rhabdomyosarcoma treatment and outcome at a multidisciplinary pediatric cancer center in lebanon

Pediatric Hematology and Oncology, 29:322–334, 2012Copyright C© Informa Healthcare USA, Inc.ISSN: 0888-0018 print / 1521-0669 onlineDOI: 10.3109/08880018.2012.676721

ORIGINAL ARTICLE

Rhabdomyosarcoma

Rhabdomyosarcoma Treatment and Outcomeat a Multidisciplinary Pediatric Cancer Center inLebanon

Maysaa Salman, MD,1 Hani Tamim, PhD,2 Fouad Medlej, MD,1

Tarek El-Ariss, BS,1 Fatima Saad, BS,1 Fouad Boulos, MD,3 Toufic Eid, MD,4

Samar Muwakkit, MD,1 Nabil Khoury, MD,5 Miguel Abboud, MD,1

and Raya Saab, MD1

1Department of Pediatrics, American University of Beirut, Beirut, Lebanon; 2ClinicalResearch Institute, American University of Beirut, Beirut, Lebanon; 3Department ofPathology and Laboratory Medicine, American University of Beirut, Beirut, Lebanon;4Department of Radiation Oncology, American University of Beirut, Beirut, Lebanon;5Department of Radiology, American University of Beirut, Beirut, Lebanon

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Outcome of pa-tients treated on standard protocols, in a multidisciplinary cancer center setting outside of clini-cal trials, is not well reported. We reviewed characteristics and outcome of 23 pediatric patientstreated at a single, multidisciplinary cancer center in Lebanon, between April 2002 and December2010. Median follow-up was 41 months. The most commonly affected primary site was the headand neck (48%, n = 11). Nineteen tumors (82.6%) were of embryonal histology. Tumor size was≥5 cm in eight (34.8%) patients. Sixteen patients (69.6%) had localized disease, and one (4.4%)had metastatic disease. Fifteen (65.2%) had Group III tumors. All patients received chemother-apy, for a duration ranging 21–51 weeks. Upfront surgical resection was performed in 10 patients(43.5%). Eighteen patients (78.3%) received radiation therapy. The 5-year overall and disease-freesurvival rates were 83% and 64%, respectively. Relapse correlated with absence of surgery. Treat-ment of childhood RMS in a multidisciplinary cancer center in Lebanon results in similar survivalto that in developed countries when similar protocols are applied. There was a higher incidenceof local relapse, but those were salvageable with further therapy and surgical local control.

Keywords outcome, multidisciplinary, rhabdomyosarcoma, treatment

INTRODUCTION

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood[1]. Over the past few decades, large cooperative group prospective clinical trials haveresulted in improved outcome for patients with RMS, with current overall survival at5 years exceeding 70% [2]. The backbone of RMS therapy in protocols developed bythe Intergroup Rhabdomyosarcoma Study Group (IRSG) and the soft tissue sarcoma

Received 3 January 2012; accepted 13 March 2012.Address correspondence to Raya Saab, MD, Department of Pediatrics, American University ofBeirut, Riad El Solh Street, Beirut 1107 2020, Lebanon. E-mail: [email protected]

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RMS Multidisciplinary Treatment in a Developing Country

committee of the Children’s Oncology Group relies on vincristine, actinomycin D, andcyclophosphamide (VAC) [3, 4]. With current therapy, patients with nonmetastaticdisease have an overall 3-year survival exceeding 80% and a failure-free survivalexceeding 70% [5], while those with metastatic disease have an overall survivalat 4 years of 30%–40% [6]. Further risk stratification depends on presurgical andpostsurgical staging, and integrates tumor site, size, and patient age, resulting instratification of patients into low-risk, intermediate-risk, and high-risk subgroups [7].With current chemotherapy and local control using surgery and/or radiation therapy,reported 5-year overall survival rates are greater than 90% for patients with low-riskdisease, ∼70% for those with intermediate-risk disease, and less than 30% for thosewith high-risk disease [4, 5, 8].

