[The importance of adherence to oral therapies in the field of oncology: the example of breast cancer]. / L'adhésion thérapeutique aux traitements oraux : enjeux en oncologie - l'exemple du cancer du sein.

Today, over 40 different oral anticancer therapies are available in the French prescription pricing authority dictionary. Adherence to these therapies has become a major issue in the field of oncology. Most of the available research has focused on adherence to hormonal therapy for breast cancer (BC). The objective of this paper is to synthesize current knowledge on adherence and persistence to hormonal therapy for BC. Available studies display significant heterogeneity due to variability in the measurements and data sources used, as well as in the timing of the measurements. Adherence and persistence estimates have recently been summarized in a meta-regression analysis. For tamoxifen, adherence ranges from 79% at one year to 65% at five years, and for Aromatase Inhibitors (AI), from 80% at one year to 72% at five years. Persistence decreases with the increasing duration of treatment: from a high of 86% of patients persistent at 1 year to a low of 53% at five years for tamoxifen, and from 88% to 69% for AI. Some of the modifiable determinants of adherence are directly linked to the patient-physician relation, to information provided during consultations, or to the specialty of the physician involved in the patient follow-up. Non-modifiable determinants, such as age or comorbidities, can be used to identify sub-groups of patients at high risk of non-adherence in order to target interventions. Few trials have been conducted in oncology to evaluate the efficacy of interventions to improve adherence. Adherence directly impacts both the efficacy of treatment and long-term treatment costs. Interventions to improve adherence to oral therapies should be systematically promoted in oncology. Improving adherence should be considered a priority in the field, lest physicians continue writing inefficient prescriptions for highly efficacious treatments.

Randomized study of 2 reduced-intensity conditioning strategies for human leukocyte antigen-matched, related allogeneic peripheral blood stem cell transplantation: prospective clinical and socioeconomic evaluation.

BACKGROUND: The optimal intensity of reduced-intensity conditioning (RIC) before allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains uncertain. METHODS: In this centrally randomized phase 2 study, the authors compared 2 different strategies of RIC. In total, 139 patients (median age, 54 years; range, 21-65 years) with hematologic malignancies underwent allo-HSCT from a human leukocyte antigen-identical sibling after conditioning combining fludarabine with either busulfan and rabbit antithymocyte-globulin (BU-rATG) (n = 69) or total body irradiation (TBI) (n = 70). Postgraft immunosuppression consisted of cyclosporin A in all patients with the addition of mycophenolate-mophetil after TBI. RESULTS: The median follow-up was 54 months (range, 26-88 months). One-year overall survival rate was identical in both groups. Four patients experienced graft-failure after TBI. The incidence of grade 2 through 4 acute graft-versus-host-disease was greater after BU-rATG than after TBI (47% vs 27%; P = .01), whereas no difference was observed with chronic graft-versus-host-disease. The BU-rATG group had a higher objective response rate (65% vs 46%; P = .05) and a lower relapse rate (27% vs 54%; P < .01). However, the nonrelapse mortality rate was higher after BU-rATG than after TBI (38% vs 22%; P = .027). At 5 years, the overall and progression-free survival rates were 41% and 29%, respectively, and did not differ statistically between groups. A detrimental effect on some parameters of quality of life was more pronounced after BU-rATG, but recovery was identical in both groups. The mean total cost per patient, including the cost to treat disease progression post-transplantation, did not differ statistically between groups. CONCLUSIONS: Five years after transplantation, the BU-rATG regimen was associated with greater disease control. However, because of the higher nonrelapse mortality rate, this did not translate into better overall or progression-free survival.

Loss of Bcl-2 expression in colon cancer: a prognostic factor for recurrence in stage II colon cancer.

