ESMO - European Society for Medical Oncology

Background: The purpose of this report was to review issues associated with the introduction of alternative versions of biosimilars used in the oncology setting.

Design: Data were obtained by searches of MEDLINE, PubMed, references from relevant English-language articles, and guidelines from the European Medicines Agency.

Results: When biosimilars are approved in EU, they will be considered ‘comparable’ to the reference product, but this does not ensure therapeutic equivalence. Inherent differences between biosimilars may produce dissimilarities in clinical efficacy, safety, and immunogenicity. Switching biosimilars should be considered a change in clinical management. Regulatory guidelines have been established for some biosimilar categories but, because of the limited clinical experience with biosimilars at approval, pharmacovigilance programs will be important to establish clinical databases. Guidelines also provide a mechanism for the extrapolation of clinical indications (approved indications for which the biosimilar has not been studied). This may be of concern where differences in biological activity can result in adverse outcomes or when safety is paramount (e.g. stem cell mobilization in healthy donors). These issues should be addressed in biosimilar labeling.

Conclusions: Biosimilars should provide cost savings and greater accessibility to biopharmaceuticals. A thorough knowledge surrounding biosimilars will ensure the appropriate use of biopharmaceuticals.

Bisphosphonates (BP) prevent, reduce, and delay cancer-related skeletal complications in patients, and have substantially decreased the prevalence of such events since their introduction. Today, a broad range of BP with differences in potency, efficacy, dosing, and administration as well as approved indications is available. In addition, results of clinical trials investigating the efficacy of BP in cancer treatment-induced bone loss (CTIBL) have been recently published. The purpose of this paper is to review the current evidence on the use of BP in solid tumours and provide clinical recommendations. An interdisciplinary expert panel of clinical oncologists and of specialists in metabolic bone diseases assessed the widespread evidence and information on the efficacy of BP in the metastatic and nonmetastatic setting, as well as ongoing research on the adjuvant use of BP. Based on available evidence, the panel recommends amino-bisphosphonates for patients with metastatic bone disease from breast cancer and zoledronic acid for patients with other solid tumours as primary disease. Dosing of BP should follow approved indications with adjustments if necessary. While i.v. administration is most often preferable, oral administration (clodronate, IBA) may be considered for breast cancer patients who cannot or do not need to attend regular hospital care. Early-stage cancer patients at risk of developing CTIBL should be considered for preventative BP treatment. The strongest evidence in this setting is now available for ZOL. Overall, BP are well-tolerated, and most common adverse events are influenza-like syndrome, arthralgia, and when used orally, gastrointestinal symptoms. The dose of BP may need to be adapted to renal function and initial creatinine clearance calculation is mandatory according to the panel for use of any BP. Subsequent monitoring is recommended for ZOL and PAM, as described by the regulatory authority guidelines. Patients scheduled to receive BP (mainly every 3–4 weeks i.v.) should have a dental examination and be advised on appropriate measures for reducing the risk of jaw osteonecrosis. BP are well established as supportive therapy to reduce the frequency and severity of skeletal complications in patients with bone metastases from different cancers.

Central venous catheters (CVCs) have considerably improved the management of patients with hematological malignancies, by facilitating chemotherapy, supportive therapy and blood sampling. Complications of insertion of CVCs include mechanical (arterial puncture, pneumothorax), thrombotic and infectious complications. CVC-related thrombosis and infections are frequently occurring complications and may cause significant morbidity in patients with hematological malignancies. CVC-related thrombosis and infections are related and can therefore not be seen as separate entities. The incidence of symptomatic CVC-related thrombosis had been reported to vary between 1.2 and 13.0% of patients with hematological malignancy. The incidence of CVC-related bloodstream infections varies between 0.0 and 20.8%. There is need for a specific approach regarding diagnosis and treatment of CVC-related thrombosis and infection with specific attention to the preservation of the catheter. Since data on CVC-related infections and thrombosis in hematological patients have been obtained mainly from retrospective studies of small sample size, prospective, randomized studies of prophylactic measures concerning CVC-related thrombosis and infection are warranted.

Background: The use of adjuvant carboplatin in the management of stage I seminoma of the testis has been limited by the lack of long-term data. In this study, we address this issue for the first time.

Patients and methods: Data on 199 patients treated with single-agent carboplatin for stage I seminoma of the testis were prospectively collected. Overall mortality, deaths from circulatory disease and the incidence of second cancers were compared with expected values derived from the UK general population.

