A novel metronomic chemotherapy regimen of weekly platinum and daily oral etoposide in high-risk non-small cell lung cancer patients.

The aim of this pilot phase II trial was to investigate the toxicity and anti-tumour activity of a novel metronomic regimen of weekly cisplatin (CDDP) and oral etoposide (VP16) in high-risk patients with advanced NSCLC. The study enrolled 31 high-risk patients (27 men and 4 women aged 16-82 years; mean, 64.3) with NSCLC (18 stage IIIB and 13 stage IV) and an ECOG performance status of < or = 3, all of whom received weekly CDDP 30 mg/m2 iv on days 1, 8, 14 and 28 of each cycle and oral daily etoposide 50 mg/m2 on 21 of the 28 days. The most frequent adverse events were grade III leukopenia and anemia; nevertheless, three patients died of pulmonary embolism after 2, 3 and 6 weeks of treatment. The objective response (OR) rate was 45.2% (2 complete and 12 partial), and the disease control rate was 58.1% (14 ORs and 4 disease stabilisations). The mean time to progression and survival were respectively nine months (95% CI, 6.3-15.8 months) and thirteen months (95% CI, 9.1-20.5 months). Pharmacological analysis showed that this metronomic regimen allows a much greater median monthly area under the curve of CDDP and VP16 than conventional treatment schedules. Our findings also suggest that this treatment schedule may affect tumour growth and neoangiogenesis by changing peripheral blood vascular-endothelial growth factor levels. These preliminary results indicate that our metronomic regimen is well tolerated and active, even in patients with a very poor prognosis.

Procollagen type I carboxy-terminal propeptide as a marker of osteoblastic bone metastases.

Collagen type I is the sole collagen type found in bones and tendons. Carboxyterminal propeptide, deriving and cleaved from procollagen type I (PICP) during collagen synthesis, is delivered into the blood, where it can be measured. According to current knowledge, PICP correlates with bone collagen synthesis and bone formation rate. Elevated serum levels of PICP in patients with Paget's disease, compared with normal subjects and correlated with serum alkaline phosphatase (Alk.Ph.), have been previously described. Thus, PICP may be a valuable marker of bone formation. PICP, serum Alk.Ph., serum bone Gla protein and 24-h urinary hydroxyproline:creatinine ratio have been measured in 47 cancer patients: 27 with predominantly osteolytic lesions (5 myeloma, 15 breast, 3 lung, 2 kidney, 1 bladder, 1 thyroid) and 20 with predominantly osteoblastic lesions (18 prostate and 2 breast). The higher levels of PICP were noted in patients with osteoblastic or mixed metastases. In the entire group of patients, a statistically significant correlation between PICP and bone Gla protein (r = 0.57; P < 0.001), PICP and Alk.Ph. (r = 0.80; P < 0.001), and bone Gla protein and Alk.Ph. (r = 0.44; P < 0.01) was noted. In those patients with osteoblastic metastases we observed a significant correlation only between PICP and Alk.Ph. (r = 0.62; P < 0.003). During chemotherapy, 13 of 20 patients with osteoblastic metastases who achieved objective response or stable disease showed a more rapid and significant decrease in PICP with respect to the other bone markers. Serum PICP level could be considered a good marker of osteoblastic activity.

Hypercalcemia in breast cancer.

Hypercalcemia is relatively frequent in malignancy with or without osteolytic bone metastases. It is thought that neoplastic cells may secrete substances which not only stimulate osteoclastic activity but are also capable of modifying the absorption, excretion, and resorption of calcium and phosphate ions. Since 1987, we have studied 24 breast cancer patients with hypercalcemia (22 with bone metastases and two without). The group of 22 patients with bone metastases were divided into two subgroups. The first consisted of 10 patients with high serum levels of humoral factors, such as parathyroid hormone-related protein (PTHrP), and/or prostaglandin E2 (PGE2) and/or interleukin 1 (IL-1), and high levels of bone markers, such as alkaline phosphatase, bone Gla protein and urinary hydroxyproline. The second subgroup consisted of 12 patients with high levels of bone markers alone. Bone histologic analysis showed an osteoclastic activation surrounding metastatic tumor tissue in six out of 10 patients of the first subgroup, while an evident osteolysis caused by the tumor cells was noted in seven out of 12 patients of the second subgroup. The two patients without bone metastases showed normal biochemistry and bone histologic examination. The authors, having tried to explain the pathogenesis of hypercalcemia, emphasize the importance of humoral factors secreted by tumor cells as a direct or indirect cause of hypercalcemia. The origin of hypercalcemia remains unclear in two patients without bone metastases.

