THE DENTAL EFFECTS OF CHEMOTHERAPY AND RADIATION THERAPY ON PEDIATRIC PATIENS

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Berfin Lisa Arslan

5th year, group 13

THE DENTAL EFFECTS OF CHEMOTHERAPY AND

RADIATION THERAPY ON PEDIATRIC PATIENS

Master’s Thesis

Supervisor

Assistant, Z. Kristina Matulaitiene

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LITHUANIAN UNIVERSITY OF HEALTH SCIENCES MEDICAL ACADEMY FACULTY OF ODONTOLOGY

DEPARTMENT OF PREVENTIVE AND PEDIATRIC DENTISTRY

THE DENTAL EFFECTS OF CHEMOTHERAPY AND RADIATION THERAPY ON PEDIATRIC PATIENS

Master’s Thesis

The thesis was done by student

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TABLE OF CONTENTS

SUMMARY ...7

INTRODUCTION ...8

1. METHOD AND MATERIALS...10

1.1 Identification and Search strategies...10

1.2 Inclusion criteria...12

1.3 Validity Assessments and Data Extraction...13

1.4 Study Quality and Risk of Bias...13

2. RESULTS...14

2.1 Chemotherapy’s biomechanical action...14

2.2 Radiation therapy’s biomechanical action...15

2.3 Combined chemotherapy and radiation therapy...16

2.4. Oral effects after chemotherapy and radiation therapy in childhood cancer survivors...16

2.4.1 Hyposalivatory and caries after chemotherapy and radiation therapy...16

2.5 Dental development malformations effects after radiation therapy in childhood cancer survivors...19

2.6 Dental developmental malformations after chemotherapy...21

2.7 Dental developmental abnormalities after combined chemotherapy and radiation therapy...24

2.8 Quality of life post therapy...25

3. DISCUSSION ...29

4. CONCLUSION ...34

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THE DENTAL EFFECTS OF CHEMOTHERAPY AND RADIATION THERAPY ON PEDIATRIC PATIENTS

SUMMARY

Purpose: To highlight the dental consequences of chemotherapy and radiation therapy given to children and adolescents.

Background: Cancer is a rare disease in children, however one of the leading death rate causes of children aged 1 to 14 in the United States, 1.250 children were estimated to die 2016. In the United Kingdom there are around 1,800 new cases in 2012-2014 of paediatric cancer each year and five new primary diagnoses everyday. Most common cancers types are leukemia, neuroblastoma, other CNS and intracranial tumors, soft-tissue sarcomas, renal tumors and non- Hodgkin lymphomas. Method: A qualitative systematic review presents thirty two scientific English articles, the analyses were made by the PRISMA guidelines.

Result: chemotherapy and radiation therapy are still related with numerous side effects post treatment. These include dental developmental defects that affect the patient’s quality of life. Conclusion: Hyposalivation is a common cancer treatment outcome that can contribute to increased risk of carcinogenic microorganism invasion. Health care providers can closely observe the

childhood cancer survivors for an early discovery and intervention as preventative measures. Chemotherapy and radiation therapy effect on developing dentition is still a question, however it is believe that the dental defects are mostly affected by the age of the patient.

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INTRODUCTION

Cancer is a rare disease in children, however one of the leading death rate causes of children aged 1 to 14 in the United States. In 2016, 10.380 children were estimated to be diagnosed with cancer and 1.250 out of these children would die of the cause [1]. However in the United Kingdom there are around 1,800 new cases in 2012-2014 of paediatric cancer each year and five new primary diagnoses everyday. The most common cancers in children are leukemia, neuroblastoma, other CNS and intracranial tumors, soft-tissue sarcomas, renal tumors and non- Hodgkin lymphomas but leukemia is the most commonly pediatric cancer diagnosis. Nevertheless, the cancer modality qualities and methods have improved the pediatric yearly cancer indices have not decreased since the increase of 11 % from the early 1990s. Cancer mortality rates has however decreased by 66% in the UK since the late 1970s and over the last decades the death rate has further decreased with 18%. Death rates have decreased significantly and these reductions can be further improved by applying cancer control knowledge to the population [2].

Cancer treatment for children is of combinative therapies including chemotherapy, radiation therapy and surgical therapy. Chemotherapy debuted in the 1960s and has amended the outcome of

multimodal approaches of oncological treatment over the decades [3]. Thanks to new and improved treatment therapies the survival rate of all pediatric cancers has increased significantly over the past 30 years from 58% between 1975 to 1977, to 83% in survival rate from 2005 to 2011. The survival rate of all adolescent cancer has not improved markedly over the current 5- years however the survival rates vary by cancer type [1].

According to Federica Saletta et al [3] contemporary medicine can cure four out of five children with cancer.

Pediatric cancer survivors can express chronic and late effects from therapies. Studies have shown modularity’s given aggressively resulted in 50% of the childhood cancer survivors developed a severe chronic disease by 50 years of age. Even newer and more improved modularity techniques have shown increased risks of severe health state. Developmental defects can affect approximately one-third pediatric cancer survivor and the impairments vary in severity. Treatments of cancer may even delay the normal development and maturation of teeth and therefore also impact the children’s psychological health [3].

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Objectives are:

1. To know how chemotherapy and radiation therapy works in the human body. 2. To understand the effects of chemotherapy and radiation therapy effects on developing dentition.

