Management of advanced stage intermediate grade non-Hodgkin's lymphomas.

The treatment result of 271 cases of advanced stage intermediate grade lymphoma were reviewed. Ninety-four patients received CHOP chemotherapy, 45 BACOP and 17 m-BACOD. The clinical characteristics of the three groups of patients were comparable. Patients receiving CHOP had a complete response (CR) rate of 60 per cent, the disease-free survival of CR patients was 31 per cent at 5 years. The overall survival following CHOP chemotherapy was 38 per cent at 5 years. The use of the BACOP or m-BACOD regime did not appear to improve significantly the prognosis of these patients. Clinical staging, B symptoms, age and serum lactate dehydrogenase level were the most important independent prognostic factors.     

Copp chemotherapy for elderly patients with intermediate and high grade non-Hodgkin's lymphoma

One hundred and forty-one consecutive patients above and 231 below the age of 60 years with previously untreated intermediate or high grade non-Hodgkin's lymphoma were included in this study. Patients above the age of 60 years were treated with the COPP chemotherapy regimen. The younger patients, at or below the age of 60, received a doxorubicin-containing regimen (119 had CHOP, 65 had BACOP and 47 had m-BACOD). For stage I patients, the clinical results were similar but for stage II, III or IV disease, those receiving COPP had significantly worse CR rate and survival than those who had a doxorubicin-containing regimen. Multivariate analysis on patients receiving the COPP chemotherapy revealed that the independent prognostic variables significantly determining CR rate and survival included clinical stage (p =0·04) and serum lactate dehydrogenase level (p =0·001). Myelosuppression was the major toxicity following COPP chemotherapy in this group of patients. There were 10 (7 per cent) treatment-related deaths. Compared to the reported results using doxorubicin-containing regimens to treat elderly patients with aggressive NHL in the literature, the more aggressive treatment does not appear to improve significantly the clinical outcome of this group of patients and seems to produce treatment results very much similar to COPP. However, accurate comparison is difficult because of the variation in the patient characteristics. Further prospective controlled randomized trials will be necessary to determine the optimal therapy for these patients.     

The EORTC treatment of early stages of Hodgkin's disease: the role of radiotherapy

Since 1964, the European Organisation for Research and Treatment of Cancer has conducted three subsequent clinical trials on clinical Stages (CS) I + II Hodgkin's disease (HD) in which 1059 patients have been entered. The first trial compared regional radiotherapy (RT) with mantle field or inverted Y, versus the same RT followed by a weekly injection of vinblastine for 2 years. The relapse free survival (RFS) and overall survival (S) were higher in patients treated by RT and chemotherapy (CT). This benefit, however, was significant only in patients with a mixed cellularity histologic type. The second trial compared the therapeutic efficacy of splenic irradiation versus splenectomy and found that in both arms, RFS and S were identical. Moreover, it was found that splenic involvement was correlated with an increased incidence of relapse in extranodal sites and in non irradiated lymphatic areas. In this trial, CT was given only to patients with poor histologic types, mixed cellularity or lymphocytic depletion. In the third trial, staging laparotomy was performed only to further delineate a good prognostic group which could be treated by RT alone. In this limited treatment group, there was no difference in RFS and S between mantle field and mantle field + para-aortic RT. In the extensive treatment group, total nodal irradiation (TNI) was compared with RT + MOPP. The RFS was slightly lower in the TNI arm, but there was no significant difference in S. The data of the 3 trials underline the importance of prognostic factors in the choice of optimal treatment and show that their significance depends upon the type of treatment. Multivariate statistical analyses showed that the main prognostic factors, which can help to identify the subsets of patients who can be treated by RT alone, are (1) systemic symptoms and elevated erythrocyte sedimentation rate (ESR), (2) the number of involved lymphatic areas, and (3) staging laparotomy. Extended RT (mantle + para-aortic + spleen treatment) gives satisfactory results in patients without systemic symptoms and/or elevated ESR and one or two involved sites, whereas TNI or combined modality treatment becomes mandatory for patients with 3 or more involved sites or splenic involvement and/or systemic symptoms. With proper adjustment of the irradiated volume, a very large proportion of CS I + II patients can be best treated by RT alone.     

