Annals of Oncology Advance Access originally published online on March 24, 2006
Annals of Oncology 2006 17(6):914-919; doi:10.1093/annonc/mdl063
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© 2006 European Society for Medical Oncology
Highly active antiretroviral therapy (HAART) improves survival in HIV-associated Hodgkin's disease: results of a multicenter study
1 Department of Hematology/Oncology, Hospital Harlaching, Munich; 2 Department of Infectious Diseases, Auguste Victoria Hospital, Berlin; 3 Department of Hematology/Oncology, University Hospital Frankfurt, Frankfurt; 4 Department of Internal Medicine, University Hospital Innenstadt, Munich; 5 Department of Infectious Diseases, Charité University Medicine, Berlin; 6 KIS-Curatorium for Immunodeficiency, Munich; 7 Department of Internal Medicine, University Hospital Münster; 8 Department of Internal Medicine I, University Hospital Bonn; 9 Department of Hematology/Oncology, Charité University Medicine, Berlin; 10 Clinic for Gastroenterology, Hepatology, and Infectious Diseases, University Clinic Düsseldorf; 11 Practice for Hematology, Oncology and Infectious Diseases, Bremen, Germany
* Correspondence to: Dr M. Hentrich, Munich Harlaching Hospital, Academic Teaching Hospital of the University of Munich, Department of Hemtaology-Oncology, Sanatoriumsplatz 2, 81545 Munich, Germany. Tel: +49-89-62103363; Fax: +49-89-62103320; E-mail: tumorzentrum.hentrich{at}khmh.de
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Abstract |
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Background: The purpose of the study was to evaluate the outcome of Hodgkin's disease (HD) in patients infected with the human immunodeficiency virus (HIV) with respect to the use of highly active antiretroviral therapy (HAART).
Materials and methods: This cohort study included patients with HIV-HD diagnosed from June 1984 to February 2004. Patients treated in the pre-HAART era (1984–1996) were compared with those belonging to the HAART era (1997–2004).
Results: Of 66 patients with HIV-HD, 47 (71%) presented with stage III/IV disease and 38 patients (58%) with an AIDS-defining illness. Fifty-nine of 66 patients (89.4%) underwent curative intended chemotherapy. Patients receiving HAART (n = 34) had a significantly better 2-year overall survival (OS) than those not receiving HAART (74% versus 30%, P <0.001). The 2-year OS of HAART-responders was 88% compared with 19% in patients without HAART-response (P = 0.0002). By multivariate analysis patients without HAART had a 5.6-fold higher risk for 3-year mortality [HR 5.6, 95% confidence interval (CI) 2.20–14.26]. Three-year mortality was significantly higher in patients without complete remission (HR 4.40, CI 1.77–10.99), with stage III/IV HD (HR 4.64, CI 1.31–16.49) and with CD4 cells <200/µl (HR 2.69, CI 0.99–7.33).
Conclusions: Use of HAART significantly improved the overall survival in patients with HIV-HD.
Key words: HIV infection, Hodgkin's disease, HIV-associated Hodgkin's disease, HIV-associated cancer, AIDS
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Hodgkin's disease (HD) has been shown to be the most common non-AIDS-defining malignancy in patients infected with the human immunodeficiency virus (HIV). HIV-infection increases the risk of developing HD by approximately eight to 10-fold compared with the general population [1
–3] with some studies having reported a relative risk of even 16–30 [4–6]. HIV-related HD (HIV-HD) is characterized by several unfavorable features such as higher frequency of advanced stage disease, extranodal involvement and mixed cellularity or lymphocyte depletion histological subtypes [7]. Before the introduction of highly active antiretroviral therapy (HAART) the median survival of patients with HIV-HD was less than 20 months [8–10]. Poor tolerance of, and low response rates to, chemotherapy contributed to a poor treatment outcome. Based on a limited number of patients, recent studies indicate an improved survival in patients with HIV-HD treated in the HAART era [11, 12]. However, further and more detailed data on the use of chemotherapy and concomitant HAART in patients with HIV-HD compared with those treated in the pre-HAART era are warranted. The present study was carried out to evaluate characteristics, therapy and outcome of HIV-HD, in particular with respect to the use of HAART. |
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inclusion criteria
This multicenter retrospective cohort study included all patients with histologically proven HIV-HD diagnosed and/or treated from June 1984 to February 2004 at 11 institutions in Germany. All records were reviewed with respect to: (a) HD-parameters such as age, sex, B-symptoms, date of diagnosis and stage of HD, extranodal involvement, lactate dehydrogenase (LDH), histological subtype according to the WHO classification and treatment of HD (type, duration, side effects); (b) HIV-parameters such as risk behavior, CDC category, course of CD4+ lymphocyte counts and viral load, duration and type of antiretroviral therapy used; and (c) outcome of patients with respect to HIV-infection and HD.
