Long-term overall survival and toxicities of ABVD vs BEACOPP in advanced Hodgkin lymphoma: A pooled analysis of four randomized trials.

PURPOSE: We explored the potential overall survival (OS) benefit of bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone (BEACOPP) over doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD) in a pooled analysis of four randomized trials. PATIENTS AND METHODS: Primary objective was to evaluate the OS impact of BEACOPP using individual patient data. Secondary objectives were progression-free survival (PFS), secondary cancers, and use of autologous stem cell transplantation (ASCT). RESULTS: About 1227 patients were included. The 7-year OS was 84.3% (95% CI 80.8-87.2) for ABVD vs 87.7% (95% CI 84.5-90.2) for BEACOPP. Two follow-up periods were identified based on survival curves and hazard ratio (HR) over time. For the first 18 months, there was no difference. For the second period of ≥18 months, ABVD patients had a higher death risk (HRABVD vs BEACOPP  = 1.59; 95% CI 1.09-2.33). A Cox model stratified by trial and evaluating the effect of treatment and International Prognostic Index (IPI) score as fixed effects showed that both were statistically significant (treatment, P = .0185; IPI score, P = .0107). The 7-year PFS was 71.1% (95% CI 67.1-74.6) for ABVD vs 81.1% (95% CI 77.5-84.2) for BEACOPP (P < .001). After ABVD, 25 secondary cancers (4.0%) were reported with no myelodysplasia (MDS)/acute myeloid leukemia (AML) compared to 36 (6.5%) after BEACOPP, which included 13 patients with MDS/AML. Following ABVD, 86 patients (13.8%) received ASCT vs 39 (6.4%) for BEACOPP. CONCLUSIONS: This analysis showed a slight improvement in OS for BEACOPP and confirmed a PFS benefit. Frontline use of BEACOPP instead of ABVD increased secondary leukemia incidence but halved the requirement for ASCT.

Intestinal T-cell lymphoma with enteropathy-associated T-cell lymphoma-like features arising in the setting of adult autoimmune enteropathy.

Enteropathy-associated T-cell lymphoma is regarded as a dismal, late complication of coeliac disease, though a single case of T-cell lymphoma with such features arising in the setting of autoimmune enteropathy of the adult has been reported to date. We aim to describe the case of a 41-year-old woman complaining of severe malabsorption syndrome, who was diagnosed with autoimmune enteropathy based on the presence of flat intestinal mucosa unresponsive to any dietary restriction and positivity for enterocyte autoantibodies. Steroid therapy led to a complete recovery of both mucosal and clinical findings over 12 years, when disease relapse was accompanied by the appearance of monoclonal rearrangement of T-cell receptor-γ and peculiar T-cell phenotypic abnormalities, leading to a rapid transition to an overt T-cell lymphoma with features of the enteropathy-associated subtype. Despite intensive treatment, the patient developed cerebral metastasis and died 9 months later. Our case enhances the concept of enteropathy-associated T-cell lymphoma as a disease that may arise in the setting of enteropathies other than coeliac disease, thus representing a heterogeneous entity. Moreover, our observations support the need of a close follow-up of these patients, coupled with comprehensive characterization of mucosal biopsies.

Long-Term Results of the HD2000 Trial Comparing ABVD Versus BEACOPP Versus COPP-EBV-CAD in Untreated Patients With Advanced Hodgkin Lymphoma: A Study by Fondazione Italiana Linfomi.

PURPOSE: The randomized HD2000 trial compared six cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), four escalated plus two standard cycles of BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone), and six cycles of COPP-EBV-CAD (cyclophosphamide, lomustine, vindesine, melphalan, prednisone, epidoxorubicin, vincristine, procarbazine, vinblastine, and bleomycin; CEC) in patients with advanced-stage Hodgkin lymphoma. After a median follow-up of 42 months, patients who received BEACOPP were reported to have experienced better progression-free survival (PFS) but not better overall survival (OS) results than those receiving ABVD. We here report a post hoc analysis of this trial after a median follow-up of 10 years. PATIENTS AND METHODS: Three hundred seven patients were enrolled, 295 of whom were evaluable. At the time of our analysis, the median follow-up for the entire group was 120 months (range, 4 to 169 months). RESULTS: The 10-year PFS results for the ABVD, BEACOPP, and CEC arms were 69%, 75%, and 76%, respectively; corresponding OS results were 85%, 84%, and 86%. Overall, 13 second malignancies were reported: one in the ABVD arm and six each in the BEACOPP and CEC arms. The cumulative risk of developing second malignancies at 10 years was 0.9%, 6.6%, and 6% with ABVD, BEACOPP, and CEC, respectively; the risk with either BEACOPP or CEC was significantly higher than that reported with ABVD (P = .027 and .02, respectively). CONCLUSION: With these mature results, we confirm that patients with advanced Hodgkin lymphoma have similar OS results when treated with ABVD, BEACOPP, or CEC. However, with longer follow-up, we were not able to confirm the superiority of BEACOPP over ABVD in terms of PFS, mainly because of higher mortality rates resulting from second malignancies observed after treatment with BEACOPP and CEC.

