7) and in Figure (1e4). Most of patients presented below 10 years old with male predominant (66%) (Table 1). STS originated from the head and neck in most of patients 38 (35.8%) [Parameningeal 17 (16%), orbital 11 (10.3%), and others 10 (9.5%)], followed by Extremity 27 (25.5%) then Genitourinary 19 (17.9%) and Retroperitoneal 12 (11.3%) respectively (Table 1, Fig. 1). The predominant subtype of STS was Embryonal (61.3%) followed by Alveolar subtype (21.8%) then other types (Table 1, Fig. 2). The presenting stage of the disease was stage III 65 (61.3%) followed by stage I 23 (21.7%) then II 12 (11.3%) and IV 6 (5.7%) respectively (Table 1, Fig. 3). Nearly 69.8% of the patients received RTH with or without CTH and 43.4% of them have been resected for the primary tumor (Table 2). At the end of treatment, complete remission (CR) was achieved in92 (86.8%) of patients. Meanwhile, 8 (7.5%) of cases had disease progression and 5.7% died (Table 3). The 2-years OS was 80.2% (Table 3). However, the 2-years and 5-years DFS were 65.1% and 56.6% respectively. Moreover, 16 (15.1%) and 25 (23.6%) of patients relapsed >2 years and 5 years after the end of treatment. The rest of the patients 57 (69.5%) achieved local control. Acute Toxicity of Chemo-Radiotherapy in the present study resembled in Tables (4e6) and Figure (4): According to Common Toxicity Criteria (adopted in SIOP Trial) patients can

Table 1 e Clinical characteristics of STS patients. Items

2.1.3.

Chemotherapy

Patients received VAC regimen for 40e47 weeks according to the grades of the disease: - Vincristine (V): 1.5 mg/m2 (max 2 mg) IV push. In patient <1 year as 0.025 mg/kg IV push.

Age: - <10 years - >10 years Tumor size: >5 cm <5 cm

No

%

64 42

60.4 39.6

73 33

68.9 31.1

Items Sex: - Male - Female Metastasis: Present Absent

No 70 36 6 100

% 66 34 5.7 94.3

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Table 2 e Treatment modalities in the studied group. Type

No.

%

Radiotherapy: Radiotherapy alone Chemo-radiotherapy No radiotherapy Radiotherapy doses 36 GY 41.40 GY 45 GY 50.40 GY 59.60 GY

27 47 32

25.5 44.3 30.2

25 45 16 15 5

23.6 42.5 15.1 14.1 4.7

Surgery: Initial surgery Delayed surgery (at w12) Biopsy alone Surgery at the end

48 32 23 3

45.3 30.2 21.7 2.8

Total

%

74

69.8

46

43.4

be categorized in 4 grades: Hematological, GIT toxicity and also, Alopecia were seen in all patients. The use of G-CSF is highly statistically significant regarding anemia and neutropenia (P-value was 0.0041 and 0.0036 respectively). Elevated liver enzymes were reported in 14 (13.2%) of patients with detection of hepatitis C viral infection in 7 (6.6%) of them. Twelve patients (11.3%) developed Cyclophosphamide induced hemorrhagic cystitis. All of them showed marked improvement with dose reduction and continuous Mesna infusion. Peripheral neuritis grade 2 was reported in 4 (3.8%) patients following week 3. Vincristine was withheld in this patient for the remaining courses. Only one patient (0.9%) with nasopharyngeal mass and extensive intracranial component developed convulsions following week 4. Skin complications were observed in 30 (28.3%) of patients. 20 (18.9%) of them were complaining of erythema grade I, 5 (4.7%) with dry desquamation, and 5 (4.7%) with wet desquamation due to RTH. One patient from the wet desquamation group occurs in the previously irradiated field following Actinomycin D. Among the 38 cases of head and neck tumor 25 (23.6%) cases received RTH. Sixteen cases (15.1%) of whom received RTH developed mucositis, 9 (8.5%) of them were grade 3. However, dysphagia and dysphonia were reported in 5 (4.7%) cases and impaired taste sensation in 2 (1.9%) cases only. Additionally, among the 9 (8.5%) cases that received orbital irradiation 7 (6.6%) of them developed transient conjunctivitis that improved with medications. On the other hand, among the 31 (29.2%) pelvi-abdominal site patients, 20 (18.9%) cases received RTH, 9 (8.5%) cases of them developed grade 2 diarrhea and vomiting (Fig. 4).

