REMAP: A Framework for Goals of Care Conversations

Although oncologists frequently have conversations about goals of care with patients, these conversations remain challenging and junior physicians may feel they lack the training to have these discussions effectively and in a timely manner. Because of this, the authors of this paper propose a guiding framework around which to structure the discussion: REMAP – Reframe, Expect emotion, Map out patient goals, Align with goals, Propose a plan.
Reframe refers to setting up the conversation to deliver bad news (often that cancer treatments will not result in a cure) and to gauge a patient’s understanding. Expect emotion involves actively attending to the patient’s emotional response and providing appropriate reflective statements (“I know this is not something you wanted to hear”). The emotional response will guide if the patient is ready to move forward with a plan. Mapping patient values steers the discussion towards the patient’s goals for themselves and reflective statements ensure alignment. Finally, a plan can be proposed to meet those goals, which can simultaneously include further life-sustaining chemotherapy (including clinical trials) and supportive care.
This paper was limited by its adult focus and did not include discussion of some of the essential differences between pediatric and adult end of life care (specifically the challenge of transitioning away from cure-directed therapy). Regardless, many of the concepts are still relevant to the pediatric population.
The REFRAME mnemonic aims to promote patient centered decision making during a very difficult but critical conversation. It emphasizes that the conversation be guided by the patient, allowing oncologists to be flexible in their approach and ultimately aligned with the expectations of the patient in that moment. Ultimately, better communication should lead to better end of life care.

Clinical and Genetic Risk Prediction of Subsequent CNS Tumors in Survivors of Childhood Cancer: A Report From the COG ALTE03N1 Study

Survivors of childhood cancer are at risk for developing subsequent CNS tumors. Recent adult studies identified inherited predispositions to glioma and meningioma. This study aimed to use genetic information from adult studies and clinical information (including radiation exposure, age) to create a prediction model that identifies survivors of childhood cancer at high or low risk of developing CNS tumors.
Multicentre COG study ALTE03N1. Eligible participants were individuals diagnosed with a primary cancer at age 21 years or younger who subsequently developed a histologically distinct CNS tumor. For each participant, four controls were selected from a pool of survivors of childhood cancer with no evidence of subsequent neoplasms. All participants provided blood or saliva for germline DNA to identify specific single nucleotide polymorphisms (SNPs).
Phase 1: multivariate analysis to study association between SNPs and subsequent tumors in 82 participants and 228 matched controls. Phase 2: developed prediction models to identify survivors at high or low risk for subsequent CNS tumors. Phase 3: validated these models in an independent matched case-control sample with 25 participants and 54 controls.
Association between six previously published SNPs and subsequent CNS tumors in survivors of childhood cancer. Prediction model applying genetic variants with primary cancer, sex, cranial radiation had a sensitivity of 87.5%, specificity of 83.5%, PPV was 60.9% and NPV was 95.8% for predicting survivors at highest of lowest risk of subsequent CNS tumour. Validated in independent sample.
Survival bias as only living survivors included in this study. Survivors who already died due to CNS tumour were missed in this study thus underestimation of the effect size for genotypes associated with increased lethality. Slightly different cohort and control groups in the validation group but not statistically significant.
Developed prediction tool can identify childhood cancer survivors at lowest and highest risk of subsequent CNS tumors but need genetic information to apply this tool. Identifying survivors at highest risk may allow for a more intense individualized approach to screening and early detection in this patient population.

Guideline for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric cancer patients: A focused update

This article is a focused update of the 2013 guideline for prevention of nausea and vomiting in children receiving chemotherapy, illustrating the role of aprepitant and palonosetron.

Cancer incidence and mortality among young adults aged 20–39 years worldwide in 2012: a population-based study

Population based study with the aim of quantifying the global burden of cancer in young adult patients (20-39y). Young adult cancers have not received the same amount of study as cancer in children or adults.
Authors gathered data on cancer diagnosis and cancer mortality in patients aged 20-39 years from 184 different countries using the International Agency for Research on Cancer's GLOBOCAN 2012 database. They calculated age-standardised incidence and mortality rates at the global and country level. Case fatality rates were approximated by dividing the age standardized mortality rate by the age standardized incidence rate. Results are also presented by geographic region and regional development level (Human development index, HDI).
975 396 cancer cases and 358 392 cancer-related deaths were estimated to have occurred worldwide in 2012. Cancer and cancer-related death was more common among women (male:female ratio of 0.5 and 0.8 for incidence and mortality respectively). There was a higher risk of cancer in young adults than in adolescents (four fold increase) but lower than in middle-aged adults.
Breast cancer was the most common cancer type in young adults world wide (19.6% of total estimated new cases). Cervical cancer was the second most common cancer type (11.4%). Thyroid cancer was the most common cancer type in young adults in Canada. The largest contributors to cancer-related deaths worldwide were breast (13.6%), leukemia (10.1%), and liver cancer (10.1%).
Breast cancer and cervical cancer were the most common cancers in the low, medium, and high-HDI levels. At very high-HDI levels, breast cancer was most common and cervical cancer was fifth most common. Thyroid cancer, melanoma and testicular cancer were more frequent in very high-HDI regions. Cancers linked to infectious agents were more common in lower HDI settings. Mortality decreased with increasing HDI.
Data are based on estimates from GLOBOCAN database and rely on quality of source information. There is a lack of uncertainty intervals provided, which is addressed by the authors. Bone and soft tissue sarcomas were not addressed.
Globally, the most common cancers in young adults (20-39y) are breast cancer, cervical cancer and thyroid cancer. Cancer and cancer-related death is more common among women than men. Cancer risk is increased for young adults relative to adolescents.
Young adults with cancer represent an underserved population with cancer. Future research should address the questions of prevention, surveillance and treatment.