The Prognosis of Patients with Liver Metastases from Colorectal Cancer still Depends on Anatomical Presentation more than on Treatments.

BACKGROUND: The best management of liver metastases from colorectal cancer is still debated and little is known about the true impact of treatments on survival. MATERIALS AND METHODS: The study involved 122 patients (77 males), aged 64.0 ± 11.0 years (range: 27.8-86.1) at diagnosis of liver metastatization (synchronous in 59). All underwent chemotherapy and at least one procedure of radiofrequency ablation; 53 also had partial hepatic resections. Demographics, tumor characteristics and survival outcomes from liver metastatization were analyzed with univariate and multivariate techniques. This analysis was performed also taking into account relative survival as the best estimate of specific survival. RESULTS: The analysis with observed survival selected the categorized number of involved lymph nodes in the colorectal specimens as the only statistically significant predictor, while the analysis with relative survival also showed site of the primary tumor (above the sigmoid colon or otherwise) and number of liver metastases as significant factors. The standardized mortality ratio was 9.673 (95% CI: 7.668-11.663) and a total of 201.85 years of life were lost in comparison with the survival of the reference population. CONCLUSIONS: The computation of relative survival ­ better than observed survival ­ selected a more adequate number of predictors, making investigation of even limited series of patients with confounding factors reliable. The finding that prognosis was mainly dependent on the anatomical presentation of the primary tumor and of liver metastases ­ instead of treatments ­ could explain the still contrasting opinions on the role of the available therapies in this field.

Long-Term Follow-Up of Crohn Disease Fistulas After Local Injections of Bone Marrow-Derived Mesenchymal Stem Cells.

OBJECTIVE: To assess the long-term outcome of patients treated with serial intrafistular injections of autologous bone marrow-derived mesenchymal stem cells (MSCs) for refractory Crohn fistulas in terms of safety and efficacy. PATIENTS AND METHODS: Starting from January 10, 2007, through June 30, 2014, clinical evaluation, calculation of the Crohn disease activity index (CDAI), therapeutic management, and documentation of adverse events in 8 of the 10 patients (5 men; median age, 37 years) who had been injected locally with MSCs were prospectively recorded for 72 months. Cumulative probabilities of fistula recurrence and medical or surgical treatment were estimated using a Kaplan-Meier method, whereas differences among the pre- and post-MSC CDAI values were calculated with the Mann-Whitney U test. RESULTS: Following disease remission observed after 12 months from MSC treatment (P<.001), the mean CDAI score increased significantly during the subsequent 2 years (P=.007), and was then followed by a gradual decrease, with the patients achieving remission again (P=.02) at the end of the 5-year follow-up. The probability of fistula relapse-free survival was 88% at 1 year, 50% at 2 years, and 37% during the following 4 years, and the cumulative probabilities of surgery- and medical-free survival were 100% and 88% at 1 year, 75% and 25% at 2, 3, and 4 years, and 63% and 25% at 5 and 6 years, respectively. No adverse events were recorded. CONCLUSION: Locally injected MSCs constitute a safe therapy that rescues refractory patients and regains responsiveness to drugs previously proved ineffective.

Absolute Monocyte Count and Lymphocyte-Monocyte Ratio Predict Outcome in Nodular Sclerosis Hodgkin Lymphoma: Evaluation Based on Data From 1450 Patients.

