Methods: Literature review of the causes, assessment and management of menopausal symptoms in breast cancer patients.

Results: A number of nonhormonal treatments are effective in treating hot flashes. Whether pharmacological treatment is given will depend on the severity of symptoms and on patient wishes. For severe and frequent hot flashes, the best data support the use of venlafaxine, paroxetine and gabapentin in women with breast cancer. Side-effects are relatively common with all these agents. For vaginal dryness, topical estrogen treatment is the most effective but the safety of estrogens following breast cancer is not established. There are limited data on effective treatments for sexual dysfunction during menopause.

Conclusion: Menopausal symptoms after breast cancer should be evaluated and managed as warranted using a systematic approach and may benefit from multidisciplinary input.

Methods: By means of MEDLINE/PubMED/Ovid databases, we selected studies examining paraffin-embedded (PE) biopsies of HNSCC and OSCC. According to the inclusion criteria, 62 studies were analyzed. The following data were abstracted: sample size, HPV DNA prevalence, methods of detection [PCR and in situ hybridization (ISH)] and HPV genotypes. After testing the heterogeneity of the studies by the Cochran Q test, metanalysis was performed using the random effects model.

Results: The pooled prevalence of HPV DNA in the overall samples (: 4852) was 34.5%, in OSCC it was 38.1% and in the not site-specific HNSCC was 24.1%. With regard to the detection method, PCR-based studies reported a higher prevalence rate than ISH-based rates (34.8, versus 32.9%) especially in the OSCC subgroup (OSCC PCR based: 39.9%).

Conclusion: These findings support the assumption that a correct distinction of HNSCC by site, together with the use of more sensitive HPV DNA detection methods, should be considered as essential prerogatives in designing future investigations into viral prevalence in head and neck tumors.

Patients and methods: Two-hundred and four eligible patients were randomised between standard radiosensitised induction chemoradiotherapy (arm A) with cisplatin (90 mg/m² day 1) plus etoposide and daily radiosensitised induction chemoradiotherapy (arm B) with cisplatin (6 mg/m²/day) plus etoposide. Chemotherapy and chest irradiation (39.90 Gy in 15 fractions >3 weeks) both started on day 1.

Results: There was no difference in survival between both arms with respective median, 2 and 5 years of 15.5 months, 35% and 18% in arm A and 17.0 months, 38% and 21% in arm B (P = 0.50). Performance status and T status were identified as independent prognostic factors for survival. In terms of local control rate, there was a statistical trend in favour of arm A with 2% only local relapse versus 10% in arm B. Daily cisplatin radiosensitisation was associated with more oesophagitis and thrombopenia but less nephrotoxicity.

Conclusion: Induction chemoradiotherapy resulted in both arms in good long-term survival, comparable to the best reported results and without improvement by daily cisplatin administration.

Methods: Previously untreated patients with PBC T2–4a–c N0–3 M0 received one cycle of docetaxel 75 mg/m², adriamycin 50 mg/m² and cyclophosphamide 500 mg/m² administered on day 5 combined with escalating doses of oblimersen as a 24-h continuous infusion on days 1–7 followed by five cycles of combination of docetaxel, adriamycin and cyclophosphamide (TAC) without oblimersen every 3 weeks. Prophylactic antibiotic therapy and granulocyte colony-stimulating factor administration were used in all six cycles. Blood serum samples were taken throughout the treatment period for pharmacokinetic analysis.

Results: Twenty-eight patients were enrolled (median age, 50 years; ductal-invasive histology, 68%; tumorsize 2–5 cm, 61%; grade 3, 43%; hormone receptor negative, 36%; Her2 positive 18%) and received oblimersen in a dose of 3 mg/kg/day (cohort I, nine patients), 5 mg/kg/day (cohort II, nine patients) and 7 mg/kg/day (cohort III, 10 patients) respectively. No dose-limiting toxicity occurred. Following oblimersen combined with TAC, the most severe toxicity was neutropenia [National Cancer Institute—Common Toxicity Criteria (NCI-CTC) grades 1–2/3/4] which developed in 0/0/56% of patients (cohort I), 11/0/56% of patients (cohort II) and 20/20/50% of patients (cohort III). No febrile neutropenia occurred. Most common adverse events (all NCI-CTC grade ≤ 2) were fatigue, nausea, alopecia, headache and flue-like symptoms observed in 78% (cohort I), 89% (cohort II) and 90% (cohort III) of patients. With increasing dose of oblimersen, a higher incidence of grade IV leukopenia and neutropenia was noted. At the MTD of 7 mg/kg/day of oblimersen, serious adverse events occurred in 40% of the patients.