The majority of the published literature on RMS describes the outcome of patientstreated on cooperative group trials, whether in the USA or in Europe. The outcome ofpatients treated in low-resource and developing countries is much worse, as reportedby retrospective single institution and national studies [9–14]. The contribution of eth-nic differences in biology, versus lack of delivery of adequate therapy, to this adverseoutcome has not been studied. We conducted this retrospective study to evaluate thepresentation, treatment, and outcome of patients with RMS treated in the setting of amultidisciplinary pediatric cancer center, at a single tertiary care hospital in Lebanon.

PATIENTS AND METHODS

We conducted a retrospective review of medical records of patients with previouslyuntreated RMS seen at the Children’s Cancer Center of Lebanon (CCCL), from its in-ception in April 2002 till December 2010. Twenty-three patients were identified, andthe following information was collected retrospectively: patient age, sex, site of tumor,stage and clinical group, tumor histology, therapy, clinical course, and outcome. Thisstudy was approved by the American University of Beirut Medical Center (AUBMC)Institutional Review Board (IRB).

Histological diagnosis was performed by the experienced pathologists at the insti-tution (AUBMC). Site and local extent of tumor at diagnosis was assessed by computedtomography (CT) or magnetic resonance imaging (MRI), depending on disease site.Initial staging included CT scan of the chest, bone scan, and bilateral bone marrowbiopsies for all patients. Primary surgical resection was attempted if the surgeon an-ticipated a feasible gross tumor resection; otherwise only a biopsy was performed up-front for diagnosis, and chemotherapy was initiated.

For the analysis, clinical staging and grouping was performed as per the IRSG IRS-IV(Intergroup Rhabdomyosarcoma Study-IV) stratification scheme, identifying patientsin low-risk, intermediate-risk, or high-risk subgroups, based on patient age, tumorsite, size, histology, presurgical stage, and postsurgical IRS group (see SupplementalTable 1) [2, 15, 16].

All patients received chemotherapy, with a combination of vincristine and acti-nomycin D, with or without cyclophosphamide (details in Table 1). Mesna was ad-ministered for uroprotection during cyclophosphamide treatment, and granulocytecolony-stimulating factor (G-CSF) support was used after each cycle that containedcyclophosphamide.

Definitive local control was attempted at weeks 10–15 of treatment, with surgery,radiation therapy, or combination of both, as shown in Table 1. For radiation planning,the gross target volume (GTV) used was the tumor volume defined by CT scan or byMRI prior to any surgical debulking. This volume included clinically involved lymphnodes. An additional margin of 1.5–2 cm around the GTV was generated to create theclinical target volume (CTV), then an additional 0.5 cm margin was taken around the

Copyright C© Informa Healthcare USA, Inc.

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CTV to account for day-to-day setup variation. The total dose used was 50.4 Gy forgross disease, 45 Gy for orbital and eyelid sites, and 41.4 Gy for microscopic diseaseand sites of involved but resected lymph nodes. Completely resected alveolar histologytumors received 36 Gy. Clinically involved unresected lymph nodes received 50.4 Gy.The dose per fraction used was 1.8 Gy per fraction, 5 days per week, and the techniquewas by three-dimensional conformal radiation therapy.

Response was evaluated by radiological imaging (CT or MRI) after 3–4 cycles ofchemotherapy (weeks 9–12), then every 2–3 months. Survival was defined as the timeinterval from diagnosis to either death from any cause or last follow-up. Event-freesurvival was defined as time to disease progression, relapse, or death from any cause.

Immunostaining was used to evaluate the DNA damage response pathway in tu-mors of patients who received radiation therapy, to find out whether the staining pat-tern would correlate with local or regional tumor relapse. We used available archivedparaffin-embedded tumor tissue, after IRB approval. Standard histology procedureswere followed to prepare 3-µm sections for immunohistochemical staining with thefollowing antibodies: anti-p53 (DO-7, Novocastra, Newcastle, UK), and anti-phospho-S/T ATM/ATR (ataxia telangiectasia mutated/ataxia telangiectasia and Rad3-relatedprotein) substrate (Cell Signaling Technology, Danvers, MA). Digital photomicro-graphs were obtained using an Olympus DP12 camera and software, and compositeimages were formed using Adobe Photoshop CS5 software.