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1. MATERIALS AND METHODS

1.1. Identification and Search strategies

Data collection was conducted from PUBMED (Medline), CINAHIL, Wiley Online Library, Springer Link and Google Scholar. Keywords used for the search was ”dental disturbances”

”adverse effects”, ”dental complications”, ”child”, ”paediatric”, ”adolescent”, ”neoplasm”, “oral”, “quality of life”, ”chemotherapy”, ”radiation therapy”.

A broad search of the PubMed database was performed with the limitations of publications in English, human, children and adolescents aged 0 to 18 years. The cut off date was the end of April 2017. Keywords used for the search and search results are demonstrated in Table 1.

Table 1. Keywords searched on Medline (late April 2017) and number of publications found

Keyword Number of

publications

Earliest paper Latest paper

Child cancer prevalence

40425 1952 2017

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Dental disturbance chemotherapy 16 1987 2017 Dental disturbance radiation therapy 5 1989 2016

Oral adverse effect after chemotherapy

1287 1971 2016

Oral adverse effect after radiation therapy

60 1978 2016

Radiation effect on developing teeth

31 1951 2016

Chemotherapy and its effect on developing teeth

30 1977 2016

Quality of life cancer 5315 1975 2017

Quality of life post cancer

427 1982 2017

Oral quality of life post cancer

23 1997 2017

Quality of life post chemotherapy

472 1980 2017

Quality of life post radiation therapy

74 1982 2016

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Figure 1. Flowchart on one of the extensive electronic search results according to the PRSIMA

statement.

The World Wide Web was searched with similar keywords for potential articles and resulted in additional 6 articles that met the inclusion criteria. The reviewed articles reference lists were used to find any additional articles and resulted in 2 articles. CINAHIL database search resulted in 5

articles that meet the inclusion criteria.

The dental outcomes are described in categories, one for caries, second for chemotherapy related dental abnormalities, the third category for dental outcomes of radiation therapy and the forth is regarding the combined chemotherapy and radiation therapy dental abnormalities.

1.2. Inclusion criteria

The inclusion criteria was modified according to PICOS study model Population (P), Intervention (I), Comparator (C), Outcome (O), Study design (S).

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childhood or in adolescent. (C): The children’s age was limited to 1-18 years and limited to a minimum of 20 paediatric participants. (O): The outcomes of chemotherapy and radiation therapy on the dentition of paediatric survivors with the follow up period was of any time after completion cancer therapy. Also included is salivary gland dysfunction.

(S): Published studies, cohort studies, prospective randomized controlled clinical trials, prospective or retrospective clinical studies, prospective and retrospective reviews and observational studies.

1.3. Validity Assessments and Data Extraction

The study quality was determined by criteria such as clear definition of acknowledgement or intervention, suitable statistical investigation, normal measurements of outcome and the contrast between subjects. I extracted all information in other languages other than English, the sample size, the age of the patients, type of treatment, literature reviews and animal trials.

1.4. Study Quality and Risk of Bias

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2. RESULTS

2.1. Chemotherapy’s biomechanical action

The development of cancer is of a complex eventful process within the cells. Scientistsfrom Medical Oncology at Velindre Cancer Centre (Cardiff, UK) Fernando J and Jones R [4] maintain, that cancer cells are insusceptible to growth inhibition signals therefore proliferate and evades death which results in longer survival unlike normal cells where the normal cell cycle have control. The normal human cell cycle is of four stages, mitosis, gap-1, synthesis phase also known as S-phase where the DNA synthesis takes place and last gap-2. Chemotherapy is cytotoxic drugs interposing with the process of cell division. These drugs cause apoptosis by direct interposing with DNA or by targeting the necessary proteins for cell division. One of the downsides with chemo toxic drugs are their toxic action on normal dividing cells especially cells of bone marrow and mucous membranes since their high turnover rate [4].

The classification of chemo toxic drugs is according to either their biochemical properties or by their cell cycle effects. Drugs that part in the biochemical class has the same mechanism of action whilst according cell cycle differ they are specific for a phase. Therefore, advantages of these drugs are that they can be planned to combine. The difference between phase specific chemo toxic drugs and biochemical drugs is the dose-response effect up to the threshold. Phase specific drugs do not improve their apoptosis by escalation whilst biochemical agents are used in high dosages to reach a curative reaction [4].

Table 2. Biomechanics of Chemotherapeutic drugs [4].

Classification of drug Mechanism of drug Drug examples Alkylating agents Damages the function of

creating covalent bonds in DNA, RNA an d proteins

Platinum’s Melphalan,

cyclophosphamide Anti- metabolites Structurally match

metabolites of DNA, RNA synthesis. They substitute or compete with a important enzyme

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Anti- tumour antibiotics Interpolate the DNA at specific arrangements creating free radicals leading to strand damage. Act also on Topoisomerase II and I.

Anthracyclines - mitoxatrone

Topoisomerase inhibitors Topoisomerase control the morphology o DNA. Topoisomerase II function and I is to uncoil DNA when replicating.

Topoisomerase I – topotecan

Topoisomerase II - etoposide

Tubulin binding drugs Vinca alkaloids attaches to tubulin. Tubulin is important for the formation of

microtubule during mitosis including cell morphology, transportation and axonal functions.

Taxanes inhibits function of microtubules by preventing their separation

Vinca alkaloids – vincristine Taxanes - docetaxel

2.2. Radiation therapy’s biomechanical action

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Usual used dosages range from 30 Gy up to 80 Gy for tumoricidal effect and 20- 50 Gy on adjacent tissues [6].

