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Table of Contents   
ORIGINAL ARTICLE
Year : 2023  |  Volume : 28  |  Issue : 6  |  Page : 472-478
 

Looking beyond toxicities: Other health-related morbidities noted in childhood solid tumor survivors


1 Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi, India
2 Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India
3 Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India

Date of Submission07-May-2023
Date of Decision25-May-2023
Date of Acceptance23-Jul-2023
Date of Web Publication02-Nov-2023

Correspondence Address:
Vishesh Jain
Department of Pediatric Surgery, All India Institute of Medical Sciences, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jiaps.jiaps_104_23

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   Abstract 


Aim: In addition to the well-known toxicities of treatment, survivors of pediatric solid tumors can also develop other health-related conditions. They may either be an indirect consequence of therapy or could be unrelated to their prior history of malignancy. We aim to evaluate the nontoxicity related health conditions in survivors of pediatric solid tumors.
Materials and Methods: The study included a cohort of hepatoblastoma (HB), Wilm's tumor (WT), and malignant germ cell tumors (MGCT) survivors registered at pediatric surgical-oncology clinic from 1994 to 2016. Follow-up was done according to standard protocols and children were evaluated at each visit for any health-related conditions.
Results: Of the survivors, 318 survivors, comprising of 48, 81, and 189 survivors of HB, MGCT, and WT, respectively, were included in the analysis. We found 20.8% of patients with HB, 11.1% of patients with MGCT, and 16.4% of patients with WT to report nontoxicity-related health issues. A high prevalence of surgical conditions (3.4%), secondary malignancies (1.2%), gynecological conditions in girls (16.9%), tuberculosis (1.2%), gallstone disease (0.9%), pelvi-ureteral junction obstruction (0.9%), and neurological issues (0.9%) was noted. Two presumed survivors had died, one due to a late recurrence and the other due to a secondary malignancy.
Conclusions: A high prevalence of medically or surgically manageable conditions makes it imperative to keep these children under follow-up to address any health-related conditions they may subsequently develop.


Keywords: Adhesive obstruction, alopecia, neurogenic bladder, secondary malignant neoplasm, survivorship


How to cite this article:
Sehgal M, Jain V, Agarwala S, Dhua A, Goel P, Yadav DK, Bakhshi S, Kalaivani M. Looking beyond toxicities: Other health-related morbidities noted in childhood solid tumor survivors. J Indian Assoc Pediatr Surg 2023;28:472-8

How to cite this URL:
Sehgal M, Jain V, Agarwala S, Dhua A, Goel P, Yadav DK, Bakhshi S, Kalaivani M. Looking beyond toxicities: Other health-related morbidities noted in childhood solid tumor survivors. J Indian Assoc Pediatr Surg [serial online] 2023 [cited 2023 Nov 28];28:472-8. Available from: https://www.jiaps.com/text.asp?2023/28/6/472/389308





   Introduction Top


Pediatric cancers constitute <5% of the total cancer burden in India; 30% of these are malignant solid tumors.[1] With improvement in treatment modalities, there is a considerable increase in the number of survivors. Survivorship care involves holistic rehabilitation and follow-up of the child, well into adulthood, keeping a close watch for any potential medical or psychosocial issues that may subsequently develop. The focus of most follow-up visits after completion of treatment is to look for the development of long-term complications of treatment, specifically those related to the adverse effects of chemotherapy and radiotherapy, which can be progressive and irreversible. However, apart from the direct effects of the treatment received, the child may also potentially develop other health-related issues, which may or may not be a direct consequence of the treatment received. Given their long prior history of cancer treatment, these other health-related problems are better dealt with in the survivorship clinics.

Even though the number of survivors has increased, the number of studies and support groups for their rehabilitation and survivor outcomes is limited, especially from our country.[2],[3] It has been noted from the Western literature that 45%–63% of adult survivors had at least one chronic health-related condition.[4],[5] This highlights that there is a need for a prolonged long-term follow-up of these patients with close monitoring of their growth and development, medical sequelae, along with evaluation for any subsequent health-related issues. Majority of publications on this subject address toxicities noted in these patients as a result of the treatment they have received. We sought to evaluate the other nontoxicity-related health morbidities in survivors of pediatric solid tumors, which also need to be given due importance. These include those health related conditions including long term morbidities not related to specific toxicities due to chemotherapy, and also secondary malignant neoplasms (SMN).


