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Journal of Clinical Oncology, Vol 20, Issue 13 (July), 2002: 2988-2994
© 2002 American Society for Clinical Oncology

ChlVPP/EVA Hybrid Versus the Weekly VAPEC-B Regimen for Previously Untreated Hodgkin’s Disease

By J. A. Radford, A. Z.S. Rohatiner, W. D.J. Ryder, D. P. Deakin, T. Barbui, N. P. Lucie, A. Rossi, D. J. Dunlop, R. A. Cowan, P. M. Wilkinson, R. K. Gupta, R. D. James, J. Shamash, J. Chang, D. Crowther, T. A. Lister

From Christie Hospital, Manchester; St Bartholomew’s Hospital, London; and West of Scotland Lymphoma Group, Glasgow, United Kingdom; and Ospedali Riuniti, Bergamo, Italy.

Address reprint requests to J.A. Radford, MD, Cancer Research UK Department of Medical Oncology, Christie Hospital, 550 Wilmslow Road, Manchester M20 4BX, United Kingdom; email: john.radford{at}man.ac.uk


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
PURPOSE: To test the hypothesis that a chemotherapy regimen of relatively low toxicity and 11 weeks’ duration (doxorubicin, cyclophosphamide, etoposide, vincristine, bleomycin, and prednisolone [VAPEC-B]) is at least as effective in terms of disease control as 6 months’ treatment with chlorambucil, vinblastine, procarbazine, and prednisone/etoposide, vincristine, and doxorubicin (ChlVPP/EVA hybrid), which is associated with a high risk of permanent sterility.

PATIENTS AND METHODS: Two hundred eighty-two patients with previously untreated Hodgkin’s disease, clinical stages I/II (plus mediastinal bulk and/or B symptoms) and clinical stages III/IV were randomized at three United Kingdom and one Italian center to receive either six monthly cycles of ChlVPP/EVA hybrid or 11 weekly cycles of VAPEC-B. After chemotherapy and a restaging evaluation, radiotherapy was administered to sites of previous bulk or residual radiographic abnormality before patients were observed off treatment.

RESULTS: Further accrual to the trial was halted at the planned third interim analysis in September 1996. After a median follow-up of 4.9 years, freedom from progression (FFP), event-free survival (EFS), and overall survival (OS) are all significantly better in the population treated with ChlVPP/EVA than VAPEC-B, where the comparative 5-year results are 82% and 62% (FFP), 78% and 58% (EFS), and 89% and 79% (OS), respectively. The superiority of ChlVPP/EVA was seen in both low-risk and intermediate/high-risk patients, although subset analysis suggested that ChlVPP/EVA and VAPEC-B produce equivalent results in the best-prognosis patients (Hasenclever score <= 2, nonbulky disease).

CONCLUSION: Apart from possibly in the best-prognosis group, where results are equivalent, ChlVPP/EVA hybrid produces significantly better FFP, EFS, and OS than VAPEC-B in patients with previously untreated Hodgkin’s disease.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
THE TREATMENT OF advanced Hodgkin’s disease (HD) has undergone considerable change since the era of single-agent chemotherapy.1 De Vita et al2 at the National Cancer Institute introduced the combination of mustine, vincristine, procarbazine, and prednisolone (MOPP) in the early 1960s, and this important development was followed by the appearance of a number of MOPP variants including MVPP (where the neurotoxic vincristine was replaced by vinblastine)3 and ChlVPP (where the highly emetogenic mustine was replaced by chlorambucil).4 In 1975, Bonadonna et al5 at the Milan Cancer Institute devised the doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) regimen, and randomized trials comparing ABVD with MOPP showed significant advantages for the doxorubicin-containing combination in terms of complete remission (CR) rate, relapse-free survival, and overall survival (OS).5,6 A later study performed by the Milan group and involving 88 previously untreated patients with stage IV HD demonstrated a significant advantage for MOPP alternating with ABVD over MOPP alone.7 In a much larger study by the Cancer and Leukemia Group B, however, ABVD alone was found to be as effective as alternating cycles of MOPP and ABVD, with both therapies superior to MOPP alone.8 Subsequently, workers in Vancouver decided to hybridize days 1 to 7 of MOPP with ABV(D) (dacarbazine omitted) given on day 8; impressive first results for the MOPP/ABV hybrid were published in 19859 and updated 2 years later.10

