Overall survival rates for osteosarcoma have remained essentially unchanged over the past 3 decades despite attempts to improve outcome via dose intensification and modification based on response. ...This review describes recent findings from contemporary clinical trials, advances in the comprehension of osteosarcoma biology and genomic complexity, and potential opportunities using targeted and immune-mediated therapies.
Recent results from international collaborative trials have failed to demonstrate an ability to improve outcomes using a design in which the randomized question is dictated based on histologic response to preoperative chemotherapy. Novel prognostic markers assessable at diagnosis are vital to identifying subsets of osteosarcoma. Clinical trials focus has now shifted to serial phase II studies of novel agents to evaluate for activity in recurrent and refractory disease. In-depth analyses have revealed profound genomic instability and heterogeneity across patients, with nearly universal TP53 aberration. Although driver mutational events have not clearly been established, frequent derangements in specific pathways may suggest opportunities for therapeutic exploitation. Genomic complexity may lend support to a role for immune-mediated therapies.
Rigorous preclinical investigations are potentially generating novel strategies for the treatment of osteosarcoma that will inform the next generation of clinical trials, with the opportunity to identify agents that will improve survival outcomes.
Summary Since the introduction of multi-agent chemotherapy for osteosarcoma over 30 years ago, overall survival has exceeded 50%. A clear understanding of the acute complications and late effects of ...osteosarcoma therapy is required to care effectively for patients with osteosarcoma undergoing active treatment, and for the increasing number of osteosarcoma survivors. There has now been sufficient cumulative experience treating patients with osteosarcoma with active anti-osteosarcoma chemotherapy agents, high-dose methotrexate, doxorubicin, cisplatin, ifosfamide, and etoposide to recognise and understand rare toxicities associated with these agents, and to identify the late effects of osteosarcoma therapy. Late effects and rare toxicities of osteosarcoma include cardiac toxicity, acute and chronic nephrotoxicity, neurotoxicity, hearing loss, infertility, and second malignant neoplasms. Reducing the complications of osteosarcoma therapy is an important goal that will require the identification of clear prognostic indicators, the development of biologically-based therapies, and improved antidotes for the active anti-osteosarcoma cytotoxic drugs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Li-Fraumeni syndrome (LFS) is an autosomal dominantly inherited condition caused by germline mutations of the
tumor suppressor gene encoding p53, a transcription factor triggered as a protective ...cellular mechanism against different stressors. Loss of p53 function renders affected individuals highly susceptible to a broad range of solid and hematologic cancers. It has recently become evident that children and adults with LFS benefit from intensive surveillance aimed at early tumor detection. In October 2016, the American Association for Cancer Research held a meeting of international LFS experts to evaluate the current knowledge on LFS and propose consensus surveillance recommendations. Herein, we briefly summarize clinical and genetic aspects of this aggressive cancer predisposition syndrome. In addition, the expert panel concludes that there are sufficient existing data to recommend that all patients with LFS be offered cancer surveillance as soon as the clinical or molecular LFS diagnosis is established. Specifically, the panel recommends adoption of a modified version of the "Toronto protocol" that includes a combination of physical exams, blood tests, and imaging. The panel also recommends that further research be promoted to explore the feasibility and effectiveness of these risk-adapted surveillance and cancer prevention strategies while addressing the psychosocial needs of individuals and families with LFS.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
5.
Precision medicine in pediatric oncology Forrest, Suzanne J; Geoerger, Birgit; Janeway, Katherine A
Current opinion in pediatrics,
02/2018, Volume:
30, Issue:
1
Journal Article
Peer reviewed
Open access
The current review describes recent advances and unique challenges in precision medicine for pediatric cancers and highlights clinical trials assessing the clinical impact of targeted therapy matched ...to molecular alterations identified by tumor profiling.
Multiple prospective clinical sequencing studies in pediatric oncology have been reported in the last 2 years. These studies demonstrated feasibility of sequencing in the clinic and revealed a rate of actionable variants that justifies the development of precision trials for childhood cancer. A number of precision medicine trials are recently completed, underway or in development and these will be reviewed herein, with a focus on highlighting aspects of precision medicine trial design relevant to pediatric oncology.
The primary results of the first round of pediatric precision oncology clinical trials will provide us with a greater understanding of the clinical impact of linking tumor profiling to selection of targeted therapies. The aggregation of sequencing and clinical data from these trials and the results of biologic investigations linked to these trials will drive further discoveries and broaden opportunities for precision medicine for children with cancer.
Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key ...pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Infantile fibrosarcoma and congenital mesoblastic nephroma are tumors of infancy traditionally associated with the ETV6-NTRK3 gene fusion. However, a number of case reports have identified variant ...fusions in these tumors. In order to assess the frequency of variant NTRK3 fusions, and in particular whether the recently identified EML4-NTRK3 fusion is recurrent, 63 archival cases of infantile fibrosarcoma, congenital mesoblastic nephroma, mammary analog secretory carcinoma and secretory breast carcinoma (tumor types that are known to carry recurrent ETV6-NTRK3 fusions) were tested with NTRK3 break-apart FISH, EML4-NTRK3 dual fusion FISH, and targeted RNA sequencing. The EML4-NTRK3 fusion was identified in two cases of infantile fibrosarcoma (one of which was previously described), and in one case of congenital mesoblastic nephroma, demonstrating that the EML4-NTRK3 fusion is a recurrent genetic event in these related tumors. The growing spectrum of gene fusions associated with infantile fibrosarcoma and congenital mesoblastic nephroma along with the recent availability of targeted therapies directed toward inhibition of NTRK signaling argue for alternate testing strategies beyond ETV6 break-apart FISH. The use of either NTRK3 FISH or next-generation sequencing will expand the number of cases in which an oncogenic fusion is identified and facilitate optimal diagnosis and treatment for patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Von Hippel-Lindau disease (vHL) is a hereditary tumor predisposition syndrome that places affected individuals at risk for multiple tumors, which are predominantly benign and generally occur in the ...central nervous system or abdomen. Although the majority of tumors occur in adults, children and adolescents with the condition develop a significant proportion of vHL manifestations and are vulnerable to delayed tumor detection and their sequelae. Although multiple tumor screening paradigms are currently being utilized for patients with vHL, surveillance should be reassessed as the available relevant clinical information continues to expand. We propose a new vHL screening paradigm similar to existing approaches, with important modifications for some tumor types, placing an emphasis on risks in childhood. This includes advancement in the timing of surveillance initiation and increased frequency of screening evaluations. Another neuroendocrine-related familial condition is the rapidly expanding hereditary paraganglioma and pheochromocytoma syndrome (HPP). The tumor spectrum for patients with HPP syndrome includes paragangliomas, pheochromocytomas, renal cancer, and gastrointestinal stromal tumors. The majority of patients with HPP syndrome harbor an underlying variant in one of the
genes (
, and
), although other genes also have been described (
and
). Annual screening for elevated plasma or urine markers along with complete blood count and biennial whole-body MRI accompanied by focal neck MRI is recommended for older children and adults with HPP syndrome to detect tumors early and to decrease morbidity and mortality from HPP-related tumors.
Cancer treatment decisions are increasingly based on the genomic profile of the patient's tumor, a strategy called "precision oncology." Over the past few years, a growing number of clinical trials ...and case reports have provided evidence that precision oncology is an effective approach for at least some children with cancer. Here, we review key factors influencing pediatric drug development in the era of precision oncology. We describe an emerging regulatory framework that is accelerating the pace of clinical trials in children as well as design challenges that are specific to trials that involve young cancer patients. Last, we discuss new drug development approaches for pediatric cancers whose growth relies on proteins that are difficult to target therapeutically, such as transcription factors.
Innovations in Cancer Treatment of Children Helms, Lauren; Guimera, Allison E; Janeway, Katherine A ...
Pediatrics (Evanston),
2023-Dec-01, 2023-12-01, 20231201, Volume:
152, Issue:
6
Journal Article
Peer reviewed
Pediatric cancer outcomes have significantly improved, and yet this success is not spread equally across cancer types or patients. Disparities data in pediatric oncology highlight needed improvements ...in access to care, including clinical trials and advanced testing for all patients. For cancers such as brain tumors and sarcomas, continued advancement in understanding the biology of tumor heterogeneity is an essential step toward finding new therapeutic combinations to improve outcomes. Pediatric cancer survivors need access to emerging technologies aimed at reducing or better managing toxicities from therapy. With advances in treatment and survival, pediatric oncology patients continue to need longitudinal, multidisciplinary subspecialty care. Refining the communication between pediatric oncologists, primary pediatricians, survivorship clinics, and adult primary care is key in ensuring the best lifelong care of pediatric cancer survivors. In this State-of-The-Art review, we discuss 5 major domains in pediatric oncology: reducing toxicity, cancer biology, novel therapies, detection and monitoring, and access to care, to highlight recent advances and areas for continued improvement.
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