Abstract

Background: The Stanford group has reported excellent results with the Stanford V regimen for patients with bulky and/or advanced Hodgkin lymphoma (HL). However, Gobbi reported markedly inferior failure-free survival (FFS) comparing Stanford V to other regimens but included major deviations from the original program. We retrospectively examined whether treatment at our institution carefully following Stanford V guidelines would confirm the original Stanford outcome data.

Patients and methods: From June 1995 to May 2002, 126 patients with either locally extensive or advanced HL were treated with the 12-week Stanford V chemotherapy program followed by 36-Gy involved-field radiotherapy to sites initially ≥5 cm and/or to macroscopic splenic disease. Overall, 26% had stage IV disease and 20% had international prognostic score (IPS) ≥4. Overall survival (OS), disease-specific survival, progression-free survival (PFS), FFS, and freedom from second relapse (FF2R) were determined.

Results: The 5- and 7-year OS were 90% and 88%, respectively. The 5-year FFS was 78%. IPS ≥4 was a significant independent predictor of worse OS and PFS. The FF2R was 64% at 3 years.

Conclusion: Stanford V with appropriate radiotherapy is a highly effective regimen for locally extensive and advanced HL.

introduction

Several effective chemotherapy or combined-modality regimens are currently available for treatment of advanced-stage Hodgkin lymphoma (HL), but there is no consensus as to the optimal treatment regimen [1–4]. Data from recent phase III studies have not matured as yet [5–8].

National Comprehensive Cancer Network 2008 guidelines list three different options that are currently acceptable to most cancer centers in the United States for treatment of bulky and/or advanced-stage HL [9]. In North America, the combination of doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD) remains the norm to which new regimens of escalated or standard BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) or Stanford V (nitrogen mustard, doxorubicin, bleomycin, vincristine, vinblastine, etoposide, and prednisone) should be compared.

A seminal, randomized, three-arm study established the superiority of ABVD over MOPP (nitrogen mustard, vincristine, procarbazine, and prednisone)—the previous standard [10, 11]. The 5-year failure-free survival (FFS) and overall survival (OS) for ABVD were 63% and 81%, respectively. MOPP alternating with ABVD has had a similar outcome but produced more toxicity compared with ABVD alone. In a randomized intergroup study, ABVD was compared with a MOPP/ABV hybrid. The 5-year FFS for both regimens was 75%, but the hybrid produced more acute myelotoxicity and second malignancies that led to early termination of the study [12].

In an attempt to improve outcome in advanced HL, the German Hodgkin Study Group (GHSG) developed the escalated BEACOPP regimen [13]. When escalated BEACOPP was compared with a cyclophosphamide, oncovin, procarbazine, prednisone (COPP)/ABVD regimen or with a standard-dose BEACOPP, the escalated regimen had a superior outcome across all prognostic groups, particularly in the poor-risk category. At a median follow-up of 5 years, freedom from progression (FFP) and OS with escalated BEACOPP were 87% and 91%, respectively. Yet, the more effective escalated regimen was more myelotoxic and was associated with sterility and increased risk of myelodysplastic syndrome (MDS)/secondary leukemia. In North America, these toxicity concerns have curtailed the wider use of BEACOPP as a standard regimen. Although the randomized study comparing ABVD, COPP/epidoxorubicin, bleomycin, and vinblastine (EBV)/lomustine + Alkeran (CAD), and BEACOPP using a 4 : 2 combination of escalated and standard BEACOPP did not report any myelotoxicity in the BEACOPP arm, fertility was not preserved [14].

The Stanford V program is a brief (12 weeks) weekly chemotherapy program, supplemented in most patients with involved-field radiotherapy (IFRT) given to sites originally ≥5 cm and/or to macroscopic splenic disease. The objective is to maintain or improve the outcome of patients with locally extensive/or advanced HL while minimizing both short- and long-term toxicity. At Stanford, the 5-year FFP was 89% and OS was 96%. The program was well tolerated, with no pulmonary toxicity [15, 16].

A valid concern regarding the reproducibility of the Stanford results was raised when an Italian group published the outcome of a randomized study comparing Stanford V to ABVD and MEC (MOPP/EBV/CAD), another multiagent chemotherapy regimen. The estimated 3-year FFS for Stanford V, MEC, and ABVD were 53%, 87%, and 81%, respectively [17, 18]. These results differed markedly from the original Stanford results. A recent update of this trial showed equivalent OS for the three arms but FFS for the Stanford V arm remained inferior and there were two additional relapses, both occurring in the Stanford V arm [19].

