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When Quality of Life Is the Major Challenge

Institut Gustave-Roussy, Villejuif Cedex, France

IN THIS ISSUE OF the Journal of Clinical Oncology, Donaldson et al¹ describe treatment results obtained with a novel chemotherapy combination, vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) plus radiotherapy for children with early-stage I and II Hodgkin’s disease with favorable characteristics. After two cycles of chemotherapy, complete responders received 15 Gy and partial responders received 25.5 Gy of radiotherapy. Results were excellent, with 5-year overall and event-free survival rates as high as 99% and 93%, respectively.¹

Over the last four decades, cures rates in pediatric Hodgkin’s disease have improved considerably as a result of effective combination chemotherapy, innovative technologies in radiation therapy, and a better appreciation of treatment-related sequelae. This has led to highly complex, treatment decision-making in early-stage Hodgkin’s disease. Pediatric oncologists are faced both with a constant struggle between using highly effective treatments, that are clearly beneficial from a clinical point of view, and misgivings about their impact on the young patient’s quality of life.

This is the first study reported by these investigators in which the enrollment of patients was exclusively based on clinical staging, supporting that surgical staging with splenectomy is no longer indicated. The systematic use of chemotherapy, the widespread use of high-quality imaging and the complications after surgery and splenectomy prompted all the European groups to shift to clinical staging either progressively from 1982 to 1995 in Germany^2-4 or virtually overnight in 1975 in France.⁵ We have come far from the assumption by Donaldson⁶ in 1991 that, "The clinician must make a choice: aggressively stage or aggressively treat. Anything less must be regarded as investigational and/or a nonconventional approach."

Very early on, localized nodal disease (stage IA to IIIA) was associated with excellent outcomes, and with high-dose (40 to 46 Gy) extended-field radiation therapy, survival rates could easily exceed 90%. The well-known radiation-related adverse effects in children, particularly relative to soft-tissue and bone growth, led to the introduction of combination chemotherapy, first to decrease the radiation fields⁵ and then the radiation doses. Two North American teams pioneered therapy with low-dose radiation.^7,8 The good results of such a strategy were confirmed by large European studies,^9,10 and it is now widely accepted that after a good response to chemotherapy, the radiation dose can be limited to 25 Gy or less, whatever the stage.

Several trials have demonstrated the efficacy of chemotherapy alone for children with Hodgkin’s disease. Six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) are effective but cannot be recommended because of potential long-term cardiac and pulmonary toxicity, because this drug combination uses high cumulative doses of doxorubicin (300 mg/m²) and of bleomycin (120 mg/m²).¹¹ The same applies to the regimens used in the United Kingdom Children’s Cancer Study Group trial, in which six to 10 cycles of chlorambucil, vinblastine, procarbazine, and prednisone (ChlVPP) were administered,¹² or in the Australian trial, in which four to 12 courses of ChlVPP or mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) were administered.¹³ The probability of infertility is high, at least for boys, after treatment with high doses of alkylating agents, and there is also a significant risk of second malignant neoplasms. The second Australian trial used a chemotherapy-only regimen using five to six courses of vincristine, etoposide, epirubicin, and prednisolone (VEEP). They concluded that this regimen yielded an unacceptably high 35% treatment failure rate in stage I disease.¹⁴

Radiation therapy alone was the option chosen by the United Kingdom Children’s Cancer Study Group to treat selected patients with stage IA disease. They delivered 35 Gy to the involved field. The 10-year event-free survival for stage I disease was only 70%, but because of the high rate of cases salvaged after relapse, overall survival of these patients was 92%, lower than the 95% to 98% survival rates reported after combined treatment.¹² However, the burning question is whether 35 Gy of radiation therapy alone is superior to a surgical approach as it is currently considered by some teams, mainly for lymphocyte-predominant clinical stage IA Hodgkin’s disease. The risk of relapse, offset by the great likelihood of a high rate of salvage cases and the absence of late effects of surgery, must be weighed against the risk of a radiation-induced second cancer and thyroid dysfunction, especially because these very localized forms particularly plague very young children.

Combined-modality treatment protocols have yielded excellent treatment outcomes with the most favorable overall survival rate of 97% or more at 5 years.^1,15,16 For obvious reasons, these results cannot be improved further, so that the major challenge now is to design treatment strategies that strike an optimal balance between maximum efficacy and minimum late toxicity.