Results: The median follow-up for the cohort was 9.0 years (range 0.1–20.1). There has been no excess in overall mortality [standardised mortality ratio (SMR) 0.89; 95% CI 0.36–1.83], death from circulatory diseases (SMR 1.44; 95% CI 0.39–3.69) or the incidence of second nontestis cancers (standardised incidence ratio 0.96; 95% CI 0.26–2.45) in this group of patients. These findings also applied to specific follow-up periods of >5 or 10 years. Specifically, neither haematological nor solid nontestis tumours occurred in excess. There was an increase in the long-term development of contralateral testis cancers.

Conclusions: This study addresses some of the concerns surrounding the long-term safety of single-agent carboplatin. It also helps in planning long-term follow-up for patients receiving this form of treatment.

Background: The aim of this study is to determine feasibility and efficacy of the combination regimen gemcitabine, oxaliplatin, and paclitaxel (GOP) in patients with cisplatin-refractory or multiply relapsed germ-cell tumors.

Patients and methods: From April 2003 to October 2006, 41 patients refractory to cisplatin-based chemotherapy or with relapse after high-dose chemotherapy (HDCT) plus stem-cell support (peripheral blood stem-cell transplantation: PBSCT) received 800 mg/m² gemcitabine, 80 mg/m² paclitaxel (Taxol), both on days 1 + 8, and oxaliplatin 130 mg/m² on day 1 of a 3-week cycle for a minimum of two cycles. Primary end point was response rate. Patients were pretreated with a median of two lines of platin-based chemotherapy (range, 1–3), and 78% had relapsed after HDCT/PBSCT.

Results: Seventy-three percent of patients had relapsed within 3 months after the last cisplatin-based chemotherapy. Five percent of the patients achieved a complete response, and 34% and 12% a marker-negative and marker-positive partial response, respectively (overall response rate 51%). After a median follow-up of 5 months (range, 0–20), 15% of the patients remain in complete remission after GOP chemotherapy ± residual tumor resection with a median response duration of 8 months (1 to 17+). Main toxicity was leucocytopenia grade 3/4 in 15%, anemia in 7%, and thrombocytopenia in 49% of the patients.

Conclusion: Combination chemotherapy with GOP is feasible and effective with acceptable toxicity in patients with treatment-refractory germ-cell tumors.

Background: Cost of neutropenic complications of myelosuppressive chemotherapy has been reported to be substantial. Prior research, however, has focused on initial hospitalization only and has failed to account for follow-on care.

Patients and methods: Using a US health-care claims database, all adult cancer patients who received a course of chemotherapy were identified. For each such patient, each unique cycle of chemotherapy within the course and each occurrence of neutropenic complications within these cycles were characterized. Patients developing neutropenic complications in a given cycle (neutropenia patients), starting with the first, were matched (1 : 1) to those who did not develop neutropenic complications in that cycle (comparison patients), and health-care costs (i.e. expenditures) were tallied for each matched pair.

Results: Neutropenia patients (n = 373) and comparison patients were similar in terms of baseline characteristics. Costs of neutropenia-related care were $12 397 (95% confidence interval $10 274–$14 754) higher for neutropenia versus comparison patients [$14 407 ($12 357–$16 743) versus $2010 ($1490–$2553)]. Among neutropenia patients, mean cost of initial hospitalization for neutropenic complications was $7813 ($6537–$9379); cost of all subsequent neutropenia-related care averaged $6594 ($5217–$8272).

Conclusions: Neutropenic complications of myelosuppressive chemotherapy are costly. Prior research focusing on initial hospitalization only may have underestimated the cost of these complications by as much as 40%.

Background: A randomized controlled trial showed longer overall survival (OS) with docetaxel compared with paclitaxel in metastatic breast cancer patients with prior exposure to anthracycline. We report a similar comparison using population-based data.

Methods: Data on patients treated with single-agent paclitaxel or docetaxel were retrospectively reviewed. OS was compared using a two-tailed log-rank test and expressed as Kaplan–Meier plots. A cost-effectiveness analysis was carried out using cost/patient and OS.

Results: Four hundred and thirty-five patients met eligibility criteria. Prognostic factors were balanced between docetaxel and paclitaxel groups. Median OS was significantly longer for docetaxel versus paclitaxel [10.9 versus 8.3 months; hazard ratio 0.76; 95% confidence interval (CI), 0.62–0.92; P = 0.006]. The median number of cycles administered were four (docetaxel) and three (paclitaxel). The incremental cost-effectiveness ratio was $2434/per month of median survival gained. In the sensitivity analysis, the results were robust except that paclitaxel dominated when the low end of the 95% CI of survival for docetaxel was compared with the high end for paclitaxel.

