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In Reply

Institute Gustave Roussy, Villejuif, France

In Reply:

Johnson et al are concerned that the United Kingdom Lymphoma Group (UK LY09) study,¹ was incorrectly described as a three-arm randomized trial.² They reported that "multidrug regimens (MDRs) against standard ABVD ... designed with a common control arm, ABVD."¹ At least an indirect comparison has been made between ABVD and MDRs throughout the article (see text, Figs 2 and 3, and Tables 5 and 6). However, we agree that the editorial sentence "unbalanced randomized trial of ABVD versus MDRs" could have been "...versus 1 of 2 MDRs." Still, our editorial refers to "...ABVD, in the double-randomization strata of the LY09 trial, did not provide the same results." The figure and explicit legend illustrated the effective dose calculations "...within randomized comparisons" and "Red dots, IIL study; blue squares, ABVD v ChlVPP/PABlOE comparison within the UK LY study; green diamonds ABVD v ChlVPP/EVA comparison within the UK LY study." It would be hard to be more specific.

Johnson et al remarks that no direct comparison of the two multidrug arms can be made, which is correct, because this was not done. But what a pity, that the LY09 study with 807 patients, did not do it. The trial by Gobbi et al,³ indicated trends between three regimens based on half of the patients.

When compared with hybrid chlorambucil, vinblastine, procarbazine, prednisone, etoposide, vincristine, and doxorubicin (ChlVPP/EVA), doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) were more often followed by radiotherapy than with ABVD consolidation: results were inferior to ABVD in the other randomized arms. Investigators themselves did this "spontaneous, illegitimate comparison" and we agree that, because of subtle differences in patient distribution, conclusions should be drawn cautiously.

The LY09 study prompts the three key questions concerning radiation in advanced Hodgkin’s lymphoma patients, in view of late effects observed in earlier stages.⁴ In complete response after six cycles, which is the best consolidation: radiation or chemotherapy? Obviously not radiation because there was no difference in the randomized German HD-3⁵ and Groupe d'Etude des Lymphomes de l'Adulte (GELA) H89 trials.⁶ In complete response patients, is adjuvant radiotherapy (versus nothing) of any use? Confirming earlier results,⁷ the randomized European Organisation for Research and Treatment of Cancer trial answer to that question is no.⁸ In patients who reached only partial response after six cycles, does radiotherapy reverse the odds? No randomized study is available, and the results have been yes in the EORTC experience⁸ and no in the German and French experiences.^5,6

Regarding chemotherapy, we remark that the LY09 study concurs to the demonstration, made since 1975, that ABVD provides results superior to those of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and its avatars.⁹ We agree that, in the Hasenclever model, freedom from progression would better be correlated to actual, rather than to intended doses. In the LY09 trial, as approximately all drugs were administered at greater than 80% of intended dose (Table 3), the correlation between actual or intended dosing is probably close and could be checked.

Finally, Johnson et al produced extremely valuable data, particularly on individual drug doses, with thorough analyzes. These data will contribute to designing improved trials where chemotherapy and radiation will be balanced according to the respective parts they take to cure Hodgkin’s lymphoma in each different setting.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Johnson WM, Radford JA, Cullen MH, et al: Comparison of ABVD and alternating or hybrid multi-drug regimens for the treatment of advanced Hodgkin lymphoma: Results of the UK Lymphoma Group LY09 trial (ISRCTN97144519). J Clin Oncol 23:9208-9218, 2005[Abstract/Free Full Text]

2. Carde P: The chemotherapy/radiation balance in advanced Hodgkin's lymphoma: Overweight which side? J Clin Oncol 23:9058-9062, 2005[Free Full Text]

3. Gobbi PG, Levis A, Chisesi T, et al: ABVD versus modified Stanford V versus MOPPEBVCAD with optional and limited radiotherapy in intermediate- and advanced-stage Hodgkin's lymphoma: Final results of a multicenter randomized trial by the Intergruppo Italiano Linfomi. J Clin Oncol 23:9198-9207, 2005[Abstract/Free Full Text]

4. Aleman BM, van den Belt-Dusebout AW, Klokman WJ, et al: Long-term cause-specific mortality of patients treated for Hodgkin's disease. J Clin Oncol 21:3431-3439, 2003[Abstract/Free Full Text]

5. Diehl V, Loeffler M, Pfreundschuh M, et al: Further chemotherapy versus low-dose involved-field radiotherapy as consolidation of complete remission after six cycles of alternating chemotherapy in patients with advance Hodgkin's disease: German Hodgkins' Study Group (GHSG). Ann Oncol 6:901-910, 1995[Abstract/Free Full Text]

6. Ferme C, Mounier N, Casasnovas O, et al: Long-term results and competing risk analysis of the H89 trial in patients with advanced-stage Hodgkin lymphoma: A study by the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 2005-2011, 2006

7. Fabian CJ, Mansfield CM, Dahlberg S, et al: Low-dose involved field radiation after chemotherapy in advanced Hodgkin disease: A Southwest Oncology Group randomized study. Ann Intern Med 120:903-912, 1994[Abstract/Free Full Text]

8. Aleman BMP, Raemaekers JMM, Tirelli U, et al: Involved field radiotherapy in patients with advanced Hodgkin's lymphoma: An EORTC Lymphoma Group randomized controlled trial (#20884). N Engl J Med 348:2396-2406, 2003[Abstract/Free Full Text]

9. Bonadonna G, Zucali R, Monfardini S, et al: Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Cancer 36:252-259, 1975[CrossRef][Medline]

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