Several issues remain. The comparison of Donaldson’s figures with those of other published series should not lead the reader to conclude that the other protocols offered inferior therapy. Differences in eligibility criteria could account for the variability in the results, because this protocol was used to treat a very selected group of patients (clinical stage I and II, without bulky disease or B symptoms) and is, therefore, limited to only 34% of the whole cohort of children with Hodgkin’s disease.¹ The German study for early disease included 47% of the patients in the DAL-HD90 study¹⁶ and 39% in the following DAL-HD95 study¹⁷ with clinical stage I and II, whatever the bulk of the disease. Only patients with stage II disease and systemic symptoms were treated in the intermediate group. In the French study, all patients with clinical stage I and II disease were included in the vinblastine, bleomycin, etoposide, and prednisone (VBVP) protocol irrespective of systemic symptoms, tumor size, or bulk.¹⁵ This represents 60% of all the children treated for Hodgkin’s disease during the same period. All these studies have different eligibility criteria that may explain the very slight differences in outcomes between groups.

The successful therapy achieved when radiation fields were enlarged, with the advent of chemotherapy, and with the refinement of risk groups has eliminated a number of poor prognostic factors such as age, histologic subtype, mediastinal involvement, and number of involved sites. It is noteworthy that the impact of the histologic subtype on event-free survival has come back to haunt us, with the diminution of therapy. In series of patients treated with combined-modality therapy, nodular sclerosis Hodgkin’s disease seems to have an impact on event-free survival. In both Donaldson’s and the French study, the only subtype associated with increased relapses was the nodular sclerosis subtype.^1,15

Which is the best protocol among those used in other cooperative studies for early-stage favorable Hodgkin’s disease in childhood? Many drugs are effective in Hodgkin’s disease, but they all have their own long-term risks linked to the cumulative doses used, with the exception perhaps of vinca alkaloids such as vincristine or vinblastine. Alkylating agents such as procarbazine, mechlorethamine, and cyclophosphamide were the first drugs to be recognized for their efficacy in high-risk patients and for their adverse effects that lead to male sterility and leukemogenesis. Attempts have been made to avoid them or to reduce their cumulative doses in favorable stages. The cyclophosphamide, vincristine, procarbazine, and prednisone (COPP)/doxorubicin, bleomycin, and vinblastine (ABV) hybrid combination given in the Children’s Cancer Group trial contains a cumulative dose of 2.8 g/m² for procarbazine and of 2.4g/m² for cyclophosphamide.¹⁸ The German Austrian Pediatric Oncology Group (DAL/GPOH) made an effort to avoid procarbazine in boys, and the two cycles of vincristine, procarbazine, prednisone, and doxorubicin (OPPA) were replaced by two cycles of vincristine, etoposide, prednisone, and doxorubicin (OEPA) for boys in 1990.¹⁶ At the same time, the French Pediatric Group introduced a novel combination devoid of alkylating agents and anthracyclines and based on VBVP. Results published in an earlier issue of the Journal of Clinical Oncology did not appear to be different from those of other groups.¹⁵ However, since that time, the risk of leukemia has been reported: in the French study, the cumulative risk of acute leukemia was 0.8% at 5 years, although neither of the two leukemia cases observed had the 11q23 or 21q22 cytogenetic abnormalities reported in acute myeloid leukemia that are associated with topoisomerase II inhibitors.¹⁵

This raises the question of the cost-benefit effect of every new drug. Four cycles of the VAMP combination used by Donaldson et al or of ABVD contains 200 mg/m² of doxorubicin.¹ The GPOH uses two cycles of OPPA or OEPA containing 160 mg/m² of doxorubicin.¹⁶ There are data indicating that even these small doses of doxorubicin may have an adverse impact on cardiac function in the long-term.¹⁹ One should also bear in mind that half of the patients will also receive radiation to a mediastinal field, another risk factor for cardiac dysfunction. Doxorubicin also plays a role in the occurrence of second cancers, as shown by Green et al² who identified prior therapy with carmustine and doxorubicin as the only factors that were significantly associated with the risk of a second malignant tumor.³

From all these experiences, with similar excellent outcomes, it is difficult, but not impossible, to determine the protocol likely to have the least unfavorable impact on the patient’s quality of life. We need to focus on the study of undesirable late effects. All oncologists are dreaming of both effective and nontoxic new drugs, but the route is long.

ACKNOWLEDGMENTS

I thank Lorna Saint Ange for editing.

REFERENCES

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This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Oberlin, O. Search for Related Content PubMed PubMed Citation Articles by Oberlin, O. Social Bookmarking                            What's this?