Adjuvant chemotherapy of non-small cell lung cancer: a review.
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Biomedical subjects
Publications and source records attributed to G Fiorentini.
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Forty-nine patients with localized osteosarcoma of the extremities were treated with a new protocol of neoadjuvant chemotherapy. Preoperatively the patients received high-dose methotrexate intravenously, followed after a week by cisplatinum intra-arterially for a continuous infusion over a 72-hour period, plus adriamycin intravenously infused over an 8-hour period. In all cases the clinical and radiographic response was good and in 44 cases (89.7%) it was possible to perform conservative surgery. The histologic examination of the surgical specimen resulted in necrosis being "good" (greater than or equal to 90% of necrosis) in 41 patients (83.6%). This percentage of "good necrosis" was significantly higher than the percentage previously obtained in our Center as well as in others for preoperative treatment of this tumor. Up to now, patients with localized osteosarcoma of the extremities who showed a good histologic response to the preoperative chemotherapy have had a very good prognosis (82% of patients are continuously disease-free). These results suggest that this new regimen represents a substantial improvement in the treatment of this disease.
To explore the clinical applicability of the Goldie and Coldman hypothesis, we treated 28 patients with metastatic breast cancer with alternating non-cross-resistant chemotherapy. The patients received cyclophosphamide, 600 mg/m2, 5-fluorouracil, 600 mg/m2, methotrexate, 40 mg/m2, alternated every three weeks with adriamycin, 60 mg/m2, and mitomycin C, 10 mg/m2. Only one patient had previously received palliative chemotherapy. Six patients had received adjuvant CMF, and 17 patients had been pretreated with endocrine therapy (13 for advanced disease, 4 as adjuvant). Fourteen patients had bone involvement, and 10 had visceral metastases. A mean of 12 cycles was given to 24 evaluable patients. The objective response rate was 67%: 11 patients (46%) achieved complete and 5 (21%) partial remission. Response rate in soft tissues was 83.3%, in bone 50%, in liver 100%, and in lung 80%. The median duration of response was 14 months, with 7 patients still in remission. No life-threatening toxicity was observed. Our preliminary results support the validity of this approach and the efficacy of this combination chemotherapy. A large-scale randomized study is warranted.
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Twenty-four hyperechogenic nodules ranging from 0.5 cm to 2.5 cm in diameter were observed within the renal parenchyma in 22 patients. Eighteen patients did not complain of renal symptoms, one had microhematuria, one renal colic, and two pain in the right flank. Because of the sonographic features suggesting fat-containing masses, these lesions were considered to be small angiomyolipomas. Two of our patients underwent surgery, which confirmed this histopathologic interpretation. Twelve patients had a sonographic follow-up, which lasted from 4 to 30 months. We did not observe any change in size or shape of the lesions.
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BACKGROUND: Hepatic arterial infusion chemotherapy is a promising approach in liver metastases from colorectal cancer, but chemical hepatitis, biliary sclerosis, arterial thrombosis and right upper quadrant pain are limiting factors. Irinotecan (CPT-11) is an active drug in colorectal cancer. We planned a short hepatic arterial infusion of CPT-11 to describe the toxicity, to determine the dose-limiting toxicity, and to define the doses of CPT-11 to be recommended for phase II studies. PATIENTS AND METHODS: Fourteen patients with a median liver substitution of 30% (10-60%) were enrolled. All patients received hepatic arterial infusion chemotherapy with CPT-11 on an outpatient basis every 3 weeks as a short, 30-min infusion. RESULTS: At 240 mg/m2, 2 of 4 patients experienced grade 4 diarrhea and neutropenia, and 3 of them also reported grade 4 abdominal pain of the right upper quadrant. The maximum tolerated dose was reached at 240 mg/m2. The recommended doses of CPT-11 for phase II studies is 200 mg/m2, given every 3 weeks. CONCLUSIONS: CPT-11 presents a low hepatic toxic profile and could be considered a new active drug, suitable for hepatic arterial infusion in liver metastases from colorectal cancer.