2.3. Combined chemotherapy and radiation therapy

Baskar R and other scientists’ from Department of Radiation Oncology (Singapore) stated, that indication of radiation therapy differ from the purpose of curing disease to relieving symptoms of disease, therefor can be combined with other treatments for optimizing results. Combination modalities can be used to achieve the optimal results such as chemotherapy, surgical interventions or immunotherapies [5].

Dr. Barasch A (Winthrop University Hospital, Mineola, USA ) et al. [7] explains the combined treatment of chemotherapy and radiation therapy was introduced in the 1970s even if chemotherapy is the standard treatment for most local progressed solid tumors the combination of therapies show significant improvement of therapeutic ratio without compromising the patient quality of life. This ratio describes the probability dose generating a normal tissue damage concurrently same dose provides tumor control. Radiation operates in restricted areas dealing with macroscopic metastasis whereas chemotherapy acts beyond the radiated area on micro metastasis. The sequence for administration of the modalities may be neoadjuvant, concurrent or adjuvant the administration of radiotherapy. However neoadjuvant chemotherapy has not shown significant higher survival rates. Adjuvant administration has demonstrated enhancing the drug delivery after reducing the tumor that can be efficacious towards occult metastasis. According several meta-analyses propose concurrent chemotherapy approaches more advantages and has become a standard treatment option for many different kinds if cancers since it provides loco regional control with satisfactory toxicity [7].

2.4. Oral effects after chemotherapy and radiation therapy in childhood cancer survivors 2.4.1 Hyposalivatory and caries after chemotherapy and radiation therapy

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receiving bone marrow transplant. Most common oral complications related to chemotherapy are mucositis, infections, pain, bleeding, decreased taste perception and hyposalivation [6].

Dental caries is one of the most commonly described late dental complications of chemotherapy. 96 childhood cancer survivors were included in a case control study by Doctor Aysun Avsar et al. (Ondokuz Mayıs University, Samsun, Turkey) [8] where the only treatment given was

chemotherapy excluding any combinatory therapies provided the information of hyposalivation. The saliva flow rate was decreased to a median of 1.2 ml/min in the study group vs. 1.4 ml/min in the 96 healthy control group patients. Furthermore, the study group showed an increasement in cariogenic streptococci mutans and lactobacillus with a higher prevalence of 82% among the study group reported dental caries compared with 52% of the control group [8].

A similar study by Purdell- Lewis DJ et al. [9] made of 45 childhood cancer survivors vs. 300 healthy control patients showed a significant three time increase risk for dental caries in permanent dentition. Additionally Prasad L. Gawade et al. [6] reported, a case control study made from 45 childhood cancer survivors vs. 45 healthy patients a higher prevalence of fillings 7.4% was found in the permanent anterior tooth surfaces [6].

Gyea-Su Hsieh et al. [10] collected saliva from 106 childhood cancer survivors, 105 received chemotherapy, and of these 66 received no radiation 8 received total body irradiation while 19 received only head and neck irradiation. The participants showed decreased saliva flow in 18.3% and severely decreased flow was present in 27.9%. The total body irradiated group demonstrated the highest prevalence 37.5% of severely decreased saliva flow rate and 60.9% of the non-irradiated children showed average saliva flow rates Cyclophosphamide receiving survivors had a 12.4 times greater risk of developing very low saliva flow compared to those not given the drug [10].

Purdell- Lewis DJ et al. [9] also reported a co-relationship between chemotherapy and dental caries formation. The study demonstrated approximately 50% of the 45 survivors at the age of 11

demonstrated dental caries or filling on permanent dentition. The childhood cancer survivors showed on average three times greater [6.2 vs. 2.0] number of lesions compared with the control group and the activity of caries was increased in teeth not present at the time of treatment although the oral hygiene was comparable to the general population [9].

Professor of Faculty of dentistry, the University of Hong Kong, Kung A Y H and colleagues [11] worked with 69 child and adolescent cancer participants with the mean age of 9.2, 62% reported experience of dental caries. All 69 survivors have had chemotherapy or had an ongoing

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showed significant increase in risk was the maternal education; low education reported 100% higher dental caries experience [11].

Another study reported by Aysun Avsar et al [8] approximately 82 % of 96 childhood cancer survivors had caries and the mean DMFT was 7.75 +/- 4.90 compared with the control group 64% had caries and their mean score of DMFT of 4.21+/- 3.76, the statistically significant difference of [P <. 001]. The authors concluded in their study that there is an increased risk of caries compared to the healthy control group however, chemotherapy alone has not a major adverse effect on caries it may be a result of mixed dentition, gingival status, oral hygiene, changes in oral microflora and increased intake of cariogenic food and drinks [8].

The adverse effects of radiation therapy are more severe than chemotherapy however the mouth is only affected if it is in the field of irradiation according Barasch A et al. [7]. Vascular injury begins with 20-30 Gy and may begin the process of fibrosis or gradually obliterating the lumen of the vessel. This may result in ischemia, infarction and necrosis of various tissues. This information is of great value for the dentist if extraction teeth are to be executed since it may reveal the damaged tissue to the oral surrounding environment contributing to infection. The impairment of salivary glands incepts in the start of the ionizing treatment and can become a permanent complication after treatments above 50 Gy [7].