AIMS: To evaluate the prognostic value of immunohistochemical expression of Bcl-2 in colon cancers. PATIENTS AND METHODS: Two hundred and twenty-six resected and paraffin-embedded colon carcinomas were analysed by immunostaining using monoclonal antibodies for Bcl-2. We evaluated whether the Bcl-2 staining patterns, semi-quantitatively assessed, could be correlated with the pTNM stage, size and tumour circumference, differentiation, appearance, vascular invasion, perineural invasion, colloid component, margins, involvement of adjacent structures, stromal appearance, flow cytometry and the S-phase. RESULTS: Eighty patients (36%) were considered Bcl-2 positive. The extent of Bcl-2 expression by tumour cells decreased significantly with respect to increasing tumour size (P=0.042), the extension of parietal invasion pT (P=0.007), the invasive nature of the tumour (P=0.024), and extent of the circumference (P=0.024). In a multivariate analysis, Bcl-2 expression does not appear as an independent prognosis factor in the overall population as in the 166 patients with optimal resection. Of the 59 stage II patients, using univariate analysis, Bcl-2 appears to be predictive of relapse-free survival (P=0.025) but not of overall survival (P=0.09). CONCLUSION: The loss of Bcl-2 expression appears to be correlated with increase in number of relapses in the stage II colon cancers and could be a potential useful additional histo-prognostic marker in therapy decision making. Bcl-2 immunodetection seems to be associated with slower local tumour growth.

Breast cancer guidelines--Physicians' intentions and behaviors.

Guidelines are written to define what a physician should do, and networks set up to provide every patient with good practice. However, is willingness to treat according norms enough to actually implement it? Between 1997 and 2003, 4,533 women with invasive, noninflammatory, nonmetastatic breast cancer have been treated within the framework of a regional network (R2C). The rate of implementation of 5 consensual norms was assessed. The rate of "abnormal" management regarding surgical re-excision for inadequate margin was found to be 12.6%. The main explanatory variable was patient age >70 years (OR = 4.05). For nodal exploration, the sampling quality threshold was set at 10. Mean rate of lack of compliance was 25.2%. The 2 main explicative factors were surgeon's experience and women's age. The observed rate of "insufficient" irradiation dose was 18.2%. The main explanatory variables were age (with a gradient) and a negative nodal status. Concerning adjuvant chemotherapy, the rate of no treatment (despite consensual indication) was 16.0%. Again, the main explicative factor was age (with a gradient). Women's age appears to be a major explanatory variable predicting lack of physician's compliance with consensual norms. Besides the age of the women, a "better" prognosis (negative nodal status and pT < or = 20 mn) is often associated with lack of compliance. It is not clear, however, if it's the rules that do not fit the clinical situation of aging patients or the physicians who are not aware of the benefit of consensual disease management for aging patients.

[Impact on the quality of pathology reports in the R2c cancer network: analysis of 4521 pathology reports of primary breast tumors]. / Impact du réseau de cancérologie R2c sur la qualité des informations histopathologiques: analyse de 4521 dossiers de cancer du sein.

This study was designed to evaluate the impact on the quality of pathology reports of a cancer network, named R2c covering the west side of PACA region. Over a 7 year-period, we collected 4521 pathology reports on primary breast cancers, filled by pathologists belonging or not the network. The analysis focused on the 6 histo-prognostic factors from the pathology report standardized according to European recommendations. Between the 1997 and 2003 the proportion of reports filled for the 6 factors increased from 29,6 % to 75,1 % among non-member, and from 49,1 % to 89,7 % among members. The histological size or the number of nodes examined is however filled similarly in these two groups. This study shows how the direct implication of the pathologists in a network, with precise criteria improves quality of reports. Nevertheless, network participation is not the only cause of improvement. Having a clinical practice corresponding to the standards determines partly the involvement in a network aiming at rationalizing practices. Moreover, centralised data collection carried out by R2c allows an annual evaluation of the quality of the reports, providing feedback information to members. Lastly, the shared liability in oncology probably has an indirect impact on practices of non-member pathologists.

[Improvement in breast cancer survival between 1975 and 2003 in a cohort of 5722 women]. / Amélioration de la survie après cancer du sein: analyse d'une cohorte de 5,722 patientes traitées de 1975 à 2003 dans un centre de lutte contre le cancer.