In 1984, investigators at St Bartholomew’s Hospital, London, and the Christie Hospital, Manchester, United Kingdom, developed an etoposide-containing hybrid regimen; days 1 to 7 of ChlVPP were fused with etoposide, doxorubicin, and vincristine on day 8 to form the ChlVPP/EVA regimen. The three day 8 drugs had already been tested in patients with HD unresponsive or recurrent after MVPP or ChlVPP, and a response rate of 58% suggested non–cross-resistance between the regimens.11 Promising results were also obtained with the ChlVPP/EVA hybrid in patients who had relapsed after previous chemotherapy, and so it was decided to undertake a randomized trial comparing ChlVPP/EVA with MVPP in patients with newly diagnosed HD. In this trial, first reported after a median follow-up period of 4.5 years, ChlVPP/EVA hybrid was shown to be superior to MVPP in terms of freedom from progressive HD (80% v 60% at 5 years, respectively; P = .005).12 As a consequence of these data, ChlVPP/EVA hybrid was adopted as first-line treatment for newly diagnosed high-risk/advanced-stage HD at the two centers and a second trial, this time involving three United Kingdom and one Italian center/study groups, was activated. In this second trial, the investigators compared a slightly modified ChlVPP/EVA hybrid with a less toxic alternative—doxorubicin, cyclophosphamide, vincristine, bleomycin, etoposide, prednisolone, and methotrexate (VAPEC-B)—a regimen first developed for aggressive non-Hodgkin’s lymphoma (NHL)13 featuring myelosuppressive (doxorubicin, cyclophosphamide, and etoposide) and relatively nonmyelosuppressive (vincristine and bleomycin) drugs given on an alternating weekly basis for 11 weeks. Activity in HD was first established in patients with disease recurrent after previous chemotherapy14 and then confirmed in a randomized trial involving previously untreated patients with low-risk, early-stage HD.15 In the latter study, just 4 weeks of VAPEC-B (given before radiotherapy [RT]) was shown to be associated with a high response rate and to substantially reduce the progression rate compared with radiation treatment alone. Furthermore, in men with HD and NHL receiving up to 11 weeks of VAPEC-B, a permanent effect on spermatogenesis has not been observed,16 in stark contrast to the situation after ChlVPP/EVA hybrid, where virtually all men receiving six cycles or more are rendered permanently azoospermic.17 In this report, results of the ChlVPP/EVA versus VAPEC-B trial are presented after a median follow-up of 4.9 years and 4 years after premature closure of the study at the planned, third interim analysis.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility for Trial Entry
Previously untreated adults aged 16 to 75 years with a biopsy-proven diagnosis of HD and Ann Arbor stages I/II (in the presence of mediastinal bulk and/or B symptoms) or stages III and IV were eligible for randomization. Normal renal and hepatic function were also required unless abnormal function of the liver or kidneys was considered to be directly related to HD. Pregnant or lactating women, patients with a history of malignancy (apart from appropriately treated carcinoma-in-situ of the cervix and basal cell carcinoma of the skin), or those previously treated for HD with radiation or chemotherapy were ineligible.

Staging
Patients were staged on the basis of Cotswolds Committee modifications18 of Ann Arbor criteria and resulted from a full history and physical examination; plain radiography of the chest; computed tomographic (CT) scan of the thorax, abdomen, and pelvis; complete blood cell count and serum biochemical profile; and examination of a bone marrow aspirate and trephine biopsy specimen. In addition, isotope bone scans, ultrasound scans, and biopsies of suspicious lesions (pleura, skin, liver, and lung) were performed where necessary. Staging laparotomy with splenectomy was not routinely performed.

Peripheral and abdominal nodal masses >= 10 cm in any diameter or, in the mediastinum, masses with a transverse diameter >= 0.33 of the internal thoracic diameter at the level of D5/6 intervertebral disc were considered bulky.18

Patients, Randomization, and Treatment
After ethics committee approval at the four participating centers, 282 patients (Christie Hospital, n = 155; St Bartholomew’s Hospital, n = 34; West of Scotland Lymphoma Group, n = 53; and Ospedali Riuniti, n = 40) were entered onto the trial between September 1992 and September 1996, when accrual was halted at the time of the third planned interim analysis. Pretreatment characteristics are listed in Table 1, which, apart from an excess of B symptoms in the 144 patients receiving ChlVPP/EVA (68% v 48%), were well balanced between the two arms of the trial.


