Originally published as JCO Early Release 10.1200/JCO.2005.04.4644 on November 28 2005

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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carde, P. Search for Related Content PubMed PubMed Citation Articles by Carde, P. Related Articles Related Articles

The Chemotherapy/Radiation Balance in Advanced Hodgkin's Lymphoma: Overweight Which Side?

Institut Gustave Roussy, Villejuif, France

Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), without irradiation, is considered standard treatment for responding patients with advanced Hodgkin's lymphoma (HL).^1-4 Apart from escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP),⁵ which is now being tested against ABVD in poor-prognosis HL,⁶ serious challengers are mechlorethamine, doxorubicin, vinblastine, vincristine, bleomycin, etoposide, and prednisone (Stanford V), and several multidrug regimens (MDRs), which are the subject of the two reports in this issue of the Journal of Clinical Oncology by Gobbi et al⁷ and Johnson et al.⁸ Through these articles, I wish to draw attention to the pertinent questions asked by the investigators regarding combined chemotherapy and irradiation for intermediate and advanced HL.

Gobbi et al⁷ suggest that the chemotherapy part of the Stanford V treatment program,⁹ which is commonly used worldwide for advanced Hodgkin's lymphoma, provides inferior results compared with those obtained by the much older ABVD regimen,¹⁰ and by mechlorethamine, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, bleomycin (MOPPEBVCAD),¹¹ primarily used by the Italian Lymphoma Study group (IIL). Stanford V users can be reassured: the Stanford V used in this study was intentionally different from the original. The aim certainly was not to disadvantage one regimen against homemade protocols. The IIL intended to determine the best possible chemotherapy regimen for advanced HL patients and either to remove radiotherapy completely or to reduce drastically the irradiation fields. This was not achieved, due to the design of the study, in which the irradiation was different in each of the three randomized groups. Therefore, I recommend that the original Stanford V program—not a modified regimen—be used if outcomes reported by Horning are expected.

The article by Gobbi et al⁷ aimed to investigate which of three chemotherapy regimens was superior by itself; that is, which regimen allowed a less frequent usage of irradiation, and when radiation was used, allowed a greater limitation of the irradiation field extent than in the original chemotherapy/radiotherapy combinations. The irradiation component was reduced intentionally, as compared with most irradiation modalities reported in the literature, although an incredibly broad spectrum of doses and fields¹² are described as adjuvant treatment^1,5,13-17 or consolidation^18-21 for advanced disease. Indeed, in the study by Gobbi et al, no irradiation was allowed when a complete remission (CR) was achieved. When a partial remission (PR) or complete remission unconfirmed (CRu) was obtained, irradiation was administered only to those patients who had no more than two involved sites to irradiate; this meant also that a maximum of two involved sites could be irradiated (36 to 42 Gy), taking into account initial bulky site(s) plus residual CRu/PR disease. As a consequence, patients who otherwise would most require irradiation because of residual disease at the time of restaging after chemotherapy, especially those with few CRu/PR sites, were also, unfortunately, ineligible for irradiation. It should also be emphasized that chemotherapy was restricted to either 6 monthly cycles of ABVD or MOPPEBVCAD, or to 12 weeks of Stanford V chemotherapy, whereas many investigators recommend 8 months of standard-dose chemotherapy (ABVD).

The IIL results show that the two 6-month regimens (when combined with different amounts of irradiation) fared better than the 3-month modified Stanford V regimen, in terms of failure-free survival (FFS), and for ABVD, in terms of overall survival (OS; P = .04). For a correct interpretation of the data, it should be noted that the IIL study suffered from two drawbacks. The first was some imbalance in the distribution of the patients regarding patient numbers per arm and nodular sclerosis histology or bulky mediastinal disease. More importantly, the process that led to the decision of whether to administer radiation therapy was based in part on intermediary and final response evaluation, which took place twice: when two thirds and then when the entire chemotherapy regimen had been delivered. However, this decision took place at different intervals: at 16 and 24 weeks for the two 6-month regimens, compared with 8 and 12 weeks for the 3-month regimen. This discrepancy likely contributed to the different CR/CRu/PR results, which determined the irradiation decision, given that patients were not allowed to be irradiated if more than two areas were either initially bulky or not in CR after chemotherapy. For instance, Table 3 noted that there were approximately four times as many patients who were not irradiated because of their PR in more than two involved sites after Stanford V versus ABVD.⁷ Therefore, the role of irradiation acts as a major confounding factor and weakens the demonstration that ABVD for six cycles + "very limited irradiation" represents the best strategy for intermediate and advanced HL.