While the Italian study was criticized for design flaws and conduct of the Stanford V arm, particularly with regard to the radiotherapy (RT) component, some indicated that Stanford V might not be effective outside its site of design and expertise [14]. To examine this concern, we analyzed our 7-year Memorial Sloan-Kettering Cancer Center (MSKCC) experience with Stanford V ± IFRT in the treatment of advanced and locally extensive Hodgkin disease, following Stanford radiation guidelines exactly. We report OS, disease-specific survival (DSS) and progression-free survival (PFS), with an analysis of outcomes by stage and international prognostic score (IPS). We also report the management of treatment failures and freedom from second relapse (FF2R) rates for salvage patients and identify pretreatment characteristics that independently predict outcome as determined by multivariate analysis.

patients and methods

From June 1995 to May 2002, 130 consecutive patients with biopsy-proven locally extensive or advanced disease (stage III or IV) were treated at MSKCC according to the Stanford V regimen, based on physician–patient preference, and not on protocol. Four patients, who did not have RT information from outside institutions and did not have follow-up for >5 years, were excluded from this study. This retrospective study was carried out on the remaining 126 patients, after obtaining consent from the MSKCC Institutional Review Board.

The Stanford V chemotherapy regimen was given over 12 weeks, and granulocyte-colony stimulating factor was administered, as previously described according to the Stanford V protocol [16]. Patients with initially bulky disease (>5 cm in transverse diameter or ≥0.33 of the transverse diameter of the chest wall) and patients with macroscopic splenic disease were treated with RT initiated 2–4 weeks after completion of chemotherapy, with 1.8-Gy daily fractions for a total of 20 fractions (36 Gy). Patients were assessed after 8 weeks of chemotherapy, at the end of chemotherapy, at the end of RT, and at follow-up visits thereafter. Response and follow-up evaluation included physical examination; chest radiograph; complete blood count; chemistry panel; and chest, abdominal, and pelvic computed tomography (CT) scans. Bone marrow biopsy, gallium scans or positron emission tomography (PET) scans, and bone scans were carried out if positive on initial evaluation. Complete response (CR) was defined as negative PET or gallium scan with either improved [formerly CRu (uncertain complete response)] or normalized CT scan. Follow-up assessment was conducted as per the Stanford guidelines [16].

statistical analysis

OS was defined as the time from start of treatment to death from any cause or last follow-up and was estimated using the Kaplan–Meier method. Survival curves were compared using the log-rank test. DSS and PFS were defined as the time from start of treatment to last follow-up, death from disease, or first relapse. Since some patients died from other causes or died without relapse, we used methods of competing risk survival analysis to estimate and compare the cumulative incidence of DSS or PFS [20]. FFS was defined as time from start of treatment to last follow-up or disease progression, any post-treatment response less than CR, relapse, or death from any cause. FF2R was defined as time from start of salvage therapy to second relapse, death from any cause, or last follow-up.

Univariate tests for the association between prognostic factors and OS time were determined using the Cox proportional hazards model. Prognostic factors that were significant in univariate analysis (P < 0.05) were included in a multivariate model. To assess the effects of prognostic factors on DSS, multivariate competing risk regression analysis was used [21]. All statistical tests were carried out in SAS 9.1 or library cmprsk in R.

results

patient characteristics

Patient and disease characteristics are listed in Table 1. Table 2 shows the distribution of study participants according to IPS for advanced-stage HL [22].

Table 1.

Patient characteristics (N = 126)

Characteristic No. of patients (%) 
Median age, years (range) 33 (17–66) 
Gender  
    Male 61 (48) 
    Female 65 (52) 
Histology  
    Nodular sclerosis 106 (84) 
    Mixed cellularity 15 (12) 
    Other 5 (4) 
Stage  
    I 2 (2) 
        IAX 
        IBX 
    II 65 (51) 
        IIAE 
        IIAX 30 
        IIB 
        IIBX 31 
    III 26 (21) 
    IV 33 (26) 
B symptoms 73 (58) 
Pruritus 54 (43) 
Splenic involvement 21 (17) 
Mediastinal disease 111 (88) 
    Bulky mediastinala 85 (67) 
Extranodal disease 63 (49) 
    Lung 29 (23) 
    Pericardium 7 (6) 
    Pleura 7 (6) 
    Chest wall 12 (10) 
    Liver 10 (8) 
    Bone marrow 10 (8) 
    Bone 18 (14) 
Bulky diseaseb 91 (72) 
Characteristic No. of patients (%) 
Median age, years (range) 33 (17–66) 
Gender  
    Male 61 (48) 
    Female 65 (52) 
Histology  
    Nodular sclerosis 106 (84) 
    Mixed cellularity 15 (12) 
    Other 5 (4) 
Stage  
    I 2 (2) 
        IAX 
        IBX 
    II 65 (51) 
        IIAE 
        IIAX 30 
        IIB 
        IIBX 31 
    III 26 (21) 
    IV 33 (26) 
B symptoms 73 (58) 
Pruritus 54 (43) 
Splenic involvement 21 (17) 
Mediastinal disease 111 (88) 
    Bulky mediastinala 85 (67) 
Extranodal disease 63 (49) 
    Lung 29 (23) 
    Pericardium 7 (6) 
    Pleura 7 (6) 
    Chest wall 12 (10) 
    Liver 10 (8) 
    Bone marrow 10 (8) 
    Bone 18 (14) 
Bulky diseaseb 91 (72) 
a