Conclusion: Oblimersen up to a dose of 7 mg/kg/day administered as a 24-h infusion on days 1–7 can be safely administered in combination with standard TAC on day 5 as NST in patients with PBC. The safety and preliminary efficacy warrants further evaluation of oblimersen in combination with every cycle of the TAC regimen in a randomized trial.

Patients and methods: A multicenter, retrospective study of 1794 primary breast carcinomas diagnosed in Italy in 2000/2001 and scored in HER2 four categories according to immunohistochemistry was conducted.

Results: Ductal histotype, vascular invasion, grade, MIB1 positivity, estrogen and progesterone receptor expression differed significantly in HER2 3+ tumors compared with the other categories. HER2 2+ tumors almost showed values intermediate between those of the negative and the 3+ subgroups. The characteristics of HER2 1+ tumors were found to be in between those of HER2 0 and 2+ tumors. With a median follow-up of 54 months, HER2 3+ status was associated with higher relapse rates in node-positive and node-negative subgroups, while HER2 2+ only in node positive. Analysis of relapses according to type of therapy provided evidence of responsiveness of HER2-positive tumors to chemotherapy, especially taxanes.

Conclusions: The present prognostic significance of HER2 is correlated to receptor expression level and points to the need to consider HER2 2+ and HER2 3+ tumors as distinct diseases with different outcomes and specific features.

Patients and methods: Thirteen patients were treated with Imatinib administered orally at 400 mg p.o. b.i.d. (800 mg/day), until disease progression. All patients demonstrated PDGFR-β overexpression and none showed c-kit expression.

Results: No objective responses were observed among the 13 patients treated in an intention-to-treat analysis. All patients experienced disease progression, with a median time to progression of 1.2 months. Twelve patients have died, and the median overall survival was 7.7 months. No patient had a serious adverse event. Imatinib therapy had no effect on the plasma levels of the angiogenesis-related cytokines, vascular endothelial growth factor, PDGF, b-fibroblast growth factor, and E-selectin. Immune studies showed imatinib inhibits interferon- production by TCR-activated CD4⁺ T cells.

Conclusion: Imatinib as a single agent has no clinical activity in PDGFR-overexpressing MBC and has potential immunosuppressive effects.

Patients and methods: A total of 627 patients were randomly assigned to receive XELOX (n = 313) or FOLFOX-4 (n = 314) following disease progression/recurrence or intolerance to irinotecan-based chemotherapy. The primary end point was progression-free survival (PFS).

Results: PFS for XELOX was noninferior to FOLFOX-4 [hazard ratio (HR) = 0.97; 95% confidence interval (CI) 0.83–1.14] in the intention-to-treat (ITT) population. Median PFS was 4.7 months with XELOX versus 4.8 months with FOLFOX-4. The robustness of the primary analysis was supported by multivariate and subgroup analyses. Median overall survival in the ITT population was 11.9 months with XELOX versus 12.5 months with FOLFOX-4 (HR = 1.02; 95% CI 0.86–1.21). Treatment-related grade 3/4 adverse events occurred in 50% of XELOX- and 65% of FOLFOX-4-treated patients. Whereas grade 3/4 neutropenia (35% versus 5% with XELOX) and febrile neutropenia (4% versus < 1%) were more common with FOLFOX-4, grade 3/4 diarrhea (19% versus 5% with FOLFOX-4) and grade 3 hand–foot syndrome (4% versus < 1%) were more common with XELOX.

Conclusion: XELOX is noninferior to FOLFOX-4 when administered as second-line treatment in patients with metastatic colorectal cancer.

Patients and methods: We analyzed all cases of PNETs registered in the Surveillance, Epidemiology, and End Results database from 1973 to 2000. Age-adjusted incidence and survival rates were calculated and survival trends over time were evaluated.