To evaluate improvement in breast cancer management between 1975 and 2003, we constituted a cohort of 5722 women with an invasive non-metastatic breast cancer. An active follow-up was carried out and completed using administrative databases. Survival rates were computed using a classical person-time and a period analyses. Relative survival rates were also presented. Advanced cancers at diagnosis decreased from 70.7% to 45.5% between 1975 and 2003. Person-time analysis showed a 48.8% reduction in death rates over 30 years. Survival at 10 years ranged from 50% (CI95% = 45-55) for women diagnosed in 1975-1979 to 66% (CI95% = 63-69) for those diagnosed in 1990-1994. Using period analysis, we estimated the 10 year survival of women diagnosed in 2000-2003 to be 68% (CI95% = 64-72). Overall relative survival was 76% (CI95% = 71-80) at 10 years. Taking into account known prognosis factors, survival was significantly improved for recent diagnosis periods (p<0.00001). Observed improvement in survival confirmed 'in real life' data from clinical trials.

Micrometastases in sentinel lymph node in a multicentric study: predictive factors of nonsentinel lymph node involvement--Groupe des Chirurgiens de la Federation des Centres de Lutte Contre le Cancer.

PURPOSE: To determine the rate of nonsentinel lymph node (NSN) involvement at axillary lymph node dissection (ALND) and predictive factors of this involvement following detection of micrometastasis in sentinel nodes (SN). METHODS: We analyzed 700 observations of SN micrometastases with additional ALND with the characteristics of the patients, tumors, and SN. RESULTS: Involvement of SN was diagnosed 388 times by serial sections (55.4%) with standard hemoxylin and eosin staining (HES) and 312 times solely on immunohistochemical analysis (IHC; 44.6%). The accurate size of the micrometastases was indicated in 488 cases: 301 larger than 0.2 mm (61.7%) and 187 < or = 0.2 mm (38.3%). Ninety-four patients (13.4%) presented an NSN involvement with only one NSN involved in 62 cases (66%). Predictive factors of NSN involvement were in univariate analysis (pT stage [P < .000], menopausal status [P = .048], T stage [P = .006], grade [P = .013], lymphovascular invasion [LVI; P = .013], histologic tumor type [P = .017], and method of micrometastasis detection, by HES or IHC [P = .015]) and in multivariate analysis (pT stage < or = or > 20 mm [odds ratio, 2.54], micrometastases detected by HES or IHC [odds ratio,1.734], presence or absence of LVI [odds ratio, 1.706]). Micrometastasis size < or = or greater than 0.2 mm was not predictive. CONCLUSION: This study confirms the value of serial sections and the vital role played by IHC in screening for small micrometastases. Omission of additional ALND may be envisaged with minimal risk for pT1a and pT1b tumors, and pT1a-b-c tumors corresponding to tubular, colloidal, or medullar cancers.

Early allogeneic stem-cell transplantation for young adults with acute myeloblastic leukemia in first complete remission: an intent-to-treat long-term analysis of the BGMT experience.

PURPOSE: We analyzed the impact of allogeneic stem-cell transplantation (alloSCT) as an early consolidation for young patients with acute myeloblastic leukemia in first complete remission (CR1) through four successive protocols. PATIENTS AND METHODS: Of the 472 patients who achieved CR1, 182 (38%) had an HLA-identical sibling (donor group), and alloSCT was performed in 171 patients (94%). Of the 290 patients without donor (no-donor group), 62% received an autologous SCT. RESULTS: In an intent-to-treat analysis based on donor availability, the overall 10-year survival probability was 51% v 43% (P = .11) for the donor and no-donor groups, respectively. A Cox analysis determined that four factors had independent prognostic significance for survival (initial WBC count, French-American-British subtypes, cytogenetic risk, and number of induction courses). This permitted constitution of a simple index that reclassified 21% of the patients compared with usual cytogenetic classification and identified three subpopulations with different outcome and different impact of alloSCT. CONCLUSION: AlloSCT was associated with a survival advantage for an intermediate-risk group. In other groups, numbers are limited for definitive conclusion. However, early performed alloSCT does not seem to be the optimal treatment of high-risk patients or offer any advantage over intensive chemotherapy in low-risk patients.

