A multi-centre retrospective review of second-line therapy in advanced pancreatic adenocarcinoma.

INTRODUCTION: Limited information on second-line treatment in patients with pancreatic adenocarcinoma is available. At time of first-line treatment failure, approximately half of the patients are candidates for further treatment. MATERIAL AND METHODS: A retrospective review of 183 patients submitted to second-line therapy has been performed to identify prognostic factors, provides useful information for patients counseling and generates hypotheses for future studies. Inclusion criteria were: cytological or histologic diagnosis of pancreatic adenocarcinoma and prior gemcitabine-including chemotherapy. Any age, performance status (PS) and chemotherapy regimen were considered. RESULTS: One hundred and eighty-three patients (106 males; 168 metastatic; median age 62 years; median PS 1; 63 submitted to prior curative surgery, 32 to prior radiotherapy) with a median previous progression-free survival (PFS) of 6.7 months were included. Median and 6-month PFS after initiation of salvage therapy were 3.0 months and 20%. Median, 1 and 2 years, overall survival after initiation of salvage therapy were 6.2 months, 17 and 4%, respectively. Previous PFS, CA19.9 levels and age independently predicted OS. CONCLUSION: Re-challenge with gemcitabine and 5-fluorouracil administration may have a role in selected patients.

Which benefit from adding gemcitabine to vinorelbine in elderly (>or=70 years) women with metastatic breast cancer? Early interruption of a phase II study.

BACKGROUND: Since vinorelbine and gemcitabine are both active in breast cancer with moderate toxicity, in 2002 we started a phase II trial with a combination regimen in elderly patients. PATIENTS AND METHODS: To evaluate complete plus partial response rates and toxicity of first-line vinorelbine 25 mg/m2 plus gemcitabine 1000 mg/m2 on days 1 and 8, every 3 weeks, in women>or=70 years with advanced breast cancer and measurable lesions. All patients underwent multidimensional geriatric assessment before enrollment. A two-step design was applied, and the trial would be completed if an overall response rate>or=30% was obtained with a grade 3-grade 4 (G3-G4) toxicity rateor=70 years outside the setting of controlled clinical trials.

Is acute dyspnea related to oxaliplatin administration?

The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin. Oxaliplatin improves the efficacy of this combination in patients with stage III colon cancer and moreover its toxicity is well tolerable. We describe a rare clinical case of acute dyspnoea probably related to oxaliplatin at one month from the end of the adjuvant treatment. A 74-year-old man developed a locally advanced sigmoid carcinoma (pT3N1M0). A port a cath attached to an open-ended catheter was implanted in order to administer primary chemotherapy safely according to the FOLFOX4 schedule. One month following the end of the 6th cycle, the patient referred a persistent cough and moderate dyspnoea. Chest radiography displayed a change in the lung interstitium, chest CT scan confirmed this aspect of adult respiratory distress syndrome, spirometry reported a decreased carbon monoxide diffusion capacity. Antibiotic and corticosteroids were administered for 10 d, then a repeated chest X ray evidenced a progressive pulmonary infiltration. A transbronchial biopsy and cytology did not show an infective process, a CT scan reported radiological abnormalities including linear and nodular densities which were becoming confluents. Antimicotic and antiviral drugs did not evidence any benefit. The antiviral therapy was stopped and high dose metilprednisolone was started. The patient died of pulmonary distress after 10 d.

Blood oxidative status and selectins plasma levels in healthy donors receiving granulocyte-colony stimulating factor.

Recombinant human G-CSF (rHuG-CSF) is used for hematopoietic progenitor cells (HPC) mobilization and collection. Activation of polymorphonuclear leukocytes (PMN) is present during rHuG-CSF treatment and is associated with endothelial cell dysfunction and hypercoagulation. We evaluated whether PMN activation by rHuG-CSF may alter the blood oxidative status and subsequently affect the vascular cell function. Fourteen healthy individuals received rHuG-CSF for HPC harvesting. Blood was drawn before starting rHuG-CSF (T0), on the last day of rHuG-CSF (T1) and 1 week after stopping rHuG-CSF (T2). Levels of CD11b, myeloperoxidase (MPO), hydroperoxides, nitric oxide (NO), and soluble endothelium (sES), leukocyte (sLS), and platelet (sPS) selectins were measured. During rHuG-CSF, CD11b, MPO and hydroperoxides significantly increased, while NO levels significantly decreased, compared with T0. At T2 all these markers returned to baseline values. Significant increments of all selectins were observed during rHuG-CSF. At T2 sES and sEP significantly decreased back to pre-treatment values, whereas sLS remained significantly high. These data show that rHuG-CSF induces a transient inflammatory status characterized by circulating activated PMN, which release reactive oxygen species and intracellular proteases, promoting the onset of an abnormal oxidative status. This process may modify the hemostatic balance towards a pro-thrombotic state.