Conclusion: This population-based study corroborated the randomized trial's conclusion that for patients with metastatic breast cancer, docetaxel provided superior survival compared with paclitaxel. Each additional month of survival had an incremental cost of $2434.

Purpose: To identify the role of estrogen (ER), progesterone (PgR), epidermal growth factor 1 (HER1), and HER2 receptors in predicting response to preoperative chemotherapy.

Materials and methods: We reviewed the pretreatment biopsies of 485 patients with locally advanced breast cancer (cT2-T4, N0-2, M0) treated with preoperative chemotherapy. The incidence of pathological complete remission (pCR) and outcome were assessed with respect to clinical and pathological findings including ER/PgR status (absent versus expressed), HER1 (absent versus expressed) and HER2 (overexpressed versus none) expression.

Results: Patients with ER/PgR-absent tumors were 12.0 times [95% confidence interval (CI) 4.93–29.28] more likely to achieve a pCR (P < 0.0001). Predictors of disease-free survival (DFS) at the univariate analysis included HER1 [hazards ratio (HR) 1.6, 95% CI 1.04–2.32, P = 0.03] and HER2 (HR 1.6, 95% CI 1.08–2.38, P = 0.02) expression. A statistically significant difference in DFS was confirmed at the multivariate analysis for patients with ER/PgR-absent disease (HR 2.1, 95% CI 1.41–2.99, P = 0.0002).

Conclusions: The pCR rate is higher and outcome worse for patients with ER/PgR-absent tumors. HER1 and HER2 expression may have a prognostic role in locally advanced breast cancer and warrant further studies.

Background: This study aimed to identify prognostic factors for outcome in Tunisian patients with nonmetastatic inflammatory breast cancer (IBC) receiving multimodality therapy.

Patients and methods: From 1994 to 2000, 100 patients with nonmetastatic IBC were reviewed. Patients underwent neo-adjuvant chemotherapy including anthracyclines (99%), then mastectomy (93%) when feasible, radiotherapy (83%) and adjuvant chemotherapy (84%). Sixty patients (60%) had hormone therapy.

Results: Median age at diagnosis was 44 years (range 23–71). Seventy patients had premenopausal status (70%). Ten cases occurred during pregnancy (10%). Body mass index indicated overweight or obesity in 76 patients (76%). After neo-adjuvant chemotherapy, pathologic complete response (pCR) rate was 20%. Median time of follow-up for surviving patients was 44 months. Median progression-free survival (PFS) was 19 months and overall survival (OS) 30 months. Factors associated with improved survival were no pregnancy (P = 0.0095), estrogen receptor positivity (P = 0.028), tumor size <5 cm (P = 0.021), clinical complete response (cCR) (P = 0.022), pCR (P = 0.011), negative nodes (P = 0.053) and hormone therapy (P < 0.001). In multivariate analysis, cCR, negative nodes and hormone therapy were independently associated with better OS and PFS. Factors predictive to pCR were age >45 years, negative nodes and cCR.

Conclusions: Tunisian patients with IBC have particular epidemiologic characteristics, with earlier disease and context of overweight and obesity, but prognostic factors are similar to those reported in the literature. Hormone therapy seems to improve patient outcome.

Background: Although disease-free survival (DFS) is accepted as a valid end point in adjuvant breast cancer trials, improvement in 2-year DFS has never been formally established as an adequate correlate for 5-year overall survival (OS). We set out to ascertain if changes in 2-year DFS can be used to accurately predict 5-year OS changes.

Design: We conducted a systematic Medline search (1966–2006) for randomized adjuvant breast cancer trials of >100 patients per arm with 2-year DFS and 5-year OS data. A univariate regression model weighted by trial sample size was constructed to determine whether 2-year DFS differences between treatment arms within trials were predictive of 5-year OS differences.

Results: A total of 126 studies containing 149 treatment comparisons met the inclusion criteria. Difference in 2-year DFS was a significant predictor of difference in 5-year OS. For every 1% increase in 2-year DFS difference, the 5-year OS difference increased by 0.5%–0.55%. The proportion of variation explained ranged from 0.38 to 0.42, with a wide prediction interval.

Conclusion: There is a statistically significant correlation, of moderate strength, between difference in 2-year DFS between treatment comparisons and difference in 5-year OS but the correlation is not strong enough to be used as a predictor.