Bulky mediastinal disease is defined as ≥0.33 of the transverse diameter of the chest wall.

b

Bulky disease is defined as ≥10 cm in transverse diameter.

Table 2.

Distribution by international prognostic score in study participants (N = 126)

No. of factors No. of patients (%) 
15 (12) 
34 (27) 
37 (29) 
20 (16) 
≥4 20 (16) 
No. of factors No. of patients (%) 
15 (12) 
34 (27) 
37 (29) 
20 (16) 
≥4 20 (16) 

administration of therapy

The majority (97%) of patients (n = 122) completed the 12-week Stanford V chemotherapy course. Four (3%) patients received an abbreviated 11-week course of chemotherapy, three because of abnormal Pulmonary Function Tests and peripheral neuropathy and one because of an upper respiratory infection. Radiation therapy was administered to 111 patients (88%). Of the 15 patients who did not receive RT, 10 had nonbulky disease and therefore did not qualify for radiation by Stanford guidelines; five patients relapsed during or directly following chemotherapy and proceeded directly to salvage treatment.

acute and long-term toxicity

Acute toxicity was defined as toxic effects of treatment observed during chemoradiation (CMRT) or within 3 months of RT. The most common sites of acute toxicity were esophagus (n = 82), skin (n = 78), and pharynx (n = 78). Grade 1 inflammation was observed in most cases. Five patients developed radiation pneumonitis including on 1 grade 3 and 1 grade 2 pneumonitis. One patient required an abbreviated course of bleomycin due to decreased Diffusing capacity of the lung for Carbon Monoxide. Hematologic toxicity included 15 cases of absolute neutrophil count <1.0 (five grade 1, seven grade 2, and three grade 3); three patients developed grade 1 anemia, and two patients had grade 1 thrombocytopenia.

Long-term toxicity was defined as toxic effects of treatment observed >3 months after treatment. The most common long-term treatment toxicity was subclinical hypothyroidism, based on elevation in thyroid-stimulating hormone that was easily managed (n = 52). Peripheral neuropathy occurred in 42 patients, 38 of which were grade 1. Two patients developed grade 3 peripheral neuropathy, one with hand weakness and the other experienced difficulty walking. One patient developed steroid-induced avascular necrosis and underwent bilateral hip replacement. Twenty-five conceptions were recorded, including a set of twins, two successive pregnancies after treatment and five males who fathered children after treatment without sperm banking.

Ten patients developed documented second cancers; five appear to be treatment related. Four skin cancers developed: three superficial basal cell carcinoma (one related) and one malignant melanoma in situ (related). Two unrelated non-HL occurred 1 month after chemotherapy, an anaplastic large-cell lymphoma and a relapsed patient with composite HL and diffuse large-cell lymphoma. One case of acute myelogenous leukemia (AML), related to salvage treatment, occurred. Three solid cancers were observed: one colon cancer during radiation therapy (unrelated), thyroid papillary carcinoma 10 years after radiation to the mediastinum and supraclavicular area (related), and one squamous cell carcinoma of the oral tongue 7 years after treatment (related).

treatment outcome

At a median follow-up of 92 months, 112 patients were alive, with an OS of 90% [95% confidence interval (CI) 84–95] and 88% (95% CI 83–94) at 5 and 7 years, respectively (Figure 1, panel A). The 5-year FFS was 78% (95% CI 71–85; Figure 1, panel B). The 3-year probability of death due to disease was 7% (95% CI 3–12; Figure 2, panel A). Fourteen patients died: nine of disease, one of toxicity with progressive disease, one of MDS/leukemia after salvage therapy, one of colon cancer with no evidence of HL, one patient with a history of severe sarcoidosis died without evidence of lymphoma at last follow-up and at autopsy, and one patient lost to follow-up died of unknown causes. Of 26 treatment failures observed, 25 underwent salvage therapy, and the 3-year probability of progression was 19% (95% CI 12–26; Figure 2, panel B).