Taking care of older cancer patients: results of a survey addressed to the Chiefs of the Medical Oncology Divisions in Italy.

An open questionnaire on the management of older cancer patients in the Italian Divisions of Medical Oncology was sent to the Chiefs of the units in the last 4 months of the year 2004. One hundred and ninety-nine of 330 (60%) responded. The majority of the Medical Oncologists interviewed agreed that special therapeutic protocols were necessary for elderly cancer patients. Also specific guidelines were believed to be useful. In only a minority of units there were some members specifically dedicated to older patients and the Multidimensional Geriatric (MGE) was used routinely only in 12% of cases. The majority of the physicians interviewed believed that older patients accepted chemotherapy as the younger ones did, or even more (79%). Written informed consent was obtained in the majority of units (70%). Over 63% believed that oral antitumor drugs had a very important role in older patients, while 36% were sceptical or negative. More time and attention should be paid to older patients (87.4%) and more economic resources devoted to them (93.3%). In conclusion, Italian Medical Oncologists are well aware of the increasing number of old cancer patients, of the particular problems concerning drug administration and the need of specific trials and guidelines. The need of close contact with Geriatricians and the adoption of Geriatric tools (MGE) are only perceived by a minority. The majority, however, believes that more time and resources should be available in order to take care of elderly cancer patients.

Raltitrexed-eloxatin salvage chemotherapy in gemcitabine-resistant metastatic pancreatic cancer.

Limited information on salvage treatment in patients affected by pancreatic cancer is available. At failure, about half of the patients present good performance status (PS) and are candidate for further treatment. Patients >18 years, PS >or=50, with metastatic pancreatic adenocarcinoma previously treated with gemcitabine-containing chemotherapy, and progression-free survival (PFS) <12 months received a combination of raltitrexed (3 mg m(-2)) and oxaliplatin (130 mg m(-2)) every 3 weeks until progression, toxicity, or a maximum of six cycles. A total of 41 patients received 137 cycles of chemotherapy. Dose intensity for both drugs was 92% of the intended dose. Main grade >2 toxicity was: neutropenia in five patients (12%), thrombocytopenia, liver and vomiting in three (7%), fatigue in two (5%). In total, 10 patients (24%) yielded a partial response, 11 a stable disease. Progression-free survival at 6 months was 14.6%. Median survival was 5.2 months. Survival was significantly longer in patients with previous PFS >6 months and in patients without pancreatic localisation. A clinically relevant improvement of quality of life was observed in numerous domains. Raltitrexed-oxaliplatin regimen may constitute a treatment opportunity in gemcitabine-resistant metastatic pancreatic cancer. Previous PFS interval may allow the identification of patients who are more likely to benefit from salvage treatment.

Is protracted low-dose temozolomide feasible in glioma patients?

The authors investigated the safety of 75 mg/m2 temozolomide for 21 days every 28 days in glioma patients. This schedule could lead to DNA repair enzyme O6-alkylguanine-DNA alkyltransferase depletion, contributing to overcoming drug resistance. Although Phase III studies are forthcoming, no data are available on the long-term toxicity of temozolomide, which, in this series, incurred prolonged, cumulative lymphopenia, which leads to a high incidence of infections.

Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study.

BACKGROUND: The aim of the study was to evaluate tolerance and efficacy of preoperative treatment with capecitabine in combination with radiation therapy (RT) in patients with locally advanced, resectable, rectal cancer. PATIENTS AND METHODS: Fifty-three patients with potentially resectable T3, N0-2 (87%) and T4, N0-2 (13%) rectal cancer were treated with capecitabine (825 mg/m2, twice daily for 7 days/week) and concomitant RT (50.4 Gy/28 fractions). Patients underwent surgery after 6-8 weeks followed, upon physician's indications, by 4-months adjuvant capecitabine. The primary end point was to determine the rate of pathologic complete response. Secondary end points were to assess the rate of clinical response and the safety profile. RESULTS: All patients but two completed the RT programme and 47 (89%) received 81%-100% of the capecitabine dose (100% of dose in 72% patients, 81%-95% in 17% patients and 48%-74% in 11% of patients). No patient had grade 4 toxicity. Grade 3 toxicity occurred in six patients (11%) and consisted mainly of leucopenia (4%) and hand-foot syndrome (4%). Mild or moderate toxicity was common and included leucopenia (72%), diarrhea (40%), proctitis (34%) and skin toxicity (20%). The overall clinical response rate was 58% and the downstaging rate was 57%, with a pathologic complete response rate of 24%. Among 34 patients with low-lying tumors (

Carboplatin and teniposide as third-line chemotherapy in patients with recurrent oligodendroglioma or oligoastrocytoma: a phase II study.