Background: Clinical studies have demonstrated statistically significant reduction of breast cancer relapse and improved overall survival by adding trastuzumab for 1 year after adjuvant chemotherapy in human epidermal growth factor receptor-2 protein (HER2)/neu-positive breast cancer. The aim of this study was to analyze the cost-effectiveness of HER2/neu testing and the addition of 1-year adjuvant trastuzumab after adjuvant chemotherapy from a societal perspective in a Swedish setting.

Material and methods: We used a Markov state transition model to simulate HER2/neu testing and adjuvant trastuzumab treatment in a hypothetical cohort of early breast cancer patients.

Results: The cost per quality adjusted life year (QALY) gained for immunohistochemical (IHC) testing for all patients with FISH confirmation of IHC 2+ and 3+ and 1-year adjuvant trastuzumab for FISH-positive patients was estimated to 36 000. The strategy of FISH testing for all patients, with 1-year adjuvant trastuzumab for FISH-positive patients was associated with the longest quality adjusted survival of all evaluated treatment strategies and the cost per QALY gained was estimated to 41 500. The remaining testing and treatment strategies were dominated.

Conclusion: FISH testing for all patients with 1-year adjuvant trastuzumab for FISH+ patients is a cost-effective treatment option from a societal perspective.

Background: At metastatic relapse, detection of circulating tumor cells (CTC) in peripheral blood is predictive of poor survival of breast cancer patients. Detection of disseminated tumor cells (DTC) in bone marrow (BM) is an independent prognostic factor in early breast cancer. We evaluated the prognostic value of DTC detection in the BM of metastatic breast cancer patients.

Materials and methods: BM aspirates from 138 patients were screened for DTC with the pancytokeratin mAb A45-B/B3, according to the ISHAGE classification. One hundred and ten patients (80%) were enrolled before first-line treatment. Thirty-seven patients were simultaneously screened for CTC in the blood.

Results: DTC detection rate in the BM was 59%. DTC were associated with bone metastasis (P = 0.0001), but not with a poorer overall survival. Adverse significant prognostic factors were hormone receptor negativity (P = 0.0004) and more than one line of chemotherapy (P = 0.002). CTC detection in the subgroup of 37 metastatic patients was associated with shorter survival (P = 0.01).

Conclusions: Detection of CTC but not BM DTC had a prognostic significance in stage IV breast cancer patients. CTC in blood are a more reliable and a less invasive tool to evaluate prognostic and monitor tumor response in this metastatic setting.

Background: P63 belongs to the ‘p53 family’ whose role in cancer progression has been recently revisited in light of the plethora of splicing variants that are generated. We analyzed the expression of the full-length TAp63 gene and its dominant-negative form Np63 in ovarian cancer biopsies to correlate their expression with clinical outcome.

Materials and methods: Real-time RT–PCR analysis was used to determine the levels of TAp63 and Np63 in 83 stage I and in 86 stage III ovarian cancer biopsies and in seven human ovarian cancer cell.

Results: TAp63 levels were comparable in stage I and stage III, but Np63 levels increased 77-fold in stage III, independently of the p53 status. Patients with high Np63 expression had the worst overall survival (OS); patients with a Np63/TAp63 ratio >2 had a poor OS. Patients with a high Np63/TAp63 ratio were those with a poor response to platinum-based therapy.

Conclusions: Data indicate a role for Np63 as a potential biomarker to predict patient’s outcome and tumor progression in ovarian cancer. This would have particularly clinical relevance in ovarian cancer where the high rate of mortality reflects our lack of knowledge of molecular mechanisms underlying cell progression toward malignancy.

Background: KRAS mutation status is a candidate marker for predicting survival in patients with metastatic colorectal cancer (mCRC) treated with cetuximab (CTX).

Patients and methods: We studied the KRAS mutation status of 113 patients with irinotecan refractory mCRC treated with CTX in clinical trials. A predictive model for objective response (OR), progression-free survival (PFS) and overall survival (OS) was constructed using logistic and Cox regression.

Results: OR was seen in 27 of 66 KRAS wild-type (WT) patients versus 0 of 42 in KRAS mutants. Median OS was significantly better in KRAS WT versus mutants (43.0 versus 27.3 weeks; P = 0.020). Decrease in tumor sizes was significantly larger at all time points in WT patients. KRAS WT patients with an initial relative decrease of tumor size >9.66% at week 6 had a significantly better median OS compared with all other patients (74.9 versus 30.6 weeks; P = 0.0000025). Within KRAS WT patients OS was significantly better in patients with an initial decrease compared with those without [median OS: 74.9 versus 30.6 weeks (P = 0.00000012)].

