Current status and future perspectives of wilms tumor treatment in Iran

Background:

Wilms tumor (WT) is among the most common pediatric malignancies. In this study, the authors tried to evaluate the adherence to internationally-approved WT treatment protocols in our tertiary medical center in Iran.

Methods:

In this retrospective study, the medical records of 72 pathologically confirmed WT patients who underwent treatment from April 2014 to February 2020 were evaluated. Demographic characteristics, histologic features of the tumors and metastases, utilized treatments, and survival rates were subsequently investigated.

Results:

From the total of 72 patients, 31 (43.1%) and 41 (56.9%) were males and females, respectively. The median age at the time of diagnosis was 44.0 (interquartile range: 18.5, 72.0) months. Among the patients, favorable histology was observed in 68 (94.6%) patients, while 4 (5.4%) patients had unfavorable histology. Regarding chemotherapy, 34/56 (60.7%), 4/56 (7.1%), and 18/56 (32.2%) received adjuvant, neoadjuvant, and combined chemotherapy, respectively. The mean numbers of neoadjuvant and adjuvant chemotherapy sessions were 9.4±5.6 and 14.5±11.1, respectively. 32/72 (44.4%) of the patients received adjuvant radiotherapy with a mean number of 7.3±3.6 sessions. Overall survival rates were 86% at 1-year, 74% at 3-year, and 62% at 5-year.

Conclusion:

Our results suggested that while the demographic characteristics of WT patients in Iran resemble those in other countries, abidance to internationally recommended protocols is relatively low. Moreover, survival rates were rather dismal in our study compared to those from other developing countries, further signifying the need for the development of a nation-specific treatment protocol for WT.

Introduction

Highlights

• The demographics of Wilms tumor patients in Iran resemble those reported in other countries.

• Abidance to recommended treatment protocols is relatively low in Iran.

• Survival rates are rather dismal in our study compared to similar developing countries.

Wilms tumor (WT), also known as nephroblastoma, is accountable for almost 90% of pediatric renal malignancies, ranking fourth among childhood cancers1. It has been estimated that in 2019 alone more than 7700 new cases of renal malignancies have been diagnosed in children under 5 years old, globally2. Considering the substantial share of WT, it is presumable that WT is responsible for most of the burden imposed by kidney cancers in children ages.

Treatment of WT comprises of a combination of chemotherapy, surgery, and occasionally radiotherapy (RT) based on tumor stage and histology3. Despite dramatic improvements in overall survival rates during the last decades, currently reaching 90% in developed countries; survival rates are rather dismal in under-resourced, developing countries4–6.

Although this is mostly explained by the shortage of healthcare services, lack of economic resources, and delay in seeking care by parents; evidence that scarcity also plays a pivotal role in hampering effective treatment7. Previous studies from Iran have all assumed a perfect adherence to the National Wilms Tumor Study 4 (NWTS-4) treatment protocols5,8,9. Nevertheless, considering the relatively low adherence to cancer treatment protocols in developing countries, this assumption seems over-optimistic10. In this study, in addition to depicting the demographic characteristics, utilized treatments, and survival outcomes in WT patients, we tried to evaluate the abidance to internationally accredited treatment protocols in the largest referral pediatric hospital in Iran during the last decade.

Methods

Data source and study population

In this single-center retrospective medical record review, we investigated the medical records of all pathologically confirmed WT patients treated at our referral teaching hospital in Iran, from April 2014 to February 2020. All surgeries were performed by the attending urologists and chemotherapy and RT regimens were planned by the attending pediatric oncologists. Our institution follows NWTS/Children’s Oncology Group (COG) protocols11. Patient demographics, treatment plans, and follow-up data was extracted from medical records. Additional data was obtained through direct interviews with either the patient or first-degree relatives. Patients without accurate documented information were excluded. Datasheets consisting of demographic data (i.e. age and sex), initial malignancy characteristics (i.e. pathology and metastasis), therapeutic modalities (i.e. surgery, neoadjuvant or adjuvant chemotherapy, and radiation therapy), and follow-up data (i.e. remission, recurrence, and vital status) were designed and used for statistical analysis. This study has been reported in line with the PROCESS Guideline12.

Statistical analysis

The statistical analysis of all data was performed using SPSS software version 23 (IBM). Qualitative variables were reported as frequency (percentage). Data on quantitative variables was described as either mean±SD or median (interquartile range (IQR)) based on normality.