Figure 1.

OS and FFS for 126 patients with locally extensive and advanced-stage Hodgkin disease. The 5- and 7-year OS and FFS were 90% and 88% and 78% and 76%, respectively. There were no events after 7 years. Panel A: OS for 126 patients; panel B: FFS for 126 patients. OS, overall survival; FFS, failure-free survival.

Figure 1.

OS and FFS for 126 patients with locally extensive and advanced-stage Hodgkin disease. The 5- and 7-year OS and FFS were 90% and 88% and 78% and 76%, respectively. There were no events after 7 years. Panel A: OS for 126 patients; panel B: FFS for 126 patients. OS, overall survival; FFS, failure-free survival.

Figure 2.

(A) DSS for all 126 patients treated with the Stanford V regimen. Death from other causes is treated as a competing risk. There were no deaths from disease after 4 years. (B) PFS for all 126 patients treated with the Stanford V regimen. Death without relapse is treated as a competing risk. No relapses occurred after 4 years. DSS, disease-specific survival; PFS, progression-free survival.

Figure 2.

(A) DSS for all 126 patients treated with the Stanford V regimen. Death from other causes is treated as a competing risk. There were no deaths from disease after 4 years. (B) PFS for all 126 patients treated with the Stanford V regimen. Death without relapse is treated as a competing risk. No relapses occurred after 4 years. DSS, disease-specific survival; PFS, progression-free survival.

Patients with IPS ≥4 (n = 20) had an inferior OS compared with those with IPS <4 (n = 106, P = 0.002; Figure 3, panel A). Likewise, patients with IPS ≥4 had a higher probability of progression of 50% versus 11% for patients with IPS < 4. There was no significant difference in OS between stage I–III and stage IV patients (P = 0.13; Figure 4, panel A). However, patients with stage IV disease faired much worse than those with stage I–III disease in terms of disease progression (P = 0.001; Figure 4, panel B) with a 2-year probability of relapse of 36% versus 11%, respectively. Pretreatment characteristics that significantly predicted inferior outcomes on univariate analyses (P < 0.1), shown in Table 3, were entered into multivariate analysis. IPS ≥4 emerged as a significant predictor of OS (P = 0.02), PFS (P = 0.007) and DSS (P = 0.003). Of the International prognostic factors, stage IV disease was the strongest predictor of adverse PFS.

Table 3.

Predictors of treatment outcome by univariate and multivariate analyses

Analyses Overall survival Disease-specific survival Progression-free survival 
HR 95% CI P HR 95% CI P HR 95% CI P 
Univariatea          
    IPS ≥ 4 4.7 1.6–13.5 0.004 7.4 2.3–23.6 0.0008 4.6 2.1–10.2 0.0002 
    Stage IV disease 2.2 0.8–6.4 0.14 2.5 0.8–8.0 0.14 3.4 1.6–7.3 0.002 
    Hemoglobin <10.5 g/dl 2.6 0.9–7.5 0.08 4.1 1.3–13.2 0.02 2.2 1.0–4.9 0.04 
    Serum albumin < 4 g/dl 2.7 0.9–7.9 0.08 3.9 1.1–14.4 0.04 2.1 1.0–4.5 0.06 
    ECOG score ≥ 2 4.0 0.9–17.9 0.07 5.1 1.1–23.1 0.03 3.2 1.0–10.6 0.05 
    B symptoms 1.9 0.6–5.9 0.29 2.0 0.5–7.3 0.31 2.2 0.9–5.1 0.07 
Multivariate          
    IPS ≥ 4 4.2 1.3–13.5 0.02 6.6 1.9–23.0 0.003 2.7 0.9–7.6 0.07, 0.007b 
    ECOG score ≥ 2 1.5 0.3–8.0 0.62 1.5 0.3–7.6 0.60 1.0 0.3–3.7 0.96 
    Stage IV disease – – – – – – 2.5 1.0–6.1 0.04 
    B symptoms – – – – – – 1.5 0.5–4.2 0.45 
Analyses Overall survival Disease-specific survival Progression-free survival 
HR 95% CI P HR 95% CI P HR 95% CI P 
Univariatea          
    IPS ≥ 4 4.7 1.6–13.5 0.004 7.4 2.3–23.6 0.0008 4.6 2.1–10.2 0.0002 
    Stage IV disease 2.2 0.8–6.4 0.14 2.5 0.8–8.0 0.14 3.4 1.6–7.3 0.002 
    Hemoglobin <10.5 g/dl 2.6 0.9–7.5 0.08 4.1 1.3–13.2 0.02 2.2 1.0–4.9 0.04 
    Serum albumin < 4 g/dl 2.7 0.9–7.9 0.08 3.9 1.1–14.4 0.04 2.1 1.0–4.5 0.06 
    ECOG score ≥ 2 4.0 0.9–17.9 0.07 5.1 1.1–23.1 0.03 3.2 1.0–10.6 0.05 
    B symptoms 1.9 0.6–5.9 0.29 2.0 0.5–7.3 0.31 2.2 0.9–5.1 0.07 
Multivariate          
    IPS ≥ 4 4.2 1.3–13.5 0.02 6.6 1.9–23.0 0.003 2.7 0.9–7.6 0.07, 0.007b 
    ECOG score ≥ 2 1.5 0.3–8.0 0.62 1.5 0.3–7.6 0.60 1.0 0.3–3.7 0.96 
    Stage IV disease – – – – – – 2.5 1.0–6.1 0.04 
    B symptoms – – – – – – 1.5 0.5–4.2 0.45 
a