Regarding the original Stanford V program results, the authors acknowledge that they are not to be compared with those from their IIL study. This can be understood for three good reasons: the different staging and patient populations, the lower percentage of irradiated patients (62% in IIL compared with > 90% in the original Stanford program), and the "very limited fields," compared with the original Stanford study.⁹ Nevertheless, these results demonstrate—on a large scale—what has been intuitive for a long time, that in the Stanford V program, full radiotherapy (percentage patient given to, extent, and probably quality control) is essential. If radiotherapy is reduced, so is the outcome. This is of primary importance for the patients who undergo the Stanford V program anywhere in the world.

Johnson et al⁸ enrolled 807 patients in an unbalanced randomized trial of ABVD versus MDRs, alternating chlorambucil, vinblastine, procarbazine, and prednisolone (ChlVPP)/prednisolone, doxorubicin, bleomycin, vincristine, and etoposide (PABlOE) versus hybrid ChlVPP/etoposide, vincristine, and doxorubicin (EVA). Radiotherapy was administered for incomplete response or initial bulky disease. Overall, the three regimens (ABVD v the two MDRs) did not differ regarding the main end point (3-year progression-free survival [PFS]; 75%) or the OS (90% and 88%, respectively). However, toxicity was considerably higher in the MDRs, especially in patients older than 45, which may prove deleterious with longer follow-up.

Overall, the IIL results confirm that outcomes in advanced HL patients are improving in the setting of cooperative trials, and the best two arms provide a 5-year FFS of 78% and 81% for ABVD and MOPPEBVCAD, respectively. The United Kingdom Lymphoma Group study (5-year PFS of 65%) and, not surprisingly, slightly older trials with similar programs, more patients than in the IIL study, and longer follow-up, provide slightly inferior 5-year results, as in the ABVD versus MOPP/ABV Intergroup study (FFS 63% v 66%, respectively)⁴ and in the European Organisation for Research and Treatment of Cancer (EORTC) MOPP/ABV ± involved-field irradiation study (75% EFS) for all patients enrolled.¹ Both IIL and United Kingdom reports acknowledge ABVD as standard; investigators consider sadly that there is room for improvement. From where could improvement come?

Would global results be improved if irradiation is removed from the protocol? The IIL is not the only cooperative group that tested radiotherapy reduction or abolition as a result of its known immediate and late toxicity.^22-24 Indeed, a meta-analysis suggested that adjuvant irradiation brings no benefit in patients with advanced HL.²⁵ In a recent EORTC trial no advantage was seen for good responders (patients already in PR or CR after four cycles of MOPP/ABV and in CR after six cycles) who were randomly assigned to 20 Gy involved-field irradiation of all involved nodal and visceral areas.¹ This was true after a total of six or eight cycles (CR or PR after the fourth cycle, respectively). Although more relapses occurred in originally involved sites in the no-radiotherapy group (11 of 24 patients) than in the involved-field radiotherapy group (six of 22), a trend (P = .07) toward better OS was observed in the no-radiotherapy arm; this result was because of increased intercurrent deaths and deaths from second malignancies (x2, mainly secondary leukemias/myelodysplasias) in complete responders treated with radiation.¹

Conversely, the same study suggests that patients who still were in PR after six cycles benefit from rescue irradiation (30 Gy).¹ This finding also places in perspective the Groupe d'Etude des Lymphomes de l'Adulte (GELA) observation that after 6-monthly cycles of chemotherapy, either consolidative irradiation or two extra cycles of chemotherapy provide equivalent disease control, whereas patients who are not given any consolidation have poor outcomes.¹⁹ The British LY09 trial,⁸ described in this issue of the Journal of Clinical Oncology, was not designed specifically to investigate the role of irradiation in patients with incomplete response. However, although patients with continuing response after six cycles of chemotherapy received two more cycles without irradiation, those with incomplete response were instead eligible for radiotherapy to residual or initially bulky sites.⁸ The two strategies provided equivalent results, thus confirming the EORTC and GELA findings. However, the most thorough readers may wonder why ABVD, in the double-randomization strata of the LY09 trial, did not provide the same results (74% or 80% freedom from progression [FFP] at 3 years). The clue is geographic and very much informative: those British investigators, who were accustomed to the hybrid ChlVPP/EVA and chose this randomization strata, tended to balance toward radiotherapy after six cycles for "still-responding" patients because of a better access to existing radiotherapy facilities; the contrary was true for the investigators accustomed to ChlVPP/PABlOE, who balanced toward two extra cycles of ABVD instead of radiotherapy. Apparently, in this spontaneous, illegitimate comparison, two cycles of ABVD did a better job than irradiation (vox populi). As a reminder, in Europe, standard ABVD calls for eight cycles.