Protein expression profiling identifies subclasses of breast cancer and predicts prognosis.

Breast cancer is a heterogeneous disease whose evolution is difficult to predict by using classic histoclinical prognostic factors. Prognostic classification can benefit from molecular analyses such as large-scale expression profiling. Using immunohistochemistry on tissue microarrays, we have monitored the expression of 26 selected proteins in more than 1,600 cancer samples from 552 consecutive patients with early breast cancer. Both an unsupervised approach and a new supervised method were used to analyze these profiles. Hierarchical clustering identified relevant clusters of coexpressed proteins and clusters of tumors. We delineated protein clusters associated with the estrogen receptor and with proliferation. Tumor clusters correlated with several histoclinical features of samples, including 5-year metastasis-free survival (MFS), and with the recently proposed pathophysiologic taxonomy of disease. The supervised method identified a set of 21 proteins whose combined expression significantly correlated to MFS in a learning set of 368 patients (P < 0.0001) and in a validation set of 184 patients (P < 0.0001). Among the 552 patients, the 5-year MFS was 90% for patients classified in the "good-prognosis class" and 61% for those classified in the "poor-prognosis class" (P < 0.0001). This difference remained significant when the molecular grouping was applied according to lymph node or estrogen receptor status, as well as the type of adjuvant systemic therapy. In multivariate analysis, the 21-protein set was the strongest independent predictor of clinical outcome. These results show that protein expression profiling may be a clinically useful approach to assess breast cancer heterogeneity and prognosis in stage I, II, or III disease.

Salvage abdominoperineal resection after failure of conservative treatment in anal epidermoid cancer.

PURPOSE: Radiotherapy alone or with combined chemotherapy is the first therapeutic option for epidermoid carcinoma of the anal canal. Failure of this conservative treatment may benefit of salvage abdominoperineal resection. This study was designed to analyze postoperative outcome and oncologic results in a single anticancer institution. METHODS: Medical charts of 36 patients (median age, 57.9 years) who underwent salvage abdominoperineal resection after failure of conservative treatment between 1987 and 2002 were reviewed retrospectively. There were 15 patients treated for immediate failure (Group I) and 21 patients for recurrence (Group II). Twenty-two patients have undergone primary use of flap reconstruction of the perineal wound. There were ten rectus abdominis myocutaneous flaps, nine omental flaps, two gracilis muscular flaps, and one combined flap. RESULTS: There was no postoperative mortality. Median follow-up was 67 (range, 15-155) months. Primary closure of the perineum was obtained in 33 patients (92 percent). Secondary wound breakdown occurred in 23 of 33 patients (70 percent). Complications unrelated to the perineal wound occurred in 13 patients. The overall crude five-year survival after salvage abdominoperineal resection was 69.4 percent. The crude five-year survival in Group I and Group II was 60.7 and 71.5 percent respectively (P = 0.28). The crude five-year, disease-free survival in Groups I and II was 31.1 and 48.2 percent respectively (P = 0.10). Twenty-three patients experienced recurrences after salvage abdominoperineal resection (64 percent) with a mean delay of 30 months. CONCLUSIONS: Despite high incidence of perineal morbidity, salvage abdominoperineal resection for epidermoid carcinomas of the anal canal has a high long-term survival rate.

Identification of TCL1A as an immunohistochemical marker of adverse outcome in diffuse large B-cell lymphomas.

We used a combination of DNA-microarray and tissue-microarray (TMA) analyses to identify markers that could be routinely used to predict the outcome of diffuse large-B-cell lymphoma (DLCL) patients. Gene expression profiling was performed using DNA-microarrays on 52 tumour biopsy samples [31 DLCL and 21 follicular lymphomas (FL)] from 48 patients (28 DLCL and 20 FL). T-cell leukemia/lymphoma-1A (TCL1A) mRNA overexpression was correlated with relapse in DLCL patients. TMA analysis was applied on a distinct series of 36 formalin-fixed, paraffin-embedded DLCL samples and showed that TCL1A immunoexpression was correlated with either higher relapse (p=0.02) or lower 5-year overall survival (p=0.009) rates. Moreover, the prognostic value of TCL1A was independent from IPI in our series. Our data suggest that TCL1A immunodetection is an independent marker of adverse outcome that could be used in routine settings for the management of DLCL patients.