The post salivary gland function decrease salivary flow rate and the pH of the saliva become lower. This decreased pH encourages cariogenic bacteria to invade and observations have reported a direct association between radiation and caries. This was reported by Gyea-Su HsiehS et al. [10] were a study made on 45 childhood cancer survivors with a mean age of 5.4 had a higher DMFT score compared with the 45 childhood cancer survivors with chemotherapy alone [10].

Barasch A et al. [7] patients exposed to radiation therapy dosages above 40 Gy reported to suffer from chronic hyposalivation and this complication will sequel complications on hard dental tissues and soft tissues [7].

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2.5. Dental development malformations effects after radiation therapy in childhood cancer survivors

Dr. Siqueira Mellaral and other scientists of Radiation Oncology from University of San Paulo, [13] made an experimental study from 20 healthy recently extracted deciduous molar teeth that were kept in distilled water. The micro hardness of the enamel and the dentin was evaluated in three different indentation regions before any exposure to radiation secondarily with 10 Gy up to 60 Gy of irradiation. In the second experiment, some teeth were hemisected and irradiated up to 60 Gy and some were not exposed to radiation. Post experimental storage of all teeth was in artificial saliva and this saliva was changed to new artificial saliva every day [13].

The morphological analyses of the non-irradiation exposed enamel showed impressively organized prisms encircled by interprismatic areas, which was observed in cross sections and diagonal

sections. The experimentally used teeth were irradiated with 30 Gy and 60 Gy and then electron micrographs were taken which reviled alteration in the surface enamel compared with the control teeth. With the augment irradiation, there was structural alteration in the enamel prisms resulting in difficulties in identification of the prisms and when the enamel was exposed to 60 Gy the surface turn out to be shapeless preventing the view of the prisms nor the hydroxyapatite crystals or interprismatic spaces could be visualized [13].

The morphology of the non- irradiated dentin, displayed well-organized and viewable dentinal tubules. Though when irradiation was put upon there was visible changes in the surface, inter -tubular and peri-tubular dentin visible in the electron micrograph and when the dosages was increased breakdown of the collagen networks was observed. Compared with the enamel electron micrographs taken when exposed to 60 Gy the dentin resembled the enamel by the amorphous structure with unidentifiable dentinal tubules, collagen arrangements and hydroxyapatite crystals [13].

Siqueira Mellaral et al [13] also found the lowest micro hardness mean value was in the enamel prior to the irradiation and the highest mean value was in the deepest indentation region. The authors found that the micro hardness of the enamel increased in middle and surface when irradiated and as the radiation dose increased from 10 Gy up to 60 Gy the micro hardness progressively increased but in the deeper region no effect of the radiation treatment in micro hardness was not observed.

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teeth the micro hardness decreased when the dose was augmented up to 40 Gy then the mean value of micro hardness increased when the radiation dose reached 50 and 60 Gy.

No significant difference in micro hardness was found between the non -irradiated and irradiated teeth with when it came to the middle dentinal region.

The authors believe that depending on irradiation dose and region there is alteration of the micro hardness enamel and the dentine of primary teeth including morphological alterations [13].

Paediatric doctor Kaste S C from St. Jude Children's Research Hospital (Memphis, USA)et al. [14] reported odontogenesis is disturbed by the action of radiation therapy. Radiation treatment directly restrains the mitotic process of odontoblasts and children are more susceptible to this effect since children’s presecretory odontoblasts copiously divide. Radiation indirectly disturbs the normal amelogenetic process by stimulating the formation of osteodentin. A dentin composed with lesser-phosphorylated phosphoproteins, preventing enamel crystals formation of nucleus, sequels to reduced mineralization of the enamel. Also the early stages of dental development including tooth bud stages are harmed during radiation therapy and squeals dental developmental deformities. Dr. Kaste S C et al. [14] explains even a small dose as 1000 cGy can enduringly injure mature

ameloblasts and 3000 cGy can halter the maturational stages of tooth development [14]. However, Andrei Barasch et al. [7] several studies have reported radiation complications on

dentition even at dosages low as 4 Gy and that multiple variables as age of patient, size of irradiated area, radiation dose, combinations of other modularity’s, existing dental problems before treatment is related to the range of dosage [7].

Effects of radiation on dental developmental abnormalities include dental agenesis, hypodontia, hypoplasia of the enamel and root stunting. Professor of Developmental Biology Boston Children's Hospital (USA), Sonis A L and other researches of Department of Dentistry [15] reported a study among 96 childhood cancer survivors were the children was divided into different study groups according to cancer treatment. The childhood cancer survivors were either younger than 5 year receiving cranial or older. 13 survivors received 1800 cGy were younger than 5 years old, reported dental disturbances including V-shaped roots of several permanent teeth, 69% had shunting of the root and 4% had altered root number. Furthermore, 38% had enamel hypoplasia and 23%

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2.6. Dental developmental malformations after chemotherapy

Children treated with chemotherapy usually receives radiation therapy concomitantly therefore the isolated effects on dental development is difficult to distinguish Peterkova R et al. [16] explains. A study by Purdell-Lewis DJ et al. [9] 45 participants with no exposure of irradiation to the oral cavity and the mean age of 10.2 years were included. The children were treated with vincristine, methotrexate, 6-mercaptopurine, cyclophosphamide, cytosine arabinoside, actinomycin,

anthracyclines, bleomycin and corticosteroids. The authors observed that children at the age of 7 had on average four missing permanent teeth and at age 11 seven missing teeth. 80% of the survivors suffered from any type of tooth opacity, 15% of one or more malformed crowns of

permanent dentition and 8 children demonstrated delayed tooth formation with shortened, deformed roots and some showed additionally microdontia. The authors believe that the administration of chemo toxic drug and the level of defected enamel are related to the period of tooth development [9]. Sonis AL et al. [15] reported a study among 96 childhood cancer survivors were 8 patient received chemotherapy younger than 5 years presented all dental developmental defects including abnormal root form and one reported root shunting. 11 survivors received chemotherapy older than 5 years and 45% of these presented dental developmental defects including V-shaped roots and root shunting [15].