Only variables with a value of P < 0.10 on univariate analysis were considered for multivariate analysis and are included in this table. The variables that were not significant on univariate analysis were male gender, age ≥45, lymphocyte <600/mm3, leukocyte≥ 15 000/mm3, weight loss, fever, night sweats, bulky disease, and extranodal disease.

b

P = 0.07 for IPS when stage IV was entered in multivariate analysis; P = 0.007 for IPS when stage IV was not entered as a variable in multivariate analysis.

HR, hazard ratio; CI, confidence interval; IPS, international prognostic score; ECOG, Eastern Cooperative Oncology Group.

Figure 3.

(A) Overall survival for patients with international prognostic score (IPS) <4 versus ≥4. (B) Progression-free survival for patients with IPS <4 versus ≥4.

Figure 3.

(A) Overall survival for patients with international prognostic score (IPS) <4 versus ≥4. (B) Progression-free survival for patients with IPS <4 versus ≥4.

Figure 4.

(A) Overall survival for patients with stage I–III versus stage IV disease. (B) Progression-free survival for patients with stage I–III versus stage IV disease.

Figure 4.

(A) Overall survival for patients with stage I–III versus stage IV disease. (B) Progression-free survival for patients with stage I–III versus stage IV disease.

patterns of treatment failure

Table 4 describes 26 participants who relapsed or progressed during the Stanford V regimen. Sixteen (62%) had advanced-stage disease, 10 (38%) had four or more IP factors, 15 (58%) had bulky disease, 21 received radiation as part of the Stanford V regimen, seven did not receive radiation, five were refractory to chemotherapy, and two had nonbulky stage IVB disease and therefore did not qualify for RT. A total of 11 patients had an in-field failure component—two failed in the RT field alone; two failed both infield and at the RT field margin; five failed both in field and at a distant site; two patients failed in the RT field, at the RT field margin, and also distantly; and five failed at distant sites only.

Table 4.