Conclusions: KRAS WT status is associated to survival benefit in CTX treated mCRC. This benefit is even more pronounced in those patients with early radiological response. These characteristics may be exploited for response prediction.

Background: We investigated whether an endogastric capsule (EC) may be a valuable tool for collecting DNA from exfoliated cells from the gastric mucosa and for carrying out an analysis of promoter methylation status of the E-cadherin (CDH1) gene in poorly differentiated, diffuse gastric cancer (DGC).

Material and methods: Consecutive patients with a confirmed diagnosis of poorly differentiated DGC underwent collection of gastric juice by EC. Subjects without cancer and premalignant lesions were also accrued as controls. The samples of gastric juice were processed for DNA isolation and amplification. Then they were used for analysis of CDH1 promoter hypermethylation.

Results: The procedure successfully allowed the analysis of CDH1 promoter hypermethylation in 20 patients and 14 controls. This pilot study showed feasibility of the procedure and a significantly different CDH1 promoter hypermethylation status between DGC patients and controls was detected.

Conclusions: The EC may represent an innovative and noninvasive tool for the analysis of a specific epigenetic change in DGC patients. Our findings deserve additional studies as this method may represent a cost-effective tool for early detection of sporadic as well as hereditary DGC in CDH1 germline mutations carriers.

Background: This phase III trial was to compare 5-fluorouracil (5-FU), adriamycin, and polyadenylic–polyuridylic acid (poly A:U) against 5-fluorouracil plus adriamycin (FA) for operable gastric cancer.

Patients and methods: From 1984 to 1989, patients who had D_2–3 curative resection were randomly assigned to receive chemotherapy or chemoimmunotherapy. Chemotherapy consisted of 12 mg/kg 5-FU every week for 18 months and 40 mg/m² adriamycin every 3 weeks for 12 cycles. Chemoimmunotherapy consisted of FA plus 100 mg of poly A:U weekly for six cycles and was followed 6 months later by six weekly 50-mg booster injections.

Results: A total of 292 patients were enrolled. After excluding 12 ineligible patients, 142 and 138 patients were allocated to each treatment. Patients were balanced with prognostic variables: age, sex, tumor location, differentiation, degree of tumor invasion (T₂–T_4a), and lymph node status (N₀–N₂). During the 15-year follow-up, chemoimmunotherapy significantly prolonged overall (P = 0.013) and recurrence-free (P = 0.005) survivals compared with chemotherapy alone. The survival benefits were prominent in the subset of patients with T₃/T_4a, N₂, or stage III. Treatments were generally well tolerated in both arms.

Conclusions: These results indicate a survival advantage of chemoimmunotherapy with a regimen of FA and poly A:U in curatively resected gastric adenocarcinoma.

Background: Lysosome-associated protein transmembrane 4 beta (LAPTM4B) is a novel gene of the mammalian LAPTM family and has been shown to be overexpressed in human hepatocellular carcinoma. There are two alleles, LAPTM4B*1 and *2, which share the same sequence except for one segment of 19 bp in the 5' untranslated region of the exon 1. LAPTM4B*1 has one 19 bp segment, while LAPTM4B*2 has two tight tandem segments. The current case–control study was aimed to identify relationship between the gene polymorphism of LAPTM4B and the susceptibility of colorectal and esophageal cancers.

Patients and methods: Blood samples were collected from patients with colon, rectal or esophageal cancers and control subjects. Genotypes of LAPTM4B were determined by PCR to detect differences between cancer cases (n = 701) and healthy controls (n = 350). Association between the LAPTM4B polymorphism and the risk of cancer was calculated by unconditional logistic regression models.

Results: We found that there was a significant difference (P = 0.0016) in allelic frequencies of LAPTM4B*2 between colon cancer cases (33.2%) and controls (24.1%). The risk of colon cancer was elevated significantly in cases with *1/2 genotype [odds ratio (OR) = 1.474; 95% confidence interval (CI) = 1.037–2.095] and *2/2 genotype (OR = 2.531; 95% CI = 1.316–4.868) when compared with the *1/1 genotype. No significant difference was observed for LAPTM4B*2 between the rectal or esophageal cancer cases when compared with the controls. The polymorphism in LAPTM4B was associated with increased risk of colon cancer but not of rectal and esophageal cancers.

Conclusions: These results indicate that the genetic polymorphism of LAPTM4B is a potential risk factor for the development of colon cancer.

Background: Esophageal small-cell carcinoma (SCC) is rare, highly malignant and the optimal treatment approach has not been defined.

