Targeted therapy aims to more selectively attack the cancer cell or its immediate supportive environment, sparing normal tissues and therefore causing fewer side effects in the host as compared with traditional cytotoxic chemotherapy. This review will briefly discuss some examples that highlight successes at incorporation of targeted therapy in pediatric and adolescent oncology as well as other examples that highlight some of the associated challenges.
Cancers in children and adolescents are fortunately infrequent. Overall, cure rates are good, approximately 80%, although this varies by histology and stage. Targeted therapies aim to improve efficacy and decrease toxicity by more specifically affecting malignant cells or their supporting stroma. Cancers of early life are often of different histology than those seen in adults. Sometimes, the same pathway is affected, even if the histology is different. Toxicities may also be different, particularly in younger children. These factors render drug development in young people challenging. This article reviews some successes and challenges to that development, including brief discussions of imatinib, lestaurtinib, antiangiogenesis, and anti-GD2 therapies. Cancer 2011;117(10 suppl):2268–74. © 2011 American Cancer Society.
In Canada, annually there are approximately 850 new cases of cancer diagnosed in patients up to the age of 15 years,1 with another 450 cases in adolescents 15 to 19 years of age. The adolescent cases number among the approximately 2000 cases diagnosed each year in Canadian youth between the ages of 15 and 29 years.2 The population of the United States is approximately 10× that of Canada, and the number of malignant diagnoses in children, adolescents, and young adults is similarly approximately 10× the Canadian figure. In children and adolescents, acute leukemia accounts for around 25% of cases. It is more frequent and more commonly lymphoid in younger patients. Central nervous system tumors and lymphomas each include another 25% of patients, with the remainder comprised of neuroblastomas mainly in infants and toddlers, Wilms tumor mainly in toddlers, bone sarcomas predominantly in adolescents, soft tissue sarcomas in both populations, and a miscellany of other diseases. Mortality declined steadily from the mid-1970s through the late 1990s, with a less steep decline more recently. This is particularly true of the solid tumors (Fig. 1).
The goals of incorporating novel targeted agents include both an increase in efficacy, especially for those diseases that remain of poor prognosis, and a decrease both in the short-term toxicities, such as myelosuppression, infection, nausea, and vomiting, and in long-term toxicities, including neurocognitive impairment, infertility, cardiovascular morbidity and mortality, obesity, and second cancers. Targeted therapy is based on several findings. Some changes are unique to the malignant cells; for example, the product of the bcr/abl translocation in Philadelphia chromosome positive (Ph1+) leukemias or the ews/fli1 translocation in Ewing sarcoma. Some pathways are more prominent in malignant tissues, and some may be important in cancers across a broad age range. These include the insulin growth factor receptor and angiogenesis pathways. Some surface markers are relatively selective for the malignant cell and are therefore designated tumor-associated antigens, although they are not specific for only tumor tissue. These cell surface markers may or may not be the same in tumors across the age spectrum. The agents themselves can be small molecules that, for example, bind to important sites on targets, interfering with their function; antibodies that can, for example, block receptors or target a tumor for immune attack; proteins; or peptides.