BACKGROUND: This study was a phase II study of third-line chemotherapy with carboplatin plus teniposide in patients with recurrent oligodendroglioma. PATIENTS AND METHODS: Patients with oligodendroglioma progressive or recurrent after surgery, radiotherapy and chemotherapy with PCV (lomustine/procarbazine/vincristine) and temozolomide were treated with 350 mg/m(2) carboplatin on day 1, and 50 mg/m(2) teniposide on days 1-3, every 4 weeks. RESULTS: Response and toxicity were evaluated in all 23 patients enrolled in the study. Two had partial response [8.6%; 95% confidence interval (CI) 1.8% to 28.6%] and 12 stable disease (52.17%; 95% CI 30% to 73%). Median time to progression was 19 weeks (95% CI 11.4-35.0), and 34.8% of the patients (95% CI 20.0% to 61.0%) had progression-free survival at 6 months. Median survival time was 60.7 weeks (95% CI 39.8 to not achieved) and 51% of the patients (95% CI 33.5% to 79.7%) were alive at 12 months. A total of 103 cycles were administered (on average 4.4 per patient; range 1-9). Toxicity was mild and mainly hematological, with grade 4 neutropenia and grade 4 thrombocytopenia in two (8.6%) and three patients (13%), respectively. CONCLUSIONS: Although the response rate of combined carboplatin and teniposide chemotherapy in heavily pretreated oligodendroglial tumors is moderate, the toxicity is manageable, and delay of progression in responders or stable patients may still confer a relevant clinical benefit.

A multidrug combination designed for reversing resistance to BCNU in glioblastoma multiforme.

BACKGROUND: Nitrosoureas constitute the main resource of chemotherapy for glioblastoma. However, because of chemoresistance, which is intrinsic or rapidly acquired after the first administration of chemotherapy, there have been few improvements in survival. Because O(6)-alkylguanine-DNA alkyltransferase (AGT) is the main target for increasing cell sensitivity to the nitrosoureas, we postulated that preexposure to other alkylating agents might increase the therapeutic index of the nitrosoureas by saturating all the copies of AGT present in the tumor cells. OBJECTIVE: To investigate the response rate, toxic effects, time from start of chemotherapy to progression of disease or exit from the study for any reason (TTP), and progression-free survival at 6 months (PFS-6) associated with a multidrug combination that could reverse resistance to carmustine (BCNU) through AGT depletion. METHODS: We conducted a phase 2 study of patients with glioblastoma at first relapse or progression after surgery and standard radiotherapy. Patients were treated with 100 mg/m(2) of procarbazine on days 1 to 5, 80 mg/m(2) of BCNU on days 3 to 5, and 1.4 mg/m(2) of vincristine on day 3 every 8 weeks. RESULTS: Fifty-eight patients were enrolled in the study, and all were assessable for response and toxic effects. Six patients (10.3%) had a complete response, 11 (19%) had a partial response, and 17 (29.3%) had stable disease. The median TTP was 4.8 months; 42.3% of patients had PFS-6, and 15.4% had PFS at 12 months. Response to chemotherapy was the only significant prognostic factor for TTP. Neutropenia was grade 3 in 8.6% of patients and grade 4 in 5.2% of patients, and thrombocytopenia was grade 3 in 17.2% of patients and grade 4 in 12% of patients; hepatic and pulmonary toxic effects were grade 3 in 5.2% and 8.6% of patients, respectively. CONCLUSION: This regimen proved active in chemotherapy-naive patients with recurrent glioblastoma even though toxic effects were substantial.

New strategy developments in brain tumor therapy.

BACKGROUND: The incidence of brain and other central nervous system malignant neoplasias is 6.5 cases per 100,000 inhabitants-years, and appears to increase with increasing age (1.2 % per year), with the greatest rate of increase in the population over age 70 years. MATERIAL AND METHODS: Chemotherapy remains part of the treatment that includes surgery and radiation therapy for the management of malignant gliomas. This article reviews the new drugs that have been introduced in the treatment of these patients in the latest years, their specific cellular targets, the objective response, the TTP and the MST. RESULTS: The most encouraging results to date come from studies of temozolomide, which is one of the most active and best tolerated drugs in recent years, and from clinical trials of CPT11. CONCLUSIONS: New approaches to chemotherapy treatment are necessary. Enrollment of patients into rigorous, well conducted, clinical trials, both at tumor diagnosis and recurrence, will generate new information regarding investigational therapies, and may offer improved therapies for patients with malignant gliomas.

