A. Hagenbeek

Second cancer risk following Hodgkin's disease: a 20-year follow-up study.

PURPOSEnTo determine risk factors for the development of second primary cancers during long-term follow-up of patients with Hodgkins disease (HD).nnnPATIENTS AND METHODSnWe assessed the risk of second cancers (SCs) in 1939 HD patients, who were admitted to the Netherlands Cancer Institute (NKI; Amsterdam) or the Dr Daniel den Hoed Cancer Center (DDHK; Rotterdam) between 1966 and 1986. For 97% of the cohort, we obtained a medical status up to at least January 1989. The median follow-up duration of the patients was 9.2 years; for 17% of the patients, follow-up was longer than 15 years. For more than 98% of all second tumors, the diagnosis was confirmed through a pathology report.nnnRESULTSnIn all, 146 patients developed a SC, compared with 41.9 cases expected on the basis of incidence rates in the general population (relative risk [RR], 3.5; 95% confidence interval [CI], 2.9 to 4.1). The mean 20-year actuarial risk of all SCs was 20% (95% CI, 17% to 24%). Significantly increased RRs were observed for leukemia (RR, 34.7; 95% CI, 23.6 to 49.3), non-Hodgkins lymphoma (NHL) (RR, 20.6; 95% CI, 13.1 to 30.9), lung cancer (RR, 3.7; 95% CI, 2.5 to 5.3), all gastrointestinal cancers combined (RR, 2.0; 95% CI, 1.2 to 3.1), all urogenital cancers combined (RR, 2.4; 95% CI, 1.4 to 3.7), melanoma (RR, 4.9; 95% CI, 1.6 to 11.3), and soft tissue sarcoma (RR, 8.8; 95% CI, 1.8 to 25.8). As compared with the general population, the cohort experienced an excess of 63 cancer cases per 10,000 person-years. Cox-model analysis indicated the following as significant risk factors for developing leukemia: first-year treatment with chemotherapy (CT), follow-up treatment with CT, age at diagnosis of HD greater than 40 years, splenectomy, and advanced stage. Patients treated with CT in the 1980s had a substantially lower risk of leukemia than patients treated in the 1970s (10-year actuarial risks of 2.1% and 6.4%, respectively; P = .07). Significant risk factors for NHL were older age, male sex, and combined modality treatment as compared with either modality alone. Risk of lung cancer was strongly related to radiotherapy (RT), while an additional role of CT could not be demonstrated. After more than 15 years of follow-up, women treated with mantle-field irradiation before age 20 years had a greater than forty-fold increased risk of breast cancer (P < .001).nnnCONCLUSIONnWhile the long-term consequences of HD treatment as administered in the 1960s and 1970s are still evolving, it is promising that patients who received the new treatment regimens introduced in the 1980s have a much lower leukemia risk than patients treated in earlier years. Beginning 10 years after initial RT, the follow-up program of women who received mantle-field irradiation before age 30 years should routinely include breast palpation and yearly mammography.

Leukemia risk following Hodgkin's disease: relation to cumulative dose of alkylating agents, treatment with teniposide combinations, number of episodes of chemotherapy, and bone marrow damage.