Secondary central nervous system involvement by non-Hodgkin's lymphoma: the risk factors

The risk of secondary central nervous system (CNS) was estimated in 833 cases of non-Hodgkin's lymphoma diagnosed between January 1975 and December 1988. Fifty-one of them had CNS disease (51/833, 6.1 per cent). No case of low grade lymphoma developed CNS disease. However, 6.5 per cent and 16.7 per cent of patients with intermediate and high grade lymphomas, respectively, had secondary CNS involvement. Stage IV disease and the presence of B symptoms were also associated with an increased risk of CNS disease. Significantly higher incidence of CNS disease was seen in patients with lymphoma involving orbit (43 per cent), testis (40 per cent), peripheral blood (33 per cent), bone (29 per cent), nasal/paranasal sinuses region (23 per cent) and bone marrow (20 per cent). CNS prophylaxis is recommended to patients with an increased risk of CNS disease.     

Prognosis in low grade non-Hodgkin's lymphoma: relevance of the number of sites involved,absolute lymphocyte count and serum immunoglobulin level

Eighty-eight patients with low grade non-Hodgkin's lymphoma were followed for a median period of 63 months. Sixty-eight per cent of the group were centrocytic/centroblastic B cell lymphomas by the updated Kiel classification. Fifty-one (58 per cent) of the patients were stage IV by the Ann Arbor classification. In 18 of these patients the bone marrow was the only site of extranodal involvement. Univariate survival analysis showed that the sum of involved sites was more discriminatory than Ann Arbor stage. Analysis by site of involvement showed that the liver and other intraabdominal sites were associated with worse survival than involvement of peripheral lymph nodes. Bone marrow and spleen involvement were not significantly associated with short survival. Increasing age at presentation was strongly associated with shorter survival and was also inversely correlated with serum albumin. Both low absolute lymphocyte count (<1.0 × 10 ⁹/1), low serum IgG level (<10 g/1) and low total immunoglobulins on presentation were significantly associated with short survival. Multivariate analysis showed that age, serum albumin and number of involved sites gave the best survival prediction. The sum of involved sites, immunoglobulin level and absolute lymphocyte count may be useful objective markers of prognosis in low-grade non-Hodgkin's lymphoma.     

Chemotherapy alone versus chemotherapy followed by consolidative radiotherapy for limited-stage aggressive non-Hodgkin's lymphoma: A meta-analysis of randomized controlled trials

ObjectiveTo systematically investigate chemotherapy versus chemotherapy followed by involved field radiotherapy for limited-stage aggressive non-Hodgkin's lymphoma.MethodA systematic literature search of Pubmed, EMBASE, and the Cochrane central register of controlled trials was performed. Data from all randomized controlled trials comparing chemotherapy alone with chemotherapy followed by involved field radiotherapy in patients with limited-stage aggressive non-Hodgkin's lymphoma was collaborate. The primary outcome was overall survival; secondary outcomes were event-free survival and cumulative incidences of toxicity.ResultsThree randomized controlled trials, with 1263 participants in total, were analyzed. Median follow-up was 11 years. Patients receiving chemotherapy followed by involved field radiotherapy had a significant benefit on event-free survival (hazards ratio [HR] = 1.47, 95% confidence interval [CI]: 1.14 to 1.90; P = 0.003), but not improved overall survival (HR = 1.00, 95% CI: 0.80 to 1.25; P = 0.978) at 8 years, in relation to those in the chemotherapy alone arm. There were great differences in the reporting of cumulative incidences of toxicity.ConclusionChemotherapy followed by involved field radiotherapy, as compared with chemotherapy alone, is associated with better event-free survival, but no survival benefit is observed for patients for limited-stage aggressive non-Hodgkin's lymphoma. These results needed to be confirmed by high quality trials and further studies in the East.     