Results: We identified 1483 cases of PNETs. The crude annual incidence per 1 000 000 was 1.8 in females and 2.6 in males and increased with advancing age. The incidence increased over the study period. Most patients (90.8%) had nonfunctional tumors. Advanced stage, higher grade, and age were the strongest predictors of worse survival. Patients with functional tumors had better outcomes than patients with nonfunctional tumors in both univariate and multivariate analysis (P = 0.004). Survival time increased over the period from 1973 to 2000. No differences were seen in the distribution of stage or age at diagnosis among time periods.

Conclusion: PNETs are uncommon neoplasms but the incidence may be increasing. Age, grade, stage, and functional status predict survival in patients with PNETs. Survival has improved over time, but this is not explained by earlier diagnosis or stage migration.

Patients and methods: Blood samples were obtained from 125 patients with locally advanced colon cancer at University of Southern California medical facilities. DNA was extracted from peripheral blood and the genotypes were analyzed using PCR–restriction fragment length polymorphism and 5'-end [-³³P] ATP-labeled PCR protocols.

Results: Polymorphisms in vascular endothelial growth factor (VEGF) (C+936T; P = 0.003, log-rank test) and interleukin-8 (IL-8) (T–251A; P = 0.04, log-rank test) were independently associated with risk of recurrence in stage III colon cancer patients. In combined analysis, grouping alleles into favorable versus nonfavorable alleles, high expression variants of VEGF C+936T and IL-8 T–251A were associated with a higher likelihood of developing tumor recurrence (P < 0.001).

Conclusion: High expression variants of VEGF C+936T and IL-8 T–251A were associated with shorter time to tumor recurrence, indicating that the analysis of angiogenesis-related gene polymorphisms may help to identify patient subgroups at high risk for tumor recurrence.

Patients and methods: Patients with upper gastrointestinal malignancies treated with 0–2 prior chemotherapy regimens received oxaliplatin (85–100 mg/m²) as a 2-h i.v. infusion with gemcitabine (800–1000 mg/m²) at a constant rate i.v. infusion (CI) of 10 mg/m²/min on days 1 and 15 of a 28-day cycle. Capecitabine (600–800 mg/m²) was administered orally twice a day on days 1–7 and 15–21. A three per cohort dose escalation schema was used to determine the maximum tolerated dose (MTD) and the dose-limiting toxic effects (DLTs) of this combination regimen.

Results: Thirty patients with advanced upper gastrointestinal malignancies were enrolled. The MTD was defined as oxaliplatin 100 mg/m² i.v. over 2 h plus gemcitabine 800 mg/m² i.v. at a CI of 10 mg/m²/min on days 1 and 15 with capecitabine 800 mg/m² p.o. b.i.d. days 1–7 and 15–21 of a 29-day cycle. DLTs include grade 3 fatigue and grade 3 dyspnea. One complete and two partial responses were observed.

Conclusions: This biweekly schedule of oxaliplatin, gemcitabine and capecitabine is tolerable and warrants further investigation in biliary and pancreatic malignancies.

Methods: The TAX 327 database provided information about treatment after progression on first-line therapy, and survival has been updated. Investigators were asked to provide information about crossover treatment and serial PSA values.

Results: We identified 232 crossover patients. Median survival after crossover was 10 months and did not depend on direction of crossover. Data on PSA response are available for 96 patients: PSA response (≥50% reduction) occurred in 15% of 71 men receiving mitoxantrone after docetaxel and in 28% of 25 men receiving docetaxel after mitoxantrone. Median PSA progression-free survival was 3.4 months for mitoxantrone after docetaxel and 5.9 months for docetaxel after mitoxantrone.

Conclusions: One quarter of men received crossover therapy and survival was similar in the crossover groups. The PSA response rate to docetaxel after mitoxantrone was higher than that for mitoxantrone after docetaxel.

Methods: In all, 52 patients with HL receiving bleomycin-based chemotherapy with (n = 23) or without (n = 29) mediastinal radiotherapy were enrolled. Pretreatment pulmonary function tests were carried out. These were repeated at 1 month, 6 months, and 1 year after therapy.

Results: With chemotherapy alone, the median %DLCO declined significantly at 1 month but returned to baseline by 6 months. The median %DLCO did not further decrease with radiotherapy, but remained persistently reduced at 1 year. In patients who received radiotherapy, having >33% of lung volume receive 20 Gy (V20) and a mean lung dose (MLD) of >13 Gy significantly predicted for persistently reduced %DLCO at 6 months (P = 0.035). Smoking significantly predicted for a persistently reduced %DLCO at 1 year (P = 0.036). On multivariable analysis, significant predictors for decline in %DLCO at 1 year were higher baseline %DLCO (P = 0.01), higher MLD (P = 0.02), and a smoking history (P = 0.02).