Finally, the IIL study brings new information regarding the role of irradiation: all chemotherapy regimens are not the same, and the benefit of irradiation for disease control depends clearly on the cumulative dose, type, and length of the chemotherapy that has been used first, as shown by Hasenclever et al²⁶ in the rationale for BEACOPP escalation, and in the comparative evaluation of ABVD, MOPP, Stanford V, and other common regimens. Instead of the demonstration that ABVD or MOPPEBVCAD for six cycles or Stanford V chemotherapy regimens can spare irradiation to most patients, the IIL demonstrated that the balance between irradiation and chemotherapy still holds true in advanced HL patients.

One of the specific aims—and successes—of the Stanford V program was to preserve fertility in young patients,⁹ which cannot be achieved with escalated chemotherapy or intensification.²⁷ However, it is now admitted that large fields are no longer necessary when chemotherapy controls microscopic disease. To avoid irradiation's late effects, either the irradiation must be deleted (but then chemotherapy must be reinforced to control bulky/persisting disease, and there is some price to pay—to date ABVD for eight cycles is the least expensive), or irradiation must be rendered safer. The latter has not been achieved yet, even though new ways are being explored,^12,28 including the involved-node radiation therapy technique, developed by Girinsky et al²⁸ for the future H10 EORTC/GELA study. Recently, this balancing effect between the respective weights of chemotherapy and irradiation in adults was proven to be important when irradiation was deleted from one arm in randomized trials for early HL (EORTC/GELA H9 Favorable trial)²⁹ and for intermediate HL (National Cancer Institute of Canada Clinical Trials Group HD-6/ECOG JHD-06).³⁰ In these two trials, the chemotherapy-alone arm failed. This occurred because EBVP proved too brief and weak a chemotherapy regimen in the European trial, and because the number of ABVD cycles was insufficient in a number of patients in the North American trial.

Is there anything left to expect from conventional chemotherapy trials? Obviously, the concept of alternating regimens failed.^2,8,31 Conversely, the relationship between dose and cure holds true, favoring escalation of cumulative doses within a similar time frame, rather than increasing the drug delivery rate for short periods of time. This is illustrated by the success of the BEACOPP escalation, which led to improved OS,⁵ whereas late intensifications failed to do so.³² The design of this moderate dose escalation benefited from the generalized Skipper model that explored dose escalation versus shortened treatment duration in relation to the heterogeneous chemosensitivity and growth kinetics observed in the HL clinical trials. The model, which assessed the relative potency of individual drugs, predicted that both the total chemotherapy dose within a given time schedule (main variable) and treatment shortening were important. A relatively modest dose escalation in the German HD-9 study (30%) was anticipated to gain more than 10% in long-term FFP,²⁶ and it did.⁵

Probably none of the multiple BEACOPP derivatives available or tested today represents the final chemotherapy regimen for HL because their long-term hematologic and fertility toxicity is considerable. However, the concept of dose/time/response relationship is now established firmly and can be applied to new, untested regimens. An effective dose (ed) model, based on 11,000 patients included in 46 trials, took into account the number of cycles given (total dose) and treatment duration. For this editorial, Dirk Hasenclever, PhD, kindly agreed to apply the model to the results of the IIL and LY09 trials. Overall, and within these randomized comparisons, the ed model predicts perfectly the FFP differences observed inside the two trials (Fig 1). At the difference of escalated BEACOPP for eight cycles (ed = 36.1), the model predicts that the two chemotherapy regimens tested in the LY09 British trial, hybrid ChlVVP/EVA for six cycles (ed = 24.4) and alternating ChlVVP/PABlOE (ed = 21.9), do not provide sufficient effective dose escalation to improve the 3-year EFS, as compared with ABVD for eight cycles (ed = 24.4), or even for six cycles (ed = 19.9). Indeed, when present, the dose increment only induced increased toxicity, missing—and on the contrary—the goal of better survival.⁸ Similarly, the model could predict the improved 5-year FFP brought by the more intensively dosed MOPPEBVCAD (ed = 29.8), that was sought and obtained by the Italian investigators; it cannot be excluded that the 50% bleomycin dose reduction in the IIL version of ABVD (ed = 17.4 v 19.9 with full-dose bleomycin) contributed to this large difference. However, the ed model is not (yet) designed to take irradiation into account. Nevertheless, its rating (ed = 15.7), which predicts lower FFP than with MOPPEBVCAD, the poorer results observed in the Stanford V arm of the IIL study, as compared with those predicted, may be explained by additional biases, as addressed earlier in this editorial (Fig 1).