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  		Table 1. Table 1. Patient Characteristics
 
Eligible and consenting patients were randomly assigned to receive six 28-day cycles of ChlVPP/EVA hybrid or 11 weekly cycles of VAPEC-B. Drug doses and schedules for both regimens are listed in Table 2. Allopurinol 300 mg daily for 2 to 3 weeks was prescribed for all patients with bulky disease and prophylactic antibiotics/antifungals (cotrimoxazole 960 mg twice daily on Mondays, Wednesdays, and Fridays and ketoconazole 200 mg twice daily) were used for the duration of treatment with VAPEC-B but not with ChlVPP/EVA hybrid. Apart from weeks 2, 4, 6, 8, and 10 of VAPEC-B when vincristine and bleomycin were given irrespective of the blood count (excepting in circumstances of sepsis), the next cycle of treatment proceeded on schedule on both arms of the trial if the total WBC count was >= 3.0 x 109/L (and neutrophils >= 1.0 x 109/L) and the platelet count was >= 100 x 109/L. For values lower than these, treatment was delayed by 7 or 14 days to allow full hematologic recovery, but hemopoietic growth factors were not routinely used.


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  		Table 2. Table 2. Drug Doses and Schedules Used
 
Within 6 weeks of completion of chemotherapy, a full restaging evaluation was performed and all initially abnormal investigations were repeated. Remission status was determined according to the criteria of CR, CR uncertain (CR[u]) (minor residual radiographic abnormalities of uncertain significance), partial response (PR), no response, or progressive disease as defined by the Cotswolds Modifications of the Ann Arbor system.18 In this study, patients were assigned to the CR(u) category in the presence of abnormalities up to 2 cm in diameter at the site of previous nodal disease.

After reassessment, patients whose disease had responded to chemotherapy were given 30 Gy of megavoltage RT to previous sites of bulk disease or to sites of significant residual radiographic abnormality (in PR but no bulk disease at presentation). Patients with disease unresponsive to initial chemotherapy and those who later relapsed from remission were treated in accordance with local salvage protocols in force at the time.

On completion of all treatment, patients were reviewed on a regular basis (every 2 months in year 1, every 3 months in year 2, every 4 months in year 3, every 6 months in years 4 and 5, and then annually). At each of these visits, patients were examined for evidence of recurrent disease, and blood was drawn for determination of complete blood cell count, erythrocyte sedimentation rate, and serum biochemical profile. For those with mediastinal involvement at presentation, posteroanterior and lateral chest radiographs were also routinely obtained. The use of CT scans in follow-up was limited to investigation of symptoms or suspicious changes on a plain radiograph and restaging of patients in whom relapse had been established.

Statistical Methods
The trial was planned with a group-sequential monitoring schedule along the lines of Freedman et al.19 We planned to accrue 480 patients for the trial and anticipated approximately 80 disease progressions. Four analyses were planned to occur spaced by approximately 20 progressions, and adjustments to the nominal P values were to be made to control the overall type I error to 5%. On the occasion of the third interim analysis performed in September 1996, the statistical criteria for stopping the trial were met and further accrual to the trial was halted. The September 1996 analysis did not make use of the 53 cases actually randomized in that year. The analyses presented here include these additional 53 cases, and follow-up has been updated. For these reasons, the nominal P values of these analyses are presented, but the reader should bear in mind that the study was in fact terminated early.

End points analyzed were (1) freedom from progression (FFP; time to disease progression), (2) event-free survival (EFS; time to the first of disease progression or death), and (3) OS (time to death from any cause). Event-free curves were estimated using the Kaplan-Meier method, and comparisons between the trial arms and treatment arm times baseline characteristic interactions were tested using various forms of the log-rank test.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Response to Chemotherapy
Table 3 lists responses to chemotherapy in 282 patients. ChlVPP/EVA hybrid was associated with a higher CR/CR(u) rate (62% v 47%, respectively) and lower failure rate (no response or progressive disease, 3% v 7.5%) than VAPEC-B, but there were more deaths during treatment with ChlVPP/EVA hybrid (3% v 1.5%).


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  		Table 3. Table 3. Status After Chemotherapy for 282 Patients
 
RT
A total of 165 patients received RT, 84 (58%) of 144 on the ChlVPP/EVA arm and 81 (59%) of 138 on the VAPEC-B arm. It is of note that 23 patients potentially eligible for RT did not receive this treatment because of either progressive disease/death during chemotherapy (n = 18) or early progression after its completion (n = 5).