Characteristics of patients failing first-line treatment

Histology Stagea Age Sex IPS Treatment failure RT Relapse site, in/out/margin RT field Months to relapse Salvage therapy Status Months after relapse 
NSHD IIAX 29 Female Relapse Yes Margin, out ICE, ASCT NED 81 
NSHD IIAX 29 Female Relapse Yes In/margin 10 ICE, ASCT NED 79 
MCHD IIIA 31 Female Relapse Yes Out ICE, RT, ASCT DOTTb 21 
NSHD IIIBX 24 Female Relapse Yes Out 23 ICE, RT, ASCT NED 94 
NSHD IIIBXE 33 Female Refractory Yes In/out <1 ICE, RT, ASCT NED 58 
NSHD IIAX 22 Female Relapse Yes Margin 44 ICE, ASCT NED 54 
NSHD IIAX 29 Male Relapse Yes In/out ICE, ASCT, MOPP DOD 10 
NSHD IIAX 20 Male Relapse Yes In/out ICE DOD 
NSHD IIBXE 28 Female Refractory No  <1 ICE, CMOPP, RT DOD 25 
NSHD IIIBX 22 Male Relapse Yes In/out 31 ICE, RT, ASCT NED 63 
NSHD IVB 30 Female Relapse Yes Out ICE, RT, ASCT NED 70 
MCHD IVB 48 Female Relapse Yes Out 32 ICE, RT, ASCT NED 49 
NSHD IVBX 23 Female Refractory Yes In/margin/out ICE, RT, ASCT NED 73 
NSHDc IVBX 37 Female Refractory No  ICE, RT, ASCT DOD 23 
UNSPEC IVBXS 18 Female Relapse Yes In/out ICE, ASCT NED 65 
NSHD IIAE 35 Female Relapse Yes In ICE, RT, ASCT NED 80 
NSHD IIBE 38 Male Refractory No  ICE, RT, ASCT DOD 
NSHD IIBX 32 Female Refractory Yes In/margin ICE, RT, ASCT DOD 
NSHD IVB 28 Male Refractory No  <1 ICE, RT, ASCT DOD 40 
NSHD IVBX 32 Male Refractory Yes In <1 ICE, RT, ASCT NED 87 
NSHD IVBX 36 Male Relapse Yes In/margin/out ICE, GEMCIT DOD 18 
NSHD IVB 54 Female Relapse No  21 ICE, RT, ASCT NED 73 
MCHD IVB 38 Male Toxicity Yes  <1 Noned DOTT 
MCHD IVB 45 Male Refractory No  ICE, ASCT NED 83 
NSHD IVB 46 Male Relapse No  13 ICE, RT, ASCT NED 77 
UNSPEC IVBS 46 Male Relapse Yes Out ICE, RT, ASCT DOD 22 
Histology Stagea Age Sex IPS Treatment failure RT Relapse site, in/out/margin RT field Months to relapse Salvage therapy Status Months after relapse 
NSHD IIAX 29 Female Relapse Yes Margin, out ICE, ASCT NED 81 
NSHD IIAX 29 Female Relapse Yes In/margin 10 ICE, ASCT NED 79 
MCHD IIIA 31 Female Relapse Yes Out ICE, RT, ASCT DOTTb 21 
NSHD IIIBX 24 Female Relapse Yes Out 23 ICE, RT, ASCT NED 94 
NSHD IIIBXE 33 Female Refractory Yes In/out <1 ICE, RT, ASCT NED 58 
NSHD IIAX 22 Female Relapse Yes Margin 44 ICE, ASCT NED 54 
NSHD IIAX 29 Male Relapse Yes In/out ICE, ASCT, MOPP DOD 10 
NSHD IIAX 20 Male Relapse Yes In/out ICE DOD 
NSHD IIBXE 28 Female Refractory No  <1 ICE, CMOPP, RT DOD 25 
NSHD IIIBX 22 Male Relapse Yes In/out 31 ICE, RT, ASCT NED 63 
NSHD IVB 30 Female Relapse Yes Out ICE, RT, ASCT NED 70 
MCHD IVB 48 Female Relapse Yes Out 32 ICE, RT, ASCT NED 49 
NSHD IVBX 23 Female Refractory Yes In/margin/out ICE, RT, ASCT NED 73 
NSHDc IVBX 37 Female Refractory No  ICE, RT, ASCT DOD 23 
UNSPEC IVBXS 18 Female Relapse Yes In/out ICE, ASCT NED 65 
NSHD IIAE 35 Female Relapse Yes In ICE, RT, ASCT NED 80 
NSHD IIBE 38 Male Refractory No  ICE, RT, ASCT DOD 
NSHD IIBX 32 Female Refractory Yes In/margin ICE, RT, ASCT DOD 
NSHD IVB 28 Male Refractory No  <1 ICE, RT, ASCT DOD 40 
NSHD IVBX 32 Male Refractory Yes In <1 ICE, RT, ASCT NED 87 
NSHD IVBX 36 Male Relapse Yes In/margin/out ICE, GEMCIT DOD 18 
NSHD IVB 54 Female Relapse No  21 ICE, RT, ASCT NED 73 
MCHD IVB 38 Male Toxicity Yes  <1 Noned DOTT 
MCHD IVB 45 Male Refractory No  ICE, ASCT NED 83 
NSHD IVB 46 Male Relapse No  13 ICE, RT, ASCT NED 77 
UNSPEC IVBS 46 Male Relapse Yes Out ICE, RT, ASCT DOD 22 
a

Thirteen of the 19 patients who received RT as part of first-line therapy had bulky disease.

b

Patient died of leukemia after salvage therapy.

c

Patient relapsed with composite lymphoma.

d

Patient died before salvage therapy.