Examples of targeted therapy applied to this age group are discussed here, as follows:
Imatinib is a small molecule inhibitor of the bcr/abl tyrosine kinase that is characteristic of chronic myeloid leukemia (CML), 2% of childhood acute lymphoid leukemia (ALL), and up to 25% of adult ALL. It was initially shown to induce prolonged complete remissions in adults with chronic phase CML, as well as transient responses in those with blast crisis CML or ALL. In addition, it was very well tolerated.3, 4 A Children's Oncology Group phase 1 study (P9973) was opened in 2000 to investigate the role of imatinib in Ph1+ leukemias in children. Eligibility included age younger than 22 years at enrollment, recurrent or refractory CML, ALL or acute myeloid leukemia (AML), adequate organ function, and no concurrent anticonvulsant therapy. Four dosage levels were studied: 260 mg/m2 (around 400 mg for an adult), 340 mg/m2 (600 mg), 440 mg/m2 (800 mg), and 570 mg/m2 (1000 mg) each day, with all doses given continuously and a 28-day period defined as a course of therapy. Dosage escalation was in a standard 3 + 3 schema. There was only 1 dose-limiting toxicity, a 10% weight gain in the first cycle. Overall, there were few adverse events, which, in addition, were not clearly drug-related or dose-related. Efficacy reproduced that seen in adults, with excellent survival in those with recurrent chronic phase CML, and much less effect in those with more advanced disease (Fig. 2).5 A phase 2 study in those younger than 22 years with newly diagnosed chronic phase CML then followed, with standard eligibility criteria for performance status and organ function, and no concomitant anticonvulsants or Coumadin therapy, because of the possibility of drug interaction. The dosage selected was 340 mg/m2/d, because it was well tolerated in the phase 1 experience, and experience in adults had suggested the possibility of improved response with higher dose therapy. Fifty evaluable patients were enrolled, at a median age of 12 years (2-19). Imatinib was generally well tolerated. Edema or weight gain was seen in only 4% of patients. Grade 3 or 4 neutropenia was noted in 15% of patients in courses 2 to 5. Other toxicities were infrequent. The best cytogenetic response among the 46 evaluable patients was a complete response in 33 (72%), partial response in 7 (15%), minor or minimal response in 4 (9%), and no response in only 2 (4%) patients. The responses were durable. With a median follow-up of almost 4 years for patients still alive at last contact, 6 (18.1%) patients with initial complete cytogenetic remission showed evidence of recurrence of Ph1+ cells in subsequent cytogenetic evaluations 2 to 24 courses after initial documentation of complete cytogenetic remission. Nine patients died, 7 because of transplant-related mortality, 4 having been taken to transplant in complete cytogenetic remission, 3 after recurrence (Champagne et al, submitted for publication). These results are similar to those seen in adult patients (reviewed in Jabbour et al6).
For patients who develop cytogenetic or molecular recurrent or progressive disease, newer, more potent bcr/abl inhibitors have been developed, including dasatinib, nilotinib, and bosutinib. Drugs that are effective against the least responsive mutant clone (T315I) are also in development.6
The excellent efficacy and limited toxicity of imatinib and the development of second-line and third-line bcr/abl inhibitors for patients with chronic phase CML have changed the overall strategy for both adult and pediatric patients. Many adult patients are no longer treated by high-dose therapy and allogeneic stem cell transplant, the only known curative therapy for CML. In many centers, pediatric patients are similarly offered allogeneic stem cell transplant only if there is a well-matched donor, preferably a sibling donor, because the outcome of such transplants is far better than of those from less well-matched siblings.7 Because the underlying molecular abnormality of CML is the same in adults and children, the pharmacokinetics are similar,8 and as CML is uncommon in children, especially younger children, Children's Oncology Group has to date elected not to further study this population of patients, expecting clinicians to adapt guidelines from studies in adults as they develop.
In view of the success of imatinib in patients with chronic phase CML and the poor outcome of patients with Ph1+ ALL, a logical next step was to incorporate imatinib into systemic therapy for ALL. To ensure patient safety, this was done as exposure to increasing numbers of days of imatinib therapy by cohort. This also proved a success, with patients receiving continuous imatinib in addition to chemotherapy showing an improved outcome when compared with historical controls, and a trend toward improved outcome when compared with patients having undergone stem cell transplant (Fig. 3).9 Currently, Children's Oncology Group is studying the addition of a newer generation, more potent inhibitor, dasatinib, to a similar chemotherapy backbone to determine whether further improvement in outcome can be achieved (AALL0622).