Data were analyzed using the Statistical Package for Social Sciences program (SPSS)for data management and analyses. Categorical variables were summarized by calcu-lating the number and percent. Association between the different variables and theoutcome was assessed using the Chi-square test or Fisher’s exact test, as appropriate.Survival analysis was carried out and Kaplan Meier curves were constructed for thedifferent groups. Statistical significance was considered at the .05 level.

RESULTS

Patient CharacteristicsWe identified 23 pediatric patients with RMS who were treated between April 2002and December 2010. The patient characteristics, treatment, and outcome are listed inTable 1.

Median age was 8 years (range: 3 months to 17 years), with a mean of 8.4 years.Fifteen (65%) were below the age of 10 years. Male to female ratio was 1.09:1. The me-dian follow-up time was 41 months (range: 16–135; mean 57 months).

The most commonly affected primary site was the head and neck (48%, n = 11):these were orbital in four patients (17.3%), para-meningeal (PM) in two (8.7%), andhead-neck nonorbit non-PM in five patients (22%) (2 cheek, 1 nasal cavity, 1 neck,1 temporal scalp). Sites were genitourinary (GU) nonbladder nonprostate in 6 patients(26%): of these there were 4 paratesticular, 1 uterine, and 1 vaginal tumor. Two patients(8.7%) had bladder/prostate tumors, and four (17.3%) had tumor originating in theextremity.

Nineteen tumors (82.6%) were of embryonal histology, one (4.4%) was pleomor-phic, and 3 (13%) were alveolar. Tumor size was large (≥5 cm) in eight patients (34.8%).

Sixteen patients (69.6%) had localized disease, six (26%) had regional lymph nodesinvolved, and one (4.4%) had metastatic disease. Fourteen (61%) had Stage 1 disease,three (13%) had Stage 2, five (21.7%) had Stage 3, and one (4.3%) had Stage 4 disease.With respect to clinical grouping, 5 patients (21.7%) had Group I disease, 2 patients(8.7%) had Group II, 15 patients (65.2%) had Group III, and 1 patient (4.3%) had GroupIV tumors.


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For analysis, patients were stratified into low-risk, intermediate-risk, and high-risksubgroups (see Table 1), as per the stratification used in the IRS-IV protocol (see Sup-plemental Table 1) [15].

ChemotherapyAll patients received chemotherapy. As shown in Table 1, regimens were based onthose used in the IRSG trials, namely, combination chemotherapy with VAC. The du-ration of chemotherapy ranged from 21 to 51 weeks, with cumulative doses detailed inTable 1.

SurgerySurgical resection was complete with negative microscopic margins in eight patients(34.8%) and with positive margins in two (8.7%). Second-look surgery at the time oflocal control was done in four patients and at the end of therapy in one patient. Theremaining eight patients (34.8%) did not have second-look surgery because of eitherno residual tumor on imaging or inoperable disease.

RadiationEighteen patients (78.3%) received radiation therapy. Radiation was given at thetime of local control, usually started at 10–15 weeks of treatment (details in Table 1).The dose ranged from 36 to 50.4 Gy according to clinical group, tumor histology,and tumor site, as described in the Patients and Methods section, and following theguidelines described in the IRS-IV protocol [15]. Three patients started radiation early(0–3 weeks): two because of vision compromise and one due to para-meningealdisease, while five patients had a delay in radiation therapy till beyond week 15 (seeTable 1).

Response and OutcomeThere were no primary treatment failures. The 5-year overall and disease-free survivalrates were 83% and 64%, respectively (see Figure 1A). Currently, 20 patients (87%) arealive: 14 (61%) continue to be in first complete remission (CR), 5 are in second CR,and 1 is receiving second-line treatment. Relapse occurred in nine patients (39%), ata median time of 21 months (range 9–77, mean 22.4). Death of disease progressionoccurred in 3 patients (13%), at a median time of 24 months from diagnosis (range22–42 months).

