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Does Total-Body Irradiation Technique Influence Veno-Occlusive Disease Incidence?

Centre Hospitalier Universitaire Vaudois Lausanne, Switzerland

To the Editor:I read with interest the recent article by Girinsky et al¹ in the March issue of the Journal of Clinical Oncology. In this prospective randomized study, the authors compared single-dose total-body irradiation (STBI) to hyperfractionated total-body irradiation (HTBI) in 161 patients with various hematologic malignancies treated with either allogeneic or autologous bone marrow transplantation (BMT) conditioned with TBI and high-dose chemotherapy. They concluded that HTBI is probably more efficient than STBI, and both regimens induce similar toxicity, with the exception of veno-occlusive disease (VOD), which was significantly more pronounced in the STBI group.

I do not agree with their conclusion for two reasons. First, they analyzed the probability of VOD using the Kaplan-Meier product-limit estimates method² and compared the curves using the log-rank test.³ Such survival analysis methods were developed to analyze overall survival data; these methods demand results from a clinical trial before all patients have experienced treatment failure, so early analyses can be performed with incomplete follow-up information. Patients who are still being followed-up and are without treatment failure at the time of the analysis are considered censored. VOD of the liver is an early, life-threatening syndrome that is directly caused by the conditioning regimen, which usually includes a combination of TBI and high-dose chemotherapy. VOD is observed during the first 3 months after BMT and rarely occurs after this period. It is responsible for 5% to 10% of deaths in patients undergoing BMT who receive conditioning treatment with high-dose chemotherapy and TBI.⁴ The authors reported an estimated 5-month VOD incidence of 14% in the STBI group compared with 4% in the HTBI group (P = .04) by censoring the patients who did not develop VOD, with an overall median follow-up period of 8 years (range, 34 to 138 months).¹ The crude VOD incidences are not given in the article, but when counting the events in Fig 4, 10 cases of VOD of 73 patients in the STBI group and three cases of 71 patients in the HTBI group were found. When analyzing the data simply by comparing the proportions using the ² test, which should be the appropriate statistical approach, a P value of .08 is obtained. Thus, in this prospective randomized study, there is no statistically significant difference in terms of VOD between the two arms of randomization.

The second point is that even if we accept a trend between the STBI and HTBI groups, all STBI regimens should not be accused. In this study,¹ the instantaneous dose rate was .125 Gy/min in the STBI group, which is relatively high compared with those rates of the centers using STBI. In the current practice, most of the centers keep the instantaneous dose rate in the STBI setting at less than .06 Gy/min. In a randomized study comparing two instantaneous dose rates both in STBI and fractionated TBI, Ozsahin et al⁵ found that STBI with an instantaneous dose rate of .15 Gy/min was more toxic than STBI with .06 Gy/min, the toxicity of which was not different from that of HTBI. Belkacémi et al,⁶ in their retrospective study including 305 patients, clearly demonstrated that the VOD incidence was not influenced by the TBI technique, but a strong correlation was found between VOD and the type of conditioning chemotherapy.

REFERENCES

1. Girinsky T, Benhamou E, Bourhis JH, et al: Prospective randomized comparison of single-dose versus hyperfractionated total-body irradiation in patients with hematologic malignancies. J Clin Oncol 18:981–986, 2000[Abstract/Free Full Text]

2. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1957

3. Peto P, Pike MC, Armitage P, et al: Design and analysis of randomized clinical trials requiring prolonged observation of each patient: Part II. Br J Cancer 35:1–39, 1977[Medline]

4. McDonald GB, Sharma P, Matthews DE, et al: Venoocclusive disease of the liver after bone marrow transplantation: Diagnosis, incidence and predisposing factors. Hepatology 4:116–122, 1984[Medline]

5. Ozsahin M, Pène F, Touboul E, et al: Total-body irradiation before bone marrow transplantation: Results of two randomized instantaneous dose rates in 157 patients. Cancer 69:2853–2865, 1992[Medline]

6. Belkacémi Y, Ozsahin M, Rio B, et al: Is veno-occlusive disease incidence influenced by the total-body irradiation technique? Strahlenther Onkol 171:694–697, 1995[Medline]

Response

Institut Gustave Roussy Villejuif, France

In Reply:The statistical method used in our study¹ allowed us to take into account the fact that 39 patients died of causes other than veno-occlusive disease (VOD) of the liver during the first 5 months after randomization. These patients were therefore censored for VOD criteria. Although our study dose rate was perhaps higher than those used elsewhere, we believe that the fractionated total-body irradiation schedule was more likely responsible for the high incidence of VOD. Indeed, the incidence of VOD was significantly higher among patients given single-dose total-body irradiation (STBI) at a dose of 0.125 Gy/min over 4 hours (average dose rate of only 0.045 Gy/min) compared with that of patients given hyperfractionated total-body irradiation with a two-fold larger dose rate (0.250 Gy/min). Dr Ozsahin seems to corroborate this view, because he showed in his study comparing two instantaneous dose rates (0.060 Gy/min and 0.150 Gy/min) in 28 and 29 patients, respectively, who were given STBI that there were no significant differences in the incidence of VOD: three patients in the low–dose rate group and no patients in the high–dose rate group developed VOD. We agree that chemotherapy possibly plays a role in the development of VOD, but in our randomized and not retrospective study, patients were given the same conditioning regimen in both groups, and the incidence of VOD was significantly higher in the STBI group.

REFERENCES

1. Girinsky T, Benhamou E, Bourhis JH, et al: Prospective randomized comparison of single-dose versus hyperfractionated total-body irradiation in patients with hematologic malignancies. J Clin Oncol 18:981–986, 2000

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