Prognostic factors in patients with locally advanced (unresectable) or metastatic pancreatic adenocarcinoma: a retrospective analysis.

BACKGROUND: Most patients with pancreatic adenocarcinoma are diagnosed with locally advanced (unresectable) or metastatic disease. The aim of this study was to investigate possible prognostic factors of survival in such patients. PATIENTS AND METHODS: Two hundred and fifteen patients were studied retrospectively. Twenty-four potential prognostic variables (demographics, clinical parameters, biochemical markers, treatment modality) were examined. RESULTS: Mean survival was 29.0 weeks. 21.9% survived more than 36 weeks. On multivariate analysis, 10 factors had an independent effect on survival: tumour localisation, metastasis, performance status, jaundice, weight loss, C reactive protein, CEA, CA 19-9, palliative surgery and chemotherapy. Patients managed only with palliative care had a hazard ratio of 8.94 versus those offered a combination of palliative surgery and chemotherapy. CONCLUSION: Many factors could be used as predictors of survival in patients with advanced or metastatic pancreatic cancer. Chemotherapy and palliative surgery are associated with increased survival, and should be offered to all eligible patients.

Insulin resistance, growth factors and cytokine levels in overweight women with breast cancer before and after chemotherapy.

OBJECTIVE: To evaluate insulin values, insulin resistance, growth factors and cytokine levels in women suffering from breast cancer and the effect of chemotherapy on these parameters. DESIGN: In a prospective study, glucose and insulin values were determined in ten previously undiagnosed diabetic postmenopausal women with stage IV breast cancer (hepatic metastases excluded) during an oral glucose tolerance test (OGTT) carried out after a glucose load of 75 g. At baseline, leptin, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Insulin-Growth Factor-1 (IGF-1), Tumor-Necrosis-Factor-alpha (TNF-alpha), Vascular Endothelial Growth Factor (VEGF) and Platelet Derived Growth Factor (PDGF) levels were also determined using appropriate methodolody. Insulin resistance and beta-cell function were calculated (HOMA-model). All women were evaluated prior to and after chemotherapy applied for 6 months. RESULTS: 1) Insulin levels at 120 minutes of the OGTT were higher before compared to post-chemotherapy (Mean+/-SD: 170.39+/-78.07 vs 111.75+/-76.19, p=0.037). 2) Body mass index (BMI) was an important predictor of post-glucose load insulin levels both before (coefficient=1.051, p=0.004) and after chemotherapy (coefficient=0.711, p=0.003). 3) Before chemotherapy BMI values were positively related to PDGF levels (rs=0.685, p=0.029), while after chemotherapy this relationship became non-significant (rs=0.188, p=0.603). Before chemotherapy there was a negative relationship between VEGF and waist circumference (coefficient= -0.542, p=0.023). CONCLUSIONS: Post-glucose load insulin values significantly decrease after chemotherapy. There is a positive relationship between BMI and post-glucose load insulin before and after chemotherapy. The contribution of the reduction in insulin, a known growth factor, to the outcome of chemotherapy in these patients remains speculative at present.

Gemcitabine in combination with vinorelbine for heavily pretreated advanced breast cancer.

PURPOSE: To evaluate the activity and toxicity of gemcitabine and vinorelbine in patients with metastatic breast cancer (MBC), previously treated with anthracyclines alone or with taxanes. PATIENTS AND METHODS: A total of 86 pretreated patients with MBC (median age 62 years), entered the study. Thirty-six patients had been pretreated with anthracyclines and 8 were resistant. The combination of gemcitabine (1000 mg/m2) and vinorelbine (25 mg/m2) was administered on days 1 and 8 every 3 weeks, for a total of 6 cycles. RESULTS: A total of 344 cycles of chemotherapy were administered (median 4 cycles per patient). Partial responses were observed in 31 patients (36.0%; 95% CI: 23-56). The median duration of response was 7 months (range 3-11 months) and the median overall survival was 14 months (range 6-21). The scheme was well tolerated. CONCLUSION: The combination of vinorelbine and gemcitabine is an active scheme in pretreated MBC, demonstrating an acceptable toxicity profile, and may well represent a valuable therapeutic choice after anthracycline/taxane regimens.

Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on letrozole or anastrozole. A phase II trial conducted by the Hellenic Group of Oncology (HELGO).

AIMS AND BACKGROUND: The understanding of hormonal therapies in postmenopausal women with metastatic breast cancer has advanced greatly in the past several decades. With the introduction of orally active, potent and selective third-generation aromatase inhibitors (anastrozole, letrozole and exemestane), approaches to the treatment of hormone-sensitive advanced breast cancer are undergoing reevaluation. For treatment of advanced or metastatic disease that has progressed on tamoxifen, all three agents are active. The purpose of the study was to assess the antitumor efficacy and tolerance of exemestane administered as third-line hormonal therapy to postmenopausal women with metastatic breast cancer refractory to letrozole and anastrozole. STUDY DESIGN: Sixty postmenopausal women with stage IV hormone receptor-positive carcinoma of the breast were enrolled in the study. All patients had received two prior hormonal manipulations and had measurable or assessable disease. All adverse events were monitored. RESULTS: Objective tumor response was achieved in 12 (20%) patients (95% CI, 9.6-30.4). The overall clinical benefit was 38.3% (95% CI, 21.2-49.3), and the median duration of objective tumor response was 20 months (range, 9-26). The median time to death was 17.4 months (95% CI, 16.14-18.66). CONCLUSIONS: Exemestane represents an active and well-tolerated treatment option in pretreated patients with advanced breast cancer who have received standard first- and second line hormonal therapies. By extending the sequence of hormonal therapy, disease progression and the need for chemotherapy may be significantly delayed.

Gastric signet-ring adenocarcinoma presenting with breast metastasis.

Breast metastases from gastric cancer are extremely rare. A case report of a 37-year-old female with breast inflammatory invasion and ascites is described. Breast biopsy revealed carcinomatous invasion of the lymphatics from adenocarcinoma cells with signet-ring features. Estrogen (ER) and progesterone receptors (PR) and c-erb-B2 were negative. Upper gastrointestinal endoscopy revealed a prepyloric ulcerative mass. Histopathologic examination of the lesion showed infiltration from a high-grade adenocarcinoma, identical with that of the breast. Immunostaining was positive for cytokeratins CK-7 and CK-20 and CEA and negative for ER and PR. Ascitic fluid cytology was positive for adenocarcinoma cells. Mammography was not diagnostic. Abdominal CT scanning revealed large ovarian masses suggestive of metastases (Krukenberg's tumor). A cisplatin-based regimen was given but no objective response was observed. The patient died six months after initial diagnosis. A review of the literature is performed.

Gemcitabine combined with 5-fluorouracil for the treatment of advanced carcinoma of the pancreas.

BACKGROUND: Gemcitabine is an active agent in pancreatic cancer, showing clinical synergy with 5-fluorouracil (5-FU). The aim of the study was to evaluate the safety and efficacy of the combination of gemcitabine and 5-FU in patients with advanced adenocarcinoma of the pancreas. PATIENTS AND METHODS: Forty-two patients (median age, 62 years), with advanced or metastatic pancreatic adenocarcinoma, were enrolled in the study. The combination of gemcitabine (1000 mg/m2) and 5-FU (600 mg/m2) was administered on days 1, 8 and 15 and repeated every 28 days. RESULTS: A total of 168 cycles (median 4 cycles per patient) were administered. Partial responses were observed in 6 patients (14.2%) and stable disease in 11 (26.2%). The overall clinical benefit was 40.4%. Symptom relief and improvement of performance status were observed in 18 (42.8%) patients. The median time to progression, median duration of response and the median overall survival, were 6, 7 and 13 months, respectively. The most common grade 3 to 4 toxicities were neutropenia, anaemia and diarrhoea. CONCLUSION: The combination of gemcitabine and 5-FU is an active regimen for the treatment of advanced pancreatic cancer with an acceptable toxicity profile.

NSC 290205-based therapy in murine pancreatic adenocarcinoma PAN02 in combination with adriamycin (ADR).