CD8+ T cell dose affects development of acute graft-vs-host disease following reduced-intensity conditioning allogeneic peripheral blood stem cell transplantation.

OBJECTIVE: Acute graft-vs-host disease (aGVHD) remains an important cause of morbidity after reduced-intensity conditioning (RIC) allogeneic transplantation (allo-SCT). It has been shown that antithymocyte globulin (ATG) dose infused during RIC is a major determinant for the likelihood of developing aGVHD. The ATG modulation on aGVHD is likely related to in vivo T-cell depletion. PATIENTS AND METHODS: We therefore investigated the relationship between the cellular composition of the allograft and clinical outcome in 57 patients who received allogeneic peripheral blood stem cells from HLA-identical siblings following an ATG-based RIC. RESULTS: In a multivariate analysis, the CD8+ T cell dose infused was the only parameter associated with the risk of aGVHD (p=0.031; RR=1.96; 95% CI, 1.1-3.6). When looking at the extremes, patients experiencing grade III-IV aGVHD received a median of 143 x 10(6)/kg CD8+ T cells, while patients without aGVHD received a median of 96 x 10(6)/kg CD8+ T cells (p=0.021). None of the different cell subtypes contained in the allograft was associated with a significant probability of developing chronic GVHD. Patients with grade II aGVHD who received an intermediate dose of CD8+ T cells (median, 111 x 10(6)/kg) had a significantly better overall survival in comparison to patients with grade 0-I or grade III-IV aGVHD (p=0.009). CONCLUSION: In comparison to myeloablative allo-SCT, these results demonstrate that a cautious monitoring of the number of cells infused, at least in the context of ATG-based RIC, may represent an important predictive indicator of early transplant-related events and outcome after RIC allo-SCT.

A recurrent chromosome breakpoint in breast cancer at the NRG1/neuregulin 1/heregulin gene.

Most studies of genomic rearrangements in common cancers have focused on regional gains and losses, but some rearrangements may break within specific genes. We previously reported that five breast cancer cell lines have chromosome translocations that break in the NRG1 gene and that could cause abnormal NRG1 expression. NRG1 encodes the Neuregulins 1 (formerly the Heregulins), ligands for members of the ErbB/epidermal growth factor-receptor family, which includes ErbB2/HER2. We have now screened for breaks at NRG1 in paraffin sections of breast tumors. Tissue microarrays were screened by fluorescence in situ hybridization, with hybridization probes proximal and distal to the expected breakpoints. This screen detects breaks but does not distinguish between translocation or deletion breakpoints. The screen was validated with array-comparative genomic hybridization on a custom 8p12 high-density genomic array to detect a lower copy number of the sequences that were lost distal to the breaks. We also precisely mapped the breaks in five tumors with different hybridization probes. Breaks in NRG1 were detected in 6% (19 of 323) of breast cancers and in some lung and ovarian cancers. In an unselected series of 213 cases with follow-up, breast cancers where the break was detected tended to be high-grade (65% grade III compared with 28% of negative cases). They were, like breast tumors in general, mainly ErbB2 low (11 of 13 were low) and estrogen receptor positive (11 of 13 positive).

Clinical outcome in patients with locally advanced bladder carcinoma treated with conservative multimodality therapy.