Treatment of advanced colorectal cancer with high-dose intensity folinic acid and 5-fluorouracil plus supportive care.

This randomised clinical trial, involving patients with advanced colorectal cancer, was carried out to compare the effectiveness of accelerated folinic acid (FA) plus 5-fluorouracil (5-FU) with that of the conventional regimen of 5-FU alone. Both regimens were administered with simulataneous supportive care. 185 patients were eligible: 94 were randomly allocated to receive FA 200 mg/m2 i.v. plus 5-FU 400 mg/m2 i.v. on days 1-5 every 3 weeks; and 91 to receive 5-FU 400 mg/m2 i.v. on days 1-5 every 4 weeks. The response rate was 33.3% in the accelerated FA/5-FU and 18.6% in the 5-FU arm (P = 0.045). Median survival was 13.5 months in the FA/5-FU arm and 7.5 months in the 5-FU arm (P = 0.039). Toxicity was mild and slightly more pronounced in the FA/5-FU arm (P = 0.078). This study indicates that, in patients with advanced colorectal cancer, accelerated chemotherapy with FA and 5-FU and simultaneous supportive care is capable of achieving a higher response rate and longer survival than conventional 5-FU alone, without severe toxicity.

Gemcitabine increases systemic 5-fluorouracil exposure in advanced cancer patients.

A number of recent clinical trials testing the combination of 5-fluorouracil (5-FU) and gemcitabine in patients with advanced pancreatic adenocarcinoma have shown a significant clinical response rate, but also significant toxicity. As the two antimetabolites may interact at several biochemical levels along their pathways of activation, we investigated whether gemcitabine (GEM) affects 5-FU pharmacokinetics in cancer patients. Thus, we compared 5-FU pharmacokinetics in two groups of patients with various cancers who received the same schedule of 5-FU and folinic acid (FUFA), with or without GEM. There was a significant increase in systemic (5-FU) exposure and toxicity in the FUFA plus GEM group. Our finding may be useful in designing future studies of the combination in order to reduce the occurrence of side-effects and to maximise the antitumour activity.

Recruitment of dendritic cells and enhanced antigen-specific immune reactivity in cancer patients treated with hr-GM-CSF (Molgramostim) and hr-IL-2. results from a phase Ib clinical trial.

Experimental findings suggest that granulocyte-monocyte-colony stimulating factor (GM-CSF) synergistically interacts with interleukin-2 (IL-2) in generating an efficient antigen-specific immune response. We evaluated the toxicity, antitumour activity and immunobiological effects of human recombinant (hr)-GM-CSF and hr-IL-2 in 25 cancer patients who subcutaneously (s.c.) received hr-GM-CSF 150 microg/day for 5 days, followed by hrIL-2 s.c. for 10 days and 15 days rest. Two of the most common side-effects were bone pain and fever. Of the 24 patients evaluable for response, 3 achieved partial remission, 13 experienced stable disease, and 8 progressed. Cytokine treatment increased the number of monocytes, dendritic cells (DC), and lymphocytes (memory T cells) in the peripheral blood and enhanced the antigen-specific immunoreactivity of these patients. Our results show that the hr-GM-CSF and hr-IL-2 combination is active and well tolerated. Its biological activity may support tumour associated antigen (TAA)-specific anticancer immunotherapy by increasing antigen presenting cell (APC) activity and T cell immune competence in vivo.

The involvement of oxidative stress in bovine herpesvirus type 4-mediated apoptosis.