High-dose chemotherapy with bone marrow rescue for high-grade gliomas in adults.

High-grade malignant gliomas are inevitably fatal, despite every effort to improve this prognosis, including various radiotherapeutic modalities, radio- and chemotherapeutic associations, and combinations of several drugs. High-dose chemotherapy and autologous bone-marrow transplantation (ABMT) have been increasingly used in the last 10 years for solid tumors, and several phase II studies in high-grade glioma patients have been conducted in the setting of both adjuvant treatment and recurrent disease. The most frequently used drug in the conditioning regimens in BCNU at doses higher than that employed by other regimens in other pathologies (800-1000 mg/m2). These dosages involve a high toxicity that is not balanced by a significant improvement in survival. New drugs and/or regimens must be tested in randomized trials.

Multimodal treatment of peritoneal carcinomatosis and sarcomatosis.

Peritoneal carcinomatosis and sarcomatosis (PCS) are short-term fatal conditions amenable only to palliative treatment. They are generally considered as a systemic disease at clinical presentation, and are resistant to standard treatments. However, there may be in the natural history a phase of loco-regional tumour spread during which the tumour may still be curable. Surgical treatment alone, or in combination with systemic chemotherapy, has yielded poor results in terms of survival and quality of life. One approach is cytoreductive surgery (CS) combined with the intraperitoneal administration of antiblastic agents. This may diminish any residual tumour following macroscopic excision and may overcome the pharmacokinetic limits of systemic chemotherapy. A further improvement in this multimodal approach may be achieved by the use of hyperthermic intraperitoneal intraoperative chemotherapy (HIIC). Results so far have been encouraging. However, series reported in the literature are relatively small and heterogeneous, and clinical and technical factors which include the selection of patients, optimal drugs dosage and temperature, evaluation of outcome and costs are still under discussion.

Changing boundaries in the treatment of malignant gliomas.

Malignant gliomas are still among the most lethal and difficult tumors to treat; even the most intensive combinations of radio- and chemotherapy are not curative and yield only a modest impact on survival for most of these patients, as long-term survivors are less than 10%. There is a major need for new chemotherapeutic drugs and alternative therapeutic modalities. This review aims to define the best standard treatment in the common clinical practice and also summarizes the most promising lines of investigational research in the field of neuro-oncology, which will probably offer new and long-awaited valid therapy options for brain tumor patients.

Temozolomide in patients with high grade gliomas.

The incidence of central nervous system neoplasias ranges from 3.8 to 5.1 cases per 100,000 inhabitants. First-line treatment of brain tumors consists of surgery associated with radiotherapy, and followed or not by chemotherapy. When used as an adjuvant therapy after surgery and radiotherapy, chemotherapy prolongs the time to progression and the median survival time. At relapse, chemotherapy is the common therapeutic approach. In recent years, new drugs for the treatment of brain tumors have been tested, and some of them, such as temozolomide, are very promising.

New drugs in recurrent high grade gliomas.

BACKGROUND: The incidence of Central Nervous System (CNS) neoplasias ranges from 3.8 to 5.1 cases per 100,000 inhabitants. In the presence of recurrence, the treatment is problematic; chemotherapy is experimental, primarily because the response is palliative and of limited duration. MATERIALS AND METHODS: This article analyzes the new drugs that have been introduced for the treatment of these patients in recent years, the objective response, the TTP and the MST. RESULTS: The most encouraging results to date come from studies of temozolomide, which is one of the most active and best tolerated drugs in recent years. CONCLUSION: New approaches to chemotherapy treatment are necessary. Enrollment of patients into rigorous, well-conducted, clinical trials, both at tumor diagnosis and after tumor recurrence, will generate new information regarding investigational therapies and may offer improved therapies for patients with malignant gliomas.

Endocrine dysfunctions in patients treated for brain tumors: incidence and guidelines for management.

Endocrine alterations are frequently found in patients undergoing treatment for CNS tumors. Careful follow-up aimed at the early detection of recurrences, with life-long monitor of hypothalamus-pituitary (HP) function, will also reveal any endocrine dysfunctions; indeed, their appropriate diagnosis and treatment may determine a significant improvement in the quality of life of these patients.

New therapeutic agents in the treatment of recurrent high-grade gliomas.