OBJECTIVES: To describe the outcome of patients with muscle-invasive bladder carcinoma treated with multimodality therapy in our institution from 1993 to 2002. METHODS: The charts of 60 patients with Stage T2-T4N0-N1M0 treated with transurethral resection of bladder tumor followed by a chemoradiotherapy combination were retrospectively reviewed. Of the 60 patients, 22 had received neoadjuvant chemotherapy (methotrexate, cisplatin, and vinblastine or methotrexate, adriamycin, cisplatin, and vinblastine) followed by concomitant chemoradiotherapy (weekly cisplatin/carboplatin or a cisplatin and 5-fluorouracil combination), and 38 had received concomitant chemoradiotherapy alone. Radiotherapy delivered a median dose of 45 Gy to the pelvis and 65 Gy to the bladder in a once-daily or twice-daily fractionation scheme. Follow-up evaluations included cystoscopy with biopsies at regular intervals. Salvage cystectomy was recommended in the case of local persistent tumor or bladder relapse. RESULTS: The median follow-up was 48.5 months (range 10 to 126). Of the 22 patients who received neoadjuvant chemotherapy, 18 (82%) had received two or more cycles; 51 (85%) of the 60 patients received the concomitant chemotherapy as planned. Radiotherapy was completed in 56 patients. Twenty-eight patients developed relapse either locally (14 did not achieve a complete local response after chemoradiotherapy and 6 had true local relapse during follow-up) or at distant sites. The actuarial 5-year disease-specific survival and freedom from local and distant relapse rate was 54% and 42%, respectively. The actuarial local control rate with an intact bladder was 56% at 5 years. When stratified according to stage and grade, patients with Stage T2-T3, grade 2 tumors had a statistically significantly better chance of remaining relapse free than did the others (P = 0.045). Salvage cystectomy (n = 11) for isolated local failure in this population achieved limited results. CONCLUSIONS: Transurethral resection of bladder tumor with this chemoradiotherapy combination achieved satisfactory results in this unfavorable population with invasive bladder carcinoma.

The benefit of induction chemotherapy in patients age > or = 75 years.

BACKGROUND: Patients age > or = 75 years with acute myeloid leukemia (AML) generally are offered palliative treatments instead of induction chemotherapy. The authors conducted a retrospective study comparing the outcomes among these elderly patients with the outcomes among younger patients to assess the impact of intensive treatment approaches in this age group. METHODS: One hundred ten consecutive patients age > or = 75 years with newly diagnosed AML (excluding patients with acute promyelocytic leukemia) were treated in the authors' center over 10 years. Initial treatment was comprised of anthracycline-based induction chemotherapy (i.e., intravenous idarubicin or daunorubicin for 3 days plus cytarabine [ARAC] for 7 days [3 + 7 regimen] or oral idarubicin) for 62 patients (56%), antimetabolite-based chemotherapy (including low-dose ARAC, oral 6-mercaptopurine plus methotrexate, or hydroxyurea) for 40 patients (36%), and supportive care only for 8 patients (7%). Results were compared with the results from 200 patients ages 65-74 years who were treated during the same period. RESULTS: A complete response (CR) to anthracycline-based induction therapy was achieved by 23 of 62 patients (37%), and the 2-year overall survival rate was 22% (which was not statistically different from the group of patients ages 65-74 years). In a multivariate analysis of the entire study group (310 patients), treatment (anthracycline-based vs. other) and age as continuous variable were found to affect survival significantly. In a Landmark analysis, the achievement of a CR translated into improved survival in patients age > or = 75 years. CONCLUSIONS: Patients age > or = 75 years should not be excluded systematically from intensive chemotherapy regimens. Decisions should be based on stratification systems that include functional status and comorbidity assessments as well as prognostic factors, such as cytogenetics.

Immunophenotypic analysis of inflammatory breast cancers: identification of an 'inflammatory signature'.