Surgical Complications: Definitive surgery was instituted in 46 cases. Only 2 cases reported surgical complications. The 1St one was 1.5 years old female with extremities STS. She developed severe skin infection with skin necrosis that necessitates repeated dressing and antibiotic therapy for 3 weeks. The 2nd case was 16 years old female with chest wall PNET. She was subjected to excision of the lesion with the related ribs with reconstruction using synthetic mesh. She developed postoperative infection around the mesh that necessitates second look operation to remove the mesh 3 months later. Delayed complications: This can be seen 5 years or more after the end of treatment. Semen analysis was done in 15 patients who were >16 years old 5 years after the end of treatment, 7 of them 7/15 (46.7%) were found to be azoospermic. Four (3.8%) patients developed ototoxicity due to local irradiations, one of them with external ear primary tumor. However, skin fibrosis was seen in 6.6% of patients. Furthermore, Hypo- and hyperthyroidism was encountered in 8 (7.5%) of patients and growth retardation was seen in 7 (6.6%). One patient only developed urinary complications in the form of artificial bladder and urinary diversion due to radical cystectomy for bladder mass. However, 6 (5.7%) of patients developed secondary malignancy, 7 years after the end of CRTH (Table 7).

4.

Discussion

The management of STS has evolved over last two decades with the advances made in the fields of imaging, histopathology, molecular biology, cytogenetic and multimodality management (Shukla & Deo, 2011). Multimodal treatment of STS with CTH and irradiation has been introduced in the 1970s. Radiation may be administered preoperatively or postoperatively (Jakob et al., 2013). Effective risk-based therapy for the management of childhood cancer in the setting of clinical trials has been the cornerstone of the tremendous progress in OS seen over the last four decades, with 5-year survival rates now at 80% (Landier & Bhatia, 2008). This was comparable with the current study where CR was achieved in 86.8% of patients and the 2-years OS was 80.2%. However, the 2-years and 5-years DFS were 65.1% and 56.6% respectively. Moreover, 69.5% of the patients achieved local control. Dose-intensive CTH has become routine for the treatment of most pediatric sarcomas because CTH dose-intensity correlates with tumor response and outcome. Neutropenia is a common toxicity of these regimens (Ferrari et al., 2005; Grier

Table 3 e Response of STS patients to protocols of therapy. Response to therapy

Complete remission(CR) Progressive disease (PD) Death Total

At the end of treatment

After 2 years of treatment

After 5 years of treatment

NO

%

NO

%

NO

%

92 8 6 106

86.8 7.5 5.7 100

85 0 21 106

80.2 0 19.8 100

82 0 24 106

77.4 0 22.6 100

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Table 4 e Acute toxicity after chemo-radiotherapy treatment of STS. Acute toxicity

No.

Hematological toxicity: Leucopenia Neutropenia Anemia Thrombocytopenia Cardiotoxicity Use of G-CSF: Given Not given Infection (Febrile neutropenia) Skin complications

%

80 76 83 38 2

75.5 71.7 78.3 35.8 1.9

15 91 76 30

14.2 85.8 71.7 28.3

Acute toxicity

No.