The incidence of central nervous system neoplasias ranges from 3.8 to 5.1 cases per 100,000 inhabitants. In the presence of recurrence, the treatment is problematic; chemotherapy is experimental, primarily because the response is palliative and of limited duration. This article analyses the new drugs that have been introduced in the treatment of these patients in the latest years, the objective response, the time to progression and the mean survival time. The most encouraging results to date come from studies of temozolomide, which is one of the most active and best tolerated drugs in recent years. New approaches to the chemotherapy treatment are necessary. Enrolment of patients into rigorous, well-conducted, clinical trials, both at tumour diagnosis and after tumour recurrence, will generate new information regarding investigational therapies and may offer improved therapies for patients with malignant gliomas.

The treatment of cranial germ cell tumours.

Germ cell tumours of the central nervous system (CNS) include many subtypes whose response to treatment varies, even though the symptoms and radiological appearances are similar. Five-year survival rates are 96% for germinomas, 100% for mature teratomas, 67% for immature teratomas and 69% for immature teratomas mixed with germinomas; for beta-HCG secreting germinomas the rate is only 38%. Patients with choriocarcinoma, embryonal carcinoma, or yolk sac tumour have the lowest survival rates; patients with germinoma or mature teratoma have longer survival rates. Although a wider resection is associated with a higher rate of survival for patients with non-germinomatous germ cell (NGGC) tumours, to date an aggressive surgical approach has been advocated only for pineal region tumours, but not for hypothalamic/neurohypophyseal tumours. Beside the delayed injury induced by radiotherapy, the late injury induced by chemotherapy is becoming increasingly evident. Cisplatin is considered an indispensable drug, but it may cause renal damage, ototoxicity, peripheral neuropathy and sterility, while etoposide is associated with an excess frequency of second neoplasms. Taking into account all of the published literature, the following therapeutic options are suggested: in pure germinoma tumours (GT) radiotherapy alone will usually ensure adequate control of the disease, and the long-term sequelae may be limited by reducing the dose delivered, as was proposed for germ cell testicular tumours, to 30 Gy to limited fields plus 25-30 Gy to the spinal axis if there is disseminated disease. In cases of recurrence, which should be uncommon, patients may be rescued with both radiotherapy and chemotherapy. In NGGC tumours, the prognosis is more unfavourable and there is often dissemination to the spine at diagnosis; however, the tumour's high chemosensitivity suggests neoadjuvant treatment chemotherapy with cisplatin and etoposide for three cycles followed by consolidation radiotherapy with 40 Gy to the limited fields plus 30 Gy to the spinal axis if disseminated. In our opinion, a higher dose of radiotherapy in cases in which chemotherapy does not achieve a radiological complete remission is not advisable, because very often the residual radiological abnormality does not represent biologically active tumour but differentiated forms such as mature teratoma. The challenge for 2000 is to both cure these patients, and avoid the late and permanent sequelae of radiation and/or chemotherapy that may subsequently impair quality of life.

[Complementary treatment to surgery of gastric carcinoma: role of adjuvant and neoadjuvant chemotherapy]. / Terapie complementari al trattamento chirurgico del carcinoma gastrico: ruolo della chemioterapia adiuvante e neoadiuvante.

Although there has been a decline in the incidence of gastric cancer worldwide, its mortality rate is still high. In the West, attempts with adjuvant chemotherapy to improve survival have been disappointing. The promising results reported with the FAM (5-FU, Adriamycin, Mitomycin C) regimen in patients with advanced disease, have not been confirmed in an adjuvant setting. Randomized trials on adjuvant chemotherapy in Japan have shown a positive outcome in treated patients only when subgroups with advanced disease are considered. As results with adjuvant chemo-immunotherapy were better than those with chemotherapy alone, immunostimulators have been widely utilized in clinical trials conducted in Japan in recent years. However, chemo-immunotherapy may be more effective in patients with minimal residual disease, due to the combined action of a lower stage at diagnosis and to a diffuse application of standard wide lymphadenectomy. Inadequate lymphadenectomy, like that performed in many western studies, may compromised radicality in patients with "curable" disease and the concept of "minimal residual disease" must therefore be considered in future trials on adjuvant chemotherapy. Future trends for new therapeutic combinations (FAMTX, EAP, 5-FU/Cisplatin, PELF, etc) tested in phase II and III clinical trials are also discussed. Whatever the type of approach used, the high incidence of intra-abdominal recurrences indicates that an improvement in the prognosis of patients with advanced diseases will only come with the development of additional treatment modalities such as neoadjuvant or intraperitoneal chemotherapy.