Inflammatory breast cancer (IBC) is a rare but very aggressive form of breast cancer. Its definition is based on clinical criteria, but a molecular definition could be useful when data are incomplete or features are missing. Recently, the identification of overexpression of E-cadherin in IBC has improved understanding of the molecular basis of this disease. Consequently, the aim of this study was to try to determine an immunophenotypic 'signature' of IBC. A series of 80 cases of IBC were compared with 552 non-IBC control cases and a model was elaborated to evaluate the probability of an inflammatory carcinoma being present in any clinical situation. Tissue microarrays (TMAs) were used to determine the immunohistochemical profile of eight proteins including E-cadherin, EGFR, oestrogen and progesterone receptor (ER and PR), MIB1, ERBB2, MUC1, and P53. All the parameters tested were differentially expressed between IBC and control cases in univariate analysis (p < 0.001). The five variables that were significantly associated with IBC in multivariate analysis were E-cadherin > or = 300 [HR = 5.64 (2.92-10.87)], ER negative [HR = 3.00 (1.67-5.51)], MIB1 > 20 [HR = 3.54 (1.87-6.71)], MUC1 cytoplasmic staining [HR = 2.72 (1.49-4.96)], and ERBB2 positive 2+ or 3+ [HR = 2.46 (1.26-4.78)]. The probability that a breast cancer with this full phenotype at diagnosis was an IBC was 90.5%. If any one of the five parameters was missing, this probability dropped to 75% and was less than 50% when one, two, or three parameters were present. The 5-year overall survival (OS) and 5-year disease-free survival (DFS) of patients with IBC were not significantly different from those of the non-IBC control group that expressed four or five parameters (nIBC-1), but this nIBC-1 control group had a significantly worse outcome than the non-IBC control group (nIBC-2) with only 0-3 parameters (p = 0.0049 for OS and p < 0.0001 for DFS). In conclusion, an immunophenotypic signature was suggested for IBC. This could help to determine the worst cases, independent of clinical criteria.

Intensive sequential chemotherapy with hematopoietic growth factor support for non-Hodgkin lymphoma in patients infected with the human immunodeficiency virus.

BACKGROUND: Optimal treatment of human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL) has yet to be defined, because chemotherapy could exacerbate immunodeficiency, with subsequent adverse effects for patients. METHODS: The authors investigated the feasibility of an intensive chemotherapy regimen for HIV-associated NHL. Thirty-eight patients were treated with a first course of cyclophosphamide (Cy), vincristine, and prednisone; followed by 3 courses of high-dose Cy (2000 mg/m2), doxorubicin (Doxo; 50 mg/m2), vincristine, and prednisone (modified high-dose CHOP); 1 course of high-dose methotrexate (MTX; 8000 mg/m2); and 1 course of high-dose cytarabine (8000 mg/m2). Radiotherapy was added to the treatment regimen for patients with bulky disease or residual tumor. Chemotherapy was administered in conjunction with granulocyte-colony-stimulating factor and antiretroviral therapy. RESULTS: Patients received 91.5%, 93%, 66%, and 63% of the scheduled doses of Cy, Doxo, MTX, and cytarabine, respectively. The complete response rate was 60.5%, with a total response rate of 79%. The 40-month overall survival rate was 43%, the disease-free survival rate was 65%, and the recurrence-free survival rate was 39%. Both an International Prognostic Index score of 0 or 1 and Burkitt-type histology had positive effects on survival, whereas CD4-positive lymphocyte counts, viral burden, and previous highly active antiretroviral therapy did not. CD4-positive T lymphocyte levels decreased from 0.197 +/- 0.156 x10(9)/L before treatment to 0.152 +/- 0.1 x10(9)/L at 6 months after the end of treatment. A decrease in viral load, from 380,000 +/- 785,000 copies/mL before treatment to 25,000 +/- 43,000 copies/mL at 6 months after the end of treatment, also was observed. CONCLUSIONS: The results of the current study indicate that intensive chemotherapy is effective and tolerable for patients with HIV-associated NHL.

Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors.

