Annals of Oncology 17: 17271729, 2006
editorial
The impact of treatment on the risk of
second malignancy after Hodgkins
disease
In the last several decades, there has been a steady improvement
in the cure rate of patients diagnosed with Hodgkins disease as
more effective treatment and more accurate staging techniques
become available [1]. With the growing number of patients
surviving Hodgkins disease, various delayed complications are
being increasingly recognized. Second malignancy after
Hodgkins disease, first reported in the early 1970s [2], is one
of the most serious late effects and is the leading cause of death
in long-term survivors of Hodgkins disease [3, 4]. The elevated
risk has largely been attributed to leukemogenic or carcinogenic
effects of the treatments for Hodgkins disease. There are likely
other contributing factors, however, including an impaired
immune system related to treatments or the disease itself and
genetic susceptibility in some of the patients.
The identification of risk factors for the development of
second malignancy after Hodgkins disease can be helpful in
guiding practice. For patients with risk factors that are
modifiable (e.g. tobacco use, sun exposure, dietary habits),
counseling and behavioral modification both at the time of
Hodgkins disease diagnosis and during follow-up can serve to
lower the risk. Patients with risk factors that cannot be modified
(e.g. gender, young age at treatment, family history) can be
targeted for more vigilant follow-up and perhaps more intensive
cancer screening. Treatment-related risk factors can fall into
either of these two categories. They are modifiable in patients
with newly diagnosed Hodgkins disease, and data on the
contribution of the various treatment exposures to the risk of
second malignancy have motivated clinical investigators to
design trials that aim at reducing or eliminating specific
treatments. For survivors who have already completed therapy,
with known exposure to high-risk treatments, they may be
candidates for more rigorous follow-up and screening programs.
Understanding treatment-related risk factors for second
malignancy risk after Hodgkins disease is therefore crucial as it
can have management implications in both newly diagnosed
Hodgkins disease patients and in survivors of the disease.
The majority of studies analyzing second malignancy risk after
Hodgkins disease and the associated risk factors are in the
form of retrospective cohort or casecontrol studies [513]. In
evaluating second malignancy risk with respect to treatment
exposure, the main limitation of a retrospective study design is
the varying follow-up time of the different treatments as
therapeutic approaches for Hodgkins disease evolve over time.
This is especially problematic when evaluating solid tumor risk,
which typically arises after a long latency. Prospective randomized
2006 European Society for Medical Oncology
doi:10.1093/annonc/mdl433
trials provide an ideal setting to evaluate treatment-related risk
factors for developing second malignancies. In addition to similar
length of follow-up time between the treatment arms, the patient
and disease characteristics should also be evenly distributed. A
number of prospective randomized trials on Hodgkins disease
editorial
have reported on cases of second malignancies after treatment
[1420]. In trials with shorter follow-up time and in which
alkylating agent-based chemotherapy was used, the data were
mostly on leukemia risk, but in trials with longer follow-up time,
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solid tumor data are emerging. Because of the small number
of events within each individual trial, however, the available
information is largely descriptive in nature.
In the article by Franklin et al. [21] in this issue of Annals
of Oncology, the investigators collected information from
randomized trials on Hodgkins disease, selected on the basis of
the availability of individual patient information, and carried
out a meta-analysis to compare the second malignancy risks
after different treatment modalities. Meta-analysis as a research
tool improves the power to detect differences in treatment
outcome, but operates under a number of important
assumptions, such as the inclusion of all relevant research
studies, both published and unpublished, and the inclusion of
studies of comparable quality with the study quality being
weighed in the computation [22, 23]. The analysis should also
be on the basis of the studies with similar treatment arms and
relatively homogeneous patient populations. These issues need to
be taken into consideration when interpreting the results and
in judging the reliability of the conclusions of a meta-analysis.