PURPOSEnThe development of leukemia is one of the most serious long-term complications of modern treatment for Hodgkins disease (HD). This study was undertaken to examine the relation between risk of leukemia and various treatment factors (including cumulative dose of cytostatic drugs and interaction with radiotherapy [RT]), while also assessing the effect of treatment-induced bone marrow damage.nnnPATIENTS AND METHODSnWe conducted a case-control study in a cohort of 1,939 patients treated for HD between 1966 and 1986 in the Netherlands. Detailed information from the medical records was obtained for 44 cases of leukemia and 124 matched controls, in whom leukemia had not developed.nnnRESULTSnThe cumulative dose of mechlorethamine was the most important factor in determining leukemia risk. As compared with patients who received RT alone, patients treated with six or fewer cycles of combinations including nitrogen mustard (mechlorethamine) and procarbazine had an eightfold increased risk of developing leukemia (P = .08), while patients who received more than six of such cycles had a greater than 40-fold excess risk (P < .001). Treatment with lomustine or a combination of teniposide and cyclophosphamide also significantly increased the risk of leukemia. Patients who had received chemotherapy (CT) during two or more time periods had a nearly 40-fold increased risk of leukemia as compared with patients treated only once. The extent of RT did not further increase leukemia risk among patients who also received CT. A significantly increased risk of leukemia was found among patients with low platelet counts, both in response to initial therapy and during follow-up. Patients who experienced 2 or more half-year periods with platelet counts less than 75 x 10(6)/mL had an approximately fivefold risk of developing leukemia, and a similar risk increase was found for patients who responded to initial treatment with a > or = 70% decrease of platelet counts (as compared with patients who had a < or = 50% decrease).nnnCONCLUSIONnIn addition to mechlorethamine, lomustine and teniposide combinations were also linked to an elevated risk of developing leukemia. Since the number of CT episodes was found to be a strong determinant of leukemia risk, it is important that new therapies for HD continue to yield high initial cure rates. Further studies are warranted to investigate whether patients at high risk for developing leukemia may be identified from the response of their platelets to initial therapy for HD.

Efficacy of four different regimens in 64 mantle-cell lymphoma cases: clinicopathologic comparison with 498 other non-Hodgkin's lymphoma subtypes. European Organization for the Research and Treatment of Cancer Lymphoma Cooperative Group

PURPOSEnBefore recognizing mantle-cell lymphoma (MCL) as a distinct entity, these patients were grouped into low-grade (LG) or intermediate-/high-grade categories (IGHG) according to the Working Formulation and received various therapies. This was a unique opportunity to evaluate characteristics, behavior, response to treatment, and outcome of patients with MCL from two phase III trials conducted by the European Organization for the Research and Treatment of Cancer (EORTC): EORTC 20855 IGHG and EORTC 20856 LG.nnnPATIENTS AND METHODSnAfter histologic review, 64 diagnosed MCL patients (29 IGHG and 35 LG) were compared with other patients in their respective trials. In the IGHG group, patients received cyclophosphamide, doxorubicin, teniposide (VM26), prednisone, vincristine, and bleomycin (CHVmP-VB) or modified doxorubicin, cyclophosphamide, etoposide (VP 16), mechlorethamine, vincristine, procarbazine, and prednisone (ProMACE-MOPP). In the LG group, after receiving cyclophosphamide, vincristine, and prednisone (CVP) induction, patients were randomized between maintenance treatment with interferon alfa-2a (IFN) or no further treatment.nnnRESULTSnMCL patients compared with IGHG subtypes showed a similar overall survival and response rate, but shorter duration of response and progression-free survival. Comparing with LG patients, their response rate, duration of response, and progression-free survival showed no difference, while their overall survival was nearly twice shorter. MCL patients treated with CHVmP-VB had the longest survival. No treatment showed any significant improvement in terms of progression-free survival.nnnCONCLUSIONnThese data confirm that MCL represents a clinicopathologic entity. In terms of survival, it behaves like IGHG subtypes, while in terms of progression-free survival, it behaves like LG lymphoma. It is still not clear which first-line treatment offers patients with MCL the best chance to obtain both a complete response (CR) and a long-term survival.

A randomized study in stage IIIB and IV Hodgkin's disease comparing eight courses of MOPP versus an alteration of MOPP with ABVD: a European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie controlled clinical trial.