Pediatric-Specific End-of-Life Care Quality Measures: An Unmet Need of a Vulnerable Population

There continues to be a concern about the quality of end of life (EOL) care that both children and adults receive, with upwards of 45% of pediatric patients reporting distressing symptoms such as pain and fatigue at the EOL. To this effect, quality of EOL care warrants ongoing measurement in order to influence best practice guidelines which are currently lacking. This is compounded by the fact that current literature on this topic focuses on adult measures, which may not always be relevant to pediatrics. The authors of this paper explore some of the notable differences in EOL measures between children and adults, propose modifications to existing measures and suggest the formation of a task force to address this gap.
Some notable differences relevant to pediatrics include longer disease trajectories, the higher preference of a death in hospital, desire for high intensity therapy, the difficulty of symptom assessment in young children, variable access to pediatric specific palliative care, and the need to measure bereavement in parents/care givers and siblings.
This was a commentary and a paper focused specifically around American measures of quality (some of which are tied to funding. Not necessarily relevant to Canada).
End of life care in pediatrics is notably different than in adults, hence what constitutes ‘good quality care’ is not the same, and should be measured differently to ensure that care provided is in line the needs of children and families.

Stories that heal: Understanding the effects of creating digital stories with pediatric and adolescent/young adult oncology patients

This qualitative study aimed to explore if and how the creation of digital stories can be used as a therapeutic tool for children/young adults with cancer and their family members. Digital storytelling comprises multiple modalities (ex. music, narration, photos) to tell a story.
Participants were children/young adults from 5-39 years old who had either undergone treatment or were currently in treatment for a pediatric malignancy. They also included family members of cancer patients/survivors. Participants were assisted in making a digital story on iMovie through about 3, 2 hour sessions. They then underwent an interview to discuss the experience of making the story. Data analysis was with a hermeneutic approach, which aimed to deepen understanding of the effect of making a digital story on the participants.
Participants found that making the story was effective in helping others to understand their experiences. Those who were further out from treatment found that it helped them to heal or move on, whereas children on treatment enjoyed the distraction the experience provided. Many participants were surprised to find the therapeutic value in making a digital story. They reported that making the story helped in understanding and making sense of what they had experienced.
This was a small study with only 16 participants, who had a wide range of diagnoses, ages and distance from treatment. The researchers identified the different therapeutic effect of digital storytelling on those who were in treatment and those further from it. However there was limited interpretation on differences in age, diagnosis and prognosis.
This study suggests that digital storytelling may be a helpful adjunct therapeutic intervention for children and adolescents who are experiencing cancer, whether it is themselves or as a sibling.

Risk Factors for Subsequent Central Nervous System Tumors in Pediatric Allogeneic Hematopoietic Cell Transplant: A Study from the Center for International Blood and Marrow Transplant Research (CIBMTR)

This is a case control study examining the cumulative incidence of CNS neoplasms in patients after allogeneic stem cell transplant. This review was conducted by CIBMTR which comprises the largest database of HSCT information.
Using the CIBMTR database the review was conducted from 1976 to 2008 and included survivors at least one year out of transplant. All CNS tumour cases were reviewed and further information was obtained from the treating centre. A case-control comparison was performed where controls were HSCT patients who did not have a diagnosed CNS tumour. Cox regression models were used to analyze the data from the entire cohort and identify risk factors.
59/8720 participants developed CNS tumours, with half being either astrocytoma or glioblastomas. Compared to the general population, those undergoing allogeneic stem cell transplant for a hematologic malignancy had a 33 times higher than expected rate of CNS tumours (95% CI, 22.98 to 45.77; P=0.0001). The cumulative incidence of subsequent CNS tumours was 1.29% (95% CI .87 to 1.87) at 20 years after transplant. The risk factors for developing CNS tumours were: having an unrelated donor transplant, CNS disease before transplant and radiotherapy exposure before conditioning were risk factors for developing a CNS tumour.
This study is limited by its retrospective nature, and depends on the accuracy of submitted data. This is the first report of this kind and so replication would strengthen the findings.
In the large CIBMTR database no CNS tumours were found in patients transplanted for non-hematologic malignancies or who received non-myeloablative or reduced intensity conditioning (total of 4730 patients). Patients transplanted for hematologic malignancies are at an increased risk of developing a CNS tumour compared to the general population. The identified risk factors from this study are pre-transplant radiation exposure and an unrelated donor.