In the meta-analysis conducted by Franklin et al. [21], when
results of trials that compared radiation therapy alone versus
combined modality therapy were considered, the latter approach
was found to be associated with a lower risk of second
malignancy. The authors attributed this finding to the cumulative
effect of salvage therapy in patients who relapsed after radiation
therapy alone. Another potential explanation is that the
radiation therapy alone arms in 13 of the 15 trials used extended-
field or total nodal irradiation, whereas about half of the
patients were treated with a more limited radiation field in the
combined modality therapy arms of the included trials, and the
differences in radiation field size could have contributed to
the difference. The authors also reviewed trials that compared
chemotherapy alone versus combined modality therapy, and the
addition of radiation therapy was found to be associated with
an increased second malignancy risk. While this is not
a surprising finding, the results need to be viewed in the context
that the majority of the trials included in the analysis were on
advanced-stage patients, in whom a more extensive radiation
treatment field would have been used, and that over half of the
trials mandated use of subtotal or total nodal irradiation in the
editorial
combined modality therapy arms. Radiation therapy alone versus
chemotherapy alone was also compared, although it was on the
basis of the results of only three trials. The use of chemotherapy
alone was found to be associated with a higher second malignancy
risk compared with radiation therapy. This finding may be
driven by the leukemia and/or lung cancer risk with the use of
alkylating agent-based chemotherapy. As in combining trials with
different radiation fields, it is difficult to draw conclusions with
the grouping together of trials that used different chemotherapy
regimens, given that different chemotherapeutic agents can
have different leukemogenic or carcinogenic potentials. Perhaps,
the most relevant comparison in this study is that of involved-
field versus extended-field radiation therapy. The current
standard in combined modality therapy uses involved-field
radiation therapy, but there is a paucity of reliable documentation
of lower risk of late effects with the use of smaller radiation fields.
Although the authors were not able to show a lower second
malignancy risk with limited-field radiation therapy, it should
be noted that 85% of the patients included in the analysis
were from trials conducted in the 1990s, and the follow-up
is likely too short to see differences, especially with respect to
solid tumor risks.
Despite the inherent limitations associated with meta-
analysis, which have been acknowledged in detail in the article,
this international collaborative effort of combining randomized
trial results is a remarkable accomplishment, and leads the
way of using this research tool to specifically assess second
malignancy risk in relation to treatment exposure. Currently,
there are a number of ongoing or recently completed
randomized trials on Hodgkins disease, with the focus being on
treatment reduction in patients with early-stage, favorable
prognosis Hodgkins disease, while the role of more aggressive
chemotherapy regimen is being addressed in patients with
unfavorable prognosis and/or advanced-stage disease. The
increasing movement towards treatment reduction among
patients with early-stage disease may come at the expense of
a higher relapse rate, with one prime example being the use of
chemotherapy alone [19, 24, 25]. As emphasized by the
authors, continued data collection after relapses is crucial in
order to capture the contribution of additional salvage therapy,
which may involve high-dose therapy, to the overall second
malignancy risk. For patients with unfavorable prognosis and/or
advanced-stage disease, the foremost goal is improving the
Hodgkins disease cure rate. The late toxicity profile of the
newer and more intensive chemotherapy regimen needs to
be carefully documented as more of these patients become
successfully cured [15, 26]. The availability of mature results
of modern trials in the future may allow us to evaluate
more in-depth questions, such as the effect of lower doses
of radiation, more limited radiation fields such as involved-
node fields, individual types of chemotherapy and
chemotherapy dose on risks of specific types of second
malignancies.
A. K. Ng & P. M. Mauch*
Department of Radiation Oncology, Brigham and Womens
Hospital and Dana-Farber Cancer Institute,
Harvard Medical School, Boston, MA, USA
(*E-mail: pmauch@lroc.harvard.edu)
1728 | Ng & Mauch
Annals of Oncology
references
1. Ries L, Harkins D, Krapcho M et al. SEER Cancer Statistics Review, 19752003.
Bethesda, MD: National Cancer Institute. http://seer.cancer.gov/csr/1975_2003/.
(November 2005, date last accessed).
2. Arseneau JC, Sponzo RW, Levin DL et al. Nonlymphomatous malignant tumors
complicating Hodgkins disease. Possible association with intensive therapy.
N Engl J Med 1972; 287: 11191122.
3. Ng AK, Bernardo MP, Weller E et al. Long-term survival and competing causes of
death in patients with early-stage Hodgkins disease treated at age 50 or
younger. J Clin Oncol 2002; 20: 21012108.
4. Aleman BM, van den Belt-Dusebout AW, Klokman WJ et al. Long-term
cause-specific mortality of patients treated for Hodgkins disease. J Clin
Oncol 2003; 21: 34313439.
5. Biti G, Cellai E, Magrini SM et al. Second solid tumors and leukemia after
treatment for Hodgkins disease: an analysis of 1121 patients from a single
institution. Int J Radiat Oncol Biol Phys 1994; 29: 2531.
6. Cellai E, Magrini SM, Masala G et al. The risk of second malignant tumors and its
consequences for the overall survival of Hodgkins disease patients and for the
choice of their treatment at presentation: analysis of a series of 1524 cases
consecutively treated at the Florence University Hospital. Int J Radiat Oncol Biol
Downloaded from http://annonc.oxfordjournals.org/ by guest on December 11, 2016
Phys 2001; 49: 13271337.