Alternating chemotherapy regimen (P-VABEC) for intermediate and high-grade non-Hodgkin's lymphoma of the middle aged and elderly

An intensive third generation regimen (P-VABEC) including adriamycin, etoposide, cyclophosphamide, vincristine, bleomycin and prednisolone was administered to 43 unselected elderly patients with intermediate or high-grade non-Hodgkin's lymphomas (NHL). The median age was 67, 40 per cent were Ann Arbor stage IV, 73 per cent had‘B’ symptoms, 55 per cent had bulky disease, 48 per cent had serum lactate dehydrogenase greater than 450 U/1, 85 per cent had serum thymidine-kinase greater than 4 U/1. Thirty patients were previously untreated. The complete remission (CR) rate was 74 per cent, and the partial remission (PR) rate 23 per cent, with an overall response rate of 97 per cent. The regimen was carried out on an outpatient basis in all patients. No death occurred during therapy. The Kaplan-Meier actuarial survival of all patients at 3-years is 47 per cent, and 50 per cent (16/32) of all patients who attained CR remain alive and in remission at a median of 21+ months (range 6+ to 42+). These results confirm that high remission and failure-free survival rates can be achieved also in elderly unselected patients with aggressive NHL treated with curative intent.     

Proteasome inhibition with bortezomib: a new therapeutic strategy for non-Hodgkin's lymphoma

The incidence of non-Hodgkin's lymphoma (NHL) has markedly increased in the US and other westernized countries in recent years and presents a considerable clinical challenge. NHL is divided into subtypes that follow an aggressive or indolent course. Follicular lymphoma (FL), the most common indolent subtype, and mantle cell lymphoma (MCL), an aggressive subtype that accounts for approximately 5% of cases, are generally incurable. MCL has a relatively poor prognosis, with a median survival of 3-4 years. Despite improving response rates with new agents and regimens, the lack of demonstrated improvement in overall survival in many subtypes supports the development of novel approaches, such as proteasome inhibition. Bortezomib is the first proteasome inhibitor to be evaluated in human studies. It has already been approved as second-line treatment in multiple myeloma and is now under active investigation in NHL. The US FDA has granted bortezomib fast-track designation for relapsed and refractory MCL. In vitro and in vivo studies have demonstrated single-agent activity against various lymphoid tumors, and additive or synergistic effects in combination with other agents, including standard chemotherapy drugs employed in NHL. Phase 2 clinical trials indicate that bortezomib is well tolerated and active in several NHL subtypes, with response rates of 18-60% in FL and 39-56% in MCL. A number of combination trials are currently underway with a range of standard agents. Bortezomib has the potential to play a significant role throughout the NHL treatment algorithm in the future.     

Superiority of second over first generation chemotherapy in a randomized trial for stage III-IV intermediate and high-grade non-Hodgkin's lymphoma (NHL): the 1980-1985 EORTC trial. The EORTC Lymphoma Group.

