Neoplasms

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

All Conditions

Rare Diseases

Nasopharyngeal Carcinoma

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Nasopharyngeal Neoplasms

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Head and Neck Neoplasms

Nasopharyngeal Diseases

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Childhood and Adolescent Nasopharyngeal Carcinoma survivors who were treated with convention radiotherapy (CRT).

Childhood and Adolescent Nasopharyngeal Carcinoma survivors who were treated with intensity-modulated radiotherapy (IMRT).

Radiotherapy technology included conventional radiotherapy (CRT) and intensity-modulated radiotherapy (IMRT).

survivors treated with CRT

Although children and adolescents are more likely to have advanced disease at onset, they generally have a significantly better chance of survival. With combined chemotherapy and radiotherapy, overall survival has been reported more than 75% in most pediatric studies. However, little research focuses on long-term morbidities of children and adolescent nasopharyngeal carcinoma (NPC) survivors, and most studies are small scale and have short follow-up time. Therefore, this study analyzed the long-term morbidities of children and adolescent NPC survivors after radiotherapy. Factors associated with those morbidities were also analyzed.

We reviewed the medical records of all NPC patients younger than 18 years old treated at Sun Yat-sen University Cancer Center (SYSUCC) from February 1991 to October 2010. Detailed medical records were taken from our institutional database. Patients were also followed using comprehensive questionnaires and phone calls. We extracted data on clinical characteristics, histopathology, imaging findings, treatment, outcomes, and late morbidities.

Patients with early-stage (stage I and II) disease were treated with radiotherapy alone, and patients with advanced-stage disease (stage III and IV) were treated with a combination of radiotherapy and chemotherapy. Radiotherapy technology included conventional radiotherapy (CRT) and intensity-modulated radiotherapy (IMRT).

We retrospectively reviewed these medical records to collect the required data. All survivors returned to the hospital for follow-up examinations at least every 3 months for the first year, at least every 6 months in the 2nd year, and at least every one year thereafter until the latest follow-up. As part of our routine clinical practice, all patients underwent follow-up MRI examinations of the nasopharynx and neck at least every 6 to 12 months.

Radioactive toxicity on organs was evaluated based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0.

Analyses were performed using SPSS software, version 16.0 (SPSS, Chicago, IL). Chi-squared tests and binary regression analysis were used to compare the CI of treatment comorbidities between different groups of survivors. A P value of 0.05 was chosen as the criteria for statistical significance.

Introduction Nasopharyngeal carcinoma (NPC) is an uncommon childhood malignancy. As the high incidence of local-regional advanced disease, its undifferentiated histology and its close association with Epstein-Barr virus (EBV) , it is distinguishable from the adult form of the disease. Treatment strategies for childhood NPC follow guidelines established for adults. Although children and adolescents are more likely to have advanced disease at onset, they generally have a significantly better chance of survival. With combined chemotherapy and radiotherapy, overall survival has been reported more than 75% in most pediatric studies. However, late sequelae such as endocrinopathies, hearing disorder, dental problems, life-long dry mouth, and secondary neoplasms have been reported. Little research focuses on long-term morbidities of children and adolescent NPC survivors, and most studies are small scale and have short follow-up time. Therefore, this study analyzed the long-term morbidities of children and adolescent NPC survivors after radiotherapy. Factors associated with those morbidities were also analyzed.

Methods and Materials Patients We reviewed the medical records of all NPC patients younger than 18 years old treated at Sun Yat-sen University Cancer Center (SYSUCC) from February 1991 to October 2010. Detailed medical records were taken from our institutional database. Patients were also followed using comprehensive questionnaires and phone calls. All patients were restaged according to the Union for International Cancer Control (UICC) TNM classification version 2009 of NPC. We extracted data on clinical characteristics, histopathology, imaging findings, treatment, outcomes, and late morbidities. Informed consent was obtained from all patients.