%

GIT: Nausea & vomiting Diarrhea Oral complications

94 36 45

88.7 34.0 42.5

14

13.2

12 0 5 106

11.3 0 4.7 100

Hepatic toxicity Genitourinary: Bladder Nephrotoxicity Neurotoxicity Alopecia

et al., 2003; Spunt et al., 2010). Both the depth of the neutrophil nadir and duration of severe neutropenia influence the development of infectious complications. Therefore, preventing or shortening the duration of neutropenia following CTH may facilitate dose-intensity, improve safety, and control costs (Spunt et al., 2010). In the current study, Hematological toxicity was seen in all patients, 71.7% of them were neutropenic and develop febrile neutropenia (FN). However, 42.5% of neutropenic patients were grade 4. Furthermore, Anemia, leucopenia, and TCP were developed in 78.3%, 75.5%, and 35.8% of patients respectively. Additionally, the use of growth factors was needed in 14.2% of patients with improving in the hematological picture. The result is highly statistically significant regarding anemia and neutropenia (P-value was 0.0041 and 0.0036 respectively). Thrombocytopenia (TCP) is a common treatment-related Grade 3/4 AE and dose-limiting toxicity for various CTH regimens (Ang et al., 2009; Blay et al., 2008; Hensley et al., 2009; Kantarjian et al., 2010). Doxorubicin and ifosfamide, alone and in combination (AI), are active in the treatment of STS, with demonstrated positive response rates and improvements in OS; however, both agents have been associated with Grade 3/4 TCP that is cumulative with successive CTH cycles (Chawla et al., 2013; Lashkari et al., 2009; Maurel et al., 2009; Sleijfer et al., 2010; Tascilar, Loos, Seynaeve, Verweij, and Sleijfer, 2007; Worden et al., 2005). CIT may lead to dose reductions or dose delays, resulting in less than optimal disease control. In severe cases, CIT may result in hemorrhage and a need for platelet transfusions, which have cost and safety limitations (Chawla et al., 2013; Lashkari et al., 2009; Maurel et al., 2009; Schiffer et al., 2001; Worden et al., 2005). Growth factor use, results in a relative decrease in the incidence of rather than absolute prevention of FN (Spunt et al., 2010). However, Randomized clinical trials in both children and adults have demonstrated that filgrastim prophylaxis for CTH-induced neutropenia

results in reduction of duration of grade 4 neutropenia, (Crawford et al., 1991; Trillet-Lenoir et al., 1993) number of episodes of FN (Pettengell et al., 1992; Welte et al., 1996) number and duration of hospitalizations, (Crawford et al., 1991; Heil et al., 1997; Pui et al., 1997) number of documented infections, (Heil et al., 1997; Pui et al., 1997; Welte et al., 1996) and use of antibiotics (Crawford et al., 1991; Michon et al., 1998; Trillet-Lenoir et al., 1993; Welte et al., 1996). Filgrastim use has become routine in the management of pediatric sarcomas requiring CTH (Ferrari et al. 2005; Grier et al., 2003; Spunt et al., 2010; Wexler et al., 1996). Although interleukin-11 (IL-11), a hematopoietic growth factor with thrombopoietic activity, is approved for the treatment of CIT in the US, it is not approved in the EU, it has modest efficacy, and it produces substantial adverse effects that limit its use (Chawla et al., 2013; Vadhan-Raj, 2009). For example, a database analysis of 47,159 patients with both solid tumors and hematologic malignancies showed that TCP increased from 11% at baseline to 22e64% following CTH treatment (Wu, Aravind, Ranganathan, Martin, and Nalysnyk, 2009). Grade 3/ 4 TCP has been reported in 63% of patients with advanced STS treated with AI CTH (Worden et al., 2005). In the current study Grade 3/4 TCP was seen in 21.7% of patients. However, an effective agent for the treatment of CIT may allow CTH administration according to schedule and without dose delays and/or reductions (Chawla et al., 2013). A variety of radio-therapeutic approaches have been used in the adjuvant local management of STS. These include EBRT, BRT, and intraoperative radiation therapy (Viani et al., 2008). Unfortunately, radiation to soft tissues and bones within the treatment field can lead to skeletal deformity and growth retardation. Radiation to the thorax can result in pulmonary fibrosis and cardiac dysfunction, and radiation to the pelvis can result in infertility (Armstrong, Stovall, and Robison, 2010; Arndt et al., 2012; Ginsberg et al., 2010). Sterzing et al. reported

Table 5 e Hematological toxicity in STS patients. Hematological toxicity

Leucopenia Neutropenia Anemia Thrombocytopenia

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

No.