According, Kaste SC et al. [14] the adverse effects of chemo toxic drug usage and the development of dental abnormalities is dose dependent [alkylating score 1: [OR: 1.4; 95% CI: 1.2-1.6];

[alkylating score 2: [OR: 1.7; 95% CI: 1.5-2.0]]; [alkylating score 3: [OR: 2.0; 95% CI: 1.6-2.4]]. The authors also reported the risk of developing abnormalities among children of age 5 and younger treated with alkylating drugs is dose depending demonstrated > 1 dental anatomical abnormality, > dental appliances, abnormalities of roots, shape of teeth and microdontia [14].

A different study Hsieh SG et al. [17] made among childhood cancer survivors with the mean age of 5 during cyclophosphamide treatment, 106 survivors demonstrated an association between Holtta´s Defect Index [HDI] of hypodontia, microdontia and crown/ root ratio observed in

panoramic radiographs. A 13-point increase of HDI was reported in children treated with > 7.500 mg/m2 of cyclophosphamide which equals to minimum two lost teeth or three microdontic teeth compared to children with no interaction with cyclophosphamides [17].

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Table 3.Chemotherapy protocol for different cancer types [18]. Protocol Agent COPP Cyclophosphamide Oncovine Procarbazine Prednisolone LSA2-L2 Cyclophosphoamide Vincristine Prednisolone ABVD 6- mercaptopurine Adriamycin Bleomycin Vinblastine Dacarbazine BFM-90 Ifosfamide Cyclophosphoamide Cytosine Arabinocide Etoposide Dexamethasone Prednisolone Methotrexate Leucovorine Adriamycin Vindecine sulphate Vincristine

The mean of follow up period was 17 months’ post treatment and 20 same aged healthy children served as control group. The examination of all survivors was done clinically and radiographically. The authors reported that 9 survivors 23 teeth presented malformed roots [lateral incisors of both jaw showed V- shaped roots], 2 children demonstrated 4 teeth with premature apexification with root malformations and agenesis of teeth, 13 survivors had 56 unerupted teeth [31 was incisors, 14 premolars, 8 first molars and 3 second molars], 15 children reported agenesis of 48 teeth and hypoplasia of the enamel was observed in 64 teeth of 14 survivors and 147 teeth of 17 patients had discoloration.

The difference between the control group and the survivors showed a statistical significant

difference only in enamel hypoplasia and agenesis of teeth [P< .05]. However, microdontia was not reported in any of the survivors [18].

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socioeconomics and education was not significantly different between the groups [P >.05]. The authors reported enamel abnormalities in the survivor group 69.8% vs. 19.8% of control group a statistical significant difference of [P< .001]. A difference in color opacities was reported in both groups however, 52.1% of the survivors showed halted root development resulting in V-shaped malformed roots, 5.2% survivors had premature apexification. Hypoplasia of enamel was observed in 11 vs. 9 which is not statistically significant, agenesis and microdontia was also present in both groups and was not of any significant difference. The authors concluded that the prevalence of dental developmental abnormalities was of higher indices in childhood cancer survivors however; there was no significant change of abnormalities with the age of diagnosis [8].

However, Cigdem Elbek Cubukcu paediatric doctor’s, from Uludag University (Bursa, Turkey) and her colleagues’ [19] study of total 37 childhood cancer survivors, 20 were treated with

chemotherapy only while 10 survivors were treated with radiation therapy in combination with chemotherapy. A control group of 37 children with matched age and gender according the study group was included in the study The authors used Defect index during examination and 86.4% showed changes in root formation, 25/30 childhood cancer survivors had mild disturbance of root length, 20/30 showed severe disturbance and 23/30 had very severe disturbance or halted tooth development. 37.7% of all examined permanent teeth were identified as damaged. The study reported alterations equality of mild to severe disturbance tooth development in both the study group and the control group nevertheless very severe to haltered tooth development was significantly different in the chemotherapy combined with radiation therapy survivor group. Agenesis 16.2% (8 teeth) of the childhood cancer children with a mean age of 3.4 years when receiving only chemotherapy reported no increased number of missing teeth compared to the group of children receiving both chemotherapy and radiation therapy demonstrated agenesis where else the control group showed 0%. The study reported a statistically significant difference of number of missing between the survivor group and the control group (8 vs. 0; P < .01). 13.5% (19 teeth) demonstrated microdontia vs. 5.2% Childhood cancer survivors of this study presented microdontia of significant difference compared to the control group (P < 0.01)

Children treated with both chemotherapy and radiation therapy demonstrated induced severity of abnormalities when modalities are combined [19].

The normal process of tooth development begins with the completion of the dental crown and then after this it proceeds to initiate the development of the dental roots. Therefore, the authors

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2.7. Dental developmental abnormalities after combined chemotherapy and radiation therapy

Paediatric doctor Kaste SC (St. Jude Children's Research Hospital, Memphis, USA)et al. [14] studied 423 childhood cancer survivors with mean age of 4.8 years at time of treatment. 167 patients showed dental abnormalities, 24.4% reported root stunting, 18.9% were identified with microdontia, 8.5% hypodontia, taurodontism in 5.9%, 4.0% showed an increased retention of deciduous teeth. 74 survivors out of the 167 childhood cancer survivors showed more than one dental abnormality [14].

