The impact of cooperative group studies on childhood cancer: Improving outcomes and quality and international collaboration

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The Impact of Cooperative Group Studies on Childhood Cancer: Improving Outcomes and Quality and International Collaboration Peter F. Ehrlich PII: DOI: Reference:

S1055-8586(19)30115-5 https://doi.org/10.1016/j.sempedsurg.2019.150857 YSPSU 150857

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Seminars in Pediatric Surgery

Please cite this article as: Peter F. Ehrlich , The Impact of Cooperative Group Studies on Childhood Cancer: Improving Outcomes and Quality and International Collaboration, Seminars in Pediatric Surgery (2019), doi: https://doi.org/10.1016/j.sempedsurg.2019.150857

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The Impact of Cooperative Group Studies on Childhood Cancer: Improving Outcomes and Quality and International Collaboration 1. Peter F Ehrlich Section of Pediatric Surgery CS Mott Children’s Hospital University of Michigan Ann Arbor Michigan USA The author has no conflict of interests

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Introduction Pediatric cancer is a dramatic but rare event. Each year there are 1.7 million new diagnoses of adult cancer compared to 20,000 new diagnoses in children. Despite the relatively rare numbers the advances in pediatric cancer far exceed those achieved in adults.(1) The success in improving survival and minimizing late effects has been due to several reasons but work of the pediatric cancer cooperative groups is a primary reason. The cooperative group structure impacts the ability to conduct clinical research, ensure the quality of the research, and develop best practices. These cooperative group are multidisciplinary with medical oncologists, pathologists, radiologists, surgeons, radiation oncologists, scientists and most importantly the patients and families. A distinctive feature of the pediatric cooperative groups has been the high rate of participation in clinical trials contributing the success in forming effective therapies for essentially all types of cancer. History of the Cooperative Groups The National Cancer Institute(NCI) was formed through the national cancer act in 1937.(2) The first pediatric cancer cooperative groups in North America was the Children Cancer Group (CCG) which began in the 1950s. Also during this time there were pediatric cancer divisions within the adult Southwest Oncology Group (SWOG) and Cancer and Leukemia Group B (CALGB) that formed to conduct clinical trials. In the 1979 the adult SWOG and CALGB merged and the pediatric divisions separated to form the Pediatric Oncology Group (POG). Between 1979- 2000 hospitals that treated children with cancers were either in POG or CCG center. These groups ran a multitude of trials addressing different cancer in children. In addition to the general cancer groups 1

the NCI funded disease specific groups such as the National Wilms Tumor Study Group (NWTSG) and Intergroup Rhabdomyosarcoma Study (IRS) both of which conducted several seminal trials (NWTSG five trials and IRS four trials) that advanced treatments and improved outcomes.(3-8) In late 1990s and early 2000s these cooperative groups were merged into a single entity called the Children’s Oncology Group (COG). Membership is primary based in North America but does include other countries such as Israel, Switzerland, Australia and New Zealand among others. North America was not the only part of the world which recognized the power of large multidisciplinary trials. In Europe countries founded their own consortiums around disease and cancer such as the German Pediatric Oncology Group (GPOH) and the United Kingdom Children’s Cancer Study Group (formed in 1977). In 1971 the Société Internationale d’Oncologie Pédiatrique. (SIOP) was started by Dan D’angio and Aubrey Evans. This was initially and still today is an international forum for children’s cancer but SIOP became the de facto European consortium for conducting pediatric cancer studies similar to the COG. The name is used both for the professional society and the clinical trials consortium. Large ground breaking research has been conducted by the renal tumors group (SIOPRTG), neuroblastoma (SIOIPEN) and the liver group (SIOPEL) among others within SIOP.(9-12) While initially included counties in continental Europe it now includes the European Union (including the UK) and countries from South America and elsewhere. Recently the SIOP and COG subgroups have combined efforts to address cancer by harmonizing studies and terminology. International studies are ongoing in treatment of hepatoblastoma and malignant germ cell cancer.(13, 14)

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The cancers consortiums are not just limited to North America and Europe as the have been several studies from cooperative disease group in Japan and other Asian countries. Although they have much fewer resources countries in Africa and other parts of the world are working together to improve the care of children with cancer in their region Recently, a new surgeon led cancer consortium, initiated by Dr Roshni Dasgupta and Rebecka Meyers and is entitled the Pediatric Surgical Oncology Research Consortium (PSORC). This is an open international group designed to study pediatric surgical oncology questions that are unlikely to be addressed by one of the other clinical consortiums. To date there are 39 participating center, three studies have been completed with several more ongoing. Consortiums, Solids Tumors, Surgeons and International Collaboration Cooperative group consortiums study have guided advances in both liquid and solid tumors as well as late effects A complete review of all these achievements is beyond the scope of this review however a representative sample presented below