The bcr/abl gene product is essential to the life of Ph1+ leukemia cells in a more fundamental sense than for the other targets of imatinib, ckit and platelet-derived growth factor alpha. A Children's Oncology Group study yielded only 1 partial response in 59 patients with recurrent solid tumors.10 In vitro, drug levels that were inhibitory to the target protein did not cause cell death, which required much higher drug levels, different from the similarity between the protein-inhibitory and cell death-inducing levels in Ph1+ leukemias.11 In addition, although gastrointestinal stromal tumors (GISTs) in adults frequently have activating c-kit mutations and respond to imatinib,12 the rare pediatric GIST is more likely to have wild-type c-kit and not respond to imatinib.13
Other malignant cells are less exquisitely sensitive to target inhibition, as compared with the sensitivity of Ph1+ CML cells to targeting by imatinib. An example is the flt3 pathway in leukemic cells with internal tandem duplications of flt3 and an elevated allelic ratio.14 Although this pathway can be inhibited, an industry-sponsored trial of the small molecule tyrosine kinase inhibitor lestaurtinib given sequentially after induction in patients with recurrent AML showed no benefit.15 Of interest, 46 of 79 patients tested had at least 85% plasma inhibitory activity; 39% of them achieved a complete response or a complete response without full platelet recovery. This is in contrast to an only 9% rate in those with plasma inhibitory concentrations below the target. In addition, in adults with recurrent disease, as compared with those newly diagnosed, there are increased levels of circulating flt ligand, which can interfere with inhibition, and increased levels of alpha-1 acid glycoprotein, which binds lestaurtinib.16 Children's Oncology Group had initiated a study of lestaurtinib in a similar setting of recurrent AML (AAML06P1), but given the results in adults, that study has been closed after initial tolerability had been demonstrated but before the efficacy phase with a targeted plasma inhibitory activity had been completed. Other flt3 inhibitors are available that are more specific and/or more potent. Their exact role in recurrent and newly diagnosed AML remains to be defined.17 This demonstrates some of the difficulties with early selection of an agent when several are being developed and all may not survive to market, even when the pathway targeted is the same as in an adult malignancy.
Lestaurtinib has also shown preclinical activity against neuroblastoma, possibly in part by blocking the trk-B pathway.18 Lestaurtinib enhanced the preclinical activity of the cytotoxic combination of topotecan and cyclophosphamide without enhancing toxicity. In contrast, lestaurtinib in combination with the antiangiogenic bevacizumab was more toxic than predicted, with half the mice treated requiring euthanasia.19 If lestaurtinib will no longer be developed, an alternate compound affecting the same trkB pathway, possibly in addition to other receptor tyrosine kinases, such as sunitinib,20 will be required.
A nutrient supply is essential to the growth of both primary and metastatic cancers. Tumor neovascularization includes both angiogenesis, the sprouting of vascular tubes from pre-existing vessels, and vasculogenesis, the formation of new vessels from endothelial progenitor cells. Tumor cells are also capable of migrating along pre-existing blood vessels, co-opting their nutrient supply. Tumor angiogenesis often involves the vascular endothelial growth factor (VEGF) pathway (summarized in Miletic et al21). Bevacizumab is a humanized anti-VEGF antibody that may sensitize endothelial cells to cytotoxic cell death. In addition, by encouraging pruning of the abnormal vasculature, bevacizumab and other antiangiogenic agents may improve the delivery of cytotoxic chemotherapy to tumor cells, decreasing vasogenic edema by decreasing vascular permeability, decreasing interstitial pressure within the tumor, and increasing oxygenation in the tumor tissue.21 Ewing sarcoma may be a particularly attractive target for antiangiogenic therapy. The ews/fli1 oncogene down-regulates thrombospondins, which are angiogenic inhibitors,22 and up-regulates VEGF.23 Vasculogenesis, angiogenesis, and vessel mimicry are all involved (reviewed in DuBois et al24). Preclinical combination therapy with cytotoxic chemotherapy added efficacy.25 A European study randomizing the addition of bevacizumab to chemotherapy for patients with newly diagnosed metastatic Ewing sarcoma is underway, as is a study in patients with newly diagnosed osteosarcoma at St. Jude's Children's Research Hospital. Of note, 6 of 17 adult patients with metastatic sarcoma treated with the combination of bevacizumab and doxorubicin developed at least grade 2 cardiotoxicity, despite cardioprotection with dexrazoxane begun at a doxorubicin dosage of 300 mg/m2.26
Alveolar soft part sarcoma is a rare malignancy affecting mainly adolescents and young adults. It is poorly responsive to chemotherapy.27, 28 It harbors a characteristic t(X;17)(p11.2;q25) translocation resulting in MET activation, and histologically it has a prominent capillary vascular pattern.29 Responses have been seen with both sunitinib30 and cediranib,31 small molecule tyrosine kinase inhibitors that exert antivascular effects. Many other antiangiogenic compounds are being developed, including pazopanib, sunitinib, sorafenib, and cilengitide, for a variety of pediatric malignancies (Fig. 4). The exact role of each of these will be challenging to define.
