Second Malignancy after Treatment of Hodgkin’s Disease: The Influence of Treatment, Age, and Follow-up Time 

Abstract & Commentary 

Source: Abrahamsen A, et al. Ann Oncol. 2002;13:1786-1791. Synopsis: Combination chemotherapy and extensive radiotherapy introduced in the late 1960s greatly improved survival rates in Hodgkin’s disease (HD), but increased risk of second cancer was recognized from the early 1970s.1 An increased incidence of acute nonlymphocytic leukemia (ANLL) in patients treated with chemotherapy alone or combined radiation therapy and chemotherapy, and solid tumors in those treated with radiation therapy or combined radiation therapy and chemotherapy, have consistently been reported. The development of secondary non-Hodgkin’s lymphoma (NHL) has been reported following both radiation therapy and chemotherapy, which it has been claimed is not necessarily treatment related, but may be part of the natural history of HD. Increased risk of ANLL and NHL has been found up to 10 years after treatment. In contrast, second cancers increase steadily with time up to 20 years after treatment. It is not clear whether the increased risk of second cancers observed in the 10-20 years follow-up interval will continue to increase further with more prolonged follow-up, or level off or decrease at some point of time after > 20 years follow-up. In a recent study, HD patients treated during adolescence or young adulthood still had an increased risk of second cancer even > 20 years after first treatment.2-4

In this study, a follow-up of an adult patient population up to 30 years after initial treatment was presented. In the period 1968 to 1985, an unselected population of 1024 patients started treatment for HD at the Norwegian Radium Hospital and were followed for second cancer from 1969 through 1998 by the Norwegian Cancer Registry. The median age at diagnosis of HD was 40 years, and the median time at follow-up was 14 years.

There were 197 second cancers. Fourteen were ANLL, 31 NHL, and 152 solid tumors. The standardized incidence ratio (SIR) was significantly increased for second cancers as a group, and for the subgroups ANLL, NHL, lung cancer, breast cancer, stomach cancer, and melanoma. ANLL was related to heavy treatment with chemotherapy and combined chemotherapy and radiotherapy, NHL was not treatment related as there was an equal distribution among all treatment modalities, and solid tumors were related to radiotherapy only or combined modality therapy. The SIR of ANLL and NHL reached a peak between 5 and 10 years after treatment. Solid and nonsolid tumors increased with young age at diagnosis of HD and solid tumors increased with follow-up time up to 28 years. Their conclusion was that in this long-term follow-up study of HD patients of all ages, the SIR of solid tumors was high in patients treated at young age and decreased with increasing age at the time of treatment. Most solid tumors had started within or at the edge of the irradiated field, and SIR of solid tumors increased even 20-30 years after diagnosis.

Comment by Stuart M. Lichtman, MD, FACP

In addition there have been 2 recent papers addressing the same issue. Delwail and colleagues address the risk of secondary leukemia in patients treated by MOPP (mechlorethamine, vincristine, prednisone, procarbazine) or ABVD (adriamycin, bleomycin, vinblastine, DTIC) chemotherapy.5 Between 1972 and 1988, 869 adult patients received MOPP (mechlorethamine, vincristine, procarbazine and prednisone; 462 patients) or ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine; 373 patients) and subsequent high-dose irradiation for HD. Nine patients developed a leukemia after MOPP and 4 after ABVD; 11 patients were diagnosed as ANLL and 2 as acute lymphoblastic leukemia (ALL). Both cases of ALL were observed after ABVD and were associated with an 11q23 translocation. The 15-year actuarial risk of secondary leukemia was 2.4% for the whole group of patients, 3.4% after MOPP, and 1.3% after ABVD. For the MOPP subgroup, the risk of leukemia was significantly associated with the extent of irradiation: 2.4% for limited irradiation and 13.9% for extended irradiation (P < 0.001). For the ABVD subgroup, this risk remained low (1.3%) whatever the type of irradiation. Concerning ANLL, the MOPP regimen was significantly associated with a higher risk: 3.4% vs 0.7% for ABVD (P < 0.05). The 15-year risk of ALL was 0.6 after ABVD regimen. This study demonstrated that ABVD induced less ANLL than MOPP. However, a low risk of ALL with an 11q23 translocation related to topoisomerase II inhibitors was observed.

Ng and associates analyzed 1319 patients with clinical stage I-IV Hodgkin disease.6 Of these, 181 second malignancies and 18 third malignancies were observed. With a median follow-up of 12 years, the relative risk (RR) and absolute excess risk of second malignancy were 4.6 and 89.3/10,000 person-years. The RR was significantly higher with combined chemotherapy and radiation therapy than with radiation therapy alone. The risk increased with increasing radiation field size in patients who received combined modality therapy, and with time after HD. After 15 and 20 years, there was a 2.3% and 4.0% excess risk of second malignancy per person per year. The 5-year survival after development of a second malignancy was 38.1%, with the worst prognosis seen after acute leukemia and lung cancer. The excess risk of second malignancy after HD continues to be increased after 15-20 years, and there does not appear to be a plateau.

These 3 studies confirmed the excess risk of second malignancies in patients with HD. This is true for both solid tumors and hematologic malignancies. The risk seems to be extremely long and may never diminish throughout the patients’ life. It is clear that while our first priority is the cure of HD treatment planning must take into account the potential for the development of secondary malignancy. All of these studies suggest that the risks may be reduced with smaller radiation field sizes and abbreviated chemotherapy. The need for combined modality therapy should be carefully considered in light of these studies. 

Dr. Lichtman is Associate Professor of Medicine, NYU School of Medicine Division of Oncology; Don Monti Division of Medical Oncology North Shore University Hospital, Manhasset, NY.

References

1. Canellos GP, et al. Lancet. 1975;1:947-949.

2. Swerdlow AJ, et al. J Clin Oncol. 2000;18:498-509.

3. van Leeuwen FE, et al. J Clin Oncol. 2000;18:487-497.

4. Green DM, et al. J Clin Oncol. 2000;18:1492-1499.

5. Delwail V, et al. Br J Haematol. 2002;118:189-194.

6. Ng AK, et al. Blood. 2002;100:1989-1999.