Toxicities were frequent but mostly manageable. Vincristine neuropathy neces-sitating dose reduction was seen in six patients: five developed foot drop, two alsohad unilateral eyelid ptosis, and one patient developed severe lower extremity paininterfering with ambulation. All symptoms of neuropathy improved and graduallyresolved after withholding and/or reducing vincristine doses. Hematologic toxicitywas frequent, necessitating a total of 118 packed red blood cell transfusions in 13patients (range 2–21 transfusions per patient), and 89 platelet transfusions in 14 pa-tients (range 2–21 per patient). There were 95 episodes of febrile neutropenia, whichoccurred in a total of 16 patients, and was managed by prompt inpatient intravenousantibiotics. Only one episode was associated with septic shock, and responded to theappropriate management. Other encountered toxicities were neutropenia (withoutfever) in 16 patients (54 episodes), nonneutropenic fever in 3 patients (13 episodes),herpes zoster in 3 patients, and grade 2 mucositis in 3 patients (one episode each, as-sociated with radiation therapy). One patient had pyelonephritis, and one developedvaricella infection. There were no toxic deaths and no secondary malignancies.

Pediatric Hematology and Oncology

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FIGURE 1 Kaplan-Meier analysis of (A) overall and event-free survival for all patients; (B) overallsurvival estimates by intermediate- and low-risk subgroups, as indicated; and (C) event-free sur-vival estimates by intermediate- and low-risk subgroups, as indicated. The black and grey dashedlines indicate the corresponding 5-year (60 months) survival rates reported in the IRS-IV study, forthe low-risk group and the intermediate-risk group, respectively.

Prognostic VariablesBecause there was only 1 patient with metastatic disease, we preformed outcome anal-ysis with respect to known prognostic variables, limited to the 22 patients with non-metastatic disease. The results are shown in Table 2.

When analyzed by risk group, we found that 5 of 10 patients with intermediate-riskdisease experienced disease relapse: 2 with alveolar histology disease, 2 with para-meningeal tumors, and 1 with gluteal tumor. Two of these five patients are currentlyin second remission, one is alive with disease after salvage therapy, and two died ofdisease progression. As for patients in the low-risk subgroup, 3 of 12 patients (25%)experienced tumor relapse. Two of those had orbital tumors and were salvaged bysecond-line chemotherapy and surgical local control; the third had a cheek tumor thatrecurred at multiple distant sites, and is receiving second-line therapy. Overall survivalat 5 years for low-risk and intermediate-risk groups were 100% and 78%, respectively,


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TABLE 2 Analysis of Prognostic Variables

Variable Remission, N (%) Relapse, N (%) P value

Sex Male 9 (75.0%) 3 (25.0%) .15Female 5 (45.5%) 6 (55.5%)

Age 1–10 8 (57.1%) 6 (42.9%) .50<1 or >10 6 (66.7%) 3 (33.3%)

Site Orbit 2 (50.0%) 2 (50.0%) .05Paratesticular 5 (100%) 0 (0.0%)Head/Neck 1 (16.7%) 5 (83.3%)GU 2 (100%) 0 (0.0%)Bladder 2 (100%) 0 (0.0%)Extremeties 2 (50.0%) 2 (50.0%)

Size <5 cm 9 (60.0%) 6 (40.0%) .63> = 5 cm 5 (62.5%) 3 (37.5%)

Stage 1 9 (64.3%) 5 (35.7%) .222 3 (100%) 0 (0.0%)3 2 (40.0%) 3 (60.0%)4 0 (0.0%) 1 (100%)

Group I 5 (100%) 0 (0.0%) .16II 1 (50.0%) 1 (50.0%)III 8 (53.3%) 7 (46.7%)IV 0 (0.0%) 1 (100%)

Histology Alveolar 1 (33.3%) 2 (66.7%) .33Embryonal 13 (65.0%) 7 (35.0%)

Local control Surgery or combined 12 (80.0%) 3 (20.0%) .02

while event-free survivals were 83% and 45%, respectively. The Kaplan Meier survivalestimates by risk group are shown in Figures 1B and 1C.