   Materials and Methods Top


A retrospective study was conducted which included medical records of children registered at the pediatric solid tumor clinic from January 1994 to June 2016, with a diagnosis of Wilm's tumor (WT), hepatoblastoma (HB), and malignant germ cell tumor (MGCT) were accessed and reviewed for inclusion into the study. The patient was defined as a survivor if alive 5 years after diagnosis. The study included follow-up data of such patients collected from the date of ethical clearance (March 07, 2019 Ref no. IECPG-638/19.12.2018, RT-31/28.02.2019) till November 30, 2021. Patients who could not be contacted, had missing records or refused to participate in the study were excluded. Medical records of patients fulfilling the inclusion criteria were reviewed and relevant details pertinent to the demographics, the tumor and its treatment received were noted. Any missing data were complemented at the subsequent follow-up visits.

Standard protocols were followed for the treatment of individual cancers. Follow-up was also done according to the standard protocols for each cancer monthly for 3 months, 3 monthly till 1 year, 6 monthly for 2 years, and every 2–3 years subsequently. If any child had missed his/her follow-up, they had been telephonically contacted and informed regarding the missed follow-up. Each child was evaluated holistically at each visit, with a focus on the health-related effects of having been diagnosed with and treated for malignancy. Any pending investigations during follow-up were done and further imaging and investigations were done basis the clinical signs and symptoms. For the purpose of this study, chemotherapy and radiotherapy-related toxicities and behavioral issues were not included.

The data were compiled using Microsoft® Excel (Version 16.56) © 2023 Microsoft Corporation, One Microsoft Way, Redmond, (Washington, United States of America) and described using descriptive statistics.


   Results Top


During the study period, 404 patients were deemed survivors, of which 86 were excluded due to a lack of complete data. Hence, 318 survivors were included in the analysis. The majority of survivors belong to the WT group, followed by MGCT and HB, as described in [Table 1].
Table 1: Patient characteristics of collective cohort comprising of hepatoblastoma, malignant germ cell tumor, and Wilm's tumor

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Of the 318 children at follow-up, on general evaluation, most children were reported as active, with few reporting health-related issues. The health-related complications are shown in [Table 2].
Table 2: Distribution of nontoxicity related health conditions in survivors of hepatoblastoma, malignant germ cell tumor, and Wilm's tumor

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Treatment-related surgical conditions (n = 9)

Eight survivors had subacute intestinal obstruction 2 months to 11 years after completion of treatment, at a median time of 6 months after surgery. Of these, four patients were managed conservatively (two patients of HB and one patient each of WT and MGCT) and improved, however, four patients had to be operated for relieving the obstruction. The cause of obstruction was found to be an omental band in one patient, ileal stricture in one patient, adhesions and ileo-ileal intussusception in one patient. All four recovered uneventfully. Notably, all these operated patients were survivors of WT.

An incisional hernia developed in one patient of WT and had to undergo repair for the same.

Nontreatment-related surgical conditions (n = 2)

One survivor of WT had a right undescended testis for which he underwent an orchidopexy. Another survivor of WT had a right inguinal hernia for which he underwent a herniotomy.

Malignant conditions (n = 4)

Two children survivors of MGCT went on to develop secondary malignancies, one child developed a translocation acute myeloid leukemia for which she was transferred under medical oncology for further management and another child developed a thyroid nodule which was a follicle adenoma on histopathology. Both are doing well on follow-up.

One survivor of WT developed a second malignancy, detected to be a follicular variant of papillary carcinoma thyroid, for which he underwent left hemithyroidectomy and received iodine therapy and is doing well on follow-up. Another survivor of WT developed a glioblastoma 3 years after diagnosis, for which he was operated. Unfortunately, the child did not survive.