Patients and methods: We report the largest single-institution retrospective review of patients with esophageal and gastroesophageal (GE) junction SCC.

Results: Twenty-five patients were identified, with complete records available for 22. Eighty-two percent were male, 82% had pure SCC histology and 86% of tumors were in the lower esophagus or GE junction. On the basis of the Veterans’ Administration Lung Study Group criteria, 14 patients (64%) presented with limited disease (LD). Median survival was 19.8 months (range, 1.5 months to 11.2+ years); for LD patients, 22.3 months (range, 6 months to 11.2+ years); for extensive disease (ED) patients, 8.5 months (range, 1.5 months to 2.2 years, P = 0.02). With a median follow-up of 38 months, six patients (27%) are alive, one with ED and five with LD. Two LD patients are alive and free of disease for >5 years. Four of the five LD patients who are long-term survivors received induction chemotherapy followed by chemoradiotherapy without surgery.

Conclusions: Our data indicate that patients with LD esophageal SCC treated with induction chemotherapy followed by consolidative chemoradiation can achieve long-term survival. The contribution of surgery remains unclear.

Background: To determine the maximum tolerated dose of a bi- and tri-weekly combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone plus etoposide (CHOEP) regimen without stem-cell support.

Patients and methods: Randomized phase I/II multicenter four-level (cyclophosphamide: 1000–1200–1400–1600 mg/m²; doxorubicin: 55–60–65–70 mg/m²; etoposide: 375–450–525–600 mg/m²) dose escalation study with CHOEP-14 and CHOEP-21 in young patients (18–60 years) with newly diagnosed aggressive non-Hodgkin's lymphoma. Dose-limiting toxicity was defined as thrombocytopenia <80 000/mm³ and leukocytopenia <2500/mm³ on days 16 (CHOEP-14) and 23 (CHOEP-21) or prolonged (>4 days) leukocytopenia (<1000/mm³) or thrombocytopenia (<20 000/mm³).

Results: One hundred and thirty-nine patients (high-CHOEP-14: 47, high-CHOEP-21: 92) were randomly allocated to the study. Maximal tolerated dose was level 2 for CHOEP-14 and level 4 for CHOEP-21. With a less favorable profile of patients in CHOEP-14, 4-year event-free survival was 47.9% after high-CHOEP-14 and 66.2% after high-CHOEP-21, 4-year overall survival 62.1% after high-CHOEP-14 and 73.4% after high-CHOEP-21, respectively.

Conclusion: Significant dose escalations of CHOEP are possible with granulocyte colony-stimulating factor support, with different chemotherapy models favoring the maximally escalated bi- or tri-weekly regimen, respectively. Because a higher total dose can be achieved with six cycles of the tri-weekly compared with the biweekly regimen, CHOEP-21 at dose escalation level 3 was chosen for a nationwide randomized comparison with baseline CHOEP-21 in a subsequent phase III trial.

Background: The addition of etoposide to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone [etoposide to combination chemotherapy with cyclophosphamide, vincristine and prednisone (CHOEP)] improved outcome of young patients with good-prognosis aggressive lymphoma. To improve results further, the maximal dose-escalated version of CHOEP-21 tolerable without stem-cell support (high CHOEP: cyclophosphamide 1400 mg/m², doxorubicin 65 mg/m², vincristine 2 mg, etoposide 175 mg/m² x3, prednisone 100 mg x5) was compared with CHOEP-21.

Patients and methods: Intention-to-treat analysis of 389 young (18–60 years) patients with good-prognosis (age-adjusted International Prognostic Index = 0, 1) aggressive lymphoma randomized to CHOEP-21 (n = 194) or high CHOEP (n = 195).

Results: There was no difference in 3-year event-free (64% versus 67%; P = 0.734) or overall survival (83% versus 87%; P = 0.849). Neither low-risk nor low-intermediate risk patients benefited from high CHOEP. High CHOEP was more toxic than CHOEP-21 (grades 3 and 4 leukocytopenia 100% versus 87.2%, P < 0.001; thrombocytopenia 80.8% versus 9.6%, P < 0.001; infections 35% versus 11%, P < 0.001; therapy-associated deaths 3.1% versus 0%, P = 0.03).

Conclusion: Dose-escalated CHOEP-21 does not provide clinical benefit for young patients with good-prognosis aggressive lymphomas. Since differences between chemotherapy regimens are compressed by the addition of rituximab, the results of this trial have bearing on strategies aiming to improve outcome of good-prognosis aggressive lymphomas in the rituximab era.