FFP, EFS, and OS
When further accrual to the trial was halted at the time of the third planned interim analysis in September 1996, there had been 48 patients whose disease progressed in the 225 assessable cases randomized before January 1, 1996 (14 of 116 on the ChlVPP/EVA hybrid arm and 34 of 109 on the VAPEC-B arm). Now, after a median follow-up time for survivors of 4.9 years, there have been a total of 80 progressions in 282 patients (ChlVPP/EVA hybrid, n = 29 of 144; VAPEC-B, n = 51 of 138), 95 events (progression or death from any cause) (ChlVPP/EVA hybrid, n = 36; VAPEC-B, n = 59), and 48 deaths (ChlVPP/EVA hybrid, n = 18; VAPEC-B, n = 30). Kaplan-Meier plots for ChlVPP/EVA and VAPEC-B, respectively, of FFP (82% v 62% at 5 years, P = .0006), EFS (78% v 58% at 5 years, P = .0006), and OS (89% v 79% at 5 years, P = .04) are shown in Fig 1.



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  		Fig 1. Kaplan-Meier plots of (A) FFP, (B) EFS, and (C) OS after a median follow-up time of 4.9 years. The faint line represents the ChlVPP/EVA arm, and the bold line represents the VAPEC-B arm.

 
An analysis of outcome according to the Hasenclever prognostic score20 (score <= 2, low risk; score >= 3, intermediate/high risk) was performed in 279 patients (three cases were excluded because of incomplete data). Patients on the ChlVPP/EVA arm had a better EFS irrespective of whether they had low- or intermediate/high-risk characteristics and a test for treatment times Hasenclever score interaction was nonsignificant (P = .3), indicating that the magnitude of difference between ChlVPP/EVA and VAPEC-B was similar in both groups (Fig 2). Next, the possible additional effect of bulk on outcome was examined (four strata: bulk, Hasenclever score <= 2; bulk, Hasenclever score >= 3; nonbulk, Hasenclever score <= 2; and nonbulk, Hasenclever score >= 3). EFS was superior for patients receiving ChlVPP/EVA in all apart from the nonbulk, Hasenclever score <= 2 stratum, where patients receiving VAPEC-B did equally well (Fig 3). Once again, a test for treatment times prognostic group interaction was nonsignificant (P = .09).



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  		Fig 2. Kaplan-Meier plots of EFS according to Hasenclever index grouped scores <= 2 (low risk) or >= 3 (intermediate/high risk). The faint line represents the ChlVPP/EVA arm and the bold line represents the VAPEC-B arm.

 


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  		Fig 3. Kaplan-Meier plots of EFS according to Hasenclever index grouped scores (<= 2 or >= 3) and presence/absence of bulk disease. In all but the lowest risk group (nonbulky, Hasenclever score <= 2), there were significantly fewer events on the ChlVPP/EVA arm (faint line) than on the VAPEC-B arm (bold line).

 
Second Malignancy
A total of eight patients have so far developed second malignancy, and five of these have died of this complication (Table 4). In three patients, a diagnosis of acute myeloid leukemia/myelodysplastic syndrome or NHL was made, and only one of these has survived. The remainder (n = 5) developed solid tumors, usually carcinoma, but a single case of teratoma also occurred.


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  		Table 4. Table 4. Incidence of Second Malignancy
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This trial comparing ChlVPP/EVA hybrid with VAPEC-B was closed prematurely after the third planned interim analysis in September 1996, and now, with a median follow-up for survivors of 4.9 years, the substantial differences in FFP and EFS noted at that time are seen to persist. Of greater concern is that despite uniform management of progressive HD on both arms of the trial, a survival difference has been detected, with a 5-year OS of 89% for ChlVPP/EVA hybrid and 79% for VAPEC-B (P = .04).

These results seen with VAPEC-B compare unfavorably with those reported for the remarkably similar Stanford V regimen which, in a single-center, nonrandomized study was associated with an actuarial FFP at 6 years of 89% (compared with 62% at 5 years for VAPEC-B).21,22 In a subsequent multicenter study performed by the Eastern Cooperative Oncology Group and involving 47 patients,23 these excellent results were confirmed, with an actuarial FFP of 87% at 5 years. Both therapies use myelosuppressive and relatively nonmyelosuppressive drugs on an alternating, weekly basis for 11 (VAPEC-B) or 12 weeks (Stanford V), with continuous corticosteroids and prophylactic antibiotics/antifungals (plus prophylaxis for herpes zoster and steroid-induced gastritis/duodenitis in the case of the Stanford V regimen).