Late Effects Screening Guidelines after Hematopoietic Cell Transplantation for Inherited Bone Marrow Failure Syndromes: Consensus Statement From the Second Pediatric Blood and Marrow Transplant Consortium International Conference on Late Effects After Ped

This is a consensus paper regarding long-term follow-up screening that should occur for patients transplanted for inherited bone marrow failure syndromes. The paper specifically discusses follow-up for Fanconi's Anemia, Dyskeratosis Congenita and Diamond-Blackfan Anemia.

Recent Developments in Radiotherapy

This is an interesting review of the advancements in radiotherapy including treatment planning, combination therapy, and the use of radiosensitizers. Minimal discussion of hot topics in paediatrics such as proton therapy and immune modulation.

Association of Mortality With the Death of a Sibling in Childhood

The authors investigated the association between sibling death in childhood and the mortality risk among bereaved individuals. This is a population based cohort study.
Registry data was used to link live births from 1973-2004 in Denmark and from 1973-2006 in Sweden and identify the mothers and siblings. Children were placed in the exposed group if they were between 6 months to 18 years of age and had a sibling who died at any age. Children were followed until death, emigration or the end of the study. Outcomes were all-cause mortality, cause specific mortality and mortality by type of death (external causes of death or diseases).
55 818 of 5 005 029 participants experienced the death of a sibling in childhood. The median age of the bereaved siblings was 7.0 years at the time of the loss. During the follow-up period, 534 members died in the bereaved group and 25 591 died in the non bereaved group. The bereaved group had an increase in all cause mortality when their sibling died of a disease (MRR 1.72, 95% CI 1.55-1.90) or due to an external cause (1.65, 95% Cl, 1.40-1.94). Bereaved participants also had an excess of death from disease and from external cause as compared to their non-bereaved comparison. Increased mortality risks were found even after adjustment for their co-morbid diseases irrespective of the type of death of their sibling. The strongest association was found within 1 year of the sibling death. The association was also higher in same sex sibling pairs and siblings with a small age difference.
There was no data on the shared social environment of the sibling pairs or of the family environment. There may be interplay between bereavement and other factors such as social and psychological factors that may also affect the association that were not included in the data set analyzed. The study used a national data set in Denmark and Sweden and thus, results may not be generalized to all populations.
Bereaved siblings who have lost a sibling during childhood have a significantly higher mortality rate than their non-bereaved counterparts in both the short and long term. Ongoing research is needed to further understand this association.

International incidence of childhood cancer, 2001–10: a population-based registry study

Childhood cancer burden is unknown in many low- and middle-income countries. The International Agency for Research on Cancer (IARC) and the International Association of Cancer Registries (IACR) have coordinated a study to publish the International Incidence of Childhood Cancer, volume 3 (IICC-3), which will include ages 0-19 (rather than 0-14 in the two previous volumes reported in 1988 and 1998).
This paper provides an overview of the incidence of malignancies and non-malignant neoplasms of the CNS in 2001-2010 for children aged 0-19, based on data collected in 153 population-based cancer registries in 62 countries. They included only registries that met standard data quality criteria and that covered the entire decade 2001-2010.
There were 385,509 incident cases in children aged 0-19 years. The overall age-standardized incidence rate was 140.6 per million person-years in children 0-14 years, which has increased from 124.0 in the 1980s, and 155.8 for aged 0-19 years. The most common were leukemia, followed by CNS tumors, and lymphomas. In children aged 15-19 years, the most common were lymphomas and the group of epithelial tumors and melanoma. Incidence rates were slightly higher in boys than girls. Incidence varied significantly between and within regions and by cancer type, sex, age, and racial and ethnic group.
The reported rates are influenced by selecting only registries with quality-assured data for the entire decade of 2001-2010. Some large registries were excluded if they didn't cover the entire decade. The non-malignant tumors in the USA were only registered from 2004 onwards and were therefore excluded. Approximately 30 cancer registries dropped out of the study. Multi-ethnic populations in Europe and Canada could not be readily studied.
This epidemiological population-based registry study updates information on cancer incidence in children aged 0-14 and adds the first global overview of cancer incidence in young people aged 15-19 years. They report an increase in the incidence of neoplasms since the 1980s in children aged 0-14 years. This is a unique global source of childhood cancer incidence that can be used for research and to inform public health policy.