View larger version (14K): [in this window] [in a new window]   Fig 1. Freedom from progression (FFP) differences observed within randomized comparisons can be predicted by effective dose differences calculated from the chemotherapy model. The model takes into account the number of cycles administered (total dose) and treatment duration. FFP (observed) fits effective dose (calculated by D. Hasenclever according to the chemotherapy dose model described by Hasenclever et al26; see text). FFP was derived at 5 years from the Italian Lymphoma Study Group (IIL) study and 3 years from the UK Lymphoma Group (UK LY). Stanford V, doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, and prednisone; ABVD, doxorubicin, bleomycin, vinblastine, and dacarbazine; ChlVPP/PABlOE, alternating chlorambucil, vinblastine, procarbazine, prednisolone, doxorubicin, bleomycin, vincristine, etoposide; ChlVPP/EVA, hybrid chlorambucil, vinblastine, procarbazine, prednisolone, etoposide, vincristine, and doxorubicin; MOPPEBVCAD, mechlorethamine, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin. 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.

Are new treatment modalities in sight? They are slow to reach clinical practice for HL patients, probably because the market is so narrow, and because the nature and oncogenesis of HL are still so poorly understood.³⁵ What will disrupt the proinflammatory/proproliferative circle in this disease? What is the role of Epstein-Barr and other viruses?³⁶ In this respect, HL suffers from being tested on its own (ie, in individualized trials, split from the phase I/II trials enrolling other lymphomas). This was the case with new chemotherapy drugs (gemcitabine) and biologicals (monoclonals, including anti-CD30³⁷). Less ambitious but more pragmatic trials may bring new drugs (such as anti-inflammatory and antiangiogenic drugs, proteasome, tyrosine kinase, and yet-to-be-tested Janus kinase 2 inhibitors) to physicians earlier.

Would better patient stratification help? To evaluate HL aggressiveness and individualize treatment, the International Prognostic Score has been based on earlier series of patients that do less well, independent of treatment.³⁸ Improved prognostic tools, possibly based on biologic markers, microarrays, and pharmacogenomics, may select, for example, those patients at higher risk of early progression, who may emerge from any of the groups that we define as early (localized favorable), intermediate (localized unfavorable), and advanced stages.

Are late toxicities sufficiently assessed and prevented? This is still poorly taken into account, regardless of special American Society of Clinical Oncology sessions. Late toxicities relate to young patients with regard to fertility,²⁷ but many toxicities are potentially lethal.³⁹ Risk of a second cancer is a major concern, especially in younger patients. It has been shown that telomere length of pretreatment peripheral lymphocytes provides clues on the risk of second cancer, independent of the treatment applied later.⁴⁰

The conclusions of these articles are in keeping with those made by other cooperative groups regarding combined chemotherapy and radiotherapy for adult HL in early and intermediate stages: deleting irradiation is worth trying to alleviate long-term toxicities, but success is not certain; and the challenge is to find highly effective chemotherapy regimens devoid of major adverse effects.³

In the absence of consensus for intermediate and advanced HL, accrual to ongoing randomized trials that test BEACOPP and ABVD derivatives (such as the ongoing Intergroup trial⁶ or the full Stanford V program) seem to be good choices, if standard arms are not altered. These trials should be adjusted to initial prognostic stratification, and eventually to treatment response. Otherwise, standards such as eight cycles of ABVD without irradiation must be proposed until the results of the comparison ABVD/Stanford V are known. There is no need for any more testing of adjuvant or consolidative irradiation after a standard chemotherapy course (ABVD for eight cycles). For localized early²⁹ and intermediate³⁰ stages, the same prudent but persistent approach holds true regarding attempts to delete radiotherapy, provided that adequate chemotherapy is given. Finally, early response to treatment, a known favorable predictor,⁴¹ rendered more reliable through positron emission tomography⁴² (such as in the H10 EORTC/GELA trial), may help to design safer studies so clinicians can best decide where and when irradiation can be deleted.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

Acknowledgment

I thank Dr Bruce Cheson, for vivid discussions, and Dr Dirk Hasenclever who provided effective dose testing data within the three randomized comparisons and the corresponding figure.