It is difficult to ascribe the apparent large disparity in outcome to the seemingly minor differences between VAPEC-B and Stanford V, and other factors need to be considered. The most striking is RT policy. In the trial described in this article, consolidation RT was given after chemotherapy to sites of previous bulk (mediastinal masses with a maximum transverse diameter >= 0.33 of the internal thoracic diameter at T5-6 and masses at other sites >= 10 cm) or to sites of PR, a policy that resulted in 59% of patients being irradiated after VAPEC-B. At Stanford, however, 81 (86%) of 9422 and 41 (87%) of 4723 patients received consolidation RT to sites of previous bulk (defined as masses >= 5 cm), to contiguous extralymphatic sites and, for the first 25 patients treated, to spleens showing nodularity on the initial CT scan and any previously involved site not radiographically normal at the completion of chemotherapy. There is no doubt, therefore, that RT is more commonly used after Stanford V than VAPEC-B, and it is possible that this difference is critical in explaining the discrepancy in outcome between the two treatment programs. A direct comparison of the two RT policies applied to VAPEC-B and Stanford V would, of course, be required to test this hypothesis.

It is of note that the 2-year EFS and OS for ChlVPP/EVA are almost identical to those reported for etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP), a similar seven-drug, etoposide-containing regimen developed by the German Hodgkin’s Lymphoma Study Group.24,25 BEACOPP, which is cycled every 21 days (rather than every 28 days in the case of ChlVPP/EVA), has been tested in baseline (unsupported by hemopoietic growth factor) and escalated dose (supported by granulocyte colony-stimulating factor) versions and is integrated with a RT policy that results in previous sites of 5-cm bulk and residual masses being irradiated. So far, median follow-up is short (27 months), but 2-year results24 are impressive, with freedom from treatment failure and OS of 81% and 94% (BEACOPP baseline) and 89% and 96% (BEACOPP escalated), respectively, remarkably similar to the 2-year EFS and OS of 85% and 92% for ChlVPP/EVA. A previous study has shown ChlVPP/EVA to be markedly gonadotoxic17 and, although published data are not yet available, this is also likely to be the case with BEACOPP. Permanent azoospermia and premature menopause are not, however, a feature of ABVD,26 and ChlVPP/EVA has been tested against this gold-standard four-drug regimen in a national United Kingdom randomized, phase III trial (LY09) that accrued more than 800 patients between February 1998 and its closure in September 2001.

The purpose of the trial reported here was to test the hypothesis that a treatment of relatively low toxicity and short duration is at least as effective in terms of disease control as ChlVPP/EVA hybrid. The results described show that in both low- and intermediate/high-risk patients as described by Hasenclever, VAPEC-B is inferior to ChlVPP/EVA, and for this reason recruitment was halted at the planned third interim analysis. In the subgroup of patients with a Hasenclever score <= 2 and nonbulky disease, however, and with due regard to the fact that a test for treatment times prognostic group interaction was nonsignificant, outcome was uniform across the trial arms. If confirmed in a future randomized trial in a similar population, these data suggest that VAPEC-B could be incorporated into a risk-adjusted treatment strategy for HD. This would move away from a one-fits-all approach and instead aim to match intensity and duration of treatment to the number of risk factors present in an attempt to maximize cure and minimize the adverse effects of chemoradiotherapy.


   ACKNOWLEDGMENTS
 
The contribution of all histopathologists, diagnostic radiologists, nurses, and data managers to this study is gratefully acknowledged.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
1. Young RC, Anderson T, De Vita VT: The treatment of Hodgkin’s disease. Curr Probl Cancer 1: 1-29, 1977[CrossRef][Medline]

2. De Vita VT, Serpick AD, Carbone PP: Combination chemotherapy in the treatment of advanced Hodgkin’s disease. Ann Intern Med 73: 881-895, 1970[Abstract/Free Full Text]

3. Nicholson WM, Beard MEJ, Crowther D, et al: Combination chemotherapy in generalised Hodgkin’s disease. BMJ 3: 7-10, 1970[Abstract/Free Full Text]