BACKGROUND: NSC 290205 (A) is a hybrid synthetic antitumor ester, which combines a D-lactam derivative of androsterone and nitrogen mustard. In this study, the antitumor activity of A in combination with ADR (AHOP) was investigated in comparison with the standard CHOP regimen. MATERIALS AND METHODS: PAN02 adenocarcinoma was used in this study. C57Bl mice were used for chemotherapy evaluation. The activity was assessed from the inhibition of tumor growth and the oncostatic parameter T/C%. RESULTS: Treatment with A or cyclophosphamide produced almost equal borderline activity. Moreover, both the CHOP and AHOP regimens showed significant and comparable antitumor effects. AHOP caused the maximum effect, inhibiting tumor growth by 56.8%. CHOP was less effective, producing 47.7% tumor inhibition. CONCLUSION: It is very likely that the D-lactamic steroid (androstan) alkylator forA, containing the amide group -NH-CO-, combined with ADR which intercalates between DNA base-pairs, is the explanation for the higher activity of AHOP as compared to CHOP.

Serum CYFRA 21-1 in patients with invasive bladder cancer and its relevance as a tumor marker during chemotherapy.

PURPOSE: Previous studies have shown that serum levels of the degradation products of cytokeratins could be used as surrogate markers in the diagnosis and followup of patients with solid tumors, including tumors of the bladder. MATERIALS AND METHODS: The soluble cytokeratin 19 fragment CYFRA 21-1 was measured by solid phase radioimmunoassay in the serum of 142 patients with invasive transitional cell cancer of the bladder. Of the patients 56 had clinical stage I to III locally confined disease (T1-4aN0M0) and 86 had stage IV metastatic disease with lymph node and/or distant metastases. A control group consisted of 33 healthy volunteers. In a subgroup of 49 patients with metastatic disease receiving combined platinum based chemotherapy serum CYFRA 21-1 was determined prior to the initiation of therapy and after the documentation of response. RESULTS: Abnormal CYFRA 21-1 was observed in 7% of patients with locally invasive disease and in 66% of those with metastatic disease (p < 0.0001). There was no correlation of CYFRA 21-1 with tumor differentiation. Patients with abnormal CYFRA 21-1 showed statistically significant worse median overall survival. Moreover, in the subgroup of patients with metastatic disease receiving chemotherapy CYFRA 21-1 levels correlated with the response to treatment. CONCLUSIONS: Patients with transitional cell cancer of the bladder with evidence of distant metastases showed a significant increase in serum CYFRA 21-1. During chemotherapy CYFRA 21-1 appears to be a potentially sensitive and useful indicator for monitoring treatment response.

Non-invasive cardiologic findings in patients with malignant melanoma*.

Although malignant melanoma has a great propensity (38-50%) for cardiac involvement, as indicated by autopsy findings, cardiac metastases are rarely identified ante-mortem. The aim of this study was to record abnormal electrocardiographic and echocardiographic findings in patients with malignant melanoma. One hundred and eighty-five consecutive patients (male/female, 99/86; mean age, 59.6 years) with histologically proven malignant melanoma (American Joint Committee on Cancer stages II-IV), and with no known history of heart disease, were evaluated prospectively over a period of 11 years. The cardiologic findings considered were an unexpected delayed conduction of an electrical stimulus, recorded by high-resolution signal-averaged electrocardiogram (presence of ventricular late potentials), prolongation of the PR, QRS and QTc segments in a surface electrocardiogram, and abnormal Q waves. Echocardiographic findings comprised pericardial implantation/effusion or presence of intracavitary/intramyocardial metastases. Forty-one abnormal findings were recorded, pertaining to 38 of the 185 patients (19.5%). In particular, PR interval prolongation was found in eight patients (4.3%) and QTc interval prolongation in 11 (6%). Abnormal Q waves were recorded in five patients (2.7%). The filtered QRS interval was prolonged in seven patients (3.8%). Finally, echocardiographic examination showed discrete pericardial implantations and small to moderate pericardial effusion in six patients (3.2%) and intracavitary/intramyocardial metastases in four (2.1%). The median survival of these patients was 33 months (95% confidence interval, 19.9-46.1 months). It can be concluded that abnormal electrocardiographic and echocardiographic findings are recorded at the time of diagnosis of the disease in a significant percentage of patients with malignant melanoma.