REFERENCES

1. 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]

2. Canellos GP, Anderson JR, Propert KI, et al: Chemotherapy of advanced Hodgkin's disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med 327:1478-1484, 1992[Abstract]

3. Carde P, Cavalli F, Diehl V, et al: Treatment of advanced Hodgkin's disease: Is there a standard treatment? Hematol J 1:282-290, 2000[CrossRef][Medline]

4. Duggan DB, Petroni GR, Johnson JL, et al: Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment of advanced Hodgkin's disease: Report of an Intergroup trial. J Clin Oncol 21:607-614, 2003[Abstract/Free Full Text]

5. Diehl V, Franklin J, Pfreundschuh M, et al: Standard and increased-dose BEACOPP chemotherapy compared with COPP-ABVD for advanced Hodgkin's disease. N Engl J Med 348:2386-2395, 2003[Abstract/Free Full Text]

6. National Cancer Institute: EORTC protocol 20012/Intergroup trial: BEACOPP (4 cycles escalated + 4 cycles baseline) versus ABVD (8 cycles) in unfavorable (IPS 3+) stage III & IV Hodgkin Lymphoma. http://www.cancer.gov/clinicaltrials/EORTC-20012

7. 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]

8. Johnson WM, Radford JA, Cullen MH, et al: Comparison of ABVD and alternating or hybrid multidrug regimens for the treatment of advanced Hodgkin's lymphoma: Results of the United Kingdom Lymphoma Group LY09 Trial. J Clin Oncol 23:9208-9218, 2005[Abstract/Free Full Text]

9. Horning SJ, Hoppe RT, Breslin S, et al: Stanford V and radiotherapy for locally extensive and advanced Hodgkin's Disease: Mature results of a prospective clinical trial. J Clin Oncol 20:630-637, 2002[Abstract/Free Full Text]

10. Bonadonna G, Bonfante V, Viviani S, et al: ABVD plus subtotal nodal versus involved-field radiotherapy in early-stage Hodgkin's disease: Long-term results. J Clin Oncol 22:2835-2841, 2004[Abstract/Free Full Text]

11. Gobbi PG, Pieresca C, Ghirardelli ML, et al: Long-term results from MOPPEBVCAD chemotherapy with optional limited radiotherapy in advanced Hodgkin's disease. Blood 91:2704-2712, 1998[Abstract/Free Full Text]

12. Yahalom J: Transformation in the use of radiation therapy of Hodgkin lymphoma: New concepts and indications lead to modern field design and are assisted by PET imaging and intensity modulated radiation therapy (IMRT). Eur J Haematol 66:90-97, 2005

13. Canellos GP, Gollub J, Neuberg D, et al: Primary systemic treatment of advanced Hodgkin's disease with EVA (etoposide, vinblastine, doxorubicin): 10-year follow-up. Ann Oncol 14:268-272, 2003[Abstract/Free Full Text]

14. Chisesi T, Federico M, Levis A, et al: ABVD versus Stanford V versus MEC in unfavourable Hodgkin's lymphoma: Results of a randomised trial. Ann Oncol 13:102-106, 2002 (suppl 1)[Abstract]

15. Martinelli G, Cocorocchio E, Peccatori F, et al: ChlVPP/ABVVP, a first line ‘hybrid’ combination chemotherapy for advanced Hodgkin's lymphoma: A retrospective analysis. Br J Haematol 125:584-589, 2004[CrossRef][Medline]

16. Salvagno L, Soraru M, Sotti G, et al: Hybrid MOPP/ABVD and radiotherapy in advanced Hodgkin's disease. Ann Oncol 6:173-179, 1995[Abstract/Free Full Text]

17. Sieber M, Tesch H, Pfistner B, et al: Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: Final results of the German Hodgkin's Lymphoma Study Group HD6 trial. Ann Oncol 15:276-282, 2004[Abstract/Free Full Text]

18. Bartlett NL, Rosenberg SA, Hoppe RT, et al: Brief chemotherapy, Stanford V, and adjuvant radiotherapy for bulky or advanced-stage Hodgkin's disease: A preliminary report. J Clin Oncol 13:1080-1088, 1995[Abstract]