The childhood cancer survivors identified with root stunting which is a rare condition or

microdontia were demonstrated in the children below age of 8 during treatment or had received cranial radiation. Taurodontism is generally reported at 0.5- 11.3% in healthy population and is recognized as a postponement in the development and accurate positioning of the Hertwig´s root sheath after the dental crown has formed. This delay lead to the pulpal floor and the bifurcation area of the affected tooth is displaced apically resulting in thinned and shortened root structure. The authors believe that the irradiation scatter combined with aggressive chemotherapy give rise to dental developmental abnormalities and that chemotherapy given at early age can interfere the inductive odontogenic process of epithelio-mesenchymatose causing damage of Hertwig´s root sheet development [14].

Kaste SC et al. [20] analyzed 8522 childhood cancer survivors with the median age of diagnosis 6 years. A high number of the survivors received chemotherapy treatment with or without radiation treatment. 1067 childhood cancer survivors recived only radiation therapy, 2165 only chemo therapy and 4412 recived combination of the two therapies. These childhood survivors were compared with another group, which composed of their siblings. The analysis demonstrated higher frequency of all types of side effective outcomes from the modalities excluding the usage of dental bridges and prosthesis. A significantly higher prevalence of dental developmental defects was demonstrated compared with the sibling group. The results included microdontia 9.2% vs. 3.3%, hypodontia 8.2% vs. 5.3%, root development abnormalities 5.4% vs. 1.9%, hyperplasia of enamel 11.7% vs. 5.3%, more than 6 teeth are lost because of dental decay or soft tissue disease were 4.8% vs. 1.8% and the survivor group showed higher prevalence of gingival disease with 3% vs. 1.7%. Paediatric doctor Kaste SC (St. Jude Children's Research Hospital) and other researches, [21] reported that the irradiated teeth have increased risk of one or more dental health problem

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survivors below 5 years demonstrated an increased risk of dental issues. The authors stated that the post chemotherapy and radiation therapy oral – dental side effects among childhood cancer

survivors are separate risk factors [20].

Table 4. Long- term follow-up guidelines for survivors of childhood, adolescent and young adult

cancer survivors after cancer treatment [22].

2.8. Quality of life post therapy

Childhood cancer survivor patient may have undergone a lot of invasive medical and dental treatments and these may result in alterations in the health related quality of life including the oral

Treatment Possible late dental effects Risk factors

Any chemotherapy Agenesis of tooth / root

Patient without development of permanent dentition at the time of the cancer treatment

Root thinning /shortening Radiation therapy of oral cavity or salivary gland area

Dysplasia of enamel Age < 5 years at time of cancer treatment

Microdontia

Radiation Agenesis of tooth / root Age < 5 years at time of cancer treatment

Head and neck region Root thinning /shortening Gorlin´s syndrome

Dysplasia of enamel High radiation dose, >10 Gy Microdontia

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Cigdem Elbek Cubukcu et al. [22], out of these 6 received chemotherapy and radiation therapy, and a four times greater control group without cancer was included. Since there was no previous data from the survivors before any treatment, all children answered a questionnaire about their

perceptions of oral symptoms, practical restriction, emotional and social health. The children were divided into different age groups and received different amount of question according their ability to understand.

The authors observed that 8- to 10 years old survivors documented higher oral health related quality of life scores compared to the control group and that this is explained as these childhood cancer survivors have usually not experienced normal salivary flow and therefore does not complain or that the therapies that the cancer survivors have undergone has increased their perception of pain and managing capabilities. The study showed no difference in children´s oral health related quality of life after cancer treatment as after no treatment, the perception between the two groups was of no statistical significance [22].

However, the study of Dr. oncologist Yağc-Küpeli (Training and Research Hospital, Adana, Turkey) and other researches [23] were made from self-reported scores of 302 childhood cancer survivors and scores of 272 children from a control group, which was compared. The results of lower HRQOL were of significance difference (P<0.01 and P<0.001) and the female survivors younger than 16 years reported even worse HRQOL (P<0.001) in physical and emotional scores compared with same age male survivors. Calaminus G et.al [24] also made a study were the reported results of 1.202 childhood cancer survivors’ scores were comparable with the general population of 10000 individuals. The reported scores from the childhood cancer survivors were more than 10 scores lower in emotional and social functioning while fatigue and sleep were 10 scores higher than the general population. This study also described a gender difference in the HRQOL scores where the female survivors reported lower functioning and higher symptoms.

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Table 5. A summary of 10 reports of chemotherapy and radiation therapies late dental effects in

childhood cancer survivors.

First author Sample size (n)

Diagnosis Chemotherapy agents

Radiotherapy (RT) and dose

Dental late effects

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Alpaslan G [18] 30 Hodgkin´s or non- hodkin´s lymphoma Chemotherapy only (n= 30)  Root malformations  Enamel defects/ hypoplasia  Agenesis Cigdem Elbek Cubukcu [19] 37 Various cancers Chemotherapy only (n=27) Chemotherapy and Radiation therapy (n= 10)

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3. DISCUSSION

The consequences of cancer modalities in developing dentition have been explained by many authors: Gawade PL et al. [6], Thompson RF et al. [26], Dahllöf G et al. [27], Näsman M et al. [28]. According to Dr.Joel B. Epstein et al. [29] the common complications described after cancer

modularity’s are mucositis, infections, pain, bleeding, decreased taste perception and hyposalivation.