Combined chemotherapy and radiotherapy during conception and first two trimesters of gestation in a woman with metastatic breast cancer.

A 33-year-old woman with T(4c)N(3) breast cancer with metastases in the skeleton (M(1)) received five cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC regimen) before conception and during the first trimester. Salvage radiotherapy (28 Gy) was delivered during the 17th week. Tamoxifen and zolendronic acid were also administered throughout the second and third trimesters. The patient was not aware of her pregnancy until the 28th week. A female phenotypically normal infant was delivered in the 35th week of gestation by cesarean section. The child is functioning normally 12 months after delivery. The literature of anthracycline treatment during conception and the first trimester is reviewed. The effects of tamoxifen and biphosphonate therapy on the fetus during pregnancy are also discussed.

A hypothesis on the role of insulin-like growth factor I in testicular germ cell tumours.

It has already been established that the growth effects of growth hormone (GH) are mediated through insulin-like growth factor I (IGF-I). Recent studies demonstrated a relationship between IGF-I levels and various types of cancer, namely colon, prostate, breast, brain and lung cancer. In addition, many experimental observations documented a participation of the IGF-I system in tumourigenesis through enhanced cell proliferation rate, anti-apoptotic functions and stimulation of neovascularization. With the present known biological mechanisms, implicated in the pathogenesis of testicular germ cell tumours (GCT), it is difficult to interpret the consistently increasing incidence of this tumour over the last decades. On the other hand, unpublished data of our department are in accordance with previous published studies, suggesting that GCT may be positively associated with body height. Scattered publications report development of GCT secondary to acromegaly or long-term GH replacement therapy. Thus, it is possible that the IGF-I system may be implicated in this pathogenesis, thereby predisposing to an increased risk of testicular GCTs. If IGF-I and IGFBP-3 are found to correlate with a high incidence of testicular GCT, they might be useful surrogate markers for diagnosis and surveillance of tumour growth, and an early screening method to identify an increased risk of this type of cancer in the first degree young male relatives of these patients.

Weekly gemcitabine for the treatment of biliary tract and gallbladder cancer.

OBJECTIVES: To evaluate the efficacy and safety of weekly administration of gemcitabine treatment in chemotherapy-naïve patients with advanced biliary tract and gallbladder cancer. PATIENTS AND METHODS: Gemcitabine at a dose of 800 mg/m2 was administered weekly as a 30-min infusion to patients with previously operated, histologically confirmed, metastatic, or unresectable locally advanced cholangiocarcinoma. Treatment was continued until unacceptable toxicity or disease progression. RESULTS: A total of 30 patients (median age 66 years; range 54-72 years) were included in the study. A median of 14 (range, 4-33) weekly doses was administered. Out of 30 patients evaluable for response, nine partial responses were observed (30.0%), while a further 11 patients demonstrated stable disease (36.7%). The median time to disease progression was 7 months (range, 5-34). Overall response rate was superior in patients with cancer of the gallbladder (ORR = 35.7%) compared with those patients with biliary duct cancer (ORR = 27.3%). This correlated to a significantly longer time to progression of 6.4 months (95% confidence interval (CI), 5.6-7.1 months) versus 3.6 months (95% CI, 2.9-4.3 months; p = 0.03) and a significantly better overall survival of 17.1 months (95% CI, 15.8-18.5 months) versus 11.4 months (95% CI, 10.2-12.6 months, p = 0.021). Toxicities were generally mild with only one case of grade 3 neutropenia. There were no cases of febrile neutropenia and no treatment-related deaths. CONCLUSIONS: Weekly administration of gemcitabine provides a safe, well-tolerated, and effective treatment for chemotherapy naïve patients with advanced cholangiocarcinoma, particularly with a gallbladder origin.