%

No.

%

No.

%

No.

%

No.

%

26 30 23 68

24.5 28.3 21.7 64.2

10 8 26 8

9.5 7.5 24.5 7.5

15 9 28 7

14.1 8.5 26.4 6.6

16 14 20 13

15.1 13.2 18.9 12.2

39 45 9 10

36.8 42.5 8.5 9.5

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Table 6 e Gastrointestinal and genitourinary toxicity in STS patients. Item

Oral mucositis Nausea &vomiting Diarrhea Hepatic toxicity Bladder toxicity

Grade 0

Grade 1

Grade 2

Grade 3

Grade 4

No.

%

No.

%

No.

%

No.

%

No.

%

61 12 70 92 94

57.6 11.3 66.0 86.9 88.7

7 10 10 9 7

6.6 9.5 9.5 8.5 6.6

25 39 14 3 3

23.6 36.8 13.2 2.8 2.8

13 37 12 1 2

12.2 34.9 11.3 0.9 1.9

0 8 0 1 0

0 7.5 0 0.9 0

one patient developed thoracic scoliosis two years following spine irradiation. One adolescent, who was also treated with CTH, claimed of hypoaesthesia in his right forearm, two years after upper thoracic wall irradiation. In the present study, azoospermia was seen in 46.1% of post-pubertal patients. Hypo- and hyperthyroidism was encountered in 7.5% of patients and growth retardation was seen in 6.6%. Furthermore, cardiotoxicity was observed in 1.9% and Peripheral neuritis grade 2 was reported in 3.8% patients following week 3. Only one patient (0.9%) with nasopharyngeal mass and extensive intracranial component developed convulsions following week 4 and it was attributed to the disease itself. However, EBRT can cause growth retardation or adversely affect organ function in the pediatric population (Viani et al., 2008). On the other hand, Sterzing et al. reported acute side effects of RTH were low grade skin erythema (grade I-II), mucositis (grade III), local alopecia, mild nausea, mild diarrhea, loss of taste and epistaxis. In the current study, skin complications were observed 28.3% of patients. Nearly 18.9% of them were complaining of erythema grade I, 4.7% with dry desquamation, and 4.7% with wet desquamation due to RTH. One patient from the wet desquamation group occurs in the previously irradiated field following Actinomycin D. Additionally; skin fibrosis was seen in 6.6% of patients. GIT toxicity (including nausea, vomiting & diarrhea) and alopecia were seen in all patients. Furthermore, mucositis, was noticed in 42.5% of patients, 16 (15.1%) of them due to RTH. The incidence of complications after antineoplastic therapy is increasing in relation to the incidence of cancer and prolonged survival rate (Kucharska, Negrusz-Kawecka, and Gromkowska, 2012). Mucositis causes significant pain, chewing and swallowing difficulties and is considered the most debilitating acute reaction during cancer treatment (Rose-Ped et al., 2002; Schmidt Santos, Dias, Giordani, Segreto, and Comodo Segreto, 2011). Radiation affects the volume and production of saliva, as well as its composition. Patients frequently describe thickened, tenacious, ropy saliva, which may make speech difficult besides affecting swallowing and taste. Additionally, skin reactions, in the form of skin tanning, dry desquamation and