Guideline for the management of fever and neutropenia in children with cancer and hematopoietic stem-cell transplantation recipients: 2017 Update

This is an updated clinical practice guideline for the empirical management of fever and neutropenia (FN) in children with cancer and hematopoietic stem-cell transplantation recipients.
The International Pediatric Fever and Neutropenia Guideline Panel has put together this guideline (FN CPG). For questions of risk stratification and evaluation, systematic reviews of observational studies were updated. They conducted a systematic review of randomized trials of any intervention applied for the empirical management of pediatric FN. Recommendations and quality of evidence is listed throughout the manuscript.
Recommendations related to initial presentation, ongoing management, and empirical antifungal therapy of pediatric FN were reviewed; the most substantial changes were related to empirical antifungal therapy from the 2012 guideline. Summary of the major changes from the previous 2012 guideline:
1) Peripheral blood cultures concurrently with central venous catheter cultures: quality of evidence increased to moderate from low.
2) Use of monotherapy with beta-lactam, a fourth generation cephalosporin or a carbapenem as empirical therapy in pediatric high risk FN: fourth generation cephalosporin added
3) Patients at high risk of invasive fungal disease (IFD) are those with AML, HR-ALL, or relapsing acute leukemia and children undergoing HSCT. Also those with prolonged neutropenia and high-dose corticosteroids are at high risk of IFD. All other should be categorized as IFD low-risk: risk factors refined. Quality of evidence decreased to low from moderate.
4) Consider not using serum Galactomannan (GM) : now weak recommendation against GM
5) Do not use fungal PCR testing in blood: new recommendation, poor PPV and NPV not significantly high enough to be clinically useful. PCR testing not yet standardized
6) Perform CT of the lungs for IFD work-up: quality of evidence decreased to low from moderate. Lungs are consistently the most commonly affected site. Optimal timing of initial and repeated imaging not known.
7) Consider imaging of abdomen in patients without localizing signs or symptoms of IFD: New recommendation, ideal imaging modality not known.
8) Consider not routinely performing CT of sinuses if no localizing signs or symptoms of IFD: Now weak recommendation against CT sinuses
9) In IFD low-risk patients with prolonged (greater than or equal to 96 hours) FN, consider withholding empirical antifungal therapy: now weak recommendation against empirical therapy for IFD low-risk patients.
The main research gaps are listed in Table 2 of the article and fall into 3 major categories:
1) Initial presentation
Optimal temperature threshold to define fever
New serum biomarkers as diagnostic and monitoring aids
2) Ongoing management
Timing and necessity of repeated blood cultures for persistent fever
Duration of empirical antibiotics for low and high risk FN
Role of providing targeted antibiotics only vs. continuing broad-spectrum coverage in patients with positive cultures who remain neutropenic
Determining whether the diagnostic and therapeutic approach should differ between patients with prolonged continuous fever vs. recurrent fever during FN
3) Empirical antifungal management
Role of combination biomarkers for IFD evaluation and ongoing management
Identifying novel biomarkers for IFD detection
Role and timing of standard imaging on patient outcomes
Efficacy and safety of pre-emptive antifungal therapy
Appropriate duration of empirical antifungal therapy
Determining appropriate pediatric dosing for currently available antifungal agents, and identifying novel antifungal agents for empirical therapy

Overall, Cost effectiveness of different approaches to manage pediatric FN.
Key differences as summarized above from 2012 FC CPG tot he 2017 FC CPG. Implementation will be the next step. Further decision making may be further guided by cost-effectiveness studies. Individual clinician's experience will be a key influencing factors to implementation and adoption of the new FN guidelines.

Evaluation of the need for chest X-rays in the management of asymptomatic, intraluminal vascular access device occlusion in childhood cancer

Intraluminal vascular access occlusions are common complication during childhood cancer treatment. American College of Chest Physicians and the Canadian Vascular Access Association suggest that no imaging is required before thrombolysis in asymptomatic intraluminal VAD occlusion. However, some centres continue to include CXR due to concerns about administering TPA in broken or misplaced VAD and the risk of adverse bleeding events. The purpose of this research was to evaluate utility of routine CXRs prior to administering TPA for occluded VAD.
Retrospective, single centre chart review of oncology patients with line occlusions (partial or complete) leading to inability to aspirate and/or flush the line. Patients with symptomatic line occlusion (ex limb swelling) were excluded. All line occlusions were reviewed to see if CXR altered management. If so, these episodes were reviewed by a group of experts (oncologist, nurse practitioner, interventional radiologist, and thrombosis specialist) to review if administration of TPA could have resulted in harm.
85 patients experienced 123 episodes of VAD occlusion. 9 episodes of VAD occlusion were managed differently (line exchange, replace or removal) due to findings on CXR. After review by specialists only 2 episodes were thought to potentially cause harm if local TPA prior to CXR would have been instilled: port needle in wrong place and PICC broken internally. However the paper highlights the harm would not have been life threatening. The remaining 7 episodes were lines that had migrated.
Single centre study that uses interventional radiology to place lines. Retrospective study that may have missed some episodes. The potential risk of TPA instillation was assessed in a panel review which might not reflect what truly would have happened without the CXR.
This study supports the ACS statement that it is unneccessary to wait for CXR prior to local TPA administration as the CXR rarely alters management and potential harm of administering tPA in broken or misplaced line is low.