Treatment protocols The main treatment strategy for patients was based on the National Comprehensive Cancer Network Guidelines. Patients with early-stage (stage I and II) disease were treated with radiotherapy alone, and patients with advanced-stage disease (stage III and IV) were treated with a combination of radiotherapy and chemotherapy. NPC patients were treated with a high-dose of radiotherapy to the nasopharynx and the involved lymph nodes of the neck, and a moderate dose of radiation to uninvolved nodes and surrounding tissues. Radiotherapy technology included conventional radiotherapy (CRT) and intensity-modulated radiotherapy (IMRT). Patients between 1991 and 2004 received CRT. Post 2004, IMRT became the standard strategy treatment. During the study period, chemotherapy guidelines for NPC were implemented as follows: no chemotherapy for patients with stage I to II disease, and concurrent chemoradiotherapy + neoadjuvant chemotherapy for stage III to IVa-c.

Follow up We retrospectively reviewed these medical records to collect the required data. All survivors returned to the hospital for follow-up examinations at least every 3 months for the first year, at least every 6 months in the 2nd year, and at least every one year thereafter until the latest follow-up. As part of our routine clinical practice, all patients underwent follow-up MRI examinations of the nasopharynx and neck at least every 6 to 12 months.

Evaluation Criterion Radioactive toxicity on organs was evaluated based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0.

Statistical analysis Analyses were performed using SPSS software, version 16.0 (SPSS, Chicago, IL). Chi-squared tests and binary regression analysis were used to compare the CI of treatment comorbidities between different groups of survivors. A P value of 0.05 was chosen as the criteria for statistical significance.

Late Sequelae of Childhood and Adolescent Nasopharyngeal Carcinoma Survivors After Radiotherapy

Chi-squared tests and binary regression analysis were used to compare the CI of treatment comorbidities between different groups of survivors. Radioactive toxicity on organs was evaluated based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 3.0.

Yuan-hong Gao

Deputy Director，MD & PhD, Professor，Department of Radiation Oncology

Nervous System Diseases

Musculoskeletal Diseases

Glioma

Brain Neoplasms

Meningioma

Ependymoma

Craniopharyngioma

Adamantinoma

Ameloblastoma

Central Nervous System Neoplasms

Nervous System Neoplasms

Neoplasms, Nerve Tissue

Neoplasms, Vascular Tissue

Meningeal Neoplasms

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Bone Neoplasms

Bone Diseases

Neuroepithelioma

Stereotactic conformal radiotherapy (SCRT)

Conventional radiotherapy Patients in this arm will be treated with conventional radiotherapy techniques being used at the moment in the department. This involves patient being immobilised with a customised thermoplastic mask after which they will have a contrast enhanced planning CT scan. The radiation oncologist will draw the tumour on the appropriate CT slices and a margin of 1-2 cms grown for the planning target volume. Beam arrangement will be relatively simple and typically consist of 2-3 coplanar fields using 6 MV photons. Conventional planning optimisation will be carried out by the use of wedges, beam weightage and corner shields as appropriate. Radiotherapy doses, prescription and fractionation schedules will be identical to the SCRT arm

Stereotactic Conformal radiotherapy

Conventional radiotherapy

Rakesh Jalali, MD

Rajiv Sarin, MD FRCR

Brain tumours are the commonest solid tumours in children and the second most common neoplasms overall in this patient population. Radiotherapy plays an important part in the management in a majority of these tumours. While the cure rates of these tumours, especially the benign and low grade ones are quite encouraging, the treatment itself may lead to some late sequelae, which could have significant implications in the quality of life in these long-term survivors.

Stereotactic conformal radiotherapy (SCRT) is a modern high-precision radiotherapy technique, which reduces the volume of normal brain irradiated and has the capability to minimise the doses to critical structures. The present study is designed to prospectively estimate the incidence and severity of neuropsychological, cognitive and neuroendocrine dysfunction following radiotherapy delivered with conventional and stereotactic techniques and would be one of the most comprehensive studies providing very important longitudinal and reliable data regarding these sequelae. The study involving 200 patients would be to the best of our knowledge not only the largest ever study conducted so far but also the only randomised trial assessing these sequelae in patients receiving focal brain irradiation.