Background: The benefit of adding rituximab to anthracycline-based therapy for follicular lymphoma grade 3 has not been studied.

Patients and methods: We retrospectively reviewed the records of 45 patients with follicular grade 3 lymphoma who were treated with rituximab and the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) at The University of Texas MD Anderson Cancer Center. Response rate, failure-free survival (FFS), and overall survival (OS) were estimated and a historical comparison to CHOP-only-treated patients was made.

Results: The International Prognostic Index (IPI) distribution was 47% low, 36% low intermediate, 13% high intermediate, and 4% high risk. The complete response rate was 96%. Forty-four of 45 patients are still alive. Median follow-up for the alive patients is 3.5 years. The 3-year FFS rate according to the IPI was 80% [95% confidence interval (CI) 64% to 100%] in low, 81% in low intermediate (95% CI 64% to 100%), and 50% (95% CI 25% to 100%) in high-intermediate/high-risk patient group. The addition of rituximab to CHOP improved both 5-year FFS, 71% (95% CI 58% to 87%) compared with 44% (95% CI 36% to 55%) with P value of 0.019, and 5-year OS, 98% (95% CI 93% to 100%) compared with 75% (95% CI 67% to 84%) with P value of 0.0034.

Conclusion: The addition of rituximab to CHOP provided a high response rate and excellent early survival. Poor-risk patients continue to demonstrate a high rate of failure despite the use of rituximab.

Background: Overexpression of B-cell lymphoma 2 (bcl-2) protein is a simple biological adverse prognostic factor that could delimit the poor prognosis population candidate for improvement with high-dose therapy and autologous stem-cell transplantation (ASCT) in diffuse large B-cell lymphoma (DLBCL). Therefore, we conducted a risk-adapted phase II study with ASCT as consolidation therapy in low-intermediate risk (LIR) International Prognostic Index patients aged ≤60 years with bcl-2 overexpression (bcl-2⁺).

Patients and methods: Induction chemotherapy consisted of four courses of adriamycin, cyclophosphamide, vindesine, bleomycin, prednisone, once every 2 weeks. Responding bcl-2⁺ patients received ASCT as consolidation, and those without bcl-2 overexpression (bcl-2^–) conventional chemotherapy. Three hundred and sixteen LIR patients with DLBCL, aged between 18 and 60 years, were included. Of these, 177 (56%) were bcl-2⁺ and 139 (44%) bcl-2^–.

Results: Complete response rates after induction chemotherapy were similar in bcl-2⁺ and bcl-2^– patients (74% versus 78%). Estimated 2-year event-free survival and disease-free survival for the bcl-2⁺ subgroup were 79% and 87%, for bcl-2^– 84% and 92% and for the whole series 81% and 90%, respectively.

Conclusions: These results demonstrate that taking into account biological characteristics in prospective multicenter trials allow successful adjustment of treatment and indicate that ASCT may counteract the adverse prognostic value of bcl-2 overexpression in responding LIR patients.

Background: Development and growth of extranodal marginal zone B-cell lymphomas (eMZBCLs) of mucosa-associated lymphoid tissue (MALT) type are thought to be highly dependent on Helicobacter pylori and autoantigens. Receptors mediating these effects are not characterised so far. Toll-like receptors (TLRs) recognise bacterial proteins and autoantigens, which results in inflammatory reactions and influences tumour development and growth.

Materials and methods: TLR4, 5 and 9 expressions were evaluated by immunohistology and confocal microscopy in gastric eMZBCL in comparison to other lymphomas infiltrating the stomach.

Results: TLR4 was exclusively expressed on the cell surface in all eMZBCL (n = 19) and not in chronic lymphocytic leukaemia (CLL, n = 12) or mantle cell lymphoma (MCL, n = 10). TLR5 was strongly expressed in CLL and weak in some eMZBCL (15 of 19), but not in MCL. TLR4, 5 and 9 were negative in all the three lymphoma entities.

Conclusions: Exclusive TLR4 expression may enable eMZBCL to interact with H. pylori and autoantigens. Blockade of TLR4 might be a new approach for therapy of eMZBCL of MALT type.

Background: The purpose of this study was to determine whether there was a relationship between disease activity and health functioning, as measured by a range of patient-reported outcome (PRO) measures in patients with follicular lymphoma (FL).

Patients and methods: A total of 222 patients with FL were recruited from eight sites across the UK and they completed a number of PRO measures. The participants were analyzed across five disease states: ‘active disease—newly diagnosed’, ‘active disease—relapsed’, ‘partial response’, ‘complete response’ and ‘disease free’. The relationship between these disease states and their level of health functioning was assessed as well as the relationship between being ‘on’ or ‘off’ chemotherapy and disease state.

