As recent reports have documented, cancer survivors face significant challenges after finishing active treatment, from psychosocial issues to cardiac effects. One significant concern for survivors of a first primary cancer is the heightened risk of developing a second primary cancer. As treatments continue to improve and the number of people who have survived cancer approaches 10 million, unanswered questions loom about how many people might beat one cancer only to develop a second one.

"Second cancers can be viewed, in part, as a by-product of the success that we have had in treating primary cancers," says Dr. Lois B. Travis, a senior investigator in the NCI Division of Cancer Epidemiology and Genetics (DCEG), who has closely studied the issue.

The overall risk of developing a second cancer is small, Dr. Travis notes, but risk varies widely according to type of primary cancer and treatment modality. Nevertheless, there are some unsettling aspects of second cancers. First, many appear to be at least partly related to the treatment for the first cancer. Second, with several second cancers, the prognosis is often dim. With chemotherapy-induced leukemia, for example, the cure rate is only 10-20 percent. Survivors of a first primary cancer who develop chemotherapy-related acute myeloid leukemia generally have survival times of only a few months after diagnosis.

Both radiation therapy and chemotherapy at both low and high doses have been linked to second malignancies in patients with a variety of first primary cancers, including testicular cancer, ovarian cancer, and pediatric cancers. However, other factors, such as age at time of treatment, lifestyle habits after treatment (especially smoking), and environmental exposures appear to factor into the equation as well.

Genetics also can play a role. For example, children who survive a rare cancer called hereditary retinoblastoma have a much greater risk of developing osteosarcomas in the body field where they received radiation treatment, compared to children with nonhereditary retinoblastoma. Second cancers are of particular concern in children and adolescents who have more at-risk years to develop a second cancer than older survivors.

Dr. Travis and colleagues at NCI have conducted a number of studies - often relying on data collected through the NCI Surveillance, Epidemiology, and End Results (SEER) program - to better quantify the risk of second cancers in certain patient populations. In a large, international case-control study published last July in the Journal of the American Medical Association (JAMA), for example, they were able to correlate specific radiation doses in women under 30 treated for Hodgkin's lymphoma (HL) with an increased risk of developing breast cancer. Dr. Travis presented data from two NCI-led international studies at the recent American Society of Clinical Oncology meeting that linked factors - such as chemotherapy and radiation therapy doses, and smoking frequency - with increased risk of developing breast cancer and lung cancer after successful treatment for HL.

"The ultimate goal of our research is to decrease the 'price of the success' we have had in treating first primary cancers," Dr. Travis says. More clearly understanding the factors that increase the risk for second cancers, she explains, will help guide treatments and improve post-survival screening.

Anecdotally at least, oncologists appear to be paying attention to the research that has been done thus far. After reading the JAMA study, Dr. Sophie Fossa, an NCI visiting scientist, continued to follow her HL patients under the age of 40 who had been off treatment for 10 years or more, and encouraged them to come in for a mammography. Seventy-eight women were screened and two cases of breast cancer were detected.

The good news, says Dr. Joachim Yahalom, a radiation oncologist at Memorial Sloan-Kettering Cancer Center, is that treatment protocols have changed - dramatically in some instances - over the time during which the available data on second cancers were collected. Until the mid-1980s, for example, high-dose radiation was often used as a single, systemic treatment for HL. "Radiation is now being used more as an adjunct to less toxic and more effective chemotherapy regimens than we had in the past," he says, "and newer technologies, such as improved imaging devices and new radiation techniques, are allowing oncologists to more precisely target the radiation, exposing less normal tissue to potentially harmful radiation."

In addition, recent studies have shown that equally good results can be achieved in HL patients with lower doses of radiation. "As studies like Dr. Travis' have shown, the risk relates to the dose," Dr. Yahalom says. "And when you drop down to 20 Gy from 40 Gy or even from 30 Gy, you have significantly lower risk.

"Based on SEER data from 1973-2000, a monograph describing the risk of second cancers for each major cancer site is expected to be available in 2005. The monograph is a joint effort of NCI's DCEG and Division of Cancer Control and Population Sciences.