OBJECTIVE: To verify whether absolute monocyte count (AMC) and lymphocyte- monocyte ratio (LMR) at diagnosis are valid prognostic parameters in classical Hodgkin lymphoma (cHL). PATIENTS AND METHODS: Data were collected from 1450 patients with cHL treated in Israel and Italy from January 1, 1988, through December 31, 2007. RESULTS: The median age of the patients was 33 years (range, 17-72 years), and 70% (1017) of the patients had nodular sclerosis (NS); the median follow-up duration was 87 months. The best cutoff value for AMC was 750 cells/mm(3), and the best ratio for LMR was 2.1. The adverse prognostic impact of an AMC of more than 750 cells/mm(3) was confirmed for the entire cohort, and its clinical significance was particularly evident in patients with NS histology. The progression-free survival (PFS) at 10 years for an AMC of more than 750 cells/mm(3) was 65% (56%-72%), and the PFS at 10 years for an AMC of 750 cells/mm(3) or less was 81% (76%-84%; P<.001). The overall survival (OS) at 10 years for an AMC of more than 750 cells/mm(3) was 78% (70%-85%), and the OS at 10 years for an AMC of 750 cells/mm(3) or less was 88% (84%-90%; P=.01). In multivariate analysis, both AMC and LMR maintained prognostic significance for PFS (hazard ratio [HR], 1.54, P=.006, and HR, 1.50, P=.006) after adjusting for the international prognostic score, whereas the impact on OS was confirmed (HR, 1.56; P=.04) only in patients with NS and an AMC of more than 750 cells/mm(3). CONCLUSION: This study confirms that AMC has prognostic value in cHL that is particularly significant in patients with NS subtype histology. This finding links the known impact of macrophages and monocytes in Hodgkin lymphoma with routine clinical practice.

Metabolic tumour volumes measured at staging in lymphoma: methodological evaluation on phantom experiments and patients.

PURPOSE: The presence of a bulky tumour at staging on CT is an independent prognostic factor in malignant lymphomas. However, its prognostic value is limited in diffuse disease. Total metabolic tumour volume (TMTV) determined on (18)F-FDG PET/CT could give a better evaluation of the total tumour burden and may help patient stratification. Different methods of TMTV measurement established in phantoms simulating lymphoma tumours were investigated and validated in 40 patients with Hodgkin lymphoma and diffuse large B-cell lymphoma. METHODS: Data were processed by two nuclear medicine physicians in Reggio Emilia and Créteil. Nineteen phantoms filled with (18)F-saline were scanned; these comprised spherical or irregular volumes from 0.5 to 650 cm(3) with tumour-to-background ratios from 1.65 to 40. Volumes were measured with different SUVmax thresholds. In patients, TMTV was measured on PET at staging by two methods: volumes of individual lesions were measured using a fixed 41% SUVmax threshold (TMTV41) and a variable visually adjusted SUVmax threshold (TMTVvar). RESULTS: In phantoms, the 41% threshold gave the best concordance between measured and actual volumes. Interobserver agreement was almost perfect. In patients, the agreement between the reviewers for TMTV41 measurement was substantial (ρ c = 0.986, CI 0.97 - 0.99) and the difference between the means was not significant (212 ± 218 cm(3) for Créteil vs. 206 ± 219 cm(3) for Reggio Emilia, P = 0.65). By contrast the agreement was poor for TMTVvar. There was a significant direct correlation between TMTV41 and normalized LDH (r = 0.652, CI 0.42 - 0.8, P <0.001). Higher disease stages and bulky tumour were associated with higher TMTV41, but high TMTV41 could be found in patients with stage 1/2 or nonbulky tumour. CONCLUSION: Measurement of baseline TMTV in lymphoma using a fixed 41% SUVmax threshold is reproducible and correlates with the other parameters for tumour mass evaluation. It should be evaluated in prospective studies.

Tumor burden in Hodgkin's lymphoma: much more than the best prognostic factor.

The intense immunological crosstalk between the rare neoplastic cells and the prevalent reactive ones is responsible for the development of signs and symptoms of Hodgkin's lymphoma. It is likely the reason for the superior predictivity constantly demonstrated by the tumor burden, as the final expression of the whole cytological disorder. Moreover, the tumor burden is related to the probability of response and its 1-year stability, showing different relationships according to the treatment administered. The relative risk of early treatment failure can be predicted on the basis of the tumor burden at diagnosis and the therapy chosen. Tumor burden is measured from the diagnostic whole body computed tomography (CT) scan, but can also be indirectly calculated from some staging parameters when the CT-aided assessment cannot be performed. Preliminary promising results have been obtained with a semi-automatic positron emission tomography/CT scan measuring metabolically active volumes, instead of whole visible masses.