The use of high-dose chemotherapy followed by hematopoietic rescue is increasing worldwide for solid tumors. Several studies have suggested that the period of absolute neutrophil count (ANC, < 500/ml) may be shortened in patients who receive peripheral blood progenitor cells (PBPC). To estimate the clinical value of granulocyte-colony-stimulating factor, we examined a cohort of 26 consecutive patients with advanced breast cancer who received one or two cycles of high-dose chemotherapy with PBPC rescue with or without filgrastim. Thirty-five courses of high-dose ICE (ifosfamide, carboplatin, etoposide) chemotherapy were administered and evaluated. All patients received PBPC rescue. Sixteen patients (21 courses) received subcutaneous filgrastim (5 mg/kg) following PBPC infusion. Recovery to > or = 500 ANC occurred at a median time of 7 days post PBPC infusion among patients who received filgrastim versus 10 days among patients who received standard support care only (P < 0.01). The administration of filgrastim was not associated with a reduction in the duration of hospitalization, in the total number of days on nonprophylactic antibiotics, number of red blood cell transfusions, time to platelet engraftment, or number of febrile days. This could be the consequence of the high hematopoietic cell dose administered in the study. Therefore, any effect of filgrastim was probably masked by the use of a large number of PBPC. Larger prospective randomized studies, specifically focused on the utility of the administration of growth factors following high-dose chemotherapy and PBPC rescue, may be warranted to know whether the administration of filgrastim after PBPC transplantation is really necessary.
BACKGROUND: The purpose of our study was to evaluate the activity and toxicity of a sequential chemo-radiotherapeutic treatment on the basis of an earlier report by The Johns Hopkins Oncology Center. MATERIALS AND METHODS: Eighteen patients with histologically diagnosed malignant gliomas entered the study. Fifteen patients had glioblastoma multiforme (83%). BCNU (40 mg/sqm/die) and Cisplatin (40 mg/sqm/die) were administered concurrently for 3 days every 3-4 weeks. Radiotherapy consisted of 45 Gy whole cranial irradiation plus a 15 Gy boost on the preoperative volume. RESULTS: Thirteen patients had measurable disease and were evaluable for response. After chemotherapy we obtained 3 CRs (complete remission) and 4 PRs (partial remission) (RR (response rate 54%). Three PRs were converted to CRs after radiotherapy, for a complete remission rate of 46% (6/13). The median duration of response was 10 months. The median survival of the entire patients population was 9 months with 33% survival rates at 1 year. Hematological toxicity grade 4 in one patient and grade 3 in two patients were the major complications due to chemotherapy. CONCLUSIONS: Our sequential chemo-radiotherapeutic regimen appears to have significant activity in adults with newly diagnosed high-grade gliomas.
Liver metastasis of colorectal cancer is a life-threatening prognostic factor. Hepatic resection, when possible, is the best therapeutic modality, although the overall survival rate is still low (30%). The diagnosis has been carried out by clinical examination, abnormal alkaline phosphatase, lactic acid dehydrogenase and tumor markers, abdominal liver echography and computed tomography scan. Angiography and intraoperative echography are useful for resection. The number of hepatic metastases and the surgical margin are probably the most significant prognostic factors. Colorectal cancer may spread predominantly to the liver making regional treatment strategies viable options. Subtotal hepatic resections and segmentectomies are potentially curable procedures for single or small numbers of hepatic metastases without other sites of disease. However, there have been no prospective randomized trials comparing patients with unresected liver metastases and resected metastases. Regional chemotherapy with floxuridine seems useful combined with hepatic resection or as palliative therapy. Gastric ulcer and biliary sclerosis are the main related toxicities. Patients with localized, unresectable hepatic metastases or concomitant bad medical condition may be candidates for radiation, percutaneous ethanol injection, cryosurgery, radiofrequency, hypoxic flow-stop perfusions with bioreductive alkylating agents, hepatic arterial ligation, embolization and chemoembolization. These new hepatic-directed modalities of treatment are being investigated and may offer new approaches to providing palliation and prolonging survival. This review reports the possibilities of intraarterial chemotherapy and other novel hepatic directed approaches to the treatment of liver metastases from this common disease.