Bovine herpesvirus type 4 (BHV-4) belongs to the gamma-2-herpesviruses of the Gammaherpesvirinae subfamily. BHV-4 has a worldwide distribution and has been isolated in a variety of clinical diseases as well as from healthy cattle. In this report we demonstrate that BHV-4 induces apoptosis in MDBK cells. In the early phases of apoptosis, cells show an increase in the intracellular level of reactive oxygen species, which is indicative of oxidative stress. This precedes DNA fragmentation, a hallmark typical of apoptosis. Cells were protected from apoptosis only by certain antioxidants (butylated hydroxyanisole and ebselen), whereas N-acetylcysteine turned out to be ineffective. Antioxidants that protected cells from apoptosis prevented oxidative stress but failed to block virus growth. These observations suggest that oxidative stress may be a crucial event in the sequence leading to apoptotic cell death but apoptosis is not required for the multiplication of BHV-4.

Comparison between CEA, TPA, CA 15/3 and hydroxyproline, alkaline phosphatase, whole body retention of 99mTc MDP in the follow-up of bone metastases in breast cancer.

The development of bone metastases in cancer can be monitored easily using three markers: 24 h urinary hydroxyproline excretion (HOP) (an index of osteoclastic activity), serum alkaline phosphatase (Alk.Ph.) (an index of osteoblastic activity) and 24 h whole body retention of 99mTc-methylene diphosphonate (WBR%) (an index of bone turnover). To evaluate the effectiveness of this group of bone tumor markers in breast cancer we compared it with the following group of three markers which are commonly used in the monitoring of breast cancer and in the follow-up of advanced disease with or without bone metastases: carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA) and breast carcinoma antigen (CA 15/3). In 48 patients with bone metastases CEA, TPA and CA 15/3 were shown to be sensitive (79%, 85%, 90% respectively), while HOP, Alk.Ph. and WBR%, which are commonly accepted as reliable markers of bone activity, showed a lower sensitivity (67%, 46%, 75% respectively). These results may be explained by the lack of osteoclastic or osteoblastic (or both) activity at the time of diagnosis. This explanation is supported by the fact that the bone markers HOP, Alk.Ph. and WBR% were found to be more sensitive than the others in the subsequent follow-up study. We conclude that in our study, CEA, TPA and CA 15/3 are at first more sensitive than Alk.Ph., HOP and WBR% but during the follow-up Alk.Ph., HOP and WBR% are possibly both more specific and more sensitive.

Gemcitabine (GEM), 5-fluorouracil (5-FU) and folinic acid (FA) in patients with different gastroenteric malignancies.

This phase II clinical trial was performed in order to evaluate the pharmacokinetics, toxicity and anti-tumor activity of a novel combination of gemcitabine (GEM), 5-fluorouracil (5-FU) and folinic acid (FA) designed on a specific translational basis. Every 4 weeks, 44 patients with various gastroenteric malignancies, 29 of whom had pancreas carcinoma, received a short intravenous (i.v.) infusion of FA (100 mg/m2) and 5-FU (400 mg/m2) on days 1-5, and GEM 1000 mg/m2 on days 1, 8 and 16. Our results suggest that, although this treatment leads to hematological and gastroenteric toxicity, it is very active in patients with pancreatic carcinoma. We therefore believe that an improved version would merit further investigation in larger scale trials.

Traditional uses of plants in the Eastern Riviera (Liguria, Italy).

AIM OF THE STUDY: The aim of the present study was to explore the traditional plant knowledge of a zone of the Ligurian coast, known as Riviera spezzina (RS), Eastern Liguria, Italy. MATERIALS AND METHODS: Ethnobotanical information was obtained through open informal interviews. The informants were residents, belonging to families living in the study area since generations, and involved, at least partially, in agriculture. RESULTS AND CONCLUSIONS: A total of 120 botanical taxa were recorded. Ethnobotanical data included medicinal (40.4%), alimentary (46.5%), veterinary (4.6%), domestic and cosmetic (4.3%), magic and ritual (1.8%) and other uses (2.4%). Medicinal plants are used to treat a wide range of diseases, mainly disorders of digestive system, skin, and genital-urinary and respiratory traits. The key role played by undomesticated edible herbs, locally known as "erbette", in traditional cooking recipes of RS was shown. These botanicals are rich in bioactive compounds, such as polyphenols, vitamins, complex sugars, essential fatty acids and fibers, and therefore might offer a valid protection against pathological conditions. Plant uses by RS people were compared with previous ethnobotanical literature, concerning the neighbouring areas of Liguria. Our results highlight the role of the traditional use of plants in the maintenance of health and the prevention of chronic and age-related diseases.