Menstruation and gynecological issues (n = 9)

Gynecological conditions were noted to be present in 16.9% of the 53 postpubertal girls. In survivors of MGCT, one girl survivors had complaints of dysmenorrhea and another girl was diagnosed to have polycystic ovary syndrome. Another survivor had a complex right ovarian cyst after having undergone a prior left oophorectomy. One survivor was on hormone replacement therapy after bilateral oophorectomy for bilateral ovarian MGCT.

Amongst survivors of WT, 2 girl survivors reported having menstrual irregularities, and one girl survivor complained of dysmenorrhea. One girl who presented with menorrhagia was found to have a bilateral adnexal cyst. Another girl was found to have bilateral small ovarian cysts which remained stable at follow-up.

Renal (n = 5)

Amongst survivors of HB, two survivors had abnormal abdominal ultrasound findings – One had a renal cortical cyst and one patient had left hydronephrosis at follow-up. The child with hydronephrosis was evaluated and found to have left pelvi-ureteric junction obstruction, which was obstructive on renal dynamic study and had to undergo a pyeloplasty 12 years after completion of therapy. One survivor had complaints of dribbling, with Urodynamic study (UDS) revealing a small capacity normal pressure system. The child was started on Imipramine and had an improvement in symptoms.

Two survivors of MGCT were diagnosed with pelvi-ureteric junction obstruction, of which one patient required a pyeloplasty 3 years after completion of therapy.

Neurogenic bladder (n = 5)

Of the 21 long-term survivors of malignant sacrococcygeal teratoma, 10 (47.6%) survivors had a complete evaluation. Five patients (50%) had complaints of incontinence or dribbling, and four children were on medical treatment. Urodynamic findings were reported as normal in 6/10 (60%) patients, however, three patients had a low-capacity bladder and one patient had a large capacity bladder reported on urodynamic study.

Hepatobiliary and gastrointestinal (n = 8)

One patient of HB had Hepatitis C seropositivity incidentally detected. Three survivors developed symptomatic cholelithiasis (1 with HB, 1 with MGCT and 1 with WT) and had to undergo cholecystectomy. The patient with HB had previously undergone a left hepatectomy. Amongst survivors of WT, one patient had a history of pica and another patient had a rectal prolapse. One survivor was noted to have a nodule over the liver which was benign on fine needle aspiration cytology. A large benign cyst in the liver was noted in one survivor during follow-up.

Dermatological issues (n = 2)

One patient of HB had persistent alopecia areata. Another survivor of MGCT had complaints of severe hair loss.

Neurological conditions (n = 3)

Among survivors of HB, one was diagnosed with migraines and was on medical management. Among survivors of WT, one was diagnosed with focal epilepsy and is on management for the same, and another survivor developed seizures with dystonia and had to be started on Baclofen.

Miscellaneous (n = 15)

Four survivors (2 with MGCT and 2 with WT) developed tuberculosis and were on medical management for the same.

Among survivors of WT, three patients complained of exertional dyspnea and weakness. Two patients developed hypertension and had to be started on medical management. Two patients developed eosinophilic lung disease, of which one patient had massive eosinophilia and had to be admitted and needed mechanical ventilation. There were three survivors of WAGR syndrome, of which two were declared blind. Two patients developed cystic lesions on the spleen for which a splenectomy had to be done for one of them.

Deaths (n = 2)

One patient of HB died 7 years after diagnosis, possibly due to a late recurrence. However, exact cause of death is not known. One patient with a diagnosis of WT expired after developing a glioblastoma (SMN).