Ethical considerations

This study is in accordance with the Helsinki and Istanbul declarations. It has been ethically reviewed and approved by the institutional review board. The legal guardians of all patients had been counseled regarding the advantages and disadvantages of different treatment modalities and in applicable cases, the final decision had been made by the patient’s legal guardians. Written consent forms had been filled out by the legal guardians of all patients before the initiation of treatment.

Results

Patients’ characteristics and demographics

In total, 72 pathologically confirmed WT patients were treated in our tertiary medical center during the study period. The patient population consisted of 31 (43.1%) males and 41 (56.9%) females. The median age at diagnosis was 44.0 (IQR: 18.5, 72.0) months. The youngest and oldest ages at the time of diagnosis were 4 and 120 months old, respectively. The most prevalent presenting symptom was painless abdominal mass in 66 (91.7%) patients followed by painless hematuria in 6 (8.3%) cases. Considering the laterality of the tumor, 35/70 (50.0%), 30/70 (42.9%), and 5/70 (7.1%) had left, right, and bilateral tumors, respectively; while data regarding the laterality of the tumor was missing for two patients. In total, 67 (93.1%) patients underwent radical nephrectomy while five (6.9%) were not operated on due to their tumor being bilateral (N=2) or having extensive distant metastases (N=3). The remaining patients who had bilateral WT (N=3) all underwent surgery. The demographic characteristics of the patients are depicted in Table 1.

Table 1.

Demographic characteristics, tumors pathological characteristics, and cancer treatment

Age at the time of diagnosis		44.0 (IQR: 18.5, 72.0)
Age range		4–120
Sex	Female	41 (56.9%)
	Male	31 (43.1%)
Laterality (N=70)	Right	30 (42.9%)
	Left	35 (50.0%)
	Bilateral	5 (7.1%)
Histology (N=72)	Favorable	68 (94.6%)
	Unfavorable	4 (5.4%)
Surgical intervention		67 (93.1%)
chemotherapy (N=56)	N.A	4 (7.1%)
	A	34 (60.7%)
	N.A + A	18 (32.2%)
Chemotherapy cycles	N.A group	16.3±4.8
	A group	17.6±10.5
	N.A + A group	N.A (9.4±5.6) + A (14.5±11.1)
Adjuvant radiotherapy (N=72)		32 (44.4%)
Adjuvant radiotherapy sessions		7.3±3.6

A, adjuvant; N.A, neoadjuvant. Data are described as mean±standard deviation or median (interquartile range) and frequency (percentage) for quantitative and qualitative variables, respectively. All data on patients’ ages are reported in months. N indicates the total number of patients evaluated for each variable.

Tumors pathology, cancer treatment, and prognosis

In total, 68 (94.6%) patients had favorable histology and 4 (5.4%) had unfavorable histology. Pathological data was obtained from postoperative surgical pathology reports. For the five patients who were not operated on, pathological data was obtained from core needle biopsy reports. These patients were biopsied according to the criteria proposed by NWTS/COG due to the unusual age at presentation (N=3) and atypical radiological findings (N=2)13. Data regarding the chemotherapy status of 11 patients were excluded due to incomplete medical records and the 5 patients who had not undergone surgery, were also excluded. Of the 56 remaining patients, 34(60.7%) patients received adjuvant chemotherapy, 4 (7.1%) patients received neoadjuvant chemotherapy and 18 (32.2%) patients received both adjuvant and neoadjuvant chemotherapy. The chemotherapy regimen mainly consisted of dactinomycin, doxorubicin, and vincristine with minor modifications according to patients underlying comorbidities. No severe adverse events due to chemotherapy which had required medical treatment was documented in patients’ health records. The mean numbers of chemotherapy sessions in adjuvant and neoadjuvant chemotherapy groups were 17.6±10.5 and 16.3±4.8, respectively. In patients who received both neoadjuvant and adjuvant chemotherapies, the mean sessions of chemotherapy before and after surgery were 9.4±5.6 and 14.5±11.1 sessions. Additionally, 32 (44.4%) patients underwent RT according to NWTS/COG protocols (e.g. tumor bed radiation in stage 3, peritoneal seeding, gross tumor spillage, and lung radiation in case of metastasis)11,14. The mean number of RT sessions in these patients was 7.3±3.6. A summary of this data can be observed in Table 1.