exclusion criteria
Patients in which the HIV-infection was not confirmed by Western blot and those in which HD was not proven histologically, were excluded from the study. Furthermore, patients under 18 years of age were not included in the study.
staging
Patients were evaluated for the staging of HD by history, physical examination, hematology and blood chemistry tests, chest X-ray, CT-scans of chest, abdomen and pelvis, and bone marrow biopsies. Ann Arbor staging system was applied. The status of HIV infection was classified according to the 1993 Center for Disease Control and Prevention (CDC) criteria [13].
treatment and evaluation of response
HAART, which has been widely used in Germany since 1997, was defined as a combination therapy containing a protease inhibitor (PI) and/or a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a combination therapy of at least three antiretroviral drugs for a minimum of 3 months. HAART-response was defined as an increase in the CD4+ lymphocyte count of at least 100/µl and/or at least one plasma HIV-RNA viral load below 500 copies/ml following diagnosis of Hodgkin's disease. Chemotherapy regimens mainly used were: ABVD (adriamycin, bleomycin, vinblastine, dacarbazine), alone or combined in alternating cycles with COPP (cylophosphamide, vincristine, procarbazine, prednisone), CHOP (cyclophosphamide, adriamycin, vincristin, prednione), BEACOPP (bleomycin, etoposide, adriamycine, cyclophosphamide, vincristine, procarbazine, prednisone) or EBOEB (epirubicin, bleomycin, vincristine, etoposide, prednisone), the latter used in only one institution. In addition, DexaBeam (dexamethasone, carmustine, etoposide, cytarabine, melphalan) or IMVP-16 (ifosfamide, methotrexate, etoposide) served as salvage regimens. Patients who received at least two courses of chemotherapy were evaluated for response. Complete remission (CR) was defined as absence of HD by means of clinical features and imaging studies for at least 4 weeks. Partial remission (PD) was described as more than 50% reduction in the product of the perpendicular diameters of all tumors assessed with no lesions occurring. Progressive disease (PD) was defined as a reduction of less than 50% or an increase of more than 25% in the measured lesion or the occurrence of new lesions.
Toxicity was rated according to WHO criteria.
statistics
Significant associations between categorical characteristics were assessed by 
2 test; in case of not reaching Cochran's criterion, Fisher's exact test was used. Group differences in median values of continuous characteristics were analyzed by Mann–Whitney U-test.
Progression-free survival (PFS) was measured from the beginning of the treatment to the time of primary treatment failure or relapse. Overall survival (OS) was calculated from the beginning of the treatment to last follow-up or to death from any cause. PFS could be assessed for 61 patients with a median follow-up of 24 months; OS was available in all patients with a median follow-up of 25 months (range for both 0.5–98). The probability of PFS and OS was determined by the method of Kaplan–Meier and differences between subgroups of patients were assessed by the log-rank test. Cox proportional hazards models were used to assess PFS and OS in multivariate analysis.
Statistical analyses were performed using SAS software, version 9.0 (SAS Institute, Inc., Cary, NC, USA). All P values were two-sided. P values of 0.05 or less were considered statistically significant.
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patients characteristics
From June 1984 to February 2004 a total of 66 patients with histologically proven HIV-HD were identified. Forty-seven patients (71%) presented with advanced stage Hodgkin's disease and 38 (58%) were found to have an AIDS-defining illness at diagnosis. Patients' baseline characteristics are outlined in Table 1. When baseline characteristics were compared with respect to the pre-HAART and post-HAART period, no significant differences were found apart from B-symptoms which occurred less frequently in the post-HAART group of patients (Table 2). Likewise, more patients diagnosed in the pre-HAART period appeared to have AIDS and CD4 lymphocytes less than 200/µl, but the difference is not statistically significant (Table 2).
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radiotherapy
One patient with stage IA disease was treated by curative radiotherapy only (46 Gy). Furthermore, 15 of 59 patients (25.4%) received additional radiotherapy.
chemotherapy
Six of 66 patients (9.1%) did not receive antineoplastic treatment because they either refused chemotherapy (n = 1), the performance status was too poor (n = 4) or Hodgkin's disease was diagnosed post-mortem (n = 1). Fifty-nine of 66 patients (89.4%) underwent curative intended chemotherapy, consisting of ABVD (n = 18), ABVD combined in alternating cycles with COPP (n = 18), CHOP (n = 9), EBOEP alone (n = 6) or in alternating cycles with COPP (n = 2), BEACOPP (n = 4) and EBVD (n = 1). Data on the regimen used were not available in one case. The median number of completed cycles was 4.8 (range 0–13). Of note, significantly more patients in the HAART group received curative intended chemotherapy compared with patients treated in the pre-HAART era (Table 2). Eight patients underwent salvage chemotherapy for relapsed or primary progressive disease consisting of BEACOPP (n = 4), IMVP16 (n = 3) and Dexa-BEAM (n = 1).