The prognostic role of time to diagnosis and presenting symptoms in patients with pancreatic cancer.

BACKGROUND: The aim of this study was to investigate the prognostic role of diagnostic delay and clinical presentation (regarding pain, jaundice, and weight loss) in pancreatic carcinoma. METHODS: One hundred and seventy patients with pancreatic cancer were diagnosed and treated in the decade 2001-2010 (100 males and 70 females, with a mean age of 65.8 years [range, 36-91]). Patients were staged with spiral computed tomography and 75% were found to have advanced disease (28 stage III, 99 stage IV disease). Ductal adenocarcinoma was diagnosed in 147 cases, other subtypes of carcinoma in the remaining 23. Fifty patients were operated with radical intent, 19 had palliative surgery, 101 were considered inoperable because of advanced disease or heavy anesthesiologic risk; 31 of these inoperable patients underwent biliary decompression by insertion of an endoluminal or percutaneous stent. Gemcitabine-containing regimens were administered to 143 patients and radiotherapy was combined in 19. Overall and relative survival were the parameters studied. Multivariate analysis was performed by multiple regressions applied to proportional-hazards model. RESULTS: From all the clinical, pathological and therapeutical factors evaluated the statistically significant ones were time to diagnosis and surgery. Among symptoms pain was related to the shortest mean time to diagnosis, weight loss to the longest, with corresponding differences in survival. These differences of observed survival were substantially confirmed in terms of relative survival. CONCLUSIONS: The poor prognosis of pancreatic carcinoma seems to depend, in part, on diagnostic delay and this, in turn, is influenced by the type of presenting symptoms.

Hodgkin lymphoma.

Hodgkin lymphoma (HL) is a curable malignancy which shows a bimodal curve in incidence in economically developed countries; there is a putative association with Epstein-Barr virus. The WHO 2008 classification schema recognises two histological types of HL: the nodular lymphocyte predominant and the "classic" HL. The latter encompasses four entities: nodular sclerosis, mixed cellularity, lymphocyte depletion, and lymphocyte-rich. Most patients with HL present with asymptomatic superficial lymphadenopathy. The commonest sites of disease are the cervical, supraclavicular and mediastinal lymph nodes, while sub-diaphragmatic presentations and bone marrow and hepatic involvement are less common. Splenic involvement is usually concomitant with hepatic disease and systemic symptoms; extranodal presentations are quite rare. Systemic symptoms are present in ∼35% of cases. The stage of disease is defined according to the Ann Arbor staging system or its Cotswolds variant, and staging work-up includes physical examination, chest X-rays, chest and abdominal CT scan, and bone marrow biopsy. (18)FDG-PET ((18)fluordeoxyglucose positron emission tomography) plays a central role in staging, response assessment and prognosis definition. Classic HL usually spreads by contiguity within the lymphatic tissue network, with a late extension to adjacent and distant viscera. Mortality from HL has been progressively decreasing, as confirmed by the most recent 5-year survival figure of 81%. The list of putative prognostic factors in HL has been increasing, but most factors still require prospective validation. Some of these variables are used to stratify early-stage disease into "favourable" and "unfavourable" categories, with "unfavourable early-stage" being intermediate between "favourable early-stage" and "advanced-stage". ABVD (adriamycin(doxorubicin), bleomycin, vinblastine, dacarbazine) combination chemotherapy followed by involved-field irradiation is the standard treatment for patients with early-stage HL, with a 5-year OS >95%. Several trials assessing less intensive approaches for patients with favourable early-stage HL are ongoing. More intensified combinations, such as the BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine (Oncovin), procarbazine, prednisone) regimen, are being investigated, usually in patients with unfavourable early-stage HL and interim PET+. ABVD is the standard chemotherapy treatment also for patients with advanced disease. Although some evidence suggests that more intensive combinations provide better disease control, the inevitable increased risk of relevant late toxicity worries investigators. Consequently, there has been a shift towards investigating the innovative strategy of a more aggressive schedule for patients with (18)FDG-PET positive results after the first 2 courses of ABVD. High-dose chemotherapy supported by ASCT (autologous stem cell transplantation) is considered the standard of care in patients with HL which has relapsed after, or is refractory to conventional chemoradiotherapy, while allogeneic transplant is a suitable tool for patients with chemorefractory disease and patients failed after ASCT.