PURPOSEnWe report a prospective randomized study comparing the relative efficacy of alternating chemotherapy mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD) with the standard MOPP chemotherapy in patients with stage IIIB and IV Hodgkins disease (HD). The purpose is to study the influence of time of remission on clinical outcome.nnnPATIENTS AND METHODSnAfter two courses of MOPP, patients were randomized to receive six further courses of MOPP, or two courses of ABVD followed by two courses of MOPP and two courses of ABVD. Radiotherapy was given to areas presenting with masses > or = 5 cm and to residual masses after course no. 4. Evaluation of response (complete remission [CR]) took place after two courses (CR2), after four courses (CR4), at the end of chemotherapy (CR8), and after additional radiotherapy (CR(CT + RT)). Logistic regression analysis was used to study prognostic factors for response at the end of chemotherapy. Cox analysis was used to study prognostic factors for survival. Two hundred seven patients were registered, 192 (93%) of whom were randomized.nnnRESULTSnThe CR rate at the end of chemotherapy (CR8) was similar in both arms (57% v 59%). However, there were more progressions in the MOPP arm compared with the MOPP/ABVD arm (23% v 8%, P = .014). A significantly higher failure-free survival (FFS) rate was found in the MOPP/ABVD arm (60% v 43% at 6 years, P = .025). There was no difference in the relapse-free survival (RFS) or survival rate. Of patients not in CR4, only 28% still reached a CR8. RFS at 6 years of patients with CR4 (69%) was not different from that of patients with CR8 (68%); patients with a CR(CT + RT)) had a lower RFS rate (48%). CR4 (P < .001) predicted strongly for final remission at the end of chemotherapy. Cox analysis showed that age more than 50 years, six or more involved lymph node areas, no CR by the fourth cycle, chemotherapy with MOPP alone, and no radiotherapy were unfavorable factors for survival.nnnCONCLUSIONnMOPP/ABVD chemotherapy significantly improved response and FFS rates, but had no influence on RFS and survival rates. Early CR (CR4) is an important factor for final remission and might be used to select a group of patients with a good prognosis.

Maintenance of remission with human recombinant interferon alfa-2a in patients with stages III and IV low-grade malignant non-Hodgkin's lymphoma. European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group.

PURPOSEnInterferon alfa has shown significant activity in patients with low-grade malignant non-Hodgkins lymphoma (NHL). In 1985, we initiated a prospective randomized study in which the potential benefit of interferon alfa given as maintenance treatment was investigated after tumor load reduction was achieved with chemoradiotherapy in patients with advanced low-grade malignant non-Hodgkins lymphoma.nnnPATIENTS AND METHODSnThe study involved 347 patients with stage III or IV disease, 315 satisfying the eligibility criteria. All were treated with a regimen of cyclophosphamide, vincristine, and prednisone (CVP) given every 3 weeks for eight cycles. Thereafter, patients were eligible for iceberg irradiation. Finally, all patients were completely restaged, and responding and stable-disease patients were then randomized, 122 to interferon alfa-2a maintenance, 3 million U three times weekly for 1 year; and 120 to no further treatment.nnnRESULTSnSeventy-nine percent of the patients response to CVP, ie, 45% complete remissions (CR) and 34% partial remissions (PR). In the group of randomized patients, the response rate after CVP plus or minus radiotherapy was 90%. As compared with control patients, patients in the interferon (IFN) maintenance group had a tendency toward a prolonged time to progression (TTP) (median, 132 v 87 weeks; P = .054, adjusted for response to CVP). However, overall survival was similar in both groups. Interferon was well tolerated. The median dose of IFN actually received corresponded to 90% of the planned cumulative dose. The treatment had to be stopped because of toxicity in 16 patients (15% of the patients in whom IFN was started).nnnCONCLUSIONnInterferon maintenance treatment in the phase of minimal residual disease of patients with advanced low-grade malignant NHL increased TTP at the borderline of statistical significance, without remarkable toxicity. However, overall survival was not influenced.

Increased risk of breast cancer following irradiation for Hodgkin's disease is not a result of ATM germline mutations.