Chemo-hormone therapy of non-well-differentiated endocrine tumours from different anatomic sites with cisplatinum, etoposide and slow release lanreotide formulation.

We report the results of a phase II trial in patients with metastatic endocrine tumours from different sites, which aimed to evaluate the anti-tumour activity and toxicity of a cisplatinum and etoposide regimen administered in combination with the somatostatin agonist lanreotide given in slow release formulation. Between January 1999 and November 2003, 27 patients with histological diagnoses of endocrine tumours with different degrees of differentiation, excluding well differentiated carcinoid neoplasms, received intravenous (i.v.) administration of cisplatinum (30 mg m(-2)) and etoposide (100 mg m(-2)) on days 1-3 and intramuscular administration of 60 mg lanreotide on day 1, in a 21-day cycle. All of the patients were evaluable for toxicity and response. The treatment was very well tolerated as no grade 4 toxicity was observed. Four patients achieved a complete response, six a partial response, 12 experienced disease stabilisation and five disease progression. The average time to progression and to survival were 9 and 24 months respectively. These results suggest that this chemo-hormone therapy regimen is well tolerated and active in patients with non-well differentiated endocrine tumours.

Weekly chemotherapy in advanced prostatic cancer.

This randomised phase II study was performed in order to evaluate the effectiveness of a weekly chemotherapy regimen in advanced prostatic carcinoma patients (stage D2) refractory to hormonal therapy. Seventy-two cases were studied: they were randomised in a 2:1 ratio to receive either epirubicin (30 mg m-2 weekly) or doxorubicin (25 mg m-2 weekly); 48 patients received epirubicin and 24 received doxorubicin. After 12 courses of chemotherapy, the 45 evaluable patients in the epirubicin arm showed a response rate of 37.7% and the 21 evaluable patients in the doxorubicin arm showed a response rate of 33.3% (P = 0.51). Pain intensity, bone and prostatic tumour markers rapidly and significantly decreased in responders. An improvement in physical symptoms, functional conditions and in emotional well-being was observed in the majority of the treated patients. The histological analysis of bone metastases, performed before and after 12 courses of chemotherapy showed a significant reduction in neoplastic invasion and in new bone formation in responders. Cardiac performance worsened in five out of 45 patients and in ten out of 21 during the first 12 courses of epirubicin or doxorubicin respectively (P = 0.014). The median survival was 12.5 months in the epirubicin arm and 8.0 months in the doxorubicin arm (P = 0.042). Our data indicate that in advanced prostatic carcinoma, a weekly epirubicin regimen may give rapid palliative results, similar to that of doxorubicin, but with less side-effects.

Weekly epirubicin in patients with hormone-resistant prostate cancer.

The aim of this study was to investigate the benefit of weekly epirubicin in the treatment of metastatic hormone-resistant prostate cancer. One hundred and forty-eight patients with metastatic hormone-resistant prostate cancer received weekly 30-min intravenous infusions of epirubicin 30 mg m(2) of body surface area. The primary end-point was palliative response, defined as a reduction in pain intensity and an improvement in performance status. The secondary end-points were the duration of the palliative response, quality of life and survival. Fifty-seven (44%) of the 131 evaluable patients met the primary criterion of palliative response after six treatment cycles and 73 (56%) after 12 cycles; the median duration of the response was 9 months (range 1-11). The median global quality of life improved in 52% of the patients after six cycles and in 68% after 12 cycles. The 12- and 18-month survival rates were respectively 56 and 31%, with a median survival of 13+ months (range 1-36). The treatment was well tolerated: grade 3 neutropenia was observed in 8% of the patients, grade 3 anaemia in 7%, and grade 3 thrombocytopenia in 3%. None of the patients developed grade 4 toxicity or congestive heart failure. Weekly epirubicin chemotherapy can lead to a rapid and lasting palliative result in patients with metastatic HRPC, and have a positive effect on the quality of life and survival.

Folinic acid and 5-fluorouracil as adjuvant chemotherapy in colon cancer.