4. McElwain TJ, Toy J, Smith E, et al: A combination of chlorambucil, vinblastine, procarbazine and prednisolone for treatment of Hodgkin’s disease. Br J Cancer 36: 276-280, 1977[Medline]

5. Bonadonna G, Zucchi 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]

6. Santoro A, Bonadonna G, Valagussa P, et al: Long term results of combined chemotherapy-radiotherapy approach in Hodgkin’s disease: Superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol 5: 27-37, 1987[Abstract]

7. Bonadonna G, Valagussa P, Santoro A: Alternating non-cross-resistant combination chemotherapy or MOPP in stage IV Hodgkin’s disease. Ann Intern Med 104: 739-746, 1986[Abstract/Free Full Text]

8. Canellos GP, Anderson JR, Propert KJ, et al: Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD or MOPP alternating with ABVD. N Engl J Med 21: 1478-1484, 1992

9. Klimo P, Connors J: MOPP/ABV hybrid program: Combination chemotherapy based on early introduction of seven effective drugs for advanced Hodgkin’s disease. J Clin Oncol 3: 1174-1182, 1985[Abstract/Free Full Text]

10. Connors JM, Klimo P: MOPP/ABV hybrid chemotherapy for advanced Hodgkin’s disease. Semin Hematol 24: 35-40, 1987 (suppl 1)[Medline]

11. Richards MA, Waxman JH, Man T, et al: EVA treatment for recurrent or unresponsive Hodgkin’s disease. Cancer Chemother Pharmacol 18: 51-53, 1986[CrossRef][Medline]

12. Radford JA, Crowther D, Rohatiner AZS, et al: Results of a randomized trial comparing MVPP chemotherapy with a seven drug hybrid regimen ChlVPP/EVA, in the initial treatment of Hodgkin’s disease. J Clin Oncol 13: 2379-2385, 1995[Abstract/Free Full Text]

13. Radford JA, Whelan JS, Rohatiner AZS, et al: Weekly VAPEC-B chemotherapy for high grade non-Hodgkin’s lymphoma: Results of treatment in 184 patients. Ann Oncol 5: 147-151, 1994[Abstract/Free Full Text]

14. Radford JA, Crowther D: Treatment of relapsed Hodgkin’s disease using a weekly chemotherapy of short duration: Results of a pilot study in 20 patients. Ann Oncol 2: 505-509, 1991[Abstract/Free Full Text]

15. Radford JA, Cowan RA, Ryder WDJ, et al: Four weeks of neo-adjuvant chemotherapy leads to a significant reduction in progression rate in patients treated with limited field radiotherapy for clinical stage IA/IIA Hodgkin’s disease: Results of a randomised pilot study. Fourth International Symposium on Hodgkin’s Lymphoma, Cologne, Germany, March 28-April 1, 1998 (abstr 0-5)

16. Radford JA, Clark S, Crowther D, et al: Male fertility after VAPEC-B chemotherapy for Hodgkin’s disease and non-Hodgkin’s lymphoma. Br J Cancer 69: 379-381, 1994[Medline]

17. Clarke ST, Radford JA, Crowther D, et al: Gonadal function following chemotherapy for Hodgkin’s disease: A comparative study of MVPP and a seven drug hybrid regimen. J Clin Oncol 12: 134-139, 1995

18. Lister TA, Crowther D, Sutcliffe SP, et al: Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswolds Meeting. J Clin Oncol 7: 1630-1636, 1989[Abstract]

19. Freedman LS, Lowe D, Macaskill P: Stopping rules for clinical trials incorporating clinical opinion. Biometrics 40: 575-586, 1984[CrossRef][Medline]

20. Hasenclever D, Diehl V: A prognostic score for advanced Hodgkin’s disease. N Engl J Med 339: 1506-1514, 1998[Abstract/Free Full Text]

21. 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]

22. Horning SJ, Rosenberg SA, Hoppe RT: Brief chemotherapy (Stanford V) and adjuvant radiotherapy for bulky or advanced Hodgkin’s disease: An update. Ann Oncol 7: 5105-5108, 1996 (suppl 4)

23. Horning SJ, Williams J, Bartlett NL, et al: Assessment of the Stanford V 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]