7. Henry-Amar M. Second cancer after the treatment for Hodgkins disease:
a report from the International Database on Hodgkins disease. Ann Oncol 1992;
3 (Suppl 4): 117128.
8. Ng AK, Bernardo MV, Weller E et al. Second malignancy after Hodgkin disease
treated with radiation therapy with or without chemotherapy: long-term risks and
risk factors. Blood 2002; 100: 19891996.
9. Swerdlow AJ, Barber JA, Hudson GV et al. Risk of second malignancy after
Hodgkins disease in a collaborative British cohort: the relation to age at
treatment. J Clin Oncol 2000; 18: 498509.
10. van Leeuwen FE, Klokman WJ, Veer MB et al. Long-term risk of second
malignancy in survivors of Hodgkins disease treated during adolescence or
young adulthood. J Clin Oncol 2000; 18: 487497.
11. Travis LB, Gospodarowicz M, Curtis RE et al. Lung cancer following chemotherapy
and radiotherapy for Hodgkins disease. J Natl Cancer Inst 2002; 94: 182192.
12. Travis LB, Hill DA, Dores GM et al. Breast cancer following radiotherapy and
chemotherapy among young women with Hodgkin disease. JAMA 2003; 290:
465475.
13. van Leeuwen FE, Klokman WJ, Stovall M et al. Roles of radiation dose,
chemotherapy, and hormonal factors in breast cancer following Hodgkins
disease. J Natl Cancer Inst 2003; 95: 971980.
14. Duggan DB, Petroni GR, Johnson JL et al. Randomized comparison of ABVD and
MOPP/ABV hybrid for the treatment of advanced Hodgkins disease: report of an
intergroup trial. J Clin Oncol 2003; 21: 607614.
15. Diehl V, Franklin J, Pfreundschuh M et al. Standard and increased-dose
BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkins
disease. N Engl J Med 2003; 348: 23862395.
16. Aleman BM, Raemaekers JM, Tirelli U et al. Involved-field radiotherapy for
advanced Hodgkins lymphoma. N Engl J Med 2003; 348: 23962406.
17. Bonadonna G, Bonfante V, Viviani S et al. ABVD plus subtotal nodal versus
involved-field radiotherapy in early-stage Hodgkins disease: long-term results.
J Clin Oncol 2004; 22: 28352841.
18. Straus DJ, Portlock CS, Qin J et al. Results of a prospective randomized clinical
trial of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by
radiation therapy (RT) versus ABVD alone for stages I, II, and IIIA nonbulky
Hodgkin disease. Blood 2004; 104: 34833489.
19. Meyer RM, Gospodarowicz MK, Connors JM et al. Randomized comparison
of ABVD chemotherapy with a strategy that includes radiation therapy in
patients with limited-stage Hodgkins lymphoma: National Cancer Institute
of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group.
J Clin Oncol 2005; 23: 46344642.
20. Noordijk EM, Carde P, Dupouy N et al. Combined-modality therapy for clinical
stage I or II Hodgkins lymphoma: long-term results of the European Organisation
for Research and Treatment of Cancer H7 randomized controlled trials.
J Clin Oncol 2006; 24: 31283135.
Volume 17 | No. 12 | December 2006
Annals of Oncology
21. Franklin J, Pluetschow A, Paus M et al. Second malignancy risk associated with
treatment for Hodgkin lymphoma: meta-analysis of the randomised trials. Ann
Oncol 2006; 17: 17491760.
22. Egger M, Smith GD, Sterne JA. Uses and abuses of meta-analysis. Clin Med
2001; 1: 478484.
23. Mullen PD, Ramirez G. The promise and pitfalls of systematic reviews. Annu Rev
Public Health 2006; 27: 81102.
24. Nachman JB, Sposto R, Herzog P et al. Randomized comparison of low-dose
involved-field radiotherapy and no radiotherapy for children with Hodgkins
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disease who achieve a complete response to chemotherapy. J Clin Oncol 2002;
20: 37653771.
25. Laskar S, Gupta T, Vimal S et al. Consolidation radiation after complete
remission in Hodgkins disease following six cycles of doxorubicin, bleomycin,
vinblastine, and dacarbazine chemotherapy: is there a need? J Clin Oncol 2004;
22: 6268.
26. Horning SJ, Hoppe RT, Breslin S et al. Stanford V and radiotherapy for locally
extensive and advanced Hodgkins disease: mature results of a prospective
clinical trial. J Clin Oncol 2002; 20: 630637.
Downloaded from http://annonc.oxfordjournals.org/ by guest on December 11, 2016
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