Conclusions: Several factors contribute to decline in %DLCO in HL patients who received bleomycin-based computed tomography. The identification of threshold radiation dosimetric parameters for reduced lung function may provide guidance in the radiation planning of these patients.

Patients and methods: A total of 18 patients participated. Patients received 3-week cycles of bortezomib 1 mg/m² on days 1, 4, 8, and 11 plus gemcitabine 800 mg/m² on days 1 and 8.

Results: The overall response rate for all patients was 22% (95% confidence interval 3% to 42%). Three patients developed grade III transaminase elevation: one was removed from the study and two had doses of gemcitabine held. Almost all patients exhibited inhibition of proteasome activity with treatment.

Conclusions: The combination of gemcitabine and bortezomib is a less active and more toxic regimen in relapsed HL than other currently available treatments. It poses a risk of severe liver toxicity and should be pursued with caution in other types of cancer.

Aim: Detection of clinical and subclinical nonthromboembolic PH in MM patients after thalidomide treatment.

Patients and methods: Eighty-two patients, 46–82 years (median age 61 years), 42 males, were studied. They underwent echocardiographic study at baseline, 1 month thereafter, 6 months later and whenever symptoms indicating deterioration of cardiac function appeared. Echocardiographic signs of PH were especially identified.

Results: Clinical and echocardiographic evaluation revealed four patients (out of 82 patients, 4.87%) with PH. Nonimaging and imaging diagnostic methods excluded thromboembolic PH. Statistical analysis demonstrated significant correlation between structural heart disease and PH (r = 14.078; P = 0.008). No significant correlation between age (r = 0.770; P = 0.724), gender (r = 1.157; P = 0.285), International Staging System (ISS) (r = 0.316; P = 0.716) and PH was found.

Conclusions: Preexisted endothelial dysfunction due to structural cardiac disease enhances the vasoactive substances release causing increased pulmonary vascular resistance. Thalidomide possibly causes a vasodilator and vasoconstriction imbalance, which may cause abnormal pulmonary vascular response interfering to a vicious circle perpetuating PH.

Patients and methods: Patients with lymphoma who underwent concurrent PET/CT and diagnostic CT (a scan pair) were identified, and findings detected in either scan but not both were documented. Discrepancies were considered significant if they were related to either lymphoma or another disease process which potentially required intervention.

Results: Eighty-seven scan pairs were identified. PET/CT detected additional lesions over diagnostic CT in 30 patients, of which 11 demonstrated increased clinical stage. Lymphoma therapy changed based on PET/CT in two patients, and one occult rectal cancer was detected. In contrast, diagnostic CT detected five relevant findings, including two incidental findings (venous thrombosis) and three patients with splenic lesions, none of which could be confirmed as lymphoma. No patient had change of stage or lymphoma therapy based on diagnostic CT.

Conclusion: In our series, diagnostic CT did not add value to staging or restaging of lymphoma when carried out concurrently with PET/CT.

Patients and methods: We investigated the prognostic significance of the methylation status of DAPK, GSTP1, P14, P15, P16, P33, RB1, SHP1, CDH1, APC, BLU, VHL, TIMP3, and RASSF1A genes in 46 DLBCL specimens from Tunisian patients. Methylation status of each gene was correlated with clinicopathological parameters including the International Prognostic Index (IPI), the germinal center immunophenotype, and response to treatment and survival. Overall survival (OS) and disease-free survival (DFS) rates were calculated by the Kaplan–Meier method and differences were compared with the log-rank test.

Results: Hypermethylation of SHP1 was associated with elevated lactate dehydrogenase level (P = 0.031). P16 and VHL were frequently hypermethylated in patients with high IPI scores (P = 0.006 and 0.004) and a performance status of two or more (P = 0.007 and 0.047). In addition, hypermethylation of P16 was significantly associated with advanced clinical stages and B symptoms (P = 0.041 and 0.012). Interestingly, hypermethylation of DAPK was significantly correlated with resistance to treatment (P = 0.023). With regard to survival rates, promoter hypermethylation of DAPK, P16, and VHL were significantly associated with shortened OS (P = 0.003, 0.001, and 0.017, respectively) and DFS (P = 0.006, 0.003, and 0.046, respectively). In multivariate analysis, hypermethylation of DAPK remains an independent prognostic factor in predicting shortened OS (P = 0.001) and DFS (P = 0.024), as well as the IPI and the germinal center status.