19. Ferme C, Mounier N, Divine M: Current clinical trials for the treatment of adult advanced-stage Hodgkin's disease: GELA experiences—Groupe d'Etudes des Lymphomes de l'Adulte. Ann Oncol 13:96-97, 2002 (suppl 1)

20. Horning SJ, Williams J, Bartlett NL, et al: Assessment of the Stanford V regimen and consolidative radiotherapy for bulky and advanced Hodgkin's Disease: Eastern Cooperative Oncology Group pilot study E1492. J Clin Oncol 18:972-980, 2000[Abstract/Free Full Text]

21. Laskar S, Gupta T, Vimal S, et al: Consolidation radiation after complete remission in Hodgkin's disease following six cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy: Is there a need? J Clin Oncol 22:62-68, 2004[Abstract/Free Full Text]

22. Hancock SL, Hoppe RT: Long-term complications of treatment and causes of mortality after Hodgkin's disease. Semin Radiat Oncol 6:225-242, 1996[CrossRef][Medline]

23. Longo DL: Radiation therapy in the treatment of Hodgkin's disease: Do you see what I see? J Natl Cancer Inst 95:928-929, 2003[Free Full Text]

24. Mauch P, Ng AK, Aleman B, et al: Report from the Rockefeller Foundation Sponsored International Workshop on reducing mortality and improving quality of life in long-term survivors of Hodgkin's disease: July 9-16, 2003, Bellagio, Italy. Eur J Haematol 75:68-76, 2005[CrossRef][Medline]

25. Loeffler M, Hasenclever D, Sextro M, et al: Meta-analysis of chemotherapy versus combined modality treatment trials in Hodgkin's disease. International Database on Hodgkin's Disease Overview Study Group. J Clin Oncol 16:818-829, 1998[Abstract]

26. Hasenclever D, Brosteanu O, Gerike T, et al: Modelling of chemotherapy: The effective dose approach. Ann Hematol 80:B89-B94, 2001 (suppl 3)

27. Carde P: Risks of infertility and early menopause from anticancer and immunosuppressive programs: Methods of fertility preservation and palliation. Am Soc Clin Oncol Ed Book, 2004, pp 400-417

28. Girinsky T, Pichenot C, Beaudre A, et al: Is intensity-modulated radiotherapy better than conventional radiation treatment and 3D conformal radiotherapy for mediastinal masses in patients with Hodgkin's disease and is there a role for beam orientation optimization and virtual volumes? Int J Radiat Oncol Biol Phys 2005 (Sep 15 [Epub ahead of print])

29. Noordijk EM, Thomas J, Fermé C, et al: First results of the EORTC-GELA H9 randomized trials: The H9-F trial (comparing 3 radiation dose levels) and H9-U trial (comparing 3 chemotherapy schemes) in patients with favorable or unfavorable early stage Hodgkin's lymphoma (HL). J Clin Oncol 23:561, 2005 (suppl; abstr 6505)

30. 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 Hodgkin's Lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol 23:4634-4642, 2005[Abstract/Free Full Text]

31. Sieber M, Tesch H, Pfistner B, et al: Rapidly alternating COPP/ABV/IMEP is not superior to conventional alternating COPP/ABVD in combination with extended-field radiotherapy in intermediate-stage Hodgkin's lymphoma: Final results of the German Hodgkin's Lymphoma Study Group Trial HD5. J Clin Oncol 20:476-484, 2002[Abstract/Free Full Text]

32. Federico M, Bellei M, Brice P, et al: High-dose therapy and autologous stem-cell transplantation versus conventional therapy for patients with advanced Hodgkin's lymphoma responding to front-line therapy. J Clin Oncol 21:2320-2325, 2003[Abstract/Free Full Text]

33. Pfreundschuh MG, Ho A, Wolf M, et al: Treatment results of CHOP-21, CHOEP-21, MACOP-B and PMitCEBO with and without rituximab in young good-prognosis patients with aggressive lymphomas: Rituximab is an "equalizer" in the MinT (MABTHERA International Trial group) study. J Clin Oncol 23:567, 2005 (suppl; abstr 6529)

34. Brosteanu O, Hasenclever D, Loeffler M, et al: Low acute hematological toxicity during chemotherapy predicts reduced disease control in advanced Hodgkin's disease. Ann Hematol 83:176-182, 2004[CrossRef][Medline]