Wilms Tumor(WT) Clinical trials for children with WT have been highly successful with overall survival rates greater than 90%.(15, 16) However, there remains subgroups where survival is well below 90%. These include those with unfavorable histology, patients with poor molecular features, bilateral disease and patients who relapse. These subgroups comprise 25% of patients with WT. These rare subsets of patients are ideal to study 3

through international collaboration.(16) In addition, radiation therapy and anthracycline chemotherapy remain the foundation of treatment but are also the main causes of late effects.(17, 18) Finally, the improved survival for children with WT has been achieved globally because the EFS and OS in low and middle incomes countries is far lower than high income countries.(19) The difference in the SIOP and COG approach to WT are well documented and key outcomes from past studies have been summarized previously.(20) The SIOP-RTSG and the COG renal tumors committee have been meeting regularly for over 10 years and have shared ideas, data and biology specimens to help inform treatment. Two international studies have also been published. The first a retrospective study of 750 infants 6 months or less demonstrated that 34% of patients have renal tumors other than WT.(21) This provide evidence to change the approach for infants six months or less so that all these children undergo a primary nephrectomy (COG, SIOP) A second collaborative report focused on treatment of adults with WT.(22) Adults are frequently diagnosed late, there are no specific regimens and have a much harder time tolerating vincristine. They have traditionally done worse than children. However, when treated on pediatric regimens they do as well as the children. The recently complete COG trial AREN0534 was the first study dedicated to bilateral Wilms used the SIOP post chemotherapy staging criteria to direct therapy.(23) Collaborative group studies have also examined surgical quality especially for lymph node sampling, strict pathological guidelines and best practices for imaging diagnosis and follow up.(24-27) A surgeon led study further identified a subset of low risk children who can be cured by surgery alone if specific criteria have been met.(28) The international groups studying WT have

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identified four high priority groups for future collaborations. These include; stage IV patients, initially inoperative patients, bilateral and relapsed WT patients.(16) Renal tumor biology understanding has also been advanced through collaboration. Since 1992 data has been shared through the International Conferences on Renal Tumor Biology that occur every 2 to 5 years. Identification of biological prognostic markers such as LOH at1 p and 16q, 1 q gain, genetic analysis of anaplastic WT, and Micro RNA processing gene mutations have led to or are being study to develop more precise therapy.(12, 29-31)

Neuroblastoma

Neuroblastoma is an embryonic cancer arising from neural crest stem cells.(32) Progress on low and intermediate risk has been substantial while the outcomes over time have improved for high risk they are still poor outcomes for high risk remain poor.(33) A longstanding problem that hindered comparison and collaboration projects for the treatment of neuroblastoma was that until recently there were disparate classifications that were used to define risk in neuroblastoma. In 2004 leaders of the international study groups in neuroblastoma (INRG) developed a task for to consolidate the pretreatment algorithm based on 8800 patients from around the world.(34, 35) INRG task force developed consensus guidelines for molecular diagnostics detection of minimal disease in bone marrow blood and stem cell preparations and imaging and staging. Currently there are seven prognostic factors and 16 pretreatment groups 5

stratified by the prognostic markers. As the tumor biology becomes better understood there is room to incorporated new genetic and biological factors. Cooperative group scientists have identified and evaluated different inherited genetic determinants, molecular targets, immunotherapeutic targets and radio-pharmaceutical therapies for treating patients with neuroblastoma. For example, PHOX2B and ALK are inherited mutations in family neuroblastoma.(36, 37) Single –nucleotide polymorphisms (SNP) at chromosome 5q11.2 have been shown to be associated with low risk neuroblastoma as well others on chromosome 6p22 are associated with aggressive high risk neuroblastoma.(38) MYCN is the best known somatic mutation, has been hard to target therapeutically. 131I-meta iodobenzylguanidine (MIBG) is a radiopharmacological targeted therapy where cooperative group studies have shown response rates between 21-47% and MIBG is valuable both as a treatment but also as a marker for disease response and recurrence.(39) The COG phase II study with antiGD2 antibodies 3F8 and chimeric 14.8 had a significant positive impact (22% had complete response) and has led to the development of additional immunotherapies.(40, 41) Two key surgical led studies have impacted and advanced how children with neuroblastoma are treated. Nuctern et al questioned whether all newborns with adrenal masses need surgery.(42) This COG study prospectively evaluated 97 children less than six months of age with adrenal mass. Based on specific criteria expectant observation led to excellent EFS and OS while avoiding surgery in a large majority of patients. These result have led to further studies with expanded criteria so that more children may avoid surgery and toxic therapies. 6