With respect to site, all eight patients with GU tumors did well. There was one re-lapse among the three localized extremity tumors. However, there was a high relapserate in patients with localized head and neck tumors, whether orbital (2 out of 3), para-meningeal (2 out of 2), or other head and neck (3 out of 5) tumors.

We investigated whether the noted increased rate of relapse in head and neck sitescorrelated with treatment modality for local control. Indeed, we found that patientswho had radiation alone as a local control modality has a significantly higher risk ofrelapse (see Table 2 and Figure 2A). Relapse occurred within the radiated field in six ofthe nine patients (67%). However, the majority were successfully salvaged by second-line chemotherapy (as per the ARST1021 protocol) and aggressive surgical local con-trol. We reviewed the radiation planning, dosage, and delivery techniques (detailed inthe Patients and Methods section), which were based on the guidelines used in theIRS-IV protocol [15]. No major deviations from the recommended techniques wereidentified.

Because of the high failure in patients treated with radiation alone, we retrospec-tively analyzed tumor tissue for proteins involved in the DNA damage response path-way, thought to be necessary for an intact apoptotic pathway and tumor clearance af-ter radiation [17, 18]. We identified adequate pathology samples for 12 patients out of atotal of 18 who had received radiation therapy. Of these 12 patients, 7 had experiencedrelapse. We performed immunohistochemical staining for the following markers: (1)the tumor suppressor protein p53, which is involved in the DNA damage response andseems to be essential for radio-sensitivity in most settings [19] and (2) motif residues(pS/T) specifically phosphorylated by the kinases ATM and ATR, also involved in theDNA damage response [20, 21]. The results are shown in Table 3 and Figure 2B. Lowimmunostaining for at least one of those 2 markers seemed to be more common in


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FIGURE 2 (A) Number of patients with disease relapse by local control modality as indicated.Black bars denote number of patients with relapsed disease; grey bars denote those maintainedin first clinical remission. (B) Representative images of immunostaining scores for p53 and pS/TATM/ATR substrate residues, showing examples of 0, +1, +2, and +3 stain scores, as indicated.

tumors that recurred after radiation therapy (6 out of 7), in comparison to those thatdid not (2 out of 5). The small sample size precluded any definitive conclusions, butsuggests that further studies need to be performed to address this possible association.

DISCUSSION

Most studies contributing to our understanding of RMS risk factors and treatmentstratification have come from cooperative group trials in developed countries, specif-ically from the IRSG and Soft Tissue Sarcoma committee of the Children’s OncologyGroup in the USA, and from several cooperative groups in Europe. The applicability,utilization, and efficacy of such treatment in other countries are limited by the lackof multidisciplinary, centralized care. This is particularly evident in retrospective datapublished from several other countries, which show a much lower rate of disease con-trol and a high rate of abandonment [9–14]. Results of such studies from Korea, Brazil,Japan, Hong Kong, Egypt, and Morocco are summarized in Table 4.

Our study was limited primarily by the small number of patients. Also, there weresome differences in the clinical characteristics of the patients in our study as comparedwith those reported in larger studies. Specifically, our series contained an apparentlyhigher proportion of head and neck tumors and tumors at GU sites, and a decreasedproportion occurring in the trunk and extremities [22, 23]. In addition, our series

TABLE 3 Immunohistochemical Staining

Pt# Relapse p53 pS/T

13 Yes 0 2+19 Yes 3+ 011 Yes 1+ 2+10 Yes 1+ 3+12 Yes 2+ 2+22 Yes 1+ 1+20 Yes 1+ 2+6 No 1+ 2+21 No 2+ 2+7 No 0 2+17 No 2+ 3+18 No 2+ 2+


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[12]

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331∗

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24%

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edia

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pers

onal

use

onl

y.