Long term risk of subsequent malignant neoplasms after treatment of childhood cancer in the DCOG LATER study cohort: Role of chemotherapy

Childhood cancer survivors (CCS) are at increased risk for secondary malignancies. Although radiotherapy is one of the major known risk factors, less is known about the impact of chemotherapeutic agents. This is a cohort study that evaluated a large Dutch population of CCS and studied their risk of developing subsequent malignant neoplasms.
This study used a cohort of 6165 CCS with detailed information on individual treatments and information on subsequent malignant neoplasm follow-up. The cohort included patients treated before the age of 18 years in one of seven Dutch paediatric oncology centres between January 1st 1963 and December 31st 2001. Treatment-associated risks of breast cancer, sarcoma and all solid tumours were assessed.
The median follow up was 20.7 years since first diagnosis. The cumulative subsequent malignant neoplasm incidence at 25 years after first diagnosis was 3.9% and interestingly did not change noticeably among childhood cancer survivors treated in the 1990s compared with those treated earlier. Doxorubicin was associated with a dose dependent increased risk of female breast cancer (p = 0.001) whereas cyclophosphamide was associated with dose dependent increased risk of sarcoma (p = 0.01). The doxorubicin related breast cancer dose response was stronger in survivors with Li-Fraumeni syndrome-associated cancers suggesting a gene-antracycline interaction in the development of breast cancer.
A limitation of the study is that despite the large size of the cohort the number of events for most of the subsequent malignant neoplasm sites was fairly low as a result of the wide age distribution at the end of the follow-up (5.3 - 65.1 years). As with other large survivorship cohorts the authors acknowledge that correlations between patient and treatment factors can potentially hamper the ability to extract meaningful information in the multivariable analysis.
This study suggests that doxorubicin exposure in childhood cancer treatment is correlated with the risk of subsequent solid cancers and breast cancer whereas cyclophosphamide exposure is correlated with an increased risk of subsequent sarcomas. It is also shown in this cohort that genetic susceptibility may influence doxorubicin-associated breast cancer risk. However, it is unable to establish a causative role of these chemotherapeutic agents.

CCR Pediatric Oncology Series - Childhood Cancer Predisposition Guidelines

The June and July issues of Clinical Cancer Research include a collection of articles compiling the recommendation of leading pediatric oncologists regarding screening and surveillance of childhood cancer predisposition syndromes. The manuscripts are in their entirely relevant to pediatric oncologists and freely accessible.

Mixed-Methods Study of the Impact of Chronic Patient Death on Oncologists’ Personal and Professional Lives

Although it is known that oncologists experience grief when their patients die, the impact of patient death on the lives of oncologists (as it relates to burnout, compassion fatigue, and emotional response) has not been thoroughly explored in the literature.
This study used mixed methods to better define the extent to which the death of their patients affects adult oncologists both personally and professionally. Researchers used semi-structured interviews (qualitative) with a group of 22 oncologists from 3 centers in Israel to explore a variety of themes around death/dying. In parallel, 79 oncologists were surveyed (quantitative) on the topic. Survey questions were designed based on previous qualitative data and literature review.
Perhaps not surprisingly, the study showed that the death of their patients had both a positive and negative influence on the lives of oncologists. Positive effects included gaining perspective and learning from each patient death and becoming a better oncologist, whereas negative effects included personality changes, weakening of personal relationships, exhaustion and burnout. Quantitative results corroborated themes arising from the interviews. It is important to note that palliative care physicians, whose practice revolves around death/dying, do not experience significant burnout. This may relate to perspective; whereas death may be perceived as a failure for oncologists, palliative care professionals view it as an opportunity for alleviating symptoms and providing support.
This study surveyed adult oncologists, who see different diagnoses and experience the death of their patients more frequently than most pediatric oncologists (mean number of deaths/month = 5). The author published similar work in pediatrics (https://www.ncbi.nlm.nih.gov/pubmed/25214471) which support the same conclusions.
The data from this study support the profound impact that patient death has on oncologists, both professionally and personally and confirms that the experience in adult and pediatric oncology is similar. What is equally important is using this to start a dialogue about a need to change the culture in oncology such that the emotional impact of patient death is regularly discussed and normalized.