GD-2 is a ganglioside present on almost all neuroblastoma cells that continues to be expressed even after anti-GD2 therapy is administered. It was first identified on neuroblastoma cells and in the sera of patients in 1984.32 Antibodies, including the ch14.18 antibody, were then developed; ch14.18 entered a clinical trial in children with neuroblastoma and adults with melanoma in 1992. Increased antineoplastic activity was observed with the concomitant administration of interleukin-2 (IL-2).33 Another phase 1 study incorporating ch14.18 and IL-2 was initiated in 1990,34 and a follow-on study using the combination after high-dose therapy and stem cell reinfusion began in 2000.35 A phase 3 study randomizing cis-retinoic acid alone after transplant compared with combination immunotherapy followed by cis-retinoic acid began in 2001. It was closed at an interim evaluation point in 2009, with the immunotherapy arm having crossed a boundary demonstrating increased efficacy (Fig. 5).36 A study gathering further information to support a licensing application is in progress. Recent reanalysis of a German study nonrandomly assigning patients to ch14.18 after high-dose therapy supports its efficacy.37 Other studies using other antibodies or modifications of the ch14.18 antibody are in progress, and consideration is being given to using ch14.18 in other diseases, such as osteosarcoma, that express the GD2 antigen. The 25-year time course of development of this therapy, which provides a real improvement in outcome for children with advanced stage neuroblastoma, with licensure still in progress, underlines some of the difficulties associated with pediatric drug development. These are primarily related to the small population of children, adolescents, and young adults with cancer, frequently of different pathologies from those seen in adults. Drug development for such a small population is financially unappealing. Even when similar molecular pathways are involved, drug development requires pharmaceutical industry interest based on efficacy and tolerability in adults.
The most important maturation of the systems for drug metabolism and excretion occur in the first 2 years of life.38 Toxicities are sometimes heightened in such young children.39 Occasionally, older but still prepubertal children have increased sensitivity to particular toxicities of chemotherapy, as has been seen with pseudotumor cerebri in children treated with all-trans retinoic acid.40 Postpubertal adolescents and young adults most commonly demonstrate similar pharmacokinetics, as seen in 2 of the drugs discussed in this review, bevacizumab41 and imatinib.8
Summary and Conclusions
Cancer in children, adolescents, and young adults is uncommon. Overall, cure rates are good, around 80%, although variable by histology and stage. Diseases of relatively unfavorable histology, such as the bone sarcomas, often affect both adolescents and young adults. Children's Oncology Group has joined the Clinical Trials Support Unit, a project sponsored by the National Cancer Institute (NCI) for the support of a network of physicians to participate in NCI-sponsored phase 3 cancer treatment trials. This initiative is likely to facilitate the entry of young adult patients onto relevant Children's Oncology Group studies. Similarly, studies for adults with cancers that also affect youth occasionally allow study entry of patients as young as 14 years. Moreover, with increasing knowledge of the molecular basis of cancer, medications designed for cancers of adults may affect the same pathways in childhood and adolescent cancers, speeding their development. Increasing the proportion of children and adolescents from whom tumor tissue is collected will facilitate the identification of these pathways. Together, these several factors are anticipated to lead to treatments with increased efficacy and decreased short-term and long-term toxicity for the relatively underserved adolescent and young adult population. To realize these benefits, however, the major challenges of administrative and regulatory hurdles need to be overcome. An example is a simplification of the process of obtaining research ethics board approval in all institutions that may wish to use a given protocol. In addition, changes in practice patterns such that youth are cared for in a unit designed to serve their needs by practitioners specialized in their care are likely to better meet the needs of this group. Such teenage and young adult units have been and are being further developed in the United Kingdom, as outlined in more detail elsewhere in this Supplement.
Funding for the national task force on adolescents and young adults with cancer has been made possible by a financial contribution from Health Canada through the Canadian Partnership Against Cancer. Funding for the workshop was provided by C17; the Advisory Board of the Institute for Cancer Research at the Canadian Institutes for Health Research (CIHR); the Public Health Agency of Canada; the Ontario Institute for Cancer Research; the Meetings, Planning and Dissemination Grants program of the CIHR; the Terry Fox Research Institute; LIVESTRONG, formerly the Lance Armstrong Foundation; the Canadian Cancer Society Research Institute; Young Adult Cancer Canada; Hope and Cope; and the Comprehensive Cancer Centre at the Hospital for Sick Children, Toronto, in addition to the support provided by the Canadian Partnership Against Cancer to the Task Force on adolescents and young adults with cancer.
CONFLICT OF INTEREST DISCLOSURES
The author made no disclosures.