M. Salman et al.

included only one patient with metastatic disease, and most of our patients (69%) hadlocalized disease. However, as in other series, the majority of our patients (65%) hadclinical Group III tumors.

Despite the above limitations, our data suggest that the use of standard treatmentprotocols is feasible, and results in similar overall survival to that reported in cooper-ative group trials for low- and intermediate-risk disease (see Figure 1B) [4, 5, 8]. No-tably, event-free survival was lower in our series than that reported in the IRS-IV study(see Figure 1C), primarily due to local recurrence that was subsequently salvageablein four of nine patients. Local recurrence was seen primarily in patients who had re-ceived radiation therapy alone for local control. One possible explanation is that theremay be inherent biologic differences in RMS among different ethnic groups. A recentstudy showed that, for children with RMS treated on the IRSG protocols, nonwhite pa-tients were more likely to present with invasive T2 tumors, tumors with positive re-gional lymph nodes, large tumors (>5 cm), and tumors that were stage 2 or 3, com-pared with whites [24]. Differences in disease biology by ethnic groups have also beenreported in other pediatric cancers (reviewed in [25]). We attempted to identify differ-ences that may explain the increased rate of relapse in tumors that recurred locally.Immunostaining for components of the DNA damage repair pathway has been asso-ciated with the response to radiation therapy in oropharyngeal carcinoma [26]; in ourstudy, we found weak staining for DNA damage pathway components in six of seventumors that recurred, versus two of five tumors that did not. These preliminary find-ings in this small sample size need to be further explored in a larger sample of tumors.

The outcome in our patients with low- or intermediate-risk disease was superiorwhen compared with the outcome of similar patients reported from other counties(see Table 4). Furthermore, while in two series there were more patients with alveo-lar histology than in our report, survival rates in those series were not different whenanalyzed by histologic subtype (see Table 4) [13, 14]. There are several differences be-tween our series and those reported from other countries that may have contributedto the difference in outcome. First, while none of our 23 patients abandoned treat-ment, high rates of abandonment were reported by the groups from Brazil and Mo-rocco (30% and 37%, respectively) [9, 10]. This may be due to the fact that at our cen-ter, the cost of medical care is fully covered for all patients, and parents do not pay anyout-of-pocket expenses. Another possible factor contributing to low abandonment isthat Lebanon is a relatively small country, and patients from the most rural areas canreach the city within 2 hours. Further, the strong emphasis of the fact that childhoodcancer is a largely curable disease, and the involvement of a uniform team of special-ized health care workers (pediatric oncology nurses, child life specialist, social worker,and administrative staff) resulting in psychosocial support for the families, may havealso played a role.

In our series, definitive local control was pursued for all patients. This likely alsocontributed to the improved outcome. In the report from Egypt, lack of radiation andlack of radical surgery were each associated with a high rate of relapse [11]. The groupsfrom Brazil and Morocco reported that local control was not performed in 28% and46% of patients, respectively, due to either abandonment or early progressive disease[9, 10]. These are much higher numbers than the 2.2% rate of early treatment failureprecluding radiation therapy in patients with intermediate risk disease reported in theIRS-IV and D9803 protocols [27]. None of our patients had progressive disease prior tolocal control.

The chemotherapy regimen we used was based on the VAC chemotherapy back-bone, as was the case for most of the other groups. The group from Korea used theIRS-III protocol in 78% of the patients, and while overall survival was similar to ourresults for nonmetastatic disease, they reported a rate of 16% progressive disease by


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week 20 of treatment [12]. The groups from Brazil and Morocco reported similar ratesof early progressive disease [9, 10]. Only one of our patients progressed on therapy, butthis was a late failure, at 9 months from diagnosis. In our series, treatment was suc-cessfully administered with minimal delays. While this may have contributed to thelow rate of early disease progression, biologic differences between the different ethnicgroups may have also contributed and cannot be ruled out.