PURPOSEnLong-term survivors of Hodgkins disease who received mantle-field irradiation at a young age have a strongly increased risk of developing breast cancer. The purpose of this study was to investigate whether this increased risk was substantially greater among women heterozygous for a germline mutation in the ataxia-telangiectasia gene (ATM).nnnMATERIALS AND METHODSnThirty-two patients were selected who had developed breast cancer at least 10 years following irradiation for Hodgkins disease before the age of 45 years. In these patients, the complete open reading frame of the ATM gene was analysed for the presence of germline mutations using the protein truncation test and two mutation-specific tests, followed by genomic sequencing.nnnRESULTSnNo A-T disease causing germline mutations were found in these selected Hodgkin patients. However, several alternative splicing events were detected which might influence protein expression levels.nnnCONCLUSIONSnThe data suggest that truncating mutations in the ATM gene are not a major component underlying the increased risk of breast cancer following Hodgkins disease.Purpose : Long-term survivors of Hodgkin‚s disease who received mantle-field irradiation at a young age have a strongly increased risk of developing breast cancer. The purpose of this study was to investigate whether this increased risk was substantially greater among women heterozygous for a germline mutation in the ataxia-telangiectasia gene (ATM). Materials and methods : Thirty-two patients were selected who had developed breast cancer at least 10 years following irradiation for Hodgkin‚s disease before the age of 45 years. In these patients, the complete open reading frame of the ATM gene was analysed for the presence of germline mutations using the protein truncation test and two mutation-specific tests, followed by genomic sequencing. Results : No A-T disease causing germline mutations were found in these selected Hodgkin patients. However, several alternative splicing events were detected which might influence protein expression levels. Conclusions : The data suggest that truncating mutations in the ATM gene are not a major component underlying the increased risk of breast cancer following Hodgkin‚s disease.

Chimeric anti-CD20 monoclonal antibody (Mabthera) in remission induction and maintenance treatment of relapsed follicular non-Hodgkin's lymphoma: a phase III randomized clinical trial--Intergroup Collaborative Study.

l To establish in a prospective, randomized clinical trial the effect of the addition of chimeric anti-CD20 monoclonal antibody (rituximab, Mabthera) to CHOP chemotherapy on the response rate and quality (partial remission, complete remission, molecular complete remission) in relapsed/refractory low-grade non-Hodgkin’s lymphoma (NHL) of follicular type. l To establish in a prospective, randomized clinical trial the effect of maintenance treatment with chimeric antiCD20 monoclonal antibody (rituximab, Mabthera) on progression-free survival in relapsed/refractory lowgrade NHL of follicular type in remission after CHOP with or without rituximab.

Reply to U. Dührsen et al.

In their letter, Duhrsen et al disagree with our conclusion that in patients with relapsed or refractory follicular lymphoma, the presence of tumor cells in blood or bone marrow, as detected by BCL2/IgH major break point region (MBR) polymerase chain reaction (PCR) at the end of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone induction therapy, is not predictive of progression-free survival (PFS). Their major argument is that we have compared inappropriate groups because the BCL2/IgH MBR–negative group might have contained patients with tumor cells in blood or bone marrow that have escaped detection because they have t(14;18) with a break point outside the MBR. On the basis of cited literature, they mention that up to 50% of t(14;18) patients have break points outside the MBR, whereas in fact, this figure is 32%. Nevertheless, regardless of the exact frequency of BCL2/ IgHMBRpositivityamongpatientswitht(14;18), intheDiscussionofour article, we already have addressed rather extensively the issue raised by Duhrsen et al. At present, we are in the process of performing an additional minor break point region PCR analysis to further corroborate our conclusions. However, when we restricted our analysis to the group with initial BCL2/IgH MBR–positive results in blood and/or bone marrow, we found no difference in PFS between patients who converted from PCR positive to PCR negative and patients who remained PCR positive. This was true for both bone marrow and peripheral blood. This observation, which was mentioned in our article under Results, strongly supports the conclusion that in patients with relapsed or refractory follicular lymphoma, the BCL2/IgH status in peripheral blood and bone marrow at the end of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone induction therapy is not predictive for PFS.