Although “surgery” is part of the algorithm for neuroblastoma treatment large prospective studies evaluating the extent of surgery are lacking. This is especially true for stage IV disease where the definition of risk and extent of surgery have been varied. To address this, von Alllmen et al used data form the COG A3973 study to examine how the extent of surgical resection impacts local progression and survival.(43) In addition, they looked at concordance between clinical and central imaging review – based assessment of resection extent. This was first cooperative group study to really explore a surgical issue in neuroblastoma. The study revealed that “surgeons” evaluation of resection greater than 90% was associated with a better EFS even after stratification by prognostic factors but OS was not impacted. A second interesting observation was that the concordance rate between surgical assessment of greater than 90% assessment disease and central imaging review was poor. This may be due postoperative affects that are seen on the images as much as different specialty suggesting that residual disease is challenging to assess in the early post-operative period. This study provides an excellent starting point for future studies.

Hepatoblastoma There are only 150- 175 new cases of Hepatoblastoma in the United States a year. The foundation of treatment is surgical resectability.(44) Since 1972 there have been cooperative group studies for hepatoblastoma.(45) North American, SIOPEL, German Pediatric Oncology and Hematology (GPOH) liver group and Japan Children’s Cancer group have all conducted studies work has led to significant improvement in outcomes.(46-48) Similar to the neuroblastoma comparison studies have all been 7

limited because until very recently there was no common risk stratification. Based on international efforts three key initiative that were developed over the past 15 years culminated in the first Pediatric Hepatic International Tumor Trial (PHITT). The first initiative was to use the Pretreatment Extent of Tumor (PRETEXT) as the staging system.(14) Updated in 2017 PRETEXT and adopted by all, describes the extent of the hepatic tumors as well as several annotations relating to vascular and extrahepatic disease. PRETEXT combined with the tumor pathology and biology form the risk stratification for treatment. A second international initiative was the formation of the Pediatric Liver Unresectable Tumor Observatory (PLUTO) registry.(49) PLUTO is a registry developed by an international collaboration of the Liver Tumors Strategy Group (SIOPEL) of the SIOP and has been adopted by all the international groups to understand the role of liver transplant in hepatoblastoma. The third advancement is the Pediatric Hepatic International Tumor Trial (PHITT)The PHITT trial is a collaborative trial involving three major clinical groups running pediatric liver tumor trials: The Société Internationale d’Oncologie Pédiatrique (SIOPEL); the Liver Tumor Committee of the Children’s Oncology Group, USA (COG), and the Japanese Children’s Cancer Group (JCCG). This trial builds on these advances by the clinical consortiums. The trial uses a consensus risk stratification (CHIC analysis), common histologic subtype definitions, and uniform surgical guidelines for definitive resection. Based on these building blocks, a risk-adapted treatment protocol was opened that aims to reduce chemotherapy in patients with non-metastatic HB reduce cisplatin exposure and eliminating doxorubicin.

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Survivorship The increased rate of overall survivor of children cancer has comes with parallel work examine the quality of that life saved.(50) Most clinical trials are only able to follow participants for 5 to 7 years. However, longer term follow-up for children was needed. To address this, a number of survivorship groups have developed and conducted cohort studies including the Childhood Cancer Survivor Study (CCSC), British Childhood Cancer Survivor Study as well as other in Scandinavia, Switzerland and the Netherlands. Studies have documented that survivors of childhood cancer have an increased risk of chronic health conditions, second malignancies, earlier cardiovascular disease reproductive health implications and premature death.(17, 18, 51) For example, a CCSC study cohort had a 27.5% severe or life threatening condition resulting in an 8.2 x fold increase compared to siblings.(52) In the solid tumor cohort bone tumors survivors (39x) were at the highest risk with Wilms tumor (4x) at the lowest. Second Malignancies are typically due to chemotherapy induced myelodysplasia that happens within three years of treatment or exposure to radiation that occurs greater than 10 years. A disease specific example includes that 15% of women who were exposed to pulmonary radiation in WT developed breast cancer by the time they reached forty.(17) Survivorship studies have identified that there is an 8.4 fold increased risk of premature death.(53) Surgical late effects studies have looked at looked at anorectal disease, long term risk of VTE late, infection rate among asplenia patients and late intestinal obstructions.(54-57) All these studies have impacted current protocol design specifically to reducing radiation and chemotherapy burden (e.g. doxorubicin). In the COG study ARENO533 stage IV patient with WT and lung disease

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were able to be spared pulmonary radiation if their lung disease completely disappeared at 6 weeks.(58) Summary In treating rare diseases such as pediatric cancer no single investigator or institution see enough patients to develop meaningful treatments. The early leaders of the childhood cancer groups led the way by cooperating nationally and internationally to advance survival and quality of life. As risk adapted therapy developed further smaller cohorts of high-risk patients will be identified requiring further international collaboration.

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