Significant and Sustained Reduction in Chemotherapy Errors Through Improvement Science

Interest in reducing medical errors in hospitals has been steadily gaining momentum over the last 1-2 decades. As it relates to chemotherapy, with a narrow therapeutic index and high potential for harm, a number of large US hospitals have published on the systematic changes they have made within their departments in this regard.
This is a QI publication is from the Cincinnati children’s hospital, an academic institution that sees > 400 new cancer diagnoses per year and has a baseline error rate of 3.9 per 1000 chemotherapy doses and uses a completely integrated electronic health record (EPIC/BEACON). Of note, 64% of near miss errors were in prescribing and hence directly relevant to physicians.
With the launch of a chemotherapy safety working group, implementation of an additional error reporting system (to capture both near misses and errors that reached the patient) along with a daily chemotherapy safety huddle and creation of noise-reduced chemo ordering ‘safety zones’, they reduced their error rate by 50% (1.9/1000). This reduction in errors was sustained over time.
This study was limited by its generalizability to centers that are smaller in size and do not utilize an integrated electronic health record and/or may be resource limited in other ways. There was also limited discussion on educational initiatives that were implemented for prescribers (MDs) and chemo administrators (nurses) as a result of this project.
Implementing additional error surveillance systems and creating a non-punitive and transparent culture of error reporting is an effective strategy to reduce chemotherapy related errors in a large academic hospital. From an MD perspective, more work needs to be published on prescriber specific interventions that can guide educational initiatives with broad generalizability.

Acute Kidney Injury in Patients with Cancer

A good review of kidney injury in patients treated for cancer - the most useful part is at the end with a review of the effects of various antineoplastic agents on the kidney.

Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both

Good review of basket and umbrella style clinical trials and some examples of them.

Article series: Special Issue: Low to middle income countries (LMIC)

The BJH Volume 177, Issue 6 of June 2017 features a series of original and review articles on treatment of malignant and non-malignant diseases in low and middle income countries.

Long-term neurologic health and psychosocial function of adult survivors of childhood medulloblastoma/PNET: a report from the Childhood Cancer Survivor Study

The authors wanted to investigate the long term neurologic and psychosocial outcomes for adult survivors of pediatric medulloblastoma/PNET who were treated with craniospinal irradiation (CSI) and chemotherapy. This is a retrospective cohort study.
The authors used data from the Childhood Cancer Survival Study (CCSS) with patients diagnosed between 1970-1986. They randomly selected a subset of survivors of medulloblastoma/PNET, and identified and recruited siblings closest in age. A self-administered baseline questionnaire was given to survivors and siblings to understand demographics and health-outcomes. Cancer diagnosis and treatment details including chemotherapy protocol and radiation exposure were abstracted from the medical chart using CCSS protocol.
The authors recruited 380 survivors and 4031 sibling pairs to the study. 73% of suvivors were 5 years from diagnosis. Forty patients had a stroke, with 25 reported >5 years from diagnosis. Of notes, none of the cumulative incidence curves leveled off at 30 years, indicating patients were still suffering events for decades after diagnosis. 70.6% of patients were alive 30 years from diagnosis. Primary tumor recurrence was 18%. 30-year incidence of 2nd malignant neoplasm was 8% (thyroid cancer, malignant brain tumor, sarcoma). Only 25% of survivors achieved a bachelor's degree.
Retrospective study, it only represents about 30% of patients diagnosed from 1970-1986, so there could be some bias. There is also no separation between those with PNET and medulloblastoma, although they were all treated similarly in this era. This is also not representative of what many patients would be treated with today (reduced CSI dose for SR medulloblastoma of 23.4 Gy, all patients would typically receive chemotherapy), so it may not be generalizable to patients undergoing treatment today.
Survivors of medulloblastoma/PNET are at increased risk for neurologic deficits, lower academic achievement and underemployment as adults. Neurologic events, including hearing loss, seizures, cataract development and stroke continued to occur up to 30 years from diagnosis. Long term follow up including regular hearing and vision assessment is important in this population.

Cancer Risk After Pediatric Solid Organ Transplantation.

Solid organ transplant (SOT) recipients are known to have a higher risk of cancer, in particular NHL and HL. Previous studies to better understand pediatric PTLD were done in single centre settings.
This study linked the scientific registry of transplant recipients (captures all solid organ transplants in US) with 16 US state or regional central cancer registries (described as reliably capturing all cancer diagnosis, except basal cell and squamous cell carcinoma of the skin) to identify pediatric transplant recipients in the US from 1987-2011.
Pediatric solid organ transplant patients had an increased risk of cancer (>19 times higher) compared to general population. Cancers included: NHL (212 times higher), Hodgkin’s lymphoma (19 times higher), leukemia (4 times higher), myeloma, cancers or liver, soft tissue, ovary, vulva, testis, bladder, kidney and thyroid. No increased incidence of brain or bone cancers was found. Risk of NHL was highest during first year, in EBV negative recipients, intestine transplant, and induction immunosuppression.
Limited by the quality and amount of data entered into the registries (example EBV serostatus missing for 52% of included transplants). Oldest age at follow up was 38 years of age, thus we don’t know the risk of cancer later in life for pediatric SOT recipients.
Pediatric Solid organ transplant recipients have a significantly higher risk of cancer (in particular NHL, HL) but also many cancer types including leukemias and solid tumours compared to general population (and adult SOT recipients).