The results of this study indicate that any type of cancer modularity in combination or as a single agent attributes to defects in odontogenesis.

Hyposalivation is one of the most common consequences of cancer modularity’s [6, 13, 30], saliva is affected by various factors such as chemotherapy agents, opioids and other medications. A major contributor for the development of hyposalivation is radiation to the salivary glands. Which was supported by the study made by scientist Gawade PL et al. [6] were 96 childhood cancer survivors demonstrated a decrease in their saliva flow to 1.2 ml/min with a 30% increase of cariogenic microorganisms compared with the results of the control groups saliva flow rate of 1.4 ml/min. Dr.Susan Gyea-Su Hsieh et al. [10] study support the relationship between cancer modularity’s with hyposalivation, the authors found that 18.3% of 106 childhood cancer survivors showed some decrease of salivation and 37.5% showed severely decreased saliva flow. The 37.5% childhood cancer survivors were treated with the combined chemotherapy with radiation therapy. The authors also found that the children treated with cyclophosphamide had a 12.4 times greater risk of

developing very low saliva flow. Dr. Kaste SC et al. [20] reported in their study that

cyclophosphamide independent of any other therapy would increase the risk of dental abnormalities if given below the age of 5 years. These childhood cancer survivors presented microdontia,

hypodontia, and abnormal crown root ratio and according to their use of Holtta Defect Index these children had a 13-point increasement, which equals to loss of either 2 teeth or 3 teeth with

microdontia. SC Kaste et al. [14] also reported in their study an increase of 7.4% in the childhood cancer survivors demonstrated the prevalence of fillings in the permanent anterior dentition.

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The study Kung AYH et al. [11] made in Hong Kong reported that chemotherapy treated childhood cancer survivors showed an increase of dental caries experience with a mean dmft of 1.36 in the primary dentition and a mean of 2.8 DMFT in the permanent dentition. However the authors also found in this study that maternal education had a significant impact on the risk of caries experience. The low educated parents of the childhood cancer survivors’ participants’ demonstrated 100% higher cariogenic experience.

Though all of the studies of scientists Gawade PL at al. [6], Purdell- Lewis DJ et al. [9], Hsieh SG et al. [10], Kung AYH et al. [11], Kaste SC et al. [14, 20] report cancer modularity’s as a major risk factor for the development of dental caries, the study of Cigdem Elbek Cubukcu et al. [22] reported that 82% of their childhood cancer survivor study group demonstrated DMFT of 7.75+/-4.90 vs. 4.21+/-3.76 a statistical significant difference [P<. 001]. Nevertheless, through these results the authors concluded that chemotherapy it self is not a major cause of dental caries, caries would be dependent on the age of the childhood cancer survivors, the gingival status, the oral hygiene, alterations in the microflora, increased intake of cariogenic foods and drinks.

However as Dr. Cigdem Elbek Cubukcu et al. [22] reported in their study childhood cancer survivors had a oral hygiene status comparable with the general population status and therefor the conclusion made by Talitha de Siqueira Mellara et al. [13] regarding oral hygiene as one of the major cause of childhood cancer survivors for the development of dental caries is insufficient. Scientists Talitha de Siqueira Mellara et.al [15] also concluded in their study that changes in the microflora as a major cause of dental caries and not chemotherapy it self, however according to Dr. Federica Saletta et al. [3] the action of chemotherapy are targeting cell with a high turnover rate as mucous membrane cell which cause alteration of the microflora and could therefor be the contributing factor for dental caries.

The studies of researchers Gawade PL [6], Kung AYH et al. [11], Kaste S C et al. [20], Cigdem Elbek Cubukcu et al. [22] show a co-relationship between childhood cancer survivors treated with chemotherapy developing hyposalivation and increase the risk of dental caries.

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This lowered pH creates a more opportunistic environment for the cariogenic microorganisms to invade the surrounding tissues and these patients also reviled a higher DMFT score when compared to the DMFT score of childhood cancer survivors treated with only chemotherapy.

This co-relationship between the irradiation dosage and the dental tissue is expressed in the study made from Dr.Nishimura S et al. [31] where the authors found irradiation of the enamel with 30 Gy demonstrated difficulties in identifying the prisms and when the dosage reached 60 Gy the enamel expressed an amorphous surface with no morphological structures available for identification. The authors also irradiated dentine where 30 Gy broke down the collagen networks in the dentine and 60 Gy expressed an amorphous surface with no morphological structures visible. Besides this the authors saw that the micro hardness of the enamel pre -radiation was decreased and an increase in the middle indentation when irradiated. The dentine on the other hand expressed a directly opposite reaction to enamel micro hardness however when reaching the dosage of 50- 60 Gy there was an increase reported.

The authors believe that depending on the radiation dosage and the region of irradiation there are expressed alterations of micro hardness of both enamel and dentine including morphological changes in primary dentition.

Researches Kaste SC et al. [14] explained in their study that the action of radiation therapy on the odontogenous process has the direct restrain on the mitotic process of odontoblasts and an indirect action on amelogenetic processes by the stimulation of osteodentin. The authors believe that children are the most susceptible since their copious division of presecretory odontoblasts.