   Discussion Top


Survivorship is an important component of the management of childhood cancer. The most important component of the survivorship programs for follow-up involves the evaluation of long-term toxicities as a result of chemotherapy and radiotherapy, apart from the generalised evaluation of the survivor. Beyond the expected direct adverse effects, the general health status can also be impacted which can potentially impact the quality of life. A study by Oeffinger et al. on a large cohort of 10,397 adult survivors of pediatric cancers reported 62.3% had at least one chronic condition, with 27.5% having a severe or life-threatening condition.[5] The St. Jude Lifetime Cohort Study compared the cumulative burden of chronic health conditions among 4612 adolescent and young adult survivors at the ages of 18 years and 26 years and noted that survivors at the age of 18 years experienced an average of 22.3 disabling conditions per 100 individuals, described as a higher grade on the CTCAE grading system,[6] which increased to an average of 40.3 disabling conditions per 100 individuals at 26 years of age.[7] This highlights the importance of long-term follow-up for survivors, to aid in early recognition and intervention for other health-related conditions. With this study, we have tried to broaden our view of the medical morbidities, beyond toxicities secondary to chemotherapy, faced by survivors of pediatric solid tumors.

In our study, we found that nontoxicity-related health issues were reported in 20.8% of patients with HB, 11.1% of patients with MGCT, and 16.4% of patients with WT. Second malignant neoplasms, hypertension, infections, hydronephrosis and menstrual abnormalities were predominantly noted. This data would imply that 1 in every 5–6 survivors would present with a nontoxicity-related health condition, which may increase in prevalence increases as the age and duration of follow-up advances.

Surgery is uniformly a part of all treatment protocols, and with improvement in technique and more experience of surgeons, there has been a reduction in complication rates. Survivors may continue to have long-term effects of having undergone surgical excision. In our study, 2.5% of patients presented with subacute intestinal obstruction, from 6 months after excision to as long as 11 years after surgical excision. Half of these could be managed conservatively but the other half required another surgical procedure for the relief of their obstruction. Adhesive obstructions were more likely to resolve conservatively, and those that had to be operated on had an omental band, intussusception and ileal stricture. Interestingly, those with a diagnosis of WT had to undergo operative management for the management of obstruction. A higher prevalence of intestinal obstruction was reported by the Childhood cancer survivor study[8] (5.8% in abdominopelvic tumors) and National WT Study-3 (6.9% post nephrectomy). As compared to the 2.5% prevalence in our WT survivors, the National WT Study group noted a higher overall prevalence of small bowel obstruction after nephrectomy for WT, of which adhesive obstruction was the most common cause, although it is comparable to that after other major abdominal operations in children.[9] This is an important consideration, as although the prevalence of obstruction is the similar to that noted post routine nononcological surgery, which ranges between 1% and 6%,[10] it has been noted by Lautz et al. that obstruction in this population is associated with a higher prevalence of mortality and morbidity compared with others.[11] Hence, it is important to counsel parents to be aware of this possibility as it may arise even later in survivorship, and to seek treatment as soon as the need arises, even if they are not in the vicinity of the treating oncological centre.

Bladder disturbances are known complications in survivors who have undergone pelvic surgery.[12] Neurogenic bladder was an important complication noted specifically in our survivors of sacrococcygeal teratoma. We noted that 50% of the patients who were evaluated, had lower urinary tract symptoms. We also noted that 40% had an abnormal urodynamic study pattern and were on treatment for managing enuresis or incontinence. Similar findings have also been noted by Rehfuss et al., Ozkan et al. and Khanna et al., who have reported up to 50% of their patients to have urodynamic abnormalities, with 80% needing to start clean intermittent catheterization and up to 35% needing surgical intervention.[13],[14],[15] Thus, treatment of pelvic tumors can produce neuro-urological dysfunction of the lower urinary tract with high-grade reflux, and abnormal bladder and urethral function. Complete assessment, including urodynamic studies, is imperative preoperatively if possible and postoperatively. Constant vigilance is a must to maintain as near normal bladder function as possible and to prevent upper urinary tract injury.

