When the world’s two largest regulatory agencies issued their conclusions on the possibility that CAR-T cancer therapies could generate new tumors, doctors and pharmacists gave a slight nod of agreement. After all, it’s a problem they’ve been fighting for decades.
“Potentially, any treatment can produce a second tumor,” he says. Garbiñe Lizeagapharmacist at the Donostia University Hospital and coordinator of Gedefo, the group of the Spanish Society of Hospital Pharmacy dedicated to oncological therapies.
It is not just conventional treatments such as hormonal therapies, chemotherapies and radiotherapies, but treatments directed against genetic mutations and advanced therapies (such as CAR-T) are not exempt from this risk.
“It is due to the treatments’ own mechanism of action,” he explains. “Cancer is nothing more than an alteration of our own cells. The instruments we use to modify their growth will alter, sometimes temporarily, sometimes permanently, some healthy cells in our body.”
Raul Cordobahematologist at the Jiménez Díaz Foundation Hospital in Madrid and member of the board of directors of the Spanish Society of Hematology and Hemotherapy, offers other keys.
“The treatments we offer can weaken the immune system, so that the surveillance of new cancer cells is clearly reduced” and they can grow. “The risk is never zero.”
Rodrigo Sánchez-Bayonaoncologist at Hospital 12 de Octubre in Madrid and scientific secretary of the Spanish Society of Medical Oncology, points out that chemo and radiotherapy have been most commonly associated with the risk of the appearance of new tumors.
“Immunotherapy and targeted treatments may also have risks, although these are generally less known and studied due to their more recent implementation.”
Here, not so much damage to healthy cells would come into play, but rather the fact of “altering the cellular microenvironment or the immune system in ways that are not yet fully understood.”
The good news is that specialists have been addressing this problem for a long time and have managed to minimize these new tumors, different from the primary one, that appear months or years after starting treatment.
Chemotherapy
Despite its bad reputation for its notable side effects, chemotherapy has saved—and continues to do so—millions of lives. Used since the mid-20th century, its success has been unquestionable.
However, “some chemotherapy drugs are associated with an increased risk of developing secondary leukemias, particularly acute myeloid leukemia,” says Sánchez-Bayona. “This risk may be 1-5% in the first 10 years after treatment“.
Garbiñe Lizeaga points out that cyclophosphamide (used in hematological cancers and certain types of breast and lung, among others) and etoposide (used in testicle, ovarian, lung or some lymphomas) are those most associated with secondary neoplasias.
“In oral chemotherapy, lenalidomide, which is widely used in myeloma, can cause a second hematological malignancy, which is why its use has been limited to two years.”
Although not chemotherapy per se, other oral medications, such as tamoxifen for breast cancer, also have risks. “It is an anti-estrogenic treatment that controls tissues with hormone receptors such as the breasts, but also the endometrium, so it can be affected.”
Radiotherapy
The harmful effects of radiation began to be observed when survivors of the atomic bombs of Hiroshima and Nagasaki began to develop more tumors than the rest of their compatriots.
Radiotherapy is a type of radiation directed at a very specific point that “alters the DNA of cells through the ionization of atoms,” he points out. Carmen Rubiopresident of the Spanish Society of Radiation Oncology (SEOR).
“This ionization creates free radicals, which alter the DNA of cells, especially tumor cells, which are more sensitive: healthy tissue is repaired because it is more resistant.”
Although radiation dose and time are factors that increase risk, there is always an intrinsic probability of developing a secondary tumor.
It also depends on the irradiated area. “When lymphomas are treated in children and adolescents, there is an increased risk of breast cancer in women, and also of thyroid cancer.. In brain tumors there is a risk of developing sarcomas in the future.”
Rubio emphasizes that this risk must be managed very precisely in the case of minors, since they are the ones who will live the longest after having cancer and, therefore, have a greater risk of developing a tumor “within 20 or 30 years.” Hence, options such as proton therapy are especially recommended in this population.
Targeted therapies and immunotherapies
At the end of the 20th century, new treatments appeared that targeted specific mutations present in cancer cells. Monoclonal antibodies have revolutionized care for more and more tumors with much fewer side effects than chemotherapy: they target tumor cells almost exclusively.
It is known, however, that some of these ‘magic bullets’ can influence the development of new cancers, such as those that target the BRAF mutation (vemurafenib and dabrafenib) present in some melanomas.
“They have changed the treatment landscape for a very aggressive tumor,” explains Garbiñe Lizeaga, “but, as a consequence of its own mechanism of action, it favors the appearance of other skin tumors” such as squamous cell carcinomas.
“Patients treated with these medications are closely monitored and are constantly referred to dermatologists to identify and remove any neoplasia that appears in time.”
Immunotherapies are also monoclonal antibodies, but their function is different: they enhance the patient’s immune system to fight the tumor.
Despite being with us for a decade, the technical specifications of several products include side effects related to benign and malignant neoplasms, although they are infrequent and unimportant compared to other adverse reactions.
Minimize the risk of new tumors
The appearance of a new cancer in people who have already had one is not generally due to the effect of the treatment. Patients continue to be influenced by risk factors such as genetic predisposition or the effect of lifestyle.
The age at which the tumor develops is also important, since many of them appear decades after the first one. “Children treated with radiotherapy have a significantly increased risk of developing secondary tumors due to their increased susceptibility and life expectancy.“, points out Rodrigo Sánchez-Bayona. “This risk can be 3-12% over 20-30 years.”
We must not forget the effect of several therapies followed. “Patients receiving multiple lines of treatment (rescue therapies) have a higher cumulative risk of developing secondary tumors.”
Therefore, the treatment is individualized for each one. The risk of developing a new tumor is also not of the same importance in all cases. “In patients receiving treatment with curative intent, the risk of second tumors is much stricter,” recalls the scientific secretary of the SEOM.
“In patients with advanced cancer, given that life expectancy is shorter, it is assumed that the benefit of treatment outweighs the low risk of second tumors.”