Tumour burden at diagnosis as the main clinical predictor of cell resistance in patients with early stage, favourable Hodgkin lymphoma treated with VBM chemotherapy plus radiotherapy.

We verified whether early resistance to treatment can be predicted in a subset of patients with very favourable, early stage Hodgkin lymphoma, treated with VBM (vinblastine, bleomycin and methotrexate) chemotherapy and involved-field radiotherapy, an effective combination with very low early and late toxicity. The relative tumour burden (rTB) was volumetrically measured from the staging computed tomography and analysed together with the parameters of pre-therapy evaluation in 61 patients enrolled into the protocol MH-1b of the Gruppo Italiano Studio Linfomi between 1996 and 2003. Early failure, codified by either less than complete remission (i.e. partial/null response or progression) or early relapse (within 12 months from the end of therapy), was considered as clinical expression of resistance to treatment. Logistic regression and failure-free survival were the statistical tools for the analysis. The rTB demonstrated to be the best predictor of early failure, outperforming every other pre-treatment parameter, International Prognostic Score included. With a mean rTB value of 44.964 ± 34.788 cm(3)/m(2) in the 53 patients successfully treated and of 130.185 ± 63.993 cm(3)/m(2) in the eight with early treatment failure, the risk of resistance showed fivefold and 10-fold increases at rTB of 52.002 and 74.497 cm(3)/m(2), respectively. Only two patients relapsed more than 12 months after the end of therapy; both had a high initial rTB. The rTB is the best predictor of resistance also in the subset of patients with very favourable, early stage disease. Safe rTB limits are proposed for successful administration of VBM chemotherapy plus involved-field radiotherapy.

Tumor burden in Hodgkin's lymphoma can be reliably estimated from a few staging parameters.

The relative tumor burden (rTB), the tumor burden normalized to body surface area, is of prime clinical and prognostic value in Hodgkin's lymphoma. However, its measurement is rather complicated and a bedside computation cannot be proposed. We investigated the possibility of estimating, instead of measuring, rTB from elementary parameters of the initial staging. The rTB of 507 patients, treated with therapeutic protocols of the Gruppo Italiano Studio Linfomi according to their staging characteristics, was measured through their pre-therapy computed tomographies. The relationships between rTB and staging characteristics were analyzed with simple and multiple regressions both in a training sample (254 patients) for a selection of predictive parameters, and in a test sample (253 patients) for validation of the results. The number of involved sites, bulky mass and the IPI score were the variables best related to rTB. The resulting final equation {estimated rTB=-4.3+8.3xIPI2+22.7x[no. of involved sites (+3 if a bulky mass is present)]} provided the maximal approximation to the measured rTB (R2=0.671). The validity of the equation was confirmed on the test sample and the predictive superiority of the estimated rTB over IPI was still evident in terms of failure-free survival in both groups of patients. The estimated rTB is accurate enough to retain most of the prognostic advantage of the measured rTB over the IPI score. It can be easily calculated, allows a valid approximation of the measured rTB, and can be proposed as a useful tool for clinical research and practice.

How I treat enteropathy-associated T-cell lymphoma.

Enteropathy-associated T-cell lymphoma (EATL) is a complication of celiac disease (CD). This tumor derives from the neoplastic transformation of aberrant intraepithelial T lymphocytes emerging in celiac patients unresponsive to a gluten-free diet. Poor adherence to a gluten-free diet, HLA-DQ2 homozygosity, and late diagnosis of CD are recognized as risk factors for malignant evolution of CD. Recurrence of diarrhea, unexplained weight loss, abdominal pain, fever, and night sweating should alert physicians to this complication. The suspicion of EATL should lead to an extensive diagnostic workup in which magnetic resonance enteroclysis, positron emission tomography scan, and histologic identification of lesions represent the best options. Treatment includes high-dose chemotherapy preceded by surgical resection and followed by autologous stem cell transplantation, although biologic therapies seem to be promising. Strict adherence to a gluten-free diet remains the only way to prevent EATL.

Tumour burden predicts treatment resistance in patients with early unfavourable or advanced stage Hodgkin lymphoma treated with ABVD and radiotherapy.

