Chemotherapy dose threshold below which male childhood cancer
survivors are likely to have normal sperm production has been discovered by St.
Jude Children's Research Hospital investigators. The study appears in September 17 edition of the
journal Lancet Oncology.
study involved drugs called alkylating agents that are widely used to treat a
variety of pediatric cancers. Unlike other chemotherapy, alkylating agents are
known to damage sperm production. Until this study, however, there was scant
information about the risk associated with different cumulative exposures.
"Fertility preservation is important to patients and families,
which is why at St. Jude we provide fertility counseling and preservation for
active patients," said the study's first and corresponding author Daniel Green, M.D., a
member of the St. Jude Department of Epidemiology and Cancer Control.
"Until now, however, there was little information to guide clinicians,
families and patients trying to assess the risk alkylating agents will pose to
sperm production years in the future."
The U.S. is home to at least 328,000 cancer survivors who were age 20
or younger when their cancer was diagnosed. With overall childhood cancer
survival rates in the U.S. now approaching 80 percent, that number is expected
The study involved 214 men whose childhood cancer treatment at St.
Jude included cyclophosphamide and other alkylating agents. Their treatment did
not include radiation therapy, which may also impair fertility. On average, the
survivors were almost 30 years old and almost 22 years from their diagnosis
when their semen analysis was done. All were enrolled in the St. Jude Lifetime
Cohort (LIFE) study, which brings childhood cancer survivors treated at St.
Jude back to the hospital for several days of health screenings and other
tests. St. Jude LIFE participants must be at least 18 years old and 10 years
The analysis found that 47.6 percent of survivors had normal sperm
concentrations of at least 15 million per milliliter, 27.6 percent had low
sperm counts and 24.8 percent produced no sperm. In the general public, less
than 3 percent of men do not produce sperm.
To track the impact of different alkylating agents on sperm production
in survivors, St. Jude researchers developed a formula to calculate each
survivor's cumulative treatment exposure to alkylating agents as a
cyclophosphamide equivalent dose (CED). The method allowed investigators for
the first time to compare how cumulative exposure to this class of drugs
affected sperm production.
Researchers identified no uniformly safe or toxic dose of the drugs,
but reported that survivor sperm concentrations generally decreased as
cumulative exposure to alkylating agents increased. CEDs of 4 grams per meter2
) or less were associated with normal sperm concentrations.
Almost 89 percent of survivors whose CED was 4 g/m2
or less had a
normal sperm count. Their sperm were also more likely than sperm from other
survivors to look and move normally.
"Based on these results, we would recommend pre-treatment
fertility preservation be offered, whenever clinically possible, to any male
whose projected treatment is expected to include a cyclophosphamide equivalent
dose greater than 4 g/m2
," Green said.
While a lower cumulative dose of alkylating agents was associated with
normal sperm production, Green said outcomes for individual patients were
unpredictable and varied.
The quest to develop safer, more effective treatments continues, since
lower doses of alkylating agents are not an option for many patients,
particularly those with rhabdomyosarcoma, Ewing sarcoma, medulloblastoma and
other sold tumors.
Researchers are also trying to identify other factors that might
impact fertility following treatment with alkylating agents, including inherited
variations in genes.
The other study authors are Wei Liu, Kyla
Shelton, Wassim Chemaitilly, Ching-Hon Pui, James Klosky, Monika Metzger, DeoKumar Srivastava, Kirsten Ness, Leslie Robison and Melissa Hudson, all of St. Jude; Sheri Spunt, formerly of St. Jude and now of Stanford University School
of Medicine; William Kutteh
and Raymond Ke,
both of Fertility Associates of Memphis;
and Charles Sklar,
of the Memorial Sloan Kettering Cancer Center.
The study was funded in part by a grant (CA21765) from the National
Cancer Institute at the National Institutes of Health and ALSAC.