The study also examines whether the physical advantages of modern technological progress translate in clinical benefit. This could have significant implications in the radiotherapeutic management of children and young adults with brain tumours. The study is unique in design in terms of evaluating the efficacy of SCRT with respect to conventional radiotherapy in terms of long term tumour control and treatment related complications.

1.0 BACKGROUND AND RATIONALE

Brain tumours are the commonest solid tumours in children and with appropriate treatment, nearly half of them achieve long term cure. Radiotherapy is essential in the management of a majority of these tumours. Conventional radiotherapy alone or in combination with surgery and/or chemotherapy in tumours such as optic gliomas, hypothalamic gliomas, craniopharyngiomas, germ cell tumours, and other low grade tumours achieves excellent long term control rates ranging from 70 to 95%. However, while the tumour control has been effective, there have been concerns about treatment related morbidity.

which included cognitive dysfunction in 38%, motor deficit in 25%, visual impairment in 20%, hormonal dysfunction in 20% and psychological-emotional problems in 14% of the survivors.

It is difficult to ascertain from these reports the exact contribution of each of these factors and how they interact with each other. Radiotherapy is believed to be at least partly responsible although its exact role is yet to be quantified. Most of the evidence regarding post-radiotherapy neuropsychological and cognitive dysfunction is from retrospective studies involving whole brain radiotherapy.

Neuroendocrine dysfunction is well-documented late sequelae following treatment of patients with brain tumours. This could either be due to direct involvement of the pituitary hypothalamic axis (PHA) by the tumour or as a result of surgical or radiation injury to this region. For tumours not directly involving the PHA, the commonest cause of neuroendocrine dysfunction is cranial irradiation. PHA region unavoidably receives radiation with whole brain radiotherapy or if the tumour itself is arising from this region. For the treatment of tumours adjacent to PHA but not involving it, it may be frequently a part of radiotherapy planning target volume, which includes the gross tumour and a margin to account for any microscopic disease and possible daily set up inaccuracies and thus receive significant doses. The region may also sometimes come in the entry / exit path of radiation beams during treatment of tumours even away from this region. Radiation induced hormonal abnormalities are generally dose dependent and may develop many years after irradiation. To reduce the impact of endocrine dysfunctions on physical, mental and sexual development, it is important to detect and treat them timely. Early growth hormone replacement is the only way to minimise growth retardation caused by its deficiency but the treatment is expensive with significant financial implications, especially in our country. The annual cost of GH replacement is approximately Rs 200,000.00, which is prohibitive for the vast majority of the Indian parents as is the cost of LHRH analogues, which is useful to prevent early epiphyseal fusion and stunted growth in children with post radiation or tumour related precocious puberty.

1.4 Evolution of Stereotactic conformal radiotherapy (SCRT) Conventional radiotherapy techniques generally involve the use of 2-3 radiation beams covering the tumour and a margin of 1-3 cms for any subclinical disease and physical inaccuracies in the daily treatment delivery. The last decade has seen tremendous technological advances in radiotherapy planning and accurate treatment delivery. Stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT) techniques involve firm and accurate immobilisation with fixed or relocatable frames, high precision three-dimensional (3-D) target localisation with CT/CT-MRI fusion and focused radiation delivery. This is achieved either with a multiple source cobalt unit (gamma knife) or with multiple arcs using a modified conventional linear accelerator. Such conventional stereotactic irradiation techniques typically produce spherical high dose volumes and are therefore suitable only for small spherical lesions. A majority of the brain tumours considered for radiotherapy however are not spherical and frequently extend to adjacent structures. To treat large non-spherical volumes with conventional SRS requires the addition of multiple small spherical high dose volumes described as multiple isocentre treatment. The overlap of high dose spheres results in dose inhomogeneity, which has been associated with a higher incidence of radiation induced complications. It has been previously demonstrated that the optimum way of delivering high precision localised irradiation to larger non-spherical targets is with the use of multiple conformal fixed fields with individualised shielding of each radiation field conforming to the shape of the target. This principle of conformal therapy combined with the precision of stereotactic localisation and focused radiation delivery is described as stereotactic conformal radiotherapy (SCRT).