The purpose of the work was to investigate the factors predicting early resistance to treatment in Hodgkin lymphoma. Many staging parameters, including relative tumour burden (rTB), were analysed in 246 patients with Hodgkin lymphoma in relation to early failure, that is, less than complete remission (i.e. partial response, null response or progression) or occurrence of early relapse, as clinical expressions of resistance to treatment. Patients with early unfavourable disease were 129 and were treated with four to six cycles of ABVD + involved field radiotherapy; 117 patients with advanced stage disease received six cycles of ABVD + optional irradiation to no more than two sites. The rTB was volumetrically measured through the evaluation of staging computed tomography for all the lesions except bone marrow involvement, which was quantified by calculation. The relationship with early resistance was analysed with logistic regressions. The rTB demonstrated to be the best predictor of early failure in both patient subsets, being superior to the multiparameter International Prognostic Score. The rTB showed a significant exponential relationship with the relative risk of early failure, and with inclusion of the extranodal involvement into the model, a single equation became adequate to predict resistance in both early unfavourable and advanced stage patients. The conclusions are that the rTB is the best pretreatment factor related to the risk of resistance to combined ABVD + radiotherapy and that this relationship can be mathematically expressed in an easy way. A simplified assessment of rTB is highly desirable.

What has happened to VBM (vinblastine, bleomycin, and methotrexate) chemotherapy for early-stage Hodgkin lymphoma?

The VBM (vinblastine, bleomycin, methotrexate) chemotherapy combined with involved-field radiotherapy in early-stage Hodgkin lymphoma has not become popular in spite of its excellent results. Nine small trials with this combined therapy were carried out and described in eleven reports. VBM+ radiotherapy offered complete remission rates of 94-100%, with 5-year progression-free survival of 75-95% (elderly patients included). Considerable pulmonary toxicity was recorded in the first trials, but was fully controlled in the later studies through slight modifications of the schedule. The pulmonary toxicity was found related to mediastinal radiotherapy, bleomycin dose and administration of chemotherapy after radiotherapy; it is mitigated by low doses of prednisone. The very good results, the abated side effects on the lungs, the low extrapulmonary toxicity, and the anthracycline-free formulation make this combination therapy worth considering for early-stage Hodgkin lymphoma, particularly in the case of mediastinal involvement or in elderly patients.

Cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab versus epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab for the initial treatment of elderly "fit" patients with diffuse large B-cell lymphoma: results from the ANZINTER3 trial of the Intergruppo Italiano Linfomi.

We conducted a prospective study to compare epirubicin, cyclophosphamide, vinblastine, prednisone and rituximab (R-miniCEOP) with cyclophosphamide, doxorubicin, vincristine, prednisone and rituximab (R-CHOP) for the treatment of "fit" elderly patients with diffuse large B-cell lymphoma (DLBCL). Patients over the age of 65 with stage II-IV DLBCL were screened with a comprehensive geriatric assessment. Patients were randomized to receive six courses of R-miniCEOP (n = 114) or R-CHOP (n = 110). Overall, the rate of complete remission was 70% (p = 0.466). After a median follow-up of 42 months, 5-year event-free survival (EFS) rates were 46% and 48% for R-miniCEOP and R-CHOP, respectively (p = 0.538). Patients older than 72 years and with low-risk disease had a better outcome when treated with R-miniCEOP (p = 0.011). Overall R-CHOP and R-miniCEOP are similarly effective for elderly "fit" patients with DLBCL. The less intense R-miniCEOP may be an acceptable option for the treatment of relatively older patients with low-risk disease.

Chemoresistance as a function of the pretherapy tumor burden and the chemotherapy regimen administered: differences observed with 2 current chemotherapy regimens for advanced Hodgkin lymphoma.