Conclusions: This study demonstrates that DLBCLs with hypermethylated P16, VHL, DAPK, and SHP1 commonly show a biologically aggressive phenotype and worse prognosis. Interestingly, hypermethylation of DAPK was found to be an independent prognostic factor that may be used in conjunction with the conventional prognostic factors such as the IPI and the germinal center status.

Patients and methods: Stages III–IV (M0) locoregionally advanced head and neck cancer patients received carboplatin/paclitaxel (Taxol) IndCT followed by four or five cycles consisting of 5 days of paclitaxel, fluorouracil, hydroxyurea, and BID RT followed by a nine day break. RT dose to gross disease (high risk), intermediate, and low-risk volumes were reduced from cohort A (n = 68): 75, 60, and 45 Gy; to cohort B (n = 64): 75, 54, and 39 Gy; then cohort C (n = 90): 72, 51, and 36 Gy.

Results: A total of 222 patients accrued from November 1998 to September 2002. Median follow-up is 56 months. In all, 93/96/76% achieved a complete response to concurrent chemoradiotherapy (CRT) in cohort A/B/C. Three- and 5-year overall survivals (OSs) are 68% and 62%, respectively. Five-year LRC and DC are 91% and 87%, respectively. Response to IndCT predicted for OS, LRC, and time to progression (TTP). Cohort C patients had similar OS (P = 0.95), LRC, and DC, but worse (TTP) (P = 0.027).

Conclusions: IndCT before CRT reduces distant progression while maintaining high LRC. The cohort B schedule provides the best therapeutic ratio. A randomized trial investigating IndCT before CRT has been initiated.

Patients and methods: The fertility status was assessed in male HL patients enrolled into trials of the German Hodgkin Study Group from 1988 to 2003.

Results: In pre-treatment analysis (n = 202), 20% of patients had normozoospermia, 11% azoospermia and 69% had other dyspermia. In post-treatment analysis (n = 112), 64% of patients had azoospermia, 30% other dyspermia and 6% normozoospermia (P < 0.001). Azoospermia was observed in 90% of patients treated with chemotherapy alone, 67% of those treated with combined modality and 11% of those treated with radiotherapy alone (P < 0.001). Azoospermia was more frequent after 4x cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine, dacarbazine (COPP/ABVD) (91%), 8x bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone (BEACOPP) baseline (93%) and 8x BEACOPP escalated (87%) compared with 2x COPP/ABVD (56%; P = 0.003). There was a statistically significant difference in post-treatment follicle-stimulating hormone (FSH) levels between patients with azoospermia and those with preserved spermatogenesis (P = 0.001).

Conclusions: Depending on the treatment received, male HL patients are at high risk of infertility after treatment. FSH might be used as surrogate parameter for male fertility in future studies.

Patients and methods: Entry criteria for the 36 patients included normal liver function, prior doxorubicin exposure <250 mg/m², and normal cardiac function. A 1-h PLD (30 mg/m²) infusion was followed immediately by one of six trabectedin doses (0.4, 0.6, 0.75, 0.9, 1.1, and 1.3 mg/m²) infused over 3 h, repeated every 21 days until evidence of complete response (CR), disease progression, or unacceptable toxicity. Plasma samples were obtained to assess PK profiles.

Results: The MTD of trabectedin was 1.1 mg/m². Drug-related grade 3 and 4 toxic effects were neutropenia (31%) and elevated transaminases (31%). Six patients responded (one CR, five partial responses), with an overall response rate of 16.7%, and 14 had stable disease (less than a 50% reduction and less than a 25% increase in the sum of the products of two perpendicular diameters of all measured lesions and the appearance of no new lesions) >4 months (39%). Neither drug had its PK affected significantly by concomitant administration compared with trabectedin and PLD each given as a single agent.

Conclusion: Trabectedin combined with PLD is generally well tolerated at therapeutic doses of both drugs in pretreated patients with diverse tumor types and appears to provide clinical benefit. These results support the need for additional studies of this combination in appropriate cancer types.