In this prospective multicenter program, we investigated allogeneic stem cell transplantation (ASCT) from HLA-identical siblings following reduced-intensity conditioning (RIC) regimen for patients with refractory metastatic solid tumors (STs). Fifty-seven patients, of whom 39 had a progressive disease (PD) at time of ASCT, received an RIC ASCT combining fludarabine, antithymocyte globulin (ATG), and busulfan. Patients were analyzed in terms of engraftment, transplant-related mortality (TRM), disease response, and outcome. In this setting, RIC was associated with rapid engraftment and low overall TRM (9% [95% confidence interval (CI), 1%-16%]). The cumulative incidence of objective responses (ORs) reached 14% (95% CI, 6%-30%) with this being significantly higher in patients without PD (44% [95% CI, 21%-67%] versus 0; P <.0001) at time of ASCT. Achievement of OR translated into a significantly better overall survival (OS). In multivariate analysis, OS was significantly influenced by disease status at time of ASCT (odds ratio, 4.88; P <.001) and chronic graft-versus-host disease (GVHD) occurrence (odds ratio, 2.86; P <.01). Overall, these results showed that OR can occur after RIC ASCT for resistant ST with a relatively low TRM and potential benefit especially in patients with slowly progressive disease. Further studies are warranted in patients with less advanced ST.

Weekly administration of docetaxel for symptomatic metastatic hormone-refractory prostate carcinoma.

BACKGROUND: The current Phase II study investigated the clinical benefit, impact on quality of life (QOL), and tolerability of weekly docetaxel in symptomatic patients with metastatic hormone-refractory prostate carcinoma (HRPC). METHODS: Patients received weekly docetaxel 35 mg/m(2) intravenously for 6 consecutive weeks followed by a 2-week rest repeatedly for a maximum of 24 weeks of treatment. Clinical benefit evaluations, based on Karnofsky performance status (KPS) and pain, were assessed weekly during therapy. A clinical benefit response was defined as a sustained (> or = 4-week) improvement in at least one of these parameters without worsening in the other. Patient-assessed QOL (using the European Organization for Research and Treatment of Cancer QLQ-C30), changes in prostate-specific antigen (PSA) levels, tumoral response, and toxicity also were evaluated. RESULTS: Thirty men (median age, 67 years), 15 of whom had received previous chemotherapy, were treated. Overall, 46% of patients achieved a positive pain response and 48% achieved a 50%-or-greater reduction in PSA. KPS was high at baseline (80%), and no significant changes in this parameter were observed. Compared with baseline, all scores improved after the first cycle of therapy, particularly emotional (P = 0.015), pain (P = 0.001), constipation (P = 0.001), and global QOL (P = 0.011) scores. After the second cycle, dyspnea scores decreased (P = 0.010). At the last QOL assessment, there also was deterioration in terms of fatigue (P = 0.013), dyspnea (P = 0.010), and physical functioning (P = 0.017). Toxicity was mild and included neutropenia (Grade 3-4, n = 2). CONCLUSIONS: Of these elderly symptomatic patients with HRPC, half had received previous chemotherapy. Weekly docetaxel was found to be associated with improvements in clinical benefit response and in QOL and was well tolerated.

Loss of FHIT protein expression is a marker of adverse evolution in good prognosis localized breast cancer.

The FHIT tumor suppressor gene, which encompasses the fragile site FRA3B at 3p14.2, is altered frequently in many types of human cancers. To determine its importance as a prognostic marker in breast cancer, the expression of the FHIT protein was studied in a series of 452 breast carcinomas by using immunohistochemistry on sections of tissue microarrays. Three distinct levels of FHIT expression were observed: in 154 cases (34.1%) expression was unchanged as compared to normal level; in 78 (17.2%) no expression was found; in the remaining 220 cases (48.7%), expression was intermediate. Overall, two-thirds of the cases had abnormal levels of the protein. Absence of FHIT was significantly associated with a higher grade (p < 0.01) and absence of hormone receptors (p < 0.001). The patients were separated into Group I (153 node-negative good prognosis patients who did not receive adjuvant chemotherapy) and Group II (226 high-risk patients treated by adjuvant chemotherapy) according to the St.-Gallen conference consensus. The median follow-up was 48 months. Among Group I but not Group II patients, a multivariate analysis showed that FHIT expression was significantly associated with disease-free survival. The relative risk of recurrence for FHIT-negative Group I patients was 2.37 (1.21-4.64; p = 0.03). Thus, among the patients who present with tumors of apparent good prognosis, FHIT is an independent prognostic factor that distinguishes a subgroup of patients who could benefit from adjuvant treatment.