A first-generation CHOP-like cyclic combination chemotherapy (CT) regimen using cyclophosphamide 600 mg/m2 IV d1, hydroxorubicin (doxorubicin) 50 mg/m2 IV d1, VM26 60 mg/m2 IV d1, and prednisone 40 mg/m2 PO d1-5 (CHVmP) was compared to a second-generation combination wherein vincristine 1.4 mg/m2 IV and bleomycin 6 mg/m2 IM/IV were added at mid-interval (d15) to the former drugs (CHVmP + VB) in the treatment of intermediate- and high-grade malignant NHL. From April 1980 to January 1986, 141 eligible patients with stage III-IV unfavorable histologies (except T lymphoblastic NHL) entered this EORTC randomized trial. In both arms adjuvant radiotherapy (30 Gy) was given in instances of bulky or residual disease. In all patient subsets the outcome favored the second-generation regimen. The difference was even greater in patients with Diffuse Large Cell Lymphoma (DLCL). At 5 years, overall survival was 53% with CHVmP + VB versus 29% (p = 0.002). The advantage was due to a higher complete remission (CR) rate (80% versus 50%, p = 0.01). Indeed, once CR was achieved the relapse-free survival (RFS) was not significantly influenced (59% versus 49%). No significant additional toxicity could be attributed to vincristine and bleomycin. This study demonstrates a clear benefit for intermediate- and high-risk malignant NHL and particularly DLCL from intercalating non-myelotoxic drugs at mid-cycle intervals, without adverse effects.     

Improved outcome in children with advanced stage B-cell non-Hodgkin's lymphoma (B-NHL): results of the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol

From July 1990 to March 1996, 112 children with stage III or IV B-cell non-Hodgkin's lymphoma (B-NHL) with up to 70% FAB L3-type blasts (n = 42) in the bone marrow without central nervous system (CNS) disease were treated on the United Kingdom Children Cancer Study Group (UKCCSG) 9002 protocol (identical to the French LMB 84). The median age was 8.3 years. There were 81 boys and 31 girls. According to the extent of the primary disease, patients were sub-staged into three groups: IIIA with unresectable abdominal tumour (n = 39); IIIB with abdominal multiorgan involvement (n = 57) and IIIX with extra-abdominal primary lymphoma often presenting as pleural effusion (n = 16). Univariate and multivariate analyses were carried out to evaluate the prognostic significance of lactate dehydrogenase (LDH) level at diagnosis, the sub-stage and the time to achieve complete remission (CR). With a median follow up of 48 months (range 12-92), the overall and event free survival (EFS) is 87% (95% confidence interval (CI) 79.2-92.1 %) and 83.7% (95% CI 76.3-89.2%) respectively. Six patients (5.4%) never achieved CR, of whom one is alive following high-dose therapy. Eight patients (7.1%) relapsed after achieving CR, three are alive after second-line therapy. There were three early toxic deaths (2.7%), mainly from infection, and one late death from a second cancer. There was no significant difference in EFS according to LDH level at diagnosis, the sub-stage or the time to CR. This study confirms the overall good prognosis and low rate of toxic deaths in patients with advanced B-NHL treated with this intensive regimen. No significant difference in EFS according to the sub-stage, the time to achieve CR or LDH level at diagnosis making it difficult to identify a group that should not receive intensive therapy.     

The addition of oral idarubicin to a chlorambucil/dexamethasone combination has a significant impact on time to treatment failure but none on overall survival in patients with low grade non-Hodgkin's lymphoma: Results of the Scotland and Newcastle Lymphoma Group randomized NHL VIII trial

Two hundred untreated patients with low grade NHL (KIEL), including 155 follicular NHL, were randomized to six courses of treatment with chlorambucil 20 mg m^-2 for 3 days and dexamethasone 4 mg bd for 5 days (CD) vs the same regimen plus oral idarubicin 10 mg m^-2 for 3 days (CID). Responding patients could be randomized to no further treatment or maintenance treatment for up to 36 months with alpha interferon. Complete remissions/CRu were more frequent in the CID arm (35% vs 24%) but the overall response rate was similar; 87/91 (96%) vs 86/92 (93%). Overall survival (OS) did not differ between the two arms. Time to treatment failure (TTTF) was prolonged in the CID arm, p = 0.03; median time 28 vs 19 months. TTTF for the B-cell follicular group alone was for CID (77 patients) 33 months vs 18 months for CD (78 patients). Interferon conferred no apparent benefit. The Follicular Lymphoma International Prognostic Index (FLIPI) is confirmed as a good predictor of risk groups including a group of 23% with shorter survival. The addition of the oral anthracycline, idarubicin, led to a significant improvement in TTTF with low toxicity. The use of radiotherapy in this sub-group may have contributed to this result. CID is a potential for combination with antibody therapy particularly in older patient groups.     