Initial metastasis workup was done by abdominopelvic computed tomography (CT)-scan with intravenous and oral contrasts and chest CT-scan with intravenous contrast. With regards to metastasis status at the time of diagnosis, 60/65 (92.3%) had no metastasis, while 5/65 (7.7%) had metastasis. Follow-up visits were scheduled for every 3 months in the initial 2 years after diagnosis, then every 6 months for the second 2 years and annually thereafter. Abdominopelvic ultrasound and chest radiography were obtained on each follow-up visit during the first two years. In case of high clinical suspicion, abdominopelvic and/or chest CT-scans were performed to investigate possible recurrence. Annual echocardiographs were planned for all the patients who have received doxorubicin to rule out any possible cardiac toxicity. At the time of the study, 18/65 (27.7%) patients had distant recurrence. Table 2 illustrates the metastases sites. The most noticeable finding in this regard was the two patients who had metastases to their appendix, a finding which has never been reported previously in the literature.

Table 2.

Metastases sites at initial diagnosis and recurrence

Metastasis site	Initial diagnosis (N=5)	Recurrence (N=18)
Lung	N=2	N=11
Liver	N=2	N=2
Lung and liver	–	N=1
Abdominopelvic cavity	N=1	N=1
Bladder	–	N=1
Appendix	–	N=2

While assessing vital status, 13 patients were inaccessible through telephone calls and were therefore excluded from survival analysis since their present vital status could not be confirmed. At the end of this study, 53 (77.9%) patients were alive while 15 (22%) patients had died. The median follow-up time was 24.0 (IQR: 12.0, 50.0) months. Overall survival rates were 86% at 1-year, 74% at 3-year, and 62% at 5-year. Our life table analysis also indicated that the survival rate was worse among the 5 patients who had not undergone surgery with an estimated 1-year survival of only 33%. Nevertheless, since all of these patients had either bilateral WT or extensive distant metastases, this discouraging survival can be explained by the higher stages (i.e. stages 4 or 5) of their tumor at the time of diagnosis.

Discussion

Since its introduction in the late 19th century by Max Wilms, WT has been established as the most prevalent pediatric renal tumor; responsible for more than 90% percent of kidney neoplasms1,3. Mostly a cancer of children under 10 years old, WT is slightly more prevalent in girls and tends to happen bilaterally in 5–8% of patients3,15,16. In line with these previous findings, our results revealed that the median age at diagnosis was 44 months, all patients were under 10 years of age at the time of diagnosis, and 7.1% had bilateral WT. Moreover, WT was slightly more prevalent in females (56.9%) compared to males (43.1%). Interestingly, the previous studies from Iran had also reported a mean age of 40 and 45 months at diagnosis, closely resembling our results5,9. Contrary to the previous reports from our country, which showed staggering rates (32.69 and 44%) of unfavorable histology, in our study only 5.4% of the patients had unfavorable histology, which is comparable to international statistics5,9,17.

There has been a dramatic improvement in WT survival during the last five decades, currently reaching 50–90% in comparison with 20% in the 1960s6. This advancement is mostly owing to the intense scientific collaboration between the NWTS/COG and the Société Internationale d’Oncologie Pédiatrique Renal Tumor Study Group (SIOP-RTSG). However, they have contradictory recommendations for WT.