BACKGROUND/AIMS: Hepatic and biliary toxicity are still significant problems after intraarterial hepatic chemoembolization for liver metastases from large bowel cancers. In about 30-60% of the patients hepatic and biliary toxicity are the limiting aspects of intraarterial hepatic chemoembolization and exclude a lot of patients from a repeated beneficial treatment. Amifostine (Ethyol) is a prodrug that must be dephosphorylated to the free thiol in which form it can detoxify free oxygen radicals generated by radiation, hypoxia and by drugs such anthracyclines, platinum analogues and alkylating agents. Amifostine as inactive prodrug is primarily metabolized at the tissue site by membrane alkaline phosphatase, which is highly active in the cell membranes of normal endothelial cells and biliary tree cells but not in the cell membranes and neovascular capillaries of tumor. When dephosphorylated to WR-1065, amifostine is rapidly taken up into normal liver cells by a carrier-mediated facilitated diffusion transport process. The resulting high thiol content in normal liver tissue (biliary cells and hepatocytes) compared with the negligible concentration in liver metastases from large bowel cancers probably provides for selective drug resistance to intraarterial hepatic chemoembolization protecting normal tissue and allowing full therapeutic effect on tumor. METHODOLOGY: From May 1997 we planned a phase I study in patients receiving intraarterial hepatic chemoembolization for liver metastases from large bowel cancers. We started at 200 mg/m2 dissolved in 250 cc of normal saline given in 15 min in the intrahepatic artery 20 min before an intraarterial hepatic chemoembolization consisting of mitomycin 10 mg/m2, epirubicin-50, cisplatin-60 diluted in 10 mL of contrast media, mixed in 15 mL of lipiodol UF followed by a gelfoam powder solution until stagnation of the flow. The escalating dose, every 3 patients, was: 200 mg/m2, 250 mg/m2, 300 mg/m2, 350 mg/m2. RESULTS: Toxicity has been observed at 350 mg/m2: 1 patient reported transient hypotension (Blood pressure 70/50 mm Hg), 1 patient had skin flushing and dyspnoea. 300 mg/m2 are well tolerated and seem to reduce the level of transaminases, lactic acid dehydrogenase, and gamma-glutamyl transferase. Also the duration of necrotic damage, always observed after intraarterial hepatic chemoembolization, seems shorter compared with historical controls. CONCLUSIONS: Amifostine can be certainly administered at 300 mg/m2 as intraarterial infusion and could be a significant step to ameliorate the therapeutic ratio of intraarterial hepatic chemoembolization.
BACKGROUND: Stop-flow perfusion (SFP) has been recently used to enhance the effects of chemotherapy in patients with locally advanced tumors. PATIENTS AND METHODS: Over a 2-year period we performed abdominal, pelvic and thoracic SFP in 12 patients with unresectable or metastatic tumors, using balloon catheters inserted into the abdominal aorta and inferior vena cava. Blood flow was occluded and hypoxic extracorporeal perfusion or SFP was performed for advanced diseases. The chemotherapeutic agents were directly administered into the aorta and/or inferior vena cava for thoracic SFP. The procedure was repeated in each patient, with one-month interval between sessions. Haemofiltration was also applied in two patients with generalized abdominal disease in order to reduce systemic toxicity. RESULTS: At post-operative CT or MRI follow-up, tumor shrinkage of more than 50% was observed in six patients, while post-SFP chemotherapy surgical resection of the tumors became feasible in four cases. The relief of pain, wherever present, was dramatic in the immediate post-operative period. Overall clinical improvement was achieved in all 12 patients. Post-operative recovery was uneventful in all but two patients, who developed minor systemic toxicity. CONCLUSION: SFP appears to be a safe technique with low morbidity which improves the quality of life of cancer patients and allows satisfactory control of locally advanced tumors and metastatic carcinomatosis.