Peterkova R et al. [16] reported dental complications due to radiation therapy on dosages as low as 4 Gy [4000 cGy]. However Dr. Purdell- Lewis DJ et al. [9] have explained that dosages as low as 1000 cGy can injure mature ameloblasts and 3000 cGy can halter stages of tooth development. The authors [6, 32] explains possible dental effects of radiation in the head and neck region may result in agenesis, root shortening/ thinning were gorlin´s syndrome is of risk factor, enamel dysplasia with the risk factor of radiation dosages higher than 10 Gy, microdontia, dental caries, periodontal diseases and malocclusion.

Sonis AL et al. [15] reported that 5-year-old childhood cancer survivors receiving 24 Gy

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study group of 30 childhood cancer survivors with ages between 4- 15 years 15/30 expressed hypodontia, 2/30 premature apexification with root abnormalities and agenesis, 9/30 malformed roots, 13/30 unerupted teeth, 14/30 had enamel hypoplasia, 17/30 discoloration. Hypodontia and enamel hypoplasia was of statistical significance [P< 0.05], whilst microdontia was not

demonstrated in any of the childhood cancer survivors. Study of Aysun Avsar et al. [8] 69.8% demonstrated enamel abnormalities, 52.1% haltered root development and 5.2% premature

apexification. Enamel abnormalities were of statistical significance [P<0.001], enamel hypoplasia, agenesis and microdontia was present however of no significance difference between the groups. Aysun Avsar et al. [8] believe children receiving chemotherapy shows a higher prevalence of dental developmental abnormalities however there is no significant change of abnormalities presented with the age of the diagnosis.

Dr. Purdell- Lewis DJ et al. [9] study of 45 childhood cancer survivors with the mean age of 10.2 years reported that at the age of 7 the survivor group had 4 missing permanent teeth in average, 80% presented any type of tooth opacities, 15% one or more malformed crowns, 8/45 delayed tooth formation with shortened/ deformed roots with the addition of microdontia in some teeth. Purdell- Lewis DJ et al. [9] believe that the administration of the chemotherapy and the level of enamel damage are related to the period of tooth formation.

Researches Kaste SC et al. [14] study of 423 childhood cancer survivors with the mean age of 4.8 years, were 167 given combined chemotherapy and radiation therapy presented 24.4% root shunting, 18.9 % microdontia, 8.5% enamel hypodontia, 5.9 % taurodontism and 4 % expressed retention of primary dentition. The authors believe combined aggressive cancer therapies give rise to dental developmental abnormalities and chemotherapy given at a young age may interfere and damage the Hertwig´s root sheath development. Sue C. Kaste et al. [20] is another study were 8522 childhood cancer survivors with the mean age of 6 years when diagnosed. Where 1067 survivors were only treated with radiation therapy, 2165 participants with chemotherapy alone and 4412 with combined chemotherapy and radiation therapy. Of the total 8522 childhood cancer survivors 9.2% presented microdontia, 8.2% hypodontia, 5.4% root developmental abnormalities, 11.7% enamel hypoplasia, and 4.8% demonstrated more than 6 teeth missing due to dental decay or soft tissue disease and 3% had gingival disease. In this study Kaste SC et al. [20] found that irradiated teeth have increased risk of >1 dental health problem associated with the dose and that childhood cancer survivors exposed to jaw radiation vs. without jaw irradiation showed [>0 to >20 Gy: [OR: 1,3; 95%CI: 1.2-1.5]; >20 Gy: [OR: 5.6; 95%CI: 3.7-8.5]]. Therefore the authors believe that cancer modularity’s are great risk factors for the development of defective odontogenesis.

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health related quality of life experience score when compared with the control group consisting of 272 individuals. The results of Yağc Kupeli et.al [23] was enhanced by the results reported

from Dr.Calaminus G et al. [24] and Dr.Kanellopoulos A et al. [25] were these studies also found that childhood cancer survivors expressed lower HRQOL scores of physical and psychosocial variables when compared with the general population or with a control group. Including the gender differences found by Gabriele Calaminus et.al [24] and Adriani Kanellopoulos et al. [25] were female childhood cancer survivors presented even lower HRQOL scores when compared with male survivors and male controls. However, the quality of life scores regarding oral perception of health were of higher scores from the survivor group and Cigdem Elbek Cubukcu et al. [22] explained that this difference was due to the perception of pain and management are increased in these individuals and that the childhood cancer survivors have not experienced normal saliva flow therefore has no complaints.

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4. CONCLUSION

This systematic review summarizes the literature on treatment related dental consequences of childhood cancer survivors.

Evident studies present independent of cancer treatment type given hyposalivation is a common cancer treatment outcome. The consequence of hyposalivation can contribute to increased risk of carcinogenic microorganism invasion due to the altered microflora. However this need further study on cancer therapies effect on the salivary gland function and not as a general consequence.

Additionally health care workers can provide close observation for the childhood cancer survivors for a early discovery and intervention since not all dental effect are non-preventable such as dental caries which can be handled by respecting the dental health of children´s oncology guidelines. Health practitioners should also take into consideration the low HRQOL scores these patient represent in general and provide the therapies necessary.

Regarding chemotherapy and radiation therapy effect on developing dentition is still a question requiring further study. There are studies on the consequences of radiation and chemotherapy however among all studies there are lack of restriction to either cancer modularity therefor there are difficulties in the determination of the treatment methods outcome on the dentition alone.

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