NSHD, Nodular Sclerosing Hodgkin's disease; IPS, international prognostic score; RT, radiotherapy; ICE, ifosfamide, carboplatin, etoposide; ASCT, autologous stem-cell transplantation; NED, no evidence of disease; MCHD, Mixed Cellularity Hodgkin's disease; DOTT, Died of Treatment Toxicity; UNSPEC, unspecified (classical Hodgkins); MOPP, nitrogen mustard, vincristine, procarbazine, and prednisone DOD, Died of Disease; GEMCIT, Gemcitabine.

salvage therapy

Twenty-five of 26 treatment failures underwent salvage therapy (Table 4). One patient died of treatment-related toxicity before salvage; 15 were successfully salvaged with high-dose Chemo-radiation therapy ± autologous stem-cell transplantation (ASCT) and were free of disease at last follow-up. Of the 10 patients who failed second-line therapy, nine died of disease and one died of AML after salvage therapy. The 3-year FF2R was 64% (95% CI 48–86; Figure 5).

Figure 5.

FF2R for 25 patients who underwent salvage therapy. FF2R (freedom from second relapse) is defined as time from start of salvage therapy to second relapse, death from any cause or last follow up.

Figure 5.

FF2R for 25 patients who underwent salvage therapy. FF2R (freedom from second relapse) is defined as time from start of salvage therapy to second relapse, death from any cause or last follow up.

discussion

At a median follow-up of 92 months, 112 of 126 patients with bulky and/or advanced HL treated by the MSKCC group on the Stanford V protocol are alive and disease free. The 5-year OS and FFS are 90% and 78%, respectively. The 3-year probability of death due to disease and progression of disease were 7% and 19%, respectively. These results confirm the excellent results reported by the Stanford group and differ significantly from the Intergruppo Italiano Linformi randomized study (OS 82%, PFS 73%, and FFS 53%) [17, 18]. This discordance may be explained by the deviations from Stanford protocol in the Italian study, particularly those affecting the selection of patients for RT and the interval before delivering RT (Table 5) [24].

Table 5.

Guidelines and outcomes of Stanford, MSKCC, and Italian studies

Outcomes Stanford [14Aversa [22Nebraska [23MSKCC Italian Stanford arm [16
5-year OS 96 95 84 90 82a 
5-year PFS 89 86 74 81b 73 
5-year FFS NRc NRc NR 78 53a 
RT guidelines      
    % Irradiated 90 90 74 88 66 
    Definition of bulky (cm) ≥5 ≥5 ≥5 ≥5 ≥6 
    RT to macroscopic splenic disease Yes Yes Yes Yes Uncleard 
    Median chemoradiotherapy interval, weeks 2–4 2–4 3–4 
    RT to patients with more than two involved sites Yes Yes Yes Yes No 
    RT to patients with postchemotherapy CR Yes Yes Not alle Yes Nof 
Outcomes Stanford [14Aversa [22Nebraska [23MSKCC Italian Stanford arm [16
5-year OS 96 95 84 90 82a 
5-year PFS 89 86 74 81b 73 
5-year FFS NRc NRc NR 78 53a 
RT guidelines      
    % Irradiated 90 90 74 88 66 
    Definition of bulky (cm) ≥5 ≥5 ≥5 ≥5 ≥6 
    RT to macroscopic splenic disease Yes Yes Yes Yes Uncleard 
    Median chemoradiotherapy interval, weeks 2–4 2–4 3–4 
    RT to patients with more than two involved sites Yes Yes Yes Yes No 
    RT to patients with postchemotherapy CR Yes Yes Not alle Yes Nof 
a

The updated analysis showed 8-year OS for the Stanford V arm and two additional relapses both of which occurred in the Stanford V arm [19].

b

There were no events after 4 years.

c

FFS was not reported in these studies.

d

Macroscopic splenic disease was not a clear inclusion criterion; therefore, not all patients with splenic disease received RT.

e

Sixteen (14%) patients who met the criteria for bulky disease did not receive RT primarily because they achieved complete remission after chemotherapy.

f

Radiation oncologist was allowed to renounce RT in patients with unequivocal postchemotherapy CR status.

MSKCC, Memorial Sloan-Kettering Cancer Center; OS, overall survival; PFS, progression-free survival; FFS, failure-free survival; NR, not reported; RT, radiotherapy; CR, complete response.

The Stanford guidelines mandate irradiation to initial sites of bulky disease, defined as ≥5 cm, and macroscopic splenic disease, regardless of postchemotherapy CR status. Therefore, only patients with unequivocal progression of disease during or immediately after chemotherapy are excluded from RT, and there is no limit on the number of residual disease sites irradiated.