While the SIOP-RTSG protocol mostly encourages up-front chemotherapy followed by surgical intervention, NWTS/COG suggests surgery as the initial treatment13. Based on the SIOP-RTSG protocol, fewer intraoperative tumor ruptures tend to occur and the patients may have a lower postoperative stage. On the other hand, the up-front nephrectomy in the NWTS/COG protocol allows for earlier and more accurate histopathologic diagnosis, excision of tumoral material before they get exposed to chemotherapeutic agents, and precise staging before the initiation of chemotherapy18. Previous studies have shown that overall survival rates are relatively comparable with both approaches13,19. However, there exists a high-risk group, consisting of anaplastic pathology, bilateral tumor, and recurrent tumors, which constitutes nearly 25% of WT patients and selection of the optimal treatment is necessary for this group18. Our data revealed that most of the patients in our medical center underwent either adjuvant chemotherapy (60.7%) or both neoadjuvant and adjuvant chemotherapy (32.2%) and only a small share of our patient population (7.1%) were treated with only neoadjuvant chemotherapy. Of the five patients who were classified as being at high-risk due to having bilateral tumors, two were only treated with chemotherapy and were not operated on, two had both neoadjuvant and adjuvant chemotherapy and one only had neoadjuvant chemotherapy. These findings demonstrate that combination adjuvant and neoadjuvant chemotherapy is meaningfully high in our country, which can be partly justified by the higher stage of disease at diagnosis due to the delay in seeking medical care, commonly observed in developing countries5,20. According to the latest NWTS/COG and UMBRELLA SIOP-RTSG protocols, apart from patients who have had low-stage and low- or intermediate-risk tumors, all other patients must receive a minimum of 27 to 28 sessions of chemotherapy with dactinomycin, vincristine, and doxorubicin11,21. In our study, the mean number of postoperative chemotherapy sessions was 17.6 sessions, which may show a failure to abide by the recommended protocols. Nevertheless, as the stage of the disease could not be obtained in our study due to incomplete medical records in some patients; this hypothesis may be subject to bias. On the contrary, 44.4% of our study group underwent RT, which is much higher than previous reports21. These discrepancies can be partly justified by regional issues, disordered patient follow-up, the availability of chemotherapy drugs and RT equipment in Iran, and oncologists’ preferences.

According to the literature, the incidence of metastatic WT has been reported to be 10–40%, with higher rates being reported in low-income under-resourced countries3,7,21,22. Moreover, it has been suggested that metastasis is more common at the time of relapse rather than primary diagnosis23. In our study, 7.7% of the patients had metastasis at the time of diagnosis and 27.7% had distant metastasis on recurrence. The previous study from Iran had also reported a similar (9%) metastasis rate5. Similar to findings from previous reports, among our patients, the lung was the most common site of metastasis followed by the liver24–26. The most prominent and interesting finding of our study was two cases of metastasis to the appendix, which had never been reported in the literature, previously.

According to our findings, the 1, 3, and 5-year overall survival rates were estimated to be 86, 74, and 62%, respectively. These survival rates are meaningfully lower than developed countries in which survival rates had been reported to be as high as 90–95%3,18,20. Our survival rates were even dissatisfying in comparison with the previous report from Iran, which estimated a 4-year overall survival of 86%5. This discrepancy can be partly justified by the difference between cancer staging in these studies.

The main limitation of our study was the failure to obtain the cancer stage of some of our patients due to the missing data in our pathology registry. This shortcoming hindered the comparison of overall survival among various treatment groups. Similarly, due to the direct role of cancer stage in determining the suitable chemotherapy regimen and length; lack of this data hampered the accurate comparison of the efficacy of the administered chemotherapy regimens with internationally recommended protocols, with respect to patients’ overall survival. Another limitation of our study was reporting the histological classification (i.e. favorable and unfavorable) of the tumors regardless of the patient’s chemotherapy status; a factor known to profoundly affect tumor histology. Further prospective cohort and clinical trial studies are advised to determine the treatment of choice for WT, especially in resource-limited developing countries.

Conclusion

In conclusion, our study suggested that the demographic characteristics of WT patients in Iran resemble those in other countries. We also showed that compatibility with internationally recommended protocols is relatively low in Iran, which might be due to a paucity of efficient chemotherapeutic agents. Moreover, survival rates were rather dismal in our study further signifying the need for the development of a nation-specific treatment protocol for WT, other than a nationwide community-based education program aimed to raise awareness among parents with respect to this disease.

Ethical approval

This study is in accordance with Helsinki and Istanbul declarations. It has been ethically reviewed and approved by the Children’s Medical Center ethical board (reference number: IR.TUMS.CHMC.REC.1398.129).

Consent

Written consent forms had been filled out by the legal guardians of all patients before the initiation of treatment.

Sources of funding

None.

Author contributions

P.H.: study concept and design; A.A., S.H.V.: data collection; M.Z., A.A.: data analysis and interpretation; M.Z.: writing the manuscript; P.H., M.M.Z., A.-M.K.: critical review; Abdol-M.K., P.H., H.A., S.M.G., H.A.: performed surgeries; F.K.: performed chemotherapy.

Conflicts of interest disclosure

The authors have no conflict of interest to disclose.

Provenance and peer review

Not commissioned, externally peer reviewed.