BACKGROUND: Approximately 20% of patients with breast cancer present with locally advanced disease without distant metastases. This phase II double-center trial aimed at investigating the activity of epirubicin (Farmorubicin)--mitoxantrone (Onkotrone/Novantrone) combination as first-line intra-arterial chemotherapy (IAC) in locally advanced breast cancer patients. PATIENTS AND METHODS: Thirty-six patients with locally advanced disease and no prior exposure to anthracyclines received the following regimen: epirubicin (Farmorubicin) 30 mg/mq and mitoxantrone (Onkotrone/Novantrone) 10 mg/mq by IAC short infusion on day 1, every 3 weeks for up to six cycles. Prior to IAC an arteriogram of subclavian, internal mammary and lateral thoracic arteries was obtained in all patients, followed by infusion of a blue dye solution into the arteries to determine the most appropriate vessel that supplies the tumor area. RESULTS: Objective responses, confirmed at least 4 weeks after the first documentation, were observed in 25 patients (70%; 95%CI, 62% to 80%): 3 CR, 22 PR. Although three of the patients showed complete tumor regression, operative removal or toilet mastectomy became feasible in 25 patients since tumor shrinkage ranged over 75%. A total of 25 mastectomies were carried out for 36 patients. Four patients had bulky tumors (> 13 cm tumor diameter), while 8 patients had ulcerated tumors, two of which presented with complete infiltration of normal breast tissue. The median time to progression and median overall survival were 11 and 27 months, respectively. The time to local response was 3 weeks and time to mastectomy was 9 weeks. Transient neurological disorders developed in six patients and skin chemical burns with painful inflammatory reactions were encountered in ten patients. No systemic toxicity was observed in terms of bone marrow depression and hair loss. No cardiotoxicity was observed. In all specimens necrosis was reported (complete 3 cases, partial 16 and minimal 6). CONCLUSION: A combination of epirubicin (Farmorubicin) and mitoxantrone (Onkotrone/Novantrone) as IAC appears to be a safe and well tolerated treatment for locally advanced breast cancer without clinical evidence of distant metastases. When combined with surgery it offers interesting results in terms of local control and allows a high rate of mastectomies in otherwise inoperable cases.
From January to December 2004, 8 patients with pre-operative diagnosis of early gastric cancer (EGC) and no nodal involvement were submitted to sentinel node biopsy using the dual mapping procedure with endoscopic blue dye and 99mTc radio-colloid injection. All the patients underwent standard radical gastrectomy and D2 lymphadenectomy. The resected nodes were evaluated by routine (hematoxylin-eosin) histopathological examination; the sentinel (blue or hot) nodes in addition were evaluated with immunohistochemistry for cytokeratin. The preliminary results and perspectives for feasibility of sentinel node biopsy and its accuracy in predicting the nodal status in EGC are discussed.
New approach to peritoneal carcinomatosis combining cytoreductive surgery and hypertermic intraperitoneal chemotherapy suggest improved survival when it is possible to achieve a complete cytoreduction. In this study we consider the major complications related to this procedure and purpose our approach for their prevention and treatment.
New approach in treatment of peritoneal carcinomatosis combining cytoreductive surgery and intraperitoneal chemotherapy suggests improved survival when it is possible to achieve a complete cytoreduction. In this study we consider the carcinomatosis from colorectal and appendiceal adenocarcinoma. In all cases, patients in whom cytoreductive surgery was complete had a median survival much longer compared with patients in whom was not possible and, as perfusion works on minimal residual disease, peritonectomy is the only surgical technique that aim at total removal of parietal and visceral peritoneal lesions.
PURPOSE: The purpose of the study was to evalutate the feasibility of irinotecan drug-eluting beads (DC Bead) administered as trans-arterial chemoembolization (TACE) in patients with liver metastases from colorectal cancer (CRC). PATIENTS AND METHODS: Ten patients with liver metastases from CRC were treated with TACE adopting irinotecan-eluting beads at a dose of 100 mg every 3 weeks. Computed Tomography (CT) was performed 24h before and after TACE. RESULTS: TACE with irinotecan eluting beads was found to be feasible and well-tolerated. Right upper quadrant pain (RUQP) lasting 4 days (range 2-7) was reported by all the patients. After 30 days, a reduction >50% of CEA levels and of the lesional contrast enhancement was observed in all the patients. CONCLUSION: Irinotecan drug-eluting beads administered as TACE were shown to be active and safe in patients with liver metastases from CRC.