increased melanin production with telangiectasis are considered as dose-limiting for RTH. Alopecia, muscles fibrosis, self-limited transverse myelitis, and acute radiation pneumonitis (ARP) can also be caused by radiation (Schreiber, Meyers, Calhoun, and Talavera, 2013). Furthermore, dysphagia and dysphonia was reported in 4.7% of cases in the present study, and impaired taste sensation in 1.9% of cases only. BRT seems to be ideally suited for the pediatric patient when used alone or in combination with EBRT to achieve local control. It can reduce the dose of radiation to normal tissues and shortens the overall treatment time while maintaining a comparable high rate of local control. Thus, reductions in normal tissue doses decrease the probability of growth deformity, CRTH interactions, and theoretically, the rate of second tumor formation. BRT may also allow a reduction in the EBRT dose required. The local control rates were effective, but the operational difficulties to care children with BRT sources make this approach restricted to few institutions. However, the theoretical advantages of HBRT make this treatment modality an interesting option to multidisciplinary management of STS (Viani et al., 2008). Moreover, in the present work, one patient only developed urinary complications in the form of artificial bladder and urinary diversion due to radical cystectomy for bladder mass. Furthermore, 2 cases reported surgical complications in the current study. The 1St one developed severe skin infection with skin necrosis that necessitates repeated dressing and antibiotic therapy for 3 weeks. The 2nd case was subjected to excision of the lesion with the related ribs with reconstruction using synthetic mesh. She developed postoperative infection around the mesh that necessitates second look operation to remove the mesh 3 months later. But Guzik et al. reported no complications during the surgery as well as postoperative period and also, BRT. Patients at risk include those receiving cisplatin and/or carboplatin for neuroblastoma, hepatoblastoma, osteosarcoma, STS or germ-cell tumors. Cisplatin is known to cause permanent, sensorineural hearing loss, which is mostly bilateral, begins at high frequencies and progresses to involve

Table 7 e Delayed toxicity after chemo-radiotherapy treatment of STS. Delayed toxicity Gonadal dysfunction: Ototoxicity: Endocrinal problems: Hypothyroidism Hyperthyroidism Impaired growth

No.

%

Delayed toxicity

No.

%

7/15 4/106 15 5 3 7

46.7 3.8 14.2 4.7 2.8 6.6

Urinary complications: Skin fibrosis 2ry Malignancy: AML Skin cancer Thyroid cancer

1 7 6 2 3 1

0.9 6.6 5.7 1.9 2.8 0.9

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Fig. 3 e The presenting stage of STS patients.

Fig. 1 e Primary site of STS patients.

mid-frequencies with continued exposure. The reported incidence varies widely from 11 to 97% (Stohr et al.., 2005). Nitz et al. reported 49.1% of children with hearing impairment. In the present study, four (3.8%) patients developed ototoxicity due to local irradiations, one of them with external ear primary tumor. This may be explained by differences in the treatment modalities and in the populations under investigation. In addition, to date, there is no agreement regarding the definition of hearing impairment. This impedes comparisons between different studies (Stohr et al.., 2005). Cisplatininduced hearing loss has been reported to be enhanced with increasing cumulative dose (Bokemeyer et al., 1998; Brock, Bellman, Yeomans, Pinkerton, and Pritchard, 1991; Schell et al., 1989), bolus administration (Reddel et al., 1982; Vermorken, Kapteijn, Hart, and Pinedo, 1983), prior cranial irradiation (Schell et al., 1989) and young age (Schell et al., 1989; Stohr et al., 2005). In comparison, the newer platinum compound carboplatin has been reported to be less ototoxic. In a number of studies no, or only low, ototoxicity was identified (Stohr et al., 2004); although severe hearing loss may occur after high-dose therapy (Parsons et al., 1998; Skinner, 2004). The severity of hearing loss is often graded according € us, to the Mu¨nster classification (Schmidt, Bartholoma Deuster, Heinecke, and Dinnesen, 2007), but also according to the Brock grading system (Brock et al., 1991) and the ASHA criteria (www.asha.org). These late effects of cisplatin and carboplatin in the treatment of children have been welldescribed (Brock et al., 1991; Schell et al., 1989; Stohr et al., 2004). The effects in adult patients, however, have not been adequately investigated (Nitz et al., 2013). Since the beginning of its use, radiation in medical practice has raised concerns regarding the risk of inducing cancers in treatment recipients (Kam, Anthony, and Shek, 2013). All children who receive RTH as a component of treatment are at

Fig. 2 e Histological subtype of STS patients.

