CME Author: Vicki Brower
Study Authors: Lindsay M. Morton, Graça M. Dores, et al.
Target Audience and Goal Statement:
Oncologists, pediatric oncologists, family medicine specialists, and internists
The goal is to determine the association of treatment-related myelodysplastic syndrome/acute myeloid leukemia (tMDS/AML) with chemotherapy in patients previously treated for solid cancer tumors.
- Can we quantify tMDS/AML risks following chemotherapy?
- What are the relative risks of these treatment-related conditions compared with the general population?
- Which patients have the highest risk of tMDS/AML, and in what interval post-treatment does the greatest risk occur?
Study Synopsis and Perspective:
In this large-scale population-based cohort study, patients treated with chemotherapy for 22 of 23 solid tumor types had a statistically significant increased risk of developing tMDS/AML, ranging from 1.5- to 10-fold higher than the general population. The highest risk occurred among younger patients, reported Lindsay Morton, PhD, of the National Cancer Institute (NCI) in Bethesda, Maryland, and colleagues in JAMA Oncology. Overall survival of patients with tMDS/AML is extremely poor, about 7 months; 78.4% of patients diagnosed died during the study period.
Therapy-related MDS/AML occurred significantly more often than anticipated following initial chemotherapy for all primary solid tumors except for colon cancer, possibly because colon cancer is often diagnosed late in life, and may develop very slowly, the authors hypothesized.
In addition to tying chemoradiotherapy to the highest rates of tMDS/AML, researchers found that the chemotherapies most closely associated with tMDS/AML were platinum-based agents, topoisomerase II inhibitors, and alkylating drugs such as melphalan.
“We’ve known for a long time that the development of myeloid leukemia is a very rare adverse effect of some types of cancer treatments that damage cells,” Morton said in a statement from the NCI. “There have been many changes in cancer treatment over time, including the introduction of new chemotherapy drugs and drug combinations, but we didn’t know what the risk of therapy-related leukemia looked like for patients since these changes were made.”
In the new study, Morton and colleagues examined the records of 1,619 patients with tMDS/AML from among more than 700,000 adults diagnosed with a first primary solid cancer from the year 2000 to 2013 who received chemotherapy and survived at least 1 year, as reported to the Surveillance, Epidemiology, and End Results (SEER) Program. Additional descriptive analyses were conducted using linked SEER and Medicare data on 165,820 older adults who received initial chemotherapy for a first primary cancer during this stretch of time.
They found that the highest standardized incidence ratio (SIR) occurred in cancer of the bone (SIR 39.0), soft tissue (SIR 10.4), and testis (SIR 12.3), all of which are typically diagnosed in younger patients, the researchers wrote. SIRs ranged from 5-fold to 9-fold for peritoneum, small cell lung, ovary, fallopian tube, brain, and central nervous system cancers, and from 1.5-fold to 4-fold in all remaining cancers that were examined.
Patients had a greater risk for tMDS/AML within 5 years of diagnosis, compared with 5 or more years post-diagnosis for esophageal, stomach, soft-tissue, breast, uterine corpus, and testis cancers, the researchers reported. For 15 of the 23 primary solid tumors examined, the risk for MDS/AML remained statistically significantly elevated 5 years or more after the primary diagnosis.
From the year 2000 to 2013, the researchers noted a shifting pattern of chemotherapy — they saw an increase in the use of alkylating drugs, platinum drugs, and topoisomerase II drugs — from 57% in 2000-2001 to 81% in 2012-2013. Platinum-based drugs drove the increase, from 35% in 2000-2001 to 59% in 2012-2013. Treatment with platinum drugs increased most notably for cancers of the gastrointestinal tract, oral cavity, peritoneum, and non-small cell lung cancers, among others.
“While advances in cancer treatment approaches have improved the prognosis for many types of cancer, the number of patients at risk of developing rare, therapy-related leukemia after cancer chemotherapy in the modern treatment era has markedly expanded,” Morton said. “Assessments of treatment risks and benefits should balance these risks and other adverse effects of chemotherapy against potential gains in survival following treatment for the initial solid cancer.”