response to chemotherapy
Fifty-eight of 59 patients receiving chemotherapy were evaluable for response. Thirty-four patients (58.6%) achieved a complete response (CR) and 14 patients (24.2%) a partial remission (PR) resulting in an overall response rate of 83%. Progressive disease was observed in 10 patients (17.2%). More patients in the HAART group achieved a complete response compared with patients in the pre-HAART group (65% versus 50%) but the difference is not significant (P = 0.153) (Table 2). Eleven of 48 patients (23%) who had initially responded to inductive chemotherapy relapsed, four of 34 (12%) after having experienced a CR and seven of 14 (50%) after PR.
toxicity
Data on hematological toxicity were available in 49 patients who underwent curative intended chemotherapy. Grade 3/4 leukopenia and thrombocytopenia occurred in 18 (36.7%) and 13 (26.5%) patients, respectively. Under chemotherapy, 26 of 59 patients (44.1%) developed opportunistic infections, in particular oropharyngeal and esophageal candidiasis (n = 22), herpes zoster (n = 11), Pneumocystis carinii pneumonia (n = 7) as well as infections caused by mycobacterium avium-intracellulare (n = 4) and cytomegalovirus (n = 2). Moreover, Kaposi's sarcoma developed in six patients (10.3%).
antiretroviral therapy
Eleven of 66 patients (16.7%) were diagnosed and treated for HIV-HD prior to 1987, the year when nucleoside reverse transcriptase inhibitor (NRTI) became available in Germany. Furthermore, detailed information on the use of antiretroviral therapy is lacking in five patients, four of those belonging to the pre-HAART and one belonging to the post-HAART period. However, the latter patient did receive HAART as documented in the records even though the drugs given are not known. Thus, antiretroviral drugs were initiated in 51 patients within the period of September 1989 to August 2002, with 34 of those (67%) receiving HAART and 17 receiving nucleoside reverse transcriptase inhibitors (NRTI) only. Data on the use of HAART at the time of HD diagnosis are available in 32 of 34 patients. Twenty-six of 32 patients (81.3%) were already on HAART and six (18.8%) proved to be HAART-naive. Finally, 21 of 29 evaluable HAART patients (72.4%) experienced a response to HAART.
survival analysis
Thirty-seven of 66 patients died (56.1%), 26 in the pre-HAART era and 11 while on HAART. Causes of death were HIV-related complications in 17 cases (14 pre-HAART), progressive HD in nine (six pre-HAART), and both progressive HIV-infection and HD in seven cases (five pre-HAART). Two patients died of cardiovascular disease while on HAART, one died of secondary non-Hodgkin's lymphoma (pre-HAART) and one patient committed suicide (HAART era). More patients in the pre-HAART era tended to die of HIV-related complications compared with post-HAART (19 of 26 versus 5 of 11) but the difference was not statistically significant (0.085). The mean progression-free survival (PFS) of the entire study population was 46.5 months (standard error 2.9) and the mean overall survival (OS) 37.9 months (standard error 3.7). The 3-year overall survival rate was 42% with no significant differences found between the histopathological subtypes (P = 0.5) (Table 3). However, the estimated 2-year survival was 74% in patients who presented with CDC stage A/B compared with 36% in those with CDC stage C (P = 0.006). Patients receiving HAART (n = 34) had a better 2-year OS compared with those in the pre-HAART group (74% versus 30%, P < 0.001) (Figure 1). The median survival was not reached in patients on HAART compared with a median survival of 11 months in patients without HAART. Moreover, the 2-year OS probability of HAART-responders was 88% compared with 19% in patients without a response to HAART in 29 patients with available information on HAART response (P = 0.0002) (Figure 2). With respect to the univariate analysis, six parameters were found to be significantly associated with a better overall survival: age 
45 years (P = 0.0014), HAART-use (P < 0.0001), HAART response (P = 0.0002), CDC category (P = 0.0064), CD4 cell count (P = 0.0037), CR after chemotherapy (P < 0.0001), and HD stage (P = 0.016) (Table 3). To test whether the association of HAART use on OS was affected by confounding variables, a multivariate analysis including those variables that proved significant by univariate testing was carried out in all patients with complete values on all covariates (56 patients with 28 having died during follow-up). To reach sufficient cell allocations, age was included as continuous, CDC category and CR after chemotherapy as dichotomous variables in the Cox model (Table 4). HAART use remained significant with a 5.6-fold higher risk for 3-years mortality in patients without HAART compared with those on HAART (hazard ratio: 5.60, 95% CI 2.20–14.26, P = 0.0003). Similar results were found for mortality over the whole follow-up time. Likewise, a non-CR to curative intended chemotherapy (HR 4.66, P = 0.0010), HD stage III/IV (HR 3.62, P = 0.0397) and CD4 cell counts <200/µl (HR 2.74, P = 0.0492) were significantly associated with a higher total mortality while CDC category at diagnosis of HD failed to remain significant (P > 0.2). Age revealed no significance in the multivariate model. By contrast, the use of HAART remained significant even after adjustment for patients in complete remission.