Traditionally, stereotactic irradiation has been delivered in a one session as single fraction radiosurgery. High doses of radiation given in one fraction are known to be associated with a high risk of radiation induced damage to normal tissue and this is particularly true for the central nervous system. Giving radiation in small individual doses allows the delivery of higher radiation doses without serious injury to the normal tissues, which is especially important for normal CNS structures. Single fraction SRS has been shown to be associated with considerable neurological toxicity to the optic apparatus the cranial nerves and normal brain. With the application of high precision relocatable non-invasive means of immobilisation, it has become possible to deliver stereotactic irradiation in a fractionated manner. The technique of SCRT combines the precision of focused radiation delivery and the radiobiological advantages of fractionation. It also ensures homogenous dose distribution within the irradiated volume further reducing the risk of damage.

The basic aim of high precision SCRT is to achieve a high dose differential between the tumour and the surrounding normal tissues. This allows for either an increase in the tumour dose to improve local control or for a potential decrease in radiation damage to the normal tissues. Further optimisation of the technique involving 3-4 conformal non-coplanar field arrangement has shown a significant dose reduction to the normal brain. Preliminary experience, mainly in adults has shown this technique to be feasible during the routine practice of a busy radiotherapy department. Early results in terms of local control are same as that with conventional radiotherapy, with an increased sparing of the surrounding normal brain and adjacent critical structures. While the experience is limited in young children, a few reports have suggested it to be feasible in this population also. The technique has the potential to minimise the dose to any critical site close to the tumour like pituitary-hypothalamic complex, cochlea, brain stem, optic apparatus and the mesial temporal lobes, which are believed to be the common sites of radiation injury leading to late morbidity.

NEED FOR THE PRESENT STUDY The finding of significant long-term effects in a large proportion of brain tumour survivors mandates the development of treatment strategies designed to minimise their impact on the quality of life. Although the precise role of radiotherapy in the causation of various post treatment sequelae is not established, it is generally believed to be at least partly responsible for these effects. There have been attempts to modify the management in terms of avoiding, delaying radiotherapy or reducing the total radiation dose to the tumour with a view to reduce its impact on the long-term toxicity. However, reduction of radiotherapy doses to the tumour has been shown to result in poorer local control rates. Also, a majority of the patients in whom the radiation is delayed eventually do require radiotherapy at later stages (37). There is also evidence that radiotherapy given upfront yields superior disease control than radiotherapy given at the time of tumour progression (38,39). In light of this data, there is therefore, an ever-increasing need to explore techniques of radiotherapy minimising the irradiation to the normal brain and critical structures without compromising radiotherapy doses essential for tumour control. SCRT is a modern high-precision radiotherapy technique, which reduces the volume of normal brain irradiated and has the capability to minimise the doses to critical structures.

The evidence of long term effects of focal irradiation so far is from retrospective studies and a few small prospective trials. There is therefore, a great need to evaluate this issue in a prospective manner in a large number of patients. The present study is designed to prospectively estimate the incidence and severity of neuropsychological, cognitive and neuroendocrine dysfunction following radiotherapy delivered with conventional and stereotactic techniques and would be one of the most comprehensive studies providing very important longitudinal and reliable data regarding these sequelae. The study involving 200 patients would be to the best of our knowledge not only the largest ever study conducted so far but also the only randomised trial assessing these sequelae in patients receiving focal brain irradiation.

The study also examines whether the physical advantages of modern technological progress translate in clinical benefit. This could have significant implications in the radiotherapeutic management of children and young adults with brain tumours. The study is unique in design in terms of evaluating the efficacy of SCRT with respect to conventional radiotherapy in terms of long term tumour control and treatment related complications.

If the present trial succeeds in reducing the incidence and severity of radiotherapy related sequelae by SCRT technique, it would undoubtedly result in a tremendous benefit to these patients. A possible reduction in the neuroendocrine sequelae not only will improve the quality of life of the patients but would also result in major financial saving. This is critical in patients living in the developing countries where the cost of endocrinological management in terms of hormonal assays and their replacement is largely prohibitive.