BACKGROUND: The mature results from trials comparing ABVD (Adriamycin [doxorubicin], bleomycin, vinblastine, dacarbazine) and BEACOPP (bleomycin, etoposide, Adriamycin [doxorubicin], cyclophosphamide, Oncovin [vincristine], procarbazine, prednisone) chemotherapies in advanced Hodgkin lymphoma will be available in some years. An early comparison of their curative potential can however be obtained from an assessment of initial tumor burden and chemoresistance. PATIENTS AND METHODS: Less than a complete remission after treatment and relapse occurring within 12 months thereafter were assumed to be clinical expressions of chemoresistance. The tumor burden was calculated from the measurements of all the lesions documented by staging computed tomography (CT) and was normalized to body surface area to give the relative tumor burden (rTB). Using logistic regression analysis, the relationship between initial rTB, chemoresistance, and chemotherapy regimen administered was retrospectively studied in 222 patients selected from those enrolled in 2 similar randomized trials. RESULTS: The median rTB volumes were 157.9 cm(3)/m(2) in the 115 patients treated with ABVD vs. 154.6 cm(3)/m(2) in the 107 patients treated with BEACOPP, and the distribution of the volumes was identical in the 2 groups. The rTB was confirmed as the best predictor of early treatment failures (22 less than complete responses plus 21 early relapses). For the same rTB, the risk of chemoresistance to BEACOPP was about half that of the chemoresistance to ABVD or, for a given risk of chemoresistance, BEACOPP cured patients with an rTB 89.1 cm(3)/m(2) greater than that cured by ABVD (ie, more than 50% of the median tumor load of patients with advanced-stage disease). CONCLUSION: This account of rTB allows an early comparative evaluation of the curative ability of different chemotherapy regimens.

Improving the AJCC/TNM classification for use in early gastric cancer.

PURPOSE: The current TNM classification is still unsatisfactory for collecting all the prognostic information from the clinical presentation of early gastric cancer: "T" is limited to two levels, the classes of "N" are still wide and "M" is generally absent. PATIENTS AND METHODS: This study involved 99 patients who underwent radical gastric resection for early gastric cancer. Clinical and histological parameters were prognostically analyzed for both observed and relative survival. Univariate and multivariate analyses were applied to the proportional hazards model. RESULTS: Number of metastatic lymph nodes and measure of the largest diameter of the tumor were the only independent prognosticators of observed and relative survival. Their similar relative hazards allowed an additive use of them in the N class. Two cut-off values of this composite clinical parameter are proposed for a good discrimination of the relative survival. DISCUSSION: The number of metastatic lymph nodes is the cornerstone of the current TNM system and was confirmed as adequate. The possibility of adding tumor size to the number of the involved lymph nodes improves and amplifies the prognostic ability, which is presently limited by the rarity of lymph node involvement and the small number of the lymph nodes usually involved.

Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study.

A prospective, multicenter, randomized trial comparing pamidronate administration (60-90 mg once a month for 1 year) versus simple observation in 177 patients with asymptomatic myeloma was performed to explore whether the administration of this drug reduces the rate of and/or the time to progression to overt, symptomatic disease. No relevant side effects were recorded in pamidronate-treated patients. With a minimum follow-up of 5 years for live patients, there were 56/89 (62.9%) progressions in the pamidronate-treated group and 55/88 (62.5%) within the controls (p = NS). Median time to progression was 46 and 48 months, respectively (p = NS). Overall survival was also similar between the two groups. Skeletal-related events at the time of progression were observed in 40/55 (72.7%) controls, but only in 22/56 (39.2%) pamidronate-treated patients (p = 0.009). In conclusion, the administration of pamidronate in asymptomatic myeloma, while reducing bone involvement at progression, did not decrease the risk of transformation and the time to progression into overt myeloma.

Prolonged survival in advanced thymoma: Effectiveness of sequential multiple lines of chemotherapy in an inoperable case.

A standard therapeutic approach for advanced malignant thymoma has yet to be defined given the rarity of this condition. We present a patient with advanced thymoma, evaluated as inoperable at diagnosis due to multiple serosal metastases. The strong constitution and determination of the patient allowed treatment with six distinct and subsequent chemotherapy regimens, all administered on an outpatient basis. A survival of 64 months from diagnosis was achieved. A favorable clinical response was obtained after the first three treatment lines, with the disappearance of all lesions on both computed tomography and positron emission tomography (PET) images. However, this result was not confirmed by surgical exploration of the thorax, undertaken with the aim of radical excision of possible residual disease. The presence of multiple pleural nodules, not evident on the imaging techniques, prevented even limited tumor debulking. The chemotherapy lines administered following detection of the lessions, stabilized the disease for a further 2 years, while a satisfactory quality of life was maintained. Only in the last months did the tumor progress and signs of cardiotoxicity appear, with the latter constituting the eventual cause of death. This case is important since the medical literature does not indicate non-cross-resistant regimens for advanced thymoma following second-line chemotherapy, and the sequence of regimens presented in this case study may serve as a feasible outline program. Moreover, we highlight the known possibility of false-negative PET studies, which can occur despite the claimed glucose avidity of thymoma tissue.