risk for secondary radiation-induced malignancy. The average latency period is 7 years, but the risk does not appear to decline over time. Results from the Childhood Cancer Survivor Study indicate a risk of 8% over 30 years for tumors excluding nonmelanoma skin cancers and an additional 9% risk of skin cancer (Arndt et al., 2012; Friedman, Whitton, and Leisenring, 2010; Ginsberg et al., 2010). In the present study the risk reached 5.7% 7 years after the end of treatment. Long-term follow-up of these patients is mandatory. Today, it is well recognized that radiation can induce malignancy, and common examples include breast (female), thyroid, lung and leukemia (Kam et al., 2013; Roychoudhuri, Evans, Robinson, and Møller, 2004). RTH-induced bone tumor has also been reported but the incidence is below 1% in 5 years after treatment, but it is believed that the risk depends on the age at which the patient receives the radiation (risk increases with younger age), size of the radiation field and the dose of radiation received. In children receiving total body irradiation, the incidence can reach as high as 29%. The typical types of bone tumors induced include benign osteochondroma and malignant sarcoma, of which osteosarcoma is the most common. As for other types of radiation-induced cancers, RTH-induced sarcoma has a latent period ranging from a couple of years to decades, with the mean lying between 10 and 20 years (Kam et al., 2013). The site of cancer development usually lies on the periphery of the radiation field (Davies, Sundaram, and James, 2009; Kam et al., 2013). Furthermore, Kam et al. present an elderly female with previous RTH for breast cancer, 30 years prior, subsequently developing a fibrosarcoma in the spine. In the current study, no one patient developed sarcomas as a 2ry malignancy, but patients developed AML (2 cases), skin cancer (3 cases) and thyroid cancer (1 case). Secondary cancer induction is dose dependent and tissue irradiated with doses below 6 Gy is known to be especially endangered to develop secondary cancer (Sterzing et al., 2009). On the other hand, the risk of t-MDS/AML following Ewing

Fig. 4 e Acute effects of radiotherapy.

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sarcoma is elevated compared with the general population. It can reach 127-fold increased risk in one cohort study. Furthermore, Bhatia et al. concluded that exposure to cyclophosphamide at 20.4 g/m2 with doxorubicin at 375 mg/m2 (in the absence of etoposide and ifosfamide) placed patients at a risk of developing t-MDS/AML that was comparable with an exposure to cyclophosphamide at 9.6 g/m2, doxorubicin at 375 mg/m2, ifosfamide at 90 g/m2, and etoposide at 5 g/m2. Additionally, one study has demonstrated that short-term use of hematopoietic cytokines, in particular, filgrastim in the setting of intensive antileukemic therapy, may increase the risk of t-MDS/AML (Bhatia et al., 2007). Despite the advances in cure rates for children and adolescents with these tumors, the long-term consequences of aggressive CTH, RTH, and surgery can be substantial. Survivors are much more likely than controls to have at least one, and often multiple, chronic medical conditions (Arndt et al., 2012). Finally, the current study concluded that there are many early and late toxicity of multidisciplinary management of STS patients that need interference. It is hoped that during the next decade we will discover which patients can have therapy reduced and still have the same good outcome, and new approaches with targeted agents and new surgical and radio-therapeutic techniques will be developed for patients with metastatic disease (Arndt et al., 2012). Therefore, recommendation regarding prospective testing via audiometry for patients treated with platinum derivative CTH. Further studies are required to further elucidate the modulation of hearing threshold improvement by a potential toxic synergy between CTH and RTH and other ototoxic drugs, including ototoxic antibiotics. Post-pubertal boys should be offered semen cryopreservation before initiation of therapy. Cryopreservation of oocytes or embryos (the latter requires use of donor sperm) is possible for post-pubertal females but may delay treatment initiation. Experimental cryopreservation of testicular or ovarian tissue has been reported in the literature but is not a current standard of care. Future approaches including radiation dose reduction, volume reduction or application of new radiation technologies are needed.

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