About INFORM

A second chance for children with cancer

When children with cancer experience a relapse, the chances of a cure are often very low. A detailed analysis of the altered genetic information of the tumor at the time of relapse aims to lay the foundation for the future use of targeted (“intelligent”) medications against the individual tumor. This is the goal of the INFORM registry (INdividualized Therapy FOr Relapsed Malignancies in Childhood). Initially, we aim to gather experience with molecular analyses and document clinical outcomes to identify the types of cancer where an individualized treatment approach can have the greatest impact. Based on this, we can design future clinical trials in a way that benefits as many affected children as possible. Under the umbrella of the Society for Pediatric Oncology and Hematology (GPOH), the INFORM registry involves 20 study groups and more than 50 recruitment centers across Germany. In 2016, the registry was expanded to include additional countries. INFORM is coordinated by scientists at the Hopp Children’s Cancer Center Heidelberg (KiTZ), a joint institution of the German Cancer Research Center (DKFZ), Heidelberg University Hospital, and Heidelberg University, as well as by the GPOH. 

Compared to adult cancer patients, children with cancer have a particularly good chance of being cured. With intensive chemotherapy and radiotherapy, cure rates of almost 75 percent can now be achieved. This impressive progress of the last four decades has slowed down considerably in recent years. Pediatric oncologists assume that the improvements that can be achieved with conventional therapies have largely been exhausted. The most pressing problem in pediatric oncology today is relapse after such intensive therapy. This affects around 500 children with cancer in Germany every year. By the time a relapse occurs, "all the powder has been spilled", i.e. the effective therapies have largely been exhausted. To date, there is only a second chance of a permanent cure for very few types of cancer (for example acute leukemia). For most other types of cancer, only about one in ten children has a chance of being cured in the event of a relapse. Today we know that the biology and genetics of tumors after such intensive "bombardment" by chemotherapy and radiotherapy differ significantly from those of the untreated primary tumor. This is the reason why originally effective therapies often fail when the tumor recurs.

More targeted and gentler treatment

By analyzing the genetic changes in the recurrences, we learn which changes in the protein composition of the cancer cells provide a survival advantage.
For example, certain molecular signaling pathways in cancer cells are incorrectly switched on permanently. In contrast to chemotherapy and radiotherapy, the new "intelligent" drugs, of which there are now several hundred, are not directed against all rapidly dividing cells, but precisely against such cancer-typical cell changes. They therefore do not kill bone marrow cells, hair root cells or cells of the intestinal surface - with the known side effects of anemia, hair loss or inflammation of the mucous membranes. Targeted drugs, perhaps in combination with chemotherapy, could further improve cure rates in children with malignant tumors and, above all, offer a new treatment option in the event of a relapse.

What are our plans?

With INFORM, we are pursuing the major goal of being able to offer individually tailored treatment to children with cancer who suffer a relapse. To do this, we first need to analyze the tumor genome from tumor material at the time of relapse, which was routinely obtained during an operation. The genetic analyses are still expensive and time-consuming at the moment, but they provide us with far more information than anything that has been collected in tumor diagnostics to date. The first question that the INFORM registry wants to clarify in a feasibility study is how much this information can contribute to offering children better treatment. In this sub-study, we are concentrating on the 12 types of cancer in which children most frequently suffer relapses, as well as individual rare cancers. We are documenting how many cases of each type of cancer can actually be biopsied again at the time of recurrence and how long the analyses take. The decisive factor is which and how many mutations, for which there are "intelligent" drugs, are found in the different types of cancer. If we discover changes in a patient's tumor cells for which drugs are already available, the treating physician can use this information and decide with the patient individually which therapy is appropriate and possible. Such individual treatments are documented at INFORM.

Clinical studies

The INFORM registry provides a solid data basis for the development of clinical studies. For example, the frequency of mutations for which suitable "intelligent" drugs are available is investigated. Together with independent experts, we select those molecular changes for which one or two of these drugs are the best match. In future clinical trials in accordance with the German Medicines Act, we will then examine whether individualized therapy achieves better healing results than standard chemotherapy for patients with these molecular changes, regardless of the type of cancer.

Why children?

Of course, we primarily hope to improve the chances of survival for young patients. This is made easier by the fact that pediatric oncologists throughout Germany, as well as internationally, have always worked closely together. This is the only way that such an extensive study is even possible, with more than fifty centers in Germany alone working together to treat the children. In addition, we now know that children's tumors have on average around a hundred times fewer mutations than most cancers in adults. This makes the task of identifying the tumor-driving mutations and linking them to the "right" intelligent drug much easier. The experience we gain from the INFORM trial will greatly benefit the planning of similar trials in adult cancer patients.

Which patients can take part?

Those who are eligible for participation in the INFORM registry are determined by the pediatric oncologist treating them. Inclusion criteria are relapsed tumors or tumors progressing under therapy with a diagnosis of ALL-HR, ALL post-SCT, AML, rhabdoid tumors, ependymoma, medulloblastoma, Ewing sarcoma, hepatoblastoma, high-grade glioma, high-risk neuroblastoma, germ cell tumor, nephroblastoma, non-Hodgkin lymphoma, malignant endocrine tumors, osteosarcoma, retinoblastoma and soft tissue sarcoma. Patients with primary disease of a high-grade glioma (incl. DIPG), a specific soft tissue sarcoma or ETMR, for whom no curative treatment options are available in the primary situation, can also be included. In exceptional cases, "other" pediatric refractory or progressive/relapsed entities, including rare tumor diseases, can be included in the registry after consultation. . Patients are between 0 and 40 years of age and have been treated under a treatment protocol of the Society for Pediatric Oncology and Hematology (GPOH) or an equivalent treatment protocol as part of their primary diagnosis. Exceptions may include HGG (incl. DIPG), specific soft tissue sarcomas, ETMR and rare tumor diseases. Although patients can be included up to the age of 40, the primary diagnosis must have been made before the age of 21.
In addition, given the duration of the analysis, only patients who have a life expectancy of at least 3 months and are in good general health can participate. We obtain the tumor material as part of the patient's routine care.

How can patients participate?

Patients (and/or parents) are informed about the INFORM registry by their treating pediatric oncologist and sign the consent form. After this, the treating pediatric oncologist can, after checking the inclusion and exclusion criteria register the patient electronically with the INFORM Registry. No examinations can be carried out without this electronic registration. Only a pediatric oncologist can register a patient with the INFORM registry.

What happens to any genetic abnormalities found?

A panel of experts (experienced pediatric oncologists, bioinformaticians, biologists, pharmacologists) classifies the changes found for each individual patient according to clinical relevance. No treatment recommendations are made within the framework of the registry, only the molecular information is passed on. The pediatric oncologist treating the patient has access to the biological information obtained on his patient and can decide independently whether and in what form to use it for his therapy decision.