Results: In terms of health-related quality of life (HRQoL), participants in the relapsed category had the lowest mean physical well-being, emotional well-being, functional well-being and social well-being score. In a regression analysis, the ‘active disease–relapsed’ group acted as a significant predictor for each PRO variable. In addition, the remission group acted as a significant predictor of high anxiety scores as measured by the Hospital Anxiety and Depression Scale.

Conclusion: The results of this study demonstrate that various aspects of patient-reported health outcomes differ according to disease state in patients with FL. For those patients who have relapsed, they are more likely to experience worse HRQoL and other patient-reported health outcomes than patients newly diagnosed, in partial or complete remission or when completely disease free.

Background: This study examined the various approaches to the management of perforation and the associated outcomes in patients with bevacizumab-associated bowel perforation at a tertiary cancer center.

Patients and methods: Our institutional pharmacy database was searched to identify all patients who had received bevacizumab over a 2-year period (January 2004 to October 2006). Medical records of these patients were examined for reports of confirmed bowel perforation or fistula, associated clinicopathological factors, treatment, and outcomes.

Results: We identified 1442 patients who had been treated with bevacizumab over the study period with perforation occurring in 24 (1.7%). The breakdown of these 24 patients by disease site was as follows: ovarian (3 of 50, 6%), gastroesophageal (2 of 38, 5.3%), pancreatic (7 of 141, 5%), unknown primary (1 of 60, 1.7%), lung (1 of 67, 1.5%), colorectal (6 of 478, 1.3%), and renal cell (4 of 269, 1.5%). The majority of patients (n = 19, 79%) were initially managed nonoperatively. Only five (21%) patients ultimately underwent surgical exploration, with a subsequent anastomotic leak developing in one patient. The overall 30-day mortality rate was 12.5%.

Conclusions: Bevacizumab-associated bowel perforation occurs in patients with various malignancies, with an incidence of 1.7%. Nonoperative treatment is a viable approach to management in selected patients.

Background: Worldwide, female melanoma patients have superior survival compared with males, which is usually ascribed to earlier detection among women and/or a more favorable site distribution. We studied gender difference in melanoma survival in a large population-based setting after adjusting for tumor-related variables and offer clues for further research.

Patients and methods: A total of 10 538 patients diagnosed with melanoma from 1993 to 2004 in The Netherlands were included. Multivariate analyses were carried out to estimate adjusted relative excess risk (RER) of dying for men compared with women, adjusted for the patient and tumor characteristics.

Results: Univariate relative survival analyses showed a RER of dying of 2.70 [95% confidence interval (CI) 2.38–3.06] for men compared with women. After adjusting for time period of diagnosis, region, age, Breslow thickness, histologic subtype, body site, nodal and metastatic status, a significant excess mortality risk was still present for males (RER 1.87, 95% CI 1.65–2.10). Among patients with advanced disease and in those <45 or ≥60, the adjusted risk estimates were similar.

Conclusions: The superior survival of women compared with men persisted after adjusting for multiple confounding variables indicating that factors other than stage at diagnosis and body site reduce mortality risk in female melanoma patients.

Background: HSP90 chaperones molecules critical for cell survival and malignant progression, including mutated B-raf. HSP90-targeting agents are in clinical trials. No large studies have been conducted on expression of HSP90 in melanomas.

Materials and methods: Tissue microarrays containing 414 nevi, 198 primary and 270 metastatic melanomas were assessed using our automated quantitative analysis (AQUA) method of in situ protein measurement; we use S-100 to define pixels as melanocytes (tumor mask) within the array spot, and measure HSP90 expression within the mask using Cy5-conjugated antibodies.

Results: HSP90 expression was higher in melanomas than nevi (P < 0.0001) and higher in metastatic than primary specimens (P < 0.0001). No association was seen between high HSP90 expression and survival in the primary or metastatic patient subsets. In primary melanomas, high HSP90 expression was associated with higher Clark level (P = 0.0167) and increased Breslow depth (P < 0.0001).

Conclusions: HSP90 expression was significantly higher in tumors than nevi and was associated with disease progression, indicating that it might be a valuable drug target in melanoma, as well as a useful diagnostic marker. Prospective studies are needed to confirm the diagnostic role of HSP90, as well as the predictive role of HSP90 expression in patients treated with HSP90 inhibitors.

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