We observed significant hematologic toxicities and neuropathies, but those weremostly manageable. There was one episode of septic shock, but no toxic deaths. Otherseries reported toxic deaths of 2%–5%, when G-CSF was not routinely used [9, 12]. In-terestingly, although the group from Hong Kong also based their treatment on the IRS-IV study, they had a high rate of toxic deaths (10%), second cancers (10%), and a highrate of National Cancer Institution grade 3–4 toxicities, including severe mucositis andelevation of liver enzymes [14]. The fact that the types of toxicities were different be-tween our patient populations strongly suggests ethnic differences in drug metabolismand toxicity, similar to what has been reported for other chemotherapeutic agents inthe Asian versus the Caucasian population [28].

CONCLUSION

In conclusion, treatment with standard VAC regimen chemotherapy, with local controlmodalities including surgery and/or radiation therapy in a multidisciplinary cancercenter setting, resulted in similar survival rates to those achieved in developed coun-tries. Factors contributing to successful treatment included prompt supportive caremeasures, and financial medical coverage contributing to a low abandonment rate.However, local recurrence was more common, despite apparently adequate radiationtherapy planning and delivery. Whether there are inherent biologic differences con-tributing to increased radio-resistance in this patient population needs to be furtherinvestigated.

Declaration of Interest

The authors acknowledge no conflicts of interest.

REFERENCES

[1] Meyer WH, Spunt SL. Soft tissue sarcomas of childhood. Cancer Treat Rev. 2004;30(3):269–280.[2] Raney RB, Maurer HM, Anderson JR, et al. The Intergroup Rhabdomyosarcoma Study Group (IRSG):

major lessons from the IRS-I through IRS-IV studies as background for the current IRS-V treatmentprotocols. Sarcoma. 2001;5(1):9–15.

[3] Spunt SL, Smith LM, Ruymann FB, et al. Cyclophosphamide dose intensification during inductiontherapy for intermediate-risk pediatric rhabdomyosarcoma is feasible but does not improve out-come: a report from the soft tissue sarcoma committee of the children’s oncology group. Clin CancerRes. 2004;10(18 Pt 1):6072–6079.

[4] Arndt CA, Stoner JA, Hawkins DS, et al. Vincristine, actinomycin, and cyclophosphamide com-pared with vincristine, actinomycin, and cyclophosphamide alternating with vincristine, topotecan,and cyclophosphamide for intermediate-risk rhabdomyosarcoma: children’s oncology group studyD9803. J Clin Oncol. 2009;27(31):5182–5188.

[5] Crist WM, Anderson JR, Meza JL, et al. Intergroup rhabdomyosarcoma study-IV: results for patientswith nonmetastatic disease. J Clin Oncol. 2001;19(12):3091–3102.

[6] Rodeberg D, Arndt C, Breneman J, et al. Characteristics and outcomes of rhabdomyosarcoma pa-tients with isolated lung metastases from IRS-IV. J Pediatr Surg. 2005;40(1):256–262.

[7] Huh WW, Skapek SX. Childhood rhabdomyosarcoma: new insight on biology and treatment. CurrOncol Rep. 2010;12(6):402–410.


Pedi

atr

Hem

atol

Onc

ol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y U

nive

rsity

of

Tor

onto

on

11/0

5/14

For

pers

onal

use

onl

y.

M. Salman et al.

[8] Oberlin O, Rey A, Lyden E, et al. Prognostic factors in metastatic rhabdomyosarcomas: re-sults of a pooled analysis from United States and European cooperative groups. J Clin Oncol.2008;26(14):2384–2389.

[9] Antillon F, Castellanos M, Valverde P, et al. Treating pediatric soft tissue sarcomas in a country withlimited resources: the experience of the Unidad Nacional de Oncologia Pediatrica in Guatemala.Pediatr Blood Cancer. 2008;51(6):760–764.

[10] Hessissen L, Kanouni L, Kili A, et al. Pediatric rhabdomyosarcoma in Morocco. Pediatr Blood Cancer.2010;54(1):25–28.