Source Reference: JAMA Oncology, online Dec. 20, 2018; DOI: 10.1001/jamaoncol.2018.5625
Study Highlights: Explanation of Findings
Morton and colleagues wrote that with the rising use of known leukemogenic drugs, from 57% during 2000-2001 to 81% in 2012-2013, their study provides “the first clear evidence of excess tMDS/AML risks following chemotherapy for oral cavity or pharynx, esophagus, stomach, rectum, larynx, bone, cervix, uterine corpus, and vagina or vulva cancers,” noting that for each of these cancers “platinum compounds have been introduced to improve outcomes.” In addition, their research detected excess tMDS/AML risks after rare peritoneum and fallopian tube cancers, which are also now treated with platinum drugs. They noted that it had already been established that excess risks of tMDS/AML existed for testis, small cell and non-small cell lung, and ovarian cancers, “which have been treated with platinum drugs for decades.”
Many cancers with the highest tMDS/AML SIRs in SEER were treated with carboplatin, they wrote, whereas the lower SIRs they saw after treatment for rectal and colon cancers may reflect the lower leukemogenicity of oxaliplatin (or less use of it, which needs to be explored, they wrote). Furthermore, they noted for the first time that treatment for liver, pancreas, bladder, and anal cancers also seems to have raised the risk of tMDS/AML, which reflects use of the alkylating drug mitomycin.
Morton’s group estimated that in 2018 about 360,000 adults will be diagnosed with one of 23 solid tumors, will undergo initial chemotherapy, and will survive at least 1 year. Of these patients, they projected that three-quarters (73.0%) of the 714 anticipated cases of tMDS/AML occurring within 5 years of diagnosis will be attributable to chemotherapy, with others due to radiation therapy, and other factors.
The authors predicted that with the introduction of newer targeted therapies, the use of chemotherapeutics is likely to change again in the upcoming years, further affecting the rates of tMDS/AML.
In an editorial accompanying the study, Shyam Patel, MD, PhD, of the Stanford Cancer Institute in California, commented that the data on risk for tMDS/AML in younger patients “is the most intriguing and clinically relevant” and leads one to “speculate that the diagnosis and treatment of a solid tumor at an early age permits a longer latency period during which clonal evolution can occur in a previously damaged bone marrow compartment.” He also noted that the risk continues in patients with long-term survival.
Patel explained that the increased risk due to “DNA damage to the hematologic system induced by chemotherapeutics remains throughout life; the surviving myeloid progenitors exposed to chemotherapy for solid tumors early in life can lead to mutations in clonal hematopoiesis, a phenomenon that increases with age.”
But he predicted that follow-up studies may reveal a relative decrease in the risk for tMDS/AML “given the recent acceleration of regulatory agency approvals of novel anticancer therapies whose clinical activity is defined by specific molecular aberrations in contrast with approval of new applications of the same cytotoxic chemotherapies.”
Patel also posited several reasons for the lack of risk associated with colon cancer, including diagnosis at later age and therefore “subclinical clonal hematopoiesis induced by chemotherapy may not have ample time to evolve into frank disease” (i.e., these older patients may first die from their primary cancer). Another possible reason is the use of third-generation platinum drugs like oxaliplatin in this cancer, which are less myelotoxic than other platinum agents.
He cited concerns about risks related to the use of newer drugs, poly (ADP-ribose) polymerase (PARP) inhibitors, which also raise risk of tMDS/AML by 0.5% to 2%, and highlighted the need to stratify patients treated with these drugs. Patel also emphasized that another subgroup of patients, those treated for early-stage breast cancer, may also be at particular risk for tMDS/AML, as they are expected to survive for decades.
Patel suggested four criteria for appropriate risk stratification of patients receiving chemotherapy for solid tumors: the probability of a chemotherapeutic agent inducing a disease-initiating event, likelihood that pathogenic events will occur at a later time, the benefit gained with respect to solid tumor regression, and the consequences of forgoing chemotherapy.
“Because patients who receive chemotherapy for solid tumors are expected to live longer, the incidence of treatment-related myeloid neoplasms is likely to increase, pending the further availability of non-DNA-damaging agents such as targeted therapy,” Patel wrote. “For these reasons, a holistic approach to risk assessment should be undertaken.”
Leah Lawrence wrote the original story for MedPage Today.