BACKGROUND/AIMS: Colon cancer is one of the major health problems in industrialized countries, and its incidence appears to be increasing. Surgical resectability is the most important prognostic determinant, although despite apparently curative surgery, recurrent tumors are common. Metastatic disease cannot be cured, and thus, there is a need for better adjuvant therapies. METHODS: Two hundred and thirty-nine patients with surgically resected colon cancer in Dukes' stage B2 or C were randomly assigned to chemotherapy or observation alone to determine whether adjuvant chemotherapy could effectively reduce the rate of cancer recurrence. One hundred and twenty-one patients in stage B2 and 118 patients in stage C were enrolled in the study. Adjuvant treatment consisted of folinic acid 200 mg/m2, intravenously, plus 5-fluorouracil 400 mg/m2, intravenously, on days 1-5 every 4 weeks for 12 cycles. RESULTS: In stage B2, no significant difference between the adjuvant arm and the observation arm was noted. In stage C, adjuvant chemotherapy produced an advantage over observation in terms of a reduction in cancer recurrence rate with prolongation of a disease-free interval (P = 0.0016) and an improvement in overall survival (P = 0.0025). CONCLUSIONS: This study shows that folinic acid plus 5-fluorouracil adjuvant chemotherapy is effective in patients with surgically resected Dukes' stage C colon carcinoma.

A parathyroid-hormone-related-protein (PTH-rP)-specific cytotoxic T cell response induced by in vitro stimulation of tumour-infiltrating lymphocytes derived from prostate cancer metastases, with epitope peptide-loaded autologous dendritic cells and low-dose IL-2.

Bone metastases are one of the most common events in patients with prostate carcinoma. PTH-rP, a protein produced by prostate carcinoma and other epithelial cancers, is a key agent for the development of bone metastases. A PTH-rP-derived peptide, designated PTR-4 was identified, which is capable to bind HLA-A2.1 molecules and to generate PTH-rP-specific cytotoxic T cell (CTL) lines from healthy HLA-A2.1(+) individual peripheral-blood-mononuclear-cells (PBMC). In this model, we investigated the in vitro possibility of generating an efficient PTH-rP specific CTL response by cyclical stimulations with IL-2 and PTR-4 peptide-pulsed autologous dendritic cells (DC), of HLA-A2.1(+) tumour infiltrating lymphocytes (TIL) derived from a patient with metastatic prostate carcinoma. A T cell line generated in this way (called TM-PTR-4) had a CD3(+), CD5(+), CD4(-), CD8(+), CD45(Ro+), CD56(-) immunophenotype and a HLA-A2.1 restricted cytotoxic activity to PTR-4-peptide pulsed CIR-A2 (HLA-A2.1(+)) target cells, PTH-rP(+)/HLA-A2.1(+) CIR-A2 transfected with PTH-rP gene, prostate carcinoma LNCaP cells, and autologous metastatic prostate cancer cells (M-CaP). These lymphocytes were not cytotoxic to HLA-A2.1(+) targets not producing PTH-rP, such as peptide-unpulsed CIR-A2 and colon carcinoma SW-1463, cell lines. Our results provide evidence that PTR-4 peptide-pulsed autologous DC may break the tolerance of human TIL against the autologous tumour by inducing a PTH-rP-specific CTL immune reaction. In conclusion PTR-4 peptide-pulsed autologous DC may be a promising approach for vaccine-therapy and antigen-specific CTL adoptive immunotherapy of hormone-resistant prostrate cancer.

A novel biweekly multidrug regimen of gemcitabine, oxaliplatin, 5-fluorouracil (5-FU), and folinic acid (FA) in pretreated patients with advanced colorectal carcinoma.

Previous results suggest that GEM affects 5-fluorouracil (5-FU) metabolism and pharmacokinetics in cancer patients, while combined with oxaliplatin, levo-folinic acid, and 5-FU (GOLF regimen), at doses achievable in cancer patients, determines high cytotoxic and proapoptotic antitumour activity in colon cancer cells in vitro. On these bases we designed a phase I-II clinical trial testing the GOLF regimen in patients with metastatic colorectal carcinoma, who had received at least a prior line of chemotherapy. In total, 29 patients (20 males and nine females) enrolled in the study received every 2 weeks, gemcitabine (patients #1-3 received 600 mg m(-2); patients # 4-6 received 850 mg m(-2); while patients # 7-29 received 1000 mg m(-2)) on the day 1, levo-folinic acid (100 mg m(-2)) on the days 1 and 2; 5-fluorouracil (400 mg m(-2)) in bolus injection, followed by a 22-h continuous infusion (800 mg m(-2)) on the days 1 and 2, and oxaliplatin (85 mg m(-2)), 6 h after the 5-FU bolus on day 2. The most frequent side effect was grade I-II haematological toxicity. In total, 28 patients were evaluable for response: three achieved a complete response, nine a partial response, 10 had a stable disease, and six progressed. The average time to progression and overall survival of the patients was, respectively, 7.26 and 22 months. Our GOLF combination is well tolerated and seems promising for the treatment of advanced colorectal cancer.