An important finding was the occurrence of SMN. In our study, we found 4 survivors who developed SMN – Two patients developed thyroid malignancy, one patient developed acute myeloid leukemia and another developed glioblastoma. These survivors belong to the MGCT and WT subgroups. No children with a diagnosis of HB developed an SMN. The prevalence of SMN reported in adulthood in a heterogeneous group of survivors of childhood cancer is 2.38% in a study by Oeffinger et al.,[5] which is higher than that reported in our study. The Childhood Cancer Survivor Study Cohort found a prevalence of SMN of 4.5% in survivors of WT and neuroblastoma.[16] Thyroid malignancies and acute myeloid leukemias were found to be the most common SMN, as also found in our patients, in a population-based study on the Australian Childhood Cancer Registry.[17] Literature on SMNs cites a cumulative incidence of 2%–3% at 20 years of follow-up and a 14.8-fold higher risk noted in survivors than in siblings.[16],[18],[19] Most of the studies on SMNs, however, include a heterogeneous group, patients of which have often received head and neck radiotherapy, which is a known risk factor. This still demonstrates the need for a prolonged follow-up as the cumulative incidence increases over the years.

A higher prevalence of transmitted viral infections like Hepatitis B and C has been noted in Indian studies on cancer survivors,[20],[21] which has been attributed to the transfusion of blood and blood products to these patients during their treatment. We did not specifically test for these infections and those detected positive were noted incidentally. However, it is encouraged to include testing as a part of follow-up protocol, with the inclusion of Human Immunodeficiency Virus testing on an opt-out basis as advocated by the Government of India guidelines.[22] Survivors have also been shown to be at an increased risk for late cholecystectomy. We noted 0.9% of our survivors have symptomatic gallstone disease, which is similar to the 0.3%–2% prevalence noted in healthy children by other Indian studies.[23] It should however be noted that a higher incidence of late cholecystectomy has been noted in survivors, as late as 27–30 years, by the Childhood Cancer Survivor Study.[24] This study has noted that exposure to high dose platins and vinca alkaloids as a part of chemotherapy and female survivors were a potential risk factor for late cholecystectomy. These drugs have been shown to cause transaminitis, cholestasis and steatosis, which increase the risk of development of gall stones, independent of the existing known risk factors. Thus, survivors should also be educated and followed up for the risk of development of gallstone disease, as the cumulative incidence increases over time.[25],[26]

We also noted a few survivors undergoing evaluation and management for pelvi-ureteral junction obstruction. The normal incidence of pelvi-ureteral junction obstruction in children is estimated to be 1 in 1000–1500 children.[27] In one of the patients of MGCT, a remanent fibrosed retroperitoneal node in absence of elevated alpha-fetoprotein levels was later found to be the cause of this obstruction. For others, the cause could not be identified but could be due to fibrosis from microscopically involved lymph nodes. Interestingly, the pelvi-ureteral junction obstruction in the survivor of HB was found on the left side, which meant it was probably not related to the previous malignancy status and was just incidentally co-existing.

Female survivors have also been noted to have menstrual abnormalities, diminished ovarian reserve, subfertility and higher pregnancy-associated complications,[28],[29] but these are predominantly noted with an alkylating agent, radiation to the pelvis or as an effect of surgery in MGCT patients. There is a role of fertility-preserving surgery in these patients which has been noted to improve reproductive outcomes.[30] None of our patients had significantly impacted menstrual function, noted only in 16.9% of postpubertal girls, which is lower than that reported by other Indian studies.[31],[32] However, eventual reproductive function and long-term prevalence of these problems in adulthood are yet to determined.

Some of the limitations of our study are that the findings are representative of patients' complaints during follow-up, and not all patients were thoroughly examined and questioned for other systemic complaints. Survivorship bias is another shortcoming inherent to the studies on childhood survivors as only those coming for follow-up are represented. Since this is a survivorship study, the morbidities of the included survivors were noted 5 years after diagnosis.


   Conclusions Top


Survivors of pediatric solid tumors need close follow-up and evaluation due to the long-term effects of the treatment received, which should not only be limited to the affected organ systems. With one in five survivors having nontoxicity-related complaints, a complete evaluation should be a part of the follow-up protocols.

Financial support and sponsorship

This work was partially supported by the Indian Council of Medical Research (Under Grant No. 5/13/21/2020/NCD-III).

Conflicts of interest

There are no conflicts of interest.



 
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