Second Primary Malignant Neoplasms and Survival in Adolescent and Young Adult Cancer Survivors

It is well known that second primary malignant neoplasms (SPMs) are often associated with prior cancer treatment. Adolescent and young adult (AYA) survivors are considered to have the highest absolute excess risk of SPMs among all age group. However, no study has assessed the survival impact of different SPMs in AYAs compared with pediatric and older patients until now.
Using data from the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program, the authors have compared survival of patients with SPMs with their corresponding first primary cancer types.
The secondary outcome was to assess if there were age-specific differences in survival after SPMs. From 13 SEER registries, all patients diagnosed with a primary malignant neoplasm (PM) or SPM during 1992 to 2008 were included. Only 14 common AYA cancers were considered for this study.
A total of 15,954 pediatric, 125,750 AYA and 878,370 older adult patients with a diagnosis of 14 cancers occurring as a PM or SPM were included in the analysis. As expected, the 5 year relative survival for all selected cancers were lower for those with SPMs than those with a PM. Focusing on AYA, with the exception of melanoma and testicular cancer who had a relative high survival for both PM and SPMs, the 5 year relative survival for all other SPMs was lower when compared to the corresponding PMs in AYAs.
In multivariable-adjusted models, secondary Hodgkin lymphoma and thyroid cancer had a more than a 3-fold increased risk of death .
There are the classical limitations of a study using the SEER registry: risk of unrecorded variables, variations in data coding and reporting, migration of patients in and out of SEER registry areas, lack of detailed treatment information.
Keeping in mind the inherent limitations, this study on a significant number of patients (1,020,074) outlines how SPMs seem to have an inferior relative survival and higher risk of cancer death for AYA and pediatric patients compared with the older population with cancer.
This underlines once more the importance of treatment protocols aiming at reduction of treatment toxicity in our pediatric and AYA patients with cancer, whenever this is appropriate and good surveillance protocols for early recognition of SMNs.

Late Effects Of Blood And Marrow Transplantation

This is a nice review on late effects in adult patients after hematopoietic stem cell transplantation focusing on detection and interventions.

Eliciting the child’s voice in adverse event reporting in oncology trials: Cognitive interview findings from the Pediatric Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events initiative

The main goal of this qualitative cognitive interview study was to establish, evaluate, and refine the PRO-CTCAE (Patient-Reported Outcomes version of the NCI's CTCAE) measures to be comprehensible to children and their caregivers, and relevant for capturing AEs, in order to improve care and precision of AE grading in trials. The study aimed to refine the measures and stratify the children into different age groups.
Children/adolescents ages 7-20 receiving treatment for cancer from 7 pediatric research hospitals and their parent-proxies were included. Pediatric PRO-CTCAE includes 130 questions that assess 62 symptomatic AEs, in child-friendly terms. First round of interviews elicited concepts and terminology from participants and was used to refine the Paediatric PRO-CTCAE questions tested in the second round to obtain specific feedback. Interviews were stratified by age group.
45 children and 42 proxies participated. Some words/stems that were found to be challenging in the first round of interviews were changed in the second round and were well understood. 7-8-year-olds had difficulty with the 7-day reference period for symptoms. Most questions in the Paediatric and Proxy PRO-CTCAE were well understood by participants and proxies. Patients who had experienced a particular AE were better able to accurately report it.
Small sample sizes for each item (although consistent with recommended guidelines). Participants likely did not represent the sickest patients. As well, some children did not feel well which may have affected their full attention during the interviews.
Development of patient reported outcome tools in pediatrics are important to improve the way adverse events are reported and graded on clinical trials. The Paediatric and Proxy PRO-CTCAE performed well, particularly among older children, who were able to read, understand, and report symptoms. The next step is to validate the tool in a longitudinal multisite study to detect changes in symptom status over time and compare self-report AEs with relevant clinical anchors.

Pregnancy outcome following hematopoietic cell transplantation for thalassemia major

Hematopoietic stem cell transplantation (HSCT) offers a definitive cure for patients with β–thalassemia major at the expense of permanent infertility as a consequence of this treatment modality. This study follows the course and outcomes of pregnancies of β-thalassemia female patients and partners of male patients who were successfully treated with allogeneic HSCT.
The methods of conception and delivery, course and outcomes of 42 post-transplant pregnancies occurring in 15 female patients and partners of 8 male patients with β–thalassemia major who were successfully treated with allogeneic HSCT in a single center from Italy were investigated. All patients received myeloablative conditioning with busulfan and cyclophosphamide (200 mg/kg), and treated with cyclosporine and methotrexate for GVHD prophylaxis.
In the female patients, 9 of the 15 patients (60%) needed post-transplant hormonal supplementation to restore normal menses. Twenty-one pregnancies (78%) were achieved with spontaneous conception in 11 women. Six pregnancies were achieved in 4 women following either in vitro fertilization and embryo transfer or heterologous ovo-donation. There were two cases of miscarriage, a high rate of complications (59%) and a remarkably high (22.7%) rate of preterm delivery. Delivery by cesarean section was observed in 18 of the 22 pregnancies (82%).
The partners of the male transplanted patients had uncomplicated pregnancies. Conception was spontaneous and natural in all cases and was followed by uncomplicated outcome with normal gestational age at birth and no miscarriage.
This study describes a small fortunate group of patients who successfully achieved pregnancy post HSCT but the actual fertility of this patient group cannot be estimated as the proportion of patients trying to get pregnant is unknown.
Some β–thalassemia major patients post allogeneic HSCT retain or recover their fertility after transplant at the expense of an excess in complications and preterm delivery.