35. Taylor CR: Hodgkin's disease is a non-Hodgkin lymphoma. Hum Pathol 36:1-4, 2005[CrossRef][Medline]

36. Engels EA, Goedert JJ: Human immunodeficiency virus/acquired immunodeficiency syndrome and cancer: Past, present, and future. J Natl Cancer Inst 97:407-409, 2005[Free Full Text]

37. Schnell R, Dietlein M, Staak JO, et al: Treatment of refractory Hodgkin's lymphoma patients with an iodine-131-labeled murine anti-CD30 monoclonal antibody. J Clin Oncol 23:4669-4678, 2005[Abstract/Free Full Text]

38. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin's disease: International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 339:1506-1514, 1998[Abstract/Free Full Text]

39. Henry-Amar M: Hodgkin's disease: Treatment sequelae and quality of life. Baillieres Clin Haematol 9:595-618, 1996[CrossRef][Medline]

40. Carde P, M'kacher R, Bennaceur-Griscelli A, et al: Shortened telomeres in peripheral lymphocytes are associated to complex chromosome anomalies and to second cancers in Hodgkin Lymphoma patients. J Clin Oncol 23:563, 2005 (suppl; abstr 6512)

41. Carde P, Koscielny S, Franklin J, et al: Early response to chemotherapy: A surrogate for final outcome of Hodgkin's disease patients that should influence initial treatment length and intensity? Ann Oncol 13:86-91, 2002 (suppl 1)[Abstract]

42. Juweid ME, Cheson BD: Role of positron emission tomography in lymphoma. J Clin Oncol 23:4577-4580, 2005[Free Full Text]

Related Articles

• 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
  Paolo G. Gobbi, Alessandro Levis, Teodoro Chisesi, Chiara Broglia, Umberto Vitolo, Caterina Stelitano, Vincenzo Pavone, Luigi Cavanna, Gino Santini, Francesco Merli, Marina Liberati, Luca Baldini, Giorgio Lambertenghi Deliliers, Emanuele Angelucci, Roberto Bordonaro, and Massimo Federico
  JCO 2005 23: 9198-9207 [Abstract] [Full Text]
• 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
  Paolo G. Gobbi, Alessandro Levis, Teodoro Chisesi, Chiara Broglia, Umberto Vitolo, Caterina Stelitano, Vincenzo Pavone, Luigi Cavanna, Gino Santini, Francesco Merli, Marina Liberati, Luca Baldini, Giorgio Lambertenghi Deliliers, Emanuele Angelucci, Roberto Bordonaro, and Massimo Federico
  JCO 2005 23: 9198-9207 [Abstract] [Full Text]
• Comparison of ABVD and Alternating or Hybrid Multidrug Regimens for the Treatment of Advanced Hodgkin's Lymphoma: Results of the United Kingdom Lymphoma Group LY09 Trial (ISRCTN97144519)
  Peter W.M. Johnson, John A. Radford, Michael H. Cullen, Matthew R. Sydes, Jan Walewski, Andrew S. Jack, Kenneth A. MacLennan, Sally P. Stenning, Simon Clawson, Paul Smith, David Ryder, and Barry W. Hancock
  JCO 2005 23: 9208-9218 [Abstract] [Full Text]

This article has been cited by other articles:

				A. Engert, J. Franklin, H. T. Eich, C. Brillant, S. Sehlen, C. Cartoni, R. Herrmann, M. Pfreundschuh, M. Sieber, H. Tesch, et al. Two Cycles of Doxorubicin, Bleomycin, Vinblastine, and Dacarbazine Plus Extended-Field Radiotherapy Is Superior to Radiotherapy Alone in Early Favorable Hodgkin's Lymphoma: Final Results of the GHSG HD7 Trial J. Clin. Oncol., August 10, 2007; 25(23): 3495 - 3502. [Abstract] [Full Text] [PDF]

				P. W.M. Johnson, J. A. Radford, M. H. Cullen, M. R. Sydes, S. P. Stenning, and B. W. Hancock Comparison of Outcomes in Studies of Advanced Hodgkin's Lymphoma J. Clin. Oncol., July 10, 2006; 24(20): 3309 - 3309. [Full Text] [PDF]

				P. Carde In Reply J. Clin. Oncol., July 10, 2006; 24(20): 3309 - 3310. [Full Text] [PDF]

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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Carde, P. Search for Related Content PubMed PubMed Citation Articles by Carde, P. Related Articles Related Articles