24. Diehl V, Franklin J, Hasenclever D, et al: BEACOPP, a new dose-escalated and accelerated regimen, is at least as effective as COPP/ABVD in patients with advanced-stage Hodgkin’s lymphoma: Interim report from a trial of the German Hodgkin’s Lymphoma Study Group. J Clin Oncol 16: 3810-3821, 1998[Abstract/Free Full Text]

25. Sieber M, Engert A, Diehl V: Treatment of Hodgkin’s disease: Results and current concepts of the German Hodgkin’s Lymphoma Study Group. Ann Oncol 11: 81-85, 2000 (suppl 1)[Abstract/Free Full Text]

26. Viviani S, Santoro A, Ragni G, et al: Gonadal toxicity after combination chemotherapy for Hodgkin’s disease: Comparative results of MOPP versus ABVD. Eur J Cancer Clin Oncol 21: 601-605, 1985[CrossRef][Medline]

Submitted November 29, 2000; accepted March 21, 2002.


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F. Trotta, G. Apolone, S. Garattini, and G. Tafuri
Stopping a trial early in oncology: for patients or for industry?
Ann. Onc., July 1, 2008; 19(7): 1347 - 1353.
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P. G. Gobbi, C. Broglia, A. Levis, A. La Sala, F. Valentino, T. Chisesi, S. Sacchi, F. Corbella, L. Cavanna, E. Iannitto, et al.
MOPPEBVCAD Chemotherapy with Limited and Conditioned Radiotherapy in Advanced Hodgkin's Lymphoma: 10-Year Results, Late Toxicity, and Second Tumors
Clin. Cancer Res., January 15, 2006; 12(2): 529 - 535.
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P. W.M. Johnson, J. A. Radford, M. H. Cullen, M. R. Sydes, J. Walewski, A. S. Jack, K. A. MacLennan, S. P. Stenning, S. Clawson, P. Smith, 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 (ISRCTN97144519)
J. Clin. Oncol., December 20, 2005; 23(36): 9208 - 9218.
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A. Engert, V. Ballova, H. Haverkamp, B. Pfistner, A. Josting, E. Duhmke, K. Muller-Hermelink, and V. Diehl
Hodgkin's Lymphoma in Elderly Patients: A Comprehensive Retrospective Analysis From the German Hodgkin's Study Group
J. Clin. Oncol., August 1, 2005; 23(22): 5052 - 5060.
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D. Re, R. K. Thomas, K. Behringer, and V. Diehl
From Hodgkin disease to Hodgkin lymphoma: biologic insights and therapeutic potential
Blood, June 15, 2005; 105(12): 4553 - 4560.
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V. Ballova, J.-U. Ruffer, H. Haverkamp, B. Pfistner, H. K. Muller-Hermelink, E. Duhmke, P. Worst, M. Wilhelmy, R. Naumann, M. Hentrich, et al.
A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin's disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly)
Ann. Onc., January 1, 2005; 16(1): 124 - 131.
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M. Bendandi, S. A. Pileri, and P. L. Zinzani
Challenging paradigms in lymphoma treatment
Ann. Onc., May 1, 2004; 15(5): 703 - 711.
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V. Diehl, J. Franklin, M. Pfreundschuh, B. Lathan, U. Paulus, D. Hasenclever, H. Tesch, R. Herrmann, B. Dorken, H.-K. Muller-Hermelink, et al.
Standard and Increased-Dose BEACOPP Chemotherapy Compared with COPP-ABVD for Advanced Hodgkin's Disease
N. Engl. J. Med., June 12, 2003; 348(24): 2386 - 2395.
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M. Sieber, H. Bredenfeld, A. Josting, T. Reineke, U. Rueffer, T. Koch, R. Naumann, F. Boissevain, P. Koch, P. Worst, et al.
14-Day Variant of the Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, and Prednisone Regimen in Advanced-Stage Hodgkin's Lymphoma: Results of a Pilot Study of the German Hodgkin's Lymphoma Study Group
J. Clin. Oncol., May 1, 2003; 21(9): 1734 - 1739.
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V. Diehl
Advanced Hodgkin's Disease: ABVD Is Better, Yet Is Not Good Enough!
J. Clin. Oncol., February 15, 2003; 21(4): 583 - 585.
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V. Diehl, H. Stein, M. Hummel, R. Zollinger, and J. M. Connors
Hodgkin's Lymphoma: Biology and Treatment Strategies for Primary, Refractory, and Relapsed Disease
Hematology, January 1, 2003; 2003(1): 225 - 247.
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