In the Italian three-arm study, the radiation oncologist was at liberty to renounce radiation if CR status was equivocal after chemotherapy. Patients with more than two sites of residual disease after chemotherapy did not receive RT, and bulky disease was defined as ≥6 cm (not ≥5 cm as specified in the Stanford V protocol). In addition, although patients with macroscopic splenic disease were not excluded, this criterion was loosely applied. In the Stanford V study, final response status, and thus decision to proceed with IFRT or salvage, was not made until evaluation after completion of chemotherapy. In contrast, in the Italian study, patients with less than partial response (PR; Partial response was defined as regression of measurable disease with ≥ 50% decrease in size of dominant masses with no increase in size of other nodes with variable FDG-avid or PET negative disease.) after only 8 weeks of chemotherapy, i.e. late responders, were considered failures and proceeded directly to salvage therapy.

With regard to the timing of adjuvant radiation, the Stanford V protocol dictates that radiation should be administered 2–4 weeks after chemotherapy because this interval is an integral factor in the development of this short-course therapy. In the Italian study, radiation was initiated at a median of 6 weeks after chemotherapy.

As a result of these collective deviations from Stanford V guidelines, only 66% (71 of 107) of patients in the Stanford V arm of the Italian study received radiation (compared with 90% in the Stanford study and 88% in our study at MSKCC). In the Italian study, only 16% (n = 17) of the patients in the Stanford arm received RT for bulky disease, and as many as 14 patients (13%) did not receive radiation because of disease involvement at more than two sites.

In our study, 111 of 126 (88%) patients received the designed IFRT (3 CR, 103 CRu, and 5 PR) within a median of 4 weeks after chemotherapy. Only 15 patients (12%) did not receive radiation: 10 patients because they did not have prechemotherapy bulky disease and five because of progression during chemotherapy. Similarly, Aversa et al. [25] treated 90% of the patients with radiation as per Stanford guidelines.

The Stanford V program is an abbreviated, dose-intense, multidrug regimen designed to reduce or abrogate cardiopulmonary toxicity, sterility, and leukemogenesis while maintaining efficacy. Integral to its design is the addition of IFRT in most patients. By this premise, significantly modifying the treatment program by foregoing radiation in many patients would result in an inferior outcome. It is reasonable to presume that an ‘unmodified’ Stanford V regimen should yield outcomes similar to those observed at Stanford. This is demonstrated by the current study, a smaller Italian study by Aversa et al., and the Nebraska study that showed superior PFS (86% versus 42%) for the irradiated patients (Table 5) [23, 25].

Notably, our results compare well with the preliminary data from the UK National Cancer Research Institute study showing equivalent 5-year outcomes for both regimens (76% versus 74% PFS and 90% versus 92% OS for ABVD and Stanford V, respectively) [26].

In a subgroup analysis, patients with stage IV disease and ≥4 IPS factors had significantly worse outcomes. Both stage IV and IPS ≥4 were independent predictors of adverse outcomes on multivariate analysis. Although we are cautious with the interpretation of the data given the number of patients and retrospective nature of this study, our results do indicate that patients with adverse factors may benefit from more aggressive treatment such as BEACOPP. In the HD12 GHSG trial, 84% of the patients had stage III–IV disease, versus only 47% in our study. However, the number of patients with IPS ≥3 was comparable (38% versus 32%) [27]. Adverse factors must be considered when determining the most effective treatment. Indeed, patients with poor prognostic factors had better outcomes with BEACOPP in the recent randomized study [14].

In the current study, fertility was well preserved and the number of second malignancies was small. The one case of MDS/AML developed only after salvage therapy and might not be related to Stanford V therapy [28]. The incidence of sterility and leukemia in our study is much lower than with escalated BEACOPP- or MOPP-based regimens [13, 29].

In the search for the optimal treatment of advanced HL, the overarching goal is to minimize toxicity while achieving high FFS, thus avoiding salvage treatment with its incumbent additional risks. This is especially important in the context of the young median age of HL patients and concerns of fertility preservation. The MSKCC data confirm that this desirable balance of efficacy and acceptable toxicity is attainable with the Stanford V program for the majority of patients with unfavorable-risk HL and signify that patients who fail the Stanford V program are highly salvageable with high-dose CMRT and ASCT.

funding

Lymphoma Foundation; Connecticut Sports Foundation against Cancer.

disclosure

There are no potential conflicts of interest or any funding sources that may generate a conflict of interest.

The authors wish to thank Carol Pearce, editor in the MSKCC Department of Medicine, for her review of this manuscript. This paper was presented in part at the 2007 American Society for Therapeutic Radiology and Oncology Annual Meeting, Boston, MA.

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