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The major finding from this study is that the prognosis of patients with HIV-associated Hodgkin's disease has considerably improved with the introduction of HAART. In addition, a CR to curative intended chemotherapy, stage I/II HD and CD4 cell counts
200/µl were independently associated with an improved OS. Whereas opportunistic infections were a common deleterious side-effect of chemotherapy in the pre-HAART era, patients apparently tolerate antineoplastic therapy better if they receive HAART in parallel to chemotherapy or immediately thereafter. Of interest, the significant impact of HAART on overall survival is independent of the remission status achieved, as patients with CR receiving HAART did significantly better than those without HAART. Thus, controlling the underlying HIV infection appears most important even if a satisfactory response to chemotherapy is achieved.
Since the baseline characteristics of HD have not changed over the period of time, the better outcome in patients post-HAART cannot be attributed to more favorable features at presentation. However, more patients with HIV-HD diagnosed in the pre-HAART era presented with previous AIDS-defining illnesses and CD4+ cell counts below 200/µl compared with patients in the post-HAART period even though the difference is not statistically significant. Conversely, patients without prior AIDS and those with CD4+ lymphocytes above 200/µl did significantly better than patients with advanced stage HIV disease. Of note, more patients belonging to the pre-HAART period tended to die of HIV-related complications than those under HAART. Overall, these observations indicate that it is of outstanding importance to control the HIV infection when antineoplastic therapy for HIV-HD has to be initiated. As HAART use was an independent prognostic factor for an improved survival in this study it should be offered to all patients undergoing antineoplastic therapy. Of note, the 88% overall survival in patients responding to HAART compares favorably with results from a smaller study reported recently [14]. The question whether antiretrovirals should be given concomitantly to chemotherapy for malignant lymphomas, remains controversial. While some investigators favor stopping HAART during antineoplastic treatment in order to reduce cumulative toxicity [15], several studies found a simultaneous approach feasible and safe [16–19]. Although possible pharmacokinetic interactions between antiretroviral and antineoplastic drugs must be considered, recent studies did not indicate clinically relevant interactions between both groups of drugs [18, 20, 21]. In our cohort, the majority of patients received HAART concomitant to chemotherapy with no serious clinical interactions observed.
Our study population is similar to those reported previously as the majority of patients presented with advanced stage disease, B symptoms and at least one extranodal manifestation [14, 22]. However, whereas most patients from southern European series were intravenous drug users [10, 23–25] the major risk factor for HIV infection in this cohort was homosexual contact. A limitation of the study is that the International Prognostic Score (IPS) established for HIV-negative patients with HD [26] cannot be applied because some parameters such as serum albumin at diagnosis were not completely available. However, the present analysis clearly identified prognostic factors adapted to a cohort of HIV-infected patients. Of note, the incidence of HD in the HIV setting has not declined with the advent of HAART thus still representing a therapeutic challenge [5, 27, 28]. A recent study even found a three-fold higher risk of HD in HIV-infected individuals treated with HAART than in those not treated [6]. Standard chemotherapy for HIV-HD has not been defined yet. Previous phase II studies on the use of ABVD or ABVD-like regimens showed response rates in the range of 43%–75% with a median survival of 11–18 months [10, 29, 30]. However, all of these trials were conducted before the introduction of HAART. The only prospective trial of chemotherapy and concomitant HAART in patients with HIV-HD published so far used the Stanford V regimen, which resulted in a CR rate of 81% and a 3-year overall survival rate of 51% [19]. Even though this represents a significant improvement it is still below what is reported in the general population [31]. Based on a limited number of patients, promising results have also been reported by using the BEACOPP regimen [32]. Thus, HAART does allow the employment of more aggressive regimens. Notably, even high-dose chemotherapy with autologous stem cell transplantation has been shown to be feasible in AIDS-related lymphoma. This approach may be potentially curative in selected patients with relapsed HIV-associated HD [33, 34]. In conclusion, the use of HAART has significantly improved the survival of patients with HIV-HD. The optimal chemotherapeutic approach for HIV-HD should be further evaluated by prospective trials.
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Acknowledgements |
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We thank Clemens Scheidegger, Oncology Practice, Munich, Germany, for participating in the study and his support in collecting the data. Furthermore, we are indebted to Jens Baumert for his expert statistical support.
Received for publication November 29, 2005. Accepted for publication February 27, 2006.
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