MOPP chemotherapy plus irradiation for Hodgkin's disease, stages IA to IIIB. Long-term results of the prospective trial H72 (1972-1976, 334 patients)

From April 1972 to December 1976, 334 patients with Hodgkin's disease, CS IA-IIIB, were prospectively treated with combined chemotherapy and radiation. The 166 stages IA and II2A were clinically staged only; the 168 other patients were randomized to clinical or pathological staging. All patients received 3 or 6 cycles of MOPP followed by Mantle field with or without mediastinal irradiation and/or inverted Y or lumbo-aortic field according to initial stage, presentation and protocol. At completion of therapy, 317 patients were in complete remission. Twenty-six patients relapsed and 43 died including 5 with leukemia and 6 with infection. Overall 12-year survival and relapse-free rates are 86.6 +/- 3.08 per cent and 91.5 +/- 3.2 per cent respectively (IA: 95.3 and 95.3 per cent; IIA: 87.8 and 92.1 per cent; IIIA: 83.3 and 100 per cent; IB, IIB: 81.7 and 89.2 per cent; IIIB: 67.8 and 73.7 per cent). The randomized comparison between clinical staging plus 6 cycles of MOPP and laparotomy staging plus 3 cycles of MOPP in final stage II3+A, IB, IIB patients showed no significant 12-year survival differences (90.8 versus 85.6 per cent). With this combined modality treatment policy, high survival rates are obtained using only 3 cycles of MOPP and radiotherapy in CS IA, II2A and in PS II3+, IB, IIB. Laparotomy staging may be unnecessary if 6 cycles of MOPP are employed before irradiation in CS IIA, IB, IIB disease and if 3 cycles of MOPP are followed by irradiation in CSIA and II2A disease. Mediastinal irradiation can be avoided in patients with supradiaphragmatic disease without mediastinal involvement.     

CHOP or THP‐COP regimens in the treatment of newly diagnosed peripheral T‐cell lymphoma,not otherwise specified: a comparison of doxorubicin and pirarubicin

The CHOP regimen consisting of cyclophosphamide, doxorubicin (DOX), vincristine and prednisolone has been the most used regimen for peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS). Pirarubicin [tetrahydropyranyladriamycin (THP)], a derivative of DOX, is an anthracycline with reportedly less cardiotoxicity than DOX. Here, we confirmed the efficacy of THP‐COP using THP instead of DOX in the treatment of PTCL‐NOS. The study protocol employed a retrospective, consecutive entry design. We retrospectively analysed 56 patients with PTCL‐NOS who had received THP‐COP or CHOP. These regimens were performed every 21 days. Twenty‐nine patients received THP‐COP, and 27 received CHOP. There were no significant differences in known prognostic factors, including in the International Prognostic Index (IPI) and the prognostic index for T‐cell lymphoma (PIT), between the two groups. Complete remission rates in patients with THP‐COP and CHOP were 52% in both groups; the 3‐year overall survival (OS) rates were 67% and 52% (p = 0.074), and the 3‐year progression‐free survival (PFS) rates were 51% and 29% (p = 0.070), respectively. In patients with low IPI (low or low‐intermediate), THP‐COP had significantly better 3‐year OS (100% vs. 64%; p < 0.001) and 3‐year PFS (75% vs. 33%; p < 0.05) than CHOP. Similar differences between THP‐COP and CHOP were observed in patients with a low PIT (groups 1 or 2). Our study showed that THP‐COP produced results equivalent to CHOP regarding efficacy and safety in patients with PTCL‐NOS. In patients with low IPI or PIT, THP‐COP resulted in significantly better prognosis. Copyright © 2015 John Wiley & Sons, Ltd.