UFT/leucovorin and oxaliplatin alternated with UFT/leucovorin and irinotecan in metastatic colorectal cancer.

A total of 41 metastatic colorectal cancer (CRC) patients received tegafur/uracil (UFT)+leucovorin (LV)+oxaliplatin alternated with UFT/LV+irinotecan. The overall response rate was 58.5% (95% confidence interval, 42.2-73.3%), and the median progression-free survival was 8.8 months. There were no grade 4 toxicities; 12 patients (29%) experienced grade 3 diarrhoea. There were no cases of hand-foot syndrome. This alternating regimen seems to be effective and well tolerated in the first-line treatment of patients with metastatic CRC.

A novel biweekly pancreatic cancer treatment schedule with gemcitabine, 5-fluorouracil and folinic acid.

Pancreatic adenocarcinoma is a common disease considered to be poorly responsive to antiblastic treatment. Recent clinical and preclinical results suggest that a combined treatment of gemcitabine (GEM), 5-flurouracil (5-FU) and folinic acid (FA) offers a clinical benefit in patients with advanced pancreas adenocarcinoma. The aim of this phase II clinical trial was to evaluate the antitumour activity and toxicity of a novel biweekly schedule of this combination in patients with pancreatic adenocarcinoma. A total of 42 patients received a 30 min infusion of FA (100 mg m(-2)) and 5-FU (400 mg m(-2)) (FUFA) on days 1-3, and GEM 1000 mg m(-2) on day 1 every 15 days. We observed 13 objective responses (two complete, 11 partial) and 23 stable diseases. The median time to progression was 9.75 months (95% Confidence Interval (CI), 6.88-12.62) and the median overall survival was 13.10 months (95% CI 9.64-16.56). There were seven cases of each grade III gastroenteric and haematological toxicity. The GEM plus FUFA combination appears to be well tolerated and very active in patients with pancreatic carcinoma.

Urinary calcium excretion in the monitoring of bone metastases from prostatic carcinoma.

BACKGROUND: One of the greatest problems in treating advanced prostate carcinoma is monitoring the therapeutic response of bone metastases. As these metastases are mainly osteosclerotic and lead to a markedly increased bone calcium requirement that may give rise to an imbalance in calcium homeostasis, the authors investigated whether changes in calcium balance may be useful for evaluating the response of bone metastases to treatment. METHODS: The study involved 268 prostate carcinoma patients: 142 in Stage A-C2 (International Union Against Cancer [UICC] staging system, 1998) and 126 with bone metastases who had failed to respond to hormone therapy and were receiving chemotherapy. Prostate-specific antigen (PSA), calcium and phosphate metabolism, and the main bone formation and resorption markers were all assayed before and after chemotherapy. RESULTS: Of the 126 patients on chemotherapy, 109 were evaluable for response: according to standard criteria, 25 (23%) had improved, 43 (39.5%) were unchanged, and 41 (37.5%) had worsened. All of the improved and 16 unchanged patients had decreased PSA and bone marker levels and an increased urinary calcium/creatinine ratio (UCa/Cr); the worsened patients had increased PSA and bone marker levels, and their UCa/Cr decreased after only six treatment cycles. PSA and UCa/Cr were the biochemical markers whose changes showed the best agreement with treatment response. CONCLUSION: The UCa/Cr ratio was the most useful marker of clinical response, mainly because it allowed an early decision to continue or to stop chemotherapy. Furthermore, UCa/Cr and PSA together identified a percentage of patients classified as unchanged on the basis of standard criteria but whose condition had actually improved.