[11] Shouman T, El-Kest I, Zaza K, et al. Rhabdomyosarcoma in childhood: a retrospective analysis of 190patients treated at a single institution. J Egypt Natl Canc Inst. 2005;17(2):67–75.

[12] Park JA, Kim EK, Kang HJ, et al. Initial response to treatment was highly associated with the prognosisof childhood rhabdomyosarcoma: a retrospective analysis of a single center experience in Korea.Cancer Res Treat. 2008;40(3):111–115.

[13] Hosoi H, Teramukai S, Matsumoto Y, et al. A review of 331 rhabdomyosarcoma cases in patientstreated between 1991 and 2002 in Japan. Int J Clin Oncol. 2007;12(2):137–145.

[14] Yuan XJ, Chan GC, Chan SK, et al. Treatment outcome of rhabdomyosarcoma in Hong Kong Chinesechildren. Hong Kong Med J. 2008;14(2):116–123.

[15] Baker KS, Anderson JR, Link MP, et al. Benefit of intensified therapy for patients with local or regionalembryonal rhabdomyosarcoma: results from the Intergroup Rhabdomyosarcoma Study IV. J ClinOncol. 2000;18(12):2427–2434.

[16] Breneman JC, Lyden E, Pappo AS, et al. Prognostic factors and clinical outcomes in children andadolescents with metastatic rhabdomyosarcoma—a report from the Intergroup RhabdomyosarcomaStudy IV. J Clin Oncol. 2003;21(1):78–84.

[17] Squatrito M, Brennan CW, Helmy K, et al. Loss of ATM/Chk2/p53 pathway components ac-celerates tumor development and contributes to radiation resistance in gliomas. Cancer Cell.2010;18(6):619–629.

[18] Jeggo P, Lavin MF. Cellular radiosensitivity: how much better do we understand it? Int J Radiat Biol.2009;85(12):1061–1081.

[19] Lu C, El-Deiry WS. Targeting p53 for enhanced radio- and chemo-sensitivity. Apoptosis.2009;14(4):597–606.

[20] Kim ST, Lim DS, Canman CE, et al. Substrate specificities and identification of putative substrates ofATM kinase family members. J Biol Chem. 1999;274(53):37538–37543.

[21] O’Neill T, Dwyer AJ, Ziv Y, et al. Utilization of oriented peptide libraries to identify substrate motifsselected by ATM. J Biol Chem. 2000;275(30):22719–22727.

[22] Dagher R, Helman L. Rhabdomyosarcoma: an overview. Oncologist. 1999;4(1):34–44.[23] Sultan I, Qaddoumi I, Yaser S, et al. Comparing adult and pediatric rhabdomyosarcoma in the

surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients. JClin Oncol. 2009;27(20):3391–3397.

[24] Baker KS, Anderson JR, Lobe TE, et al. Children from ethnic minorities have benefited equally asother children from contemporary therapy for rhabdomyosarcoma: a report from the IntergroupRhabdomyosarcoma Study Group. J Clin Oncol. 2002;20(22):4428–4433.

[25] Bhatia S. Disparities in cancer outcomes: lessons learned from children with cancer. Pediatr BloodCancer. 2011;56(6):994–1002.

[26] Grabenbauer GG, Muhlfriedel C, Rodel F, et al. Squamous cell carcinoma of the oropharynx: Ki-67and p53 can identify patients at high risk for local recurrence after surgery and postoperative radio-therapy. Int J Radiat Oncol Biol Phys. 2000;48(4):1041–1050.

[27] Minn AY, Lyden ER, Anderson JR, et al. Early treatment failure in intermediate-risk rhabdomyosar-coma: results from IRS-IV and D9803—a report from the Children’s Oncology Group. J Clin Oncol.2010;28(27):4228–4232.

[28] Phan VH, Moore MM, McLachlan AJ, et al. Ethnic differences in drug metabolism and toxicity fromchemotherapy. Expert Opin Drug Metab Toxicol. 2009;5(3):243–257.


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rhabdomyosarcoma treatment and outcome at a multidisciplinary pediatric cancer center in lebanon

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