Graft-versus-host disease targets ovary and causes female infertility in mice

Female survivors of allogeneic HSCT have a high incidence of ovarian dysfunction. While this has been assumed to be an effect of conditioning, the role of GVHD on ovarian function has not been explored.
Mouse models of GVHD were established with three different conditioning regimens - BuCy myeloablative, BuCy RIC, and TBI followed by splenocyte transplant. One cohort received prophylaxis with prednisolone, cyclosporine, or tacrolimus while a control cohort had no prophylaxis. Fertility and ovarian function were assessed by histology, measurement of granulosa cell secretions, and by mating studies.
Mice with GVHD had lower levels of ovarian function and low levels of fertility by mating studies regardless of conditioning regimen. Fertility, however, was preserved in animals who received GVHD prophylaxis. Outcomes were not dependent on the conditioning regimen.
This is a mouse study and may not necessarily translate to humans. The mice in this study also only received conditioning and did not receive the chemotherapy that precedes HSCT in humans with malignancies.
Whether GVHD affects fertility and ovarian function in women is an important question raised by this paper and needs to be further studied.

Recommendations for gonadotoxicity surveillance in male childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group in collaboration with the PanCareSurFup Consort

The International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) was developed to critically examine the evidence and harmonize existing long-term follow-up guidelines. The European Union-funded PanCareSurFup (PCSF) Consortium collaborated with IGHG to identify treatments associated with increased risk of impaired spermatogenesis, testosterone deficiency, and physical sexual dysfunction in male childhood, adolescent and young adult (CAYA) cancer survivors, and evaluate surveillance strategies.The aim of the recommendations is to enhance evidence-based care for male CAYA cancer survivors. This is a collection of systematic reviews. The senior author Dr. Dan Green is well known for cancer survivorship at St. Jude's.
Guideline representatives from the North American Children’s Oncology Group (COG), Dutch Childhood Oncology Group (DCOG), Scottish Intercollegiate Guidelines Network (SIGN), United Kingdom Children’s Cancer and Leukaemia Group (CCLG), PCSF Consortium, and other international paediatric oncology societies developed a working group of experts from nine countries.

The experts looked for areas of concordance and discordance across the COG, DCOG, SIGN, and CCLG guidelines. They devised clinical questions to address areas of discordance for surveillance of impaired spermatogenesis, testosterone deficiency, and physical limitations that lead to sexual dysfunction (subsequently described as physical sexual dysfunction) covering the following key issues: who needs surveillance; which surveillance modality should be used; how often and for how long surveillance should be performed; and when survivors should be referred.

The authors performed systematic searches in the medical literature for studies of CAYA survivors.
These are very extensive international harmonized guidelines for surveillance of male CAYA survivors and will be helpful resource for counselling and managing patients in long-term follow-up.

Family Strategies to Support Siblings of Pediatric Hematopoietic Stem Cell Transplant Patients

A systemic analysis (Gerhardt et al., PBC, 2015) concluded that siblings of children with cancer are at risk for long-term issues (including psychosocial distress, poor functioning) and should receive supportive services. This study intended to describe the strategies families have used to address the needs and concerns of siblings of children undergoing HSCT.
This was a qualitative study in three parts: (1) analysis of interviews of 26 families at 4 sites in US/Canada within a year hematopoetic stem cell transplantation (2) 6 families were interviewed to focus on sibling issues and strategies used to support siblings from 1 site (Children’s Healthcare of Atlanta) (3) 15 health care professionals were interviewed regarding strategies they use to reduce stress in siblings.
Strategies identified included: sharing information (emphasized by children more than adults), using social support (family and friends to help), taking siblings to the hospital, communicating virtually, providing special events or quality time for siblings, offering siblings a defined role to help the family, switching between parents at the hospital, keeping the sibling's life as constant as possible and arranging sibling meetings with a child life specialist or counselor.
The parent study's primary aim was different and grounded theory was used thus not all families were asked the same questions around siblings and limited numbers may not be applicable to all families.
We know it is important to support families (including siblings) during the stress of treatment. This study will help us provide concrete examples of strategies other families have used to support siblings.