We have until Januray 2009 accrued 128 patients so far in the trial

SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors

Efficacy of Stereotactic Conformal Radiotherapy (SCRT) Compared to Conventional Radiotherapy in Minimising Late Sequelae in Children and Young Adults With Brain Tumours: a Randomised Clinical Trial

Terry Fox Foundation

Tata Memorial Hospital

Professor

Skin and Connective Tissue Diseases

Sarcoma

Sarcoma, Ewing

Neuroectodermal Tumors, Primitive, Peripheral

Neoplasms, Connective and Soft Tissue

Osteosarcoma

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Soft Tissue Sarcoma

Ewing Sarcoma

Andreas Ranft, Dr.

Heribert Jürgens, Prof.

The purpose of the study is to assess the functional outcome, quality of life and late sequelae in a representative sample of 600 long-term survivors of Ewing sarcoma and to build a unique clinical and functional data pool of the underlying cohort of 3000 Ewing sarcoma patients with a follow-up of 3 decades.

Trial objective: As survival rates of bone sarcoma patients have been raised owing to improved treatment strategies the focus of investigations is now on the medical, social, and economic sequelae of intensive multimodal treatment. This study aims to assess the functional outcome, quality of life and late sequelae in a representative sample of long-term survivors of Ewing sarcoma. The data recorded combined with standardized treatment data covering a 30-year period will produce a data pool that is unique for its magnitude and will be used for the development of guidelines for further improvements of future bone sarcoma treatment.

Working plan: The working plan provides for the assessment of functional outcome and quality of life by means of validated tools (TESS, SF36, PEDQOL) and objectively measuring daily activity patterns by using the Step Activity Monitor (SAM) in 600 long-term Ewing sarcoma survivors and a control group of 300 matched healthy subjects. Information on sarcoma treatment and follow-up is obtained by re-structuring and complementing the database of the relevant patient cohort (n=3000) from four consecutive nationwide and international clinical trials between 1980 and 2008. Procedures of local treatment will be evaluated regarding functional outcome, quality of life, and survival probability and prognostic factors predicting long-term outcome will be identified.

Exploitation of results: The results will be presented at scientific meetings and will be published in international journals. Guidelines will be developed regarding improvements in the treatment, rehabilitation, and social integration of bone sarcoma patients to be utilized in guiding patients and in the decision process of medical professionals regarding their treatment. In the long run, the evidence based guidelines on treatment and follow-up are to be transferred into the health system.

Functional and Clinical Long-Term Outcome of Ewing Sarcoma Treatment

German Federal Ministry of Education and Research

University Hospital Muenster

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Late Sequelae of Childhood and Adolescent Nasopharyngeal Carcinoma Survivors After Radiotherapy	NCT03398980	Nasopharyngeal ...	survivors treat...	7 Years - 18 Years	Sun Yat-sen University
SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors	NCT00517959	Low Grade Gliom... Craniopharyngio... Ependymomas Meningiomas	Stereotactic Co... Conventional ra...	3 Years - 25 Years	Tata Memorial Hospital
SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors	NCT00517959	Low Grade Gliom... Craniopharyngio... Ependymomas Meningiomas	Stereotactic Co... Conventional ra...	3 Years - 25 Years	Tata Memorial Hospital
Functional and Clinical Long-Term Outcome of Ewing Sarcoma Treatment	NCT00824083	Sarcoma, Ewing'...		6 Years - 60 Years	University Hospital Muenster
Functional and Clinical Long-Term Outcome of Ewing Sarcoma Treatment	NCT00824083	Sarcoma, Ewing'...		6 Years - 60 Years	University Hospital Muenster
Late Sequelae of Childhood and Adolescent Nasopharyngeal Carcinoma Survivors After Radiotherapy	NCT03398980	Nasopharyngeal ...	survivors treat...	7 Years - 18 Years	Sun Yat-sen University
Late Sequelae of Childhood and Adolescent Nasopharyngeal Carcinoma Survivors After Radiotherapy	NCT03398980	Nasopharyngeal ...	survivors treat...	7 Years - 18 Years	Sun Yat-sen University

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