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1.
Fam Cancer ; 10(1): 27-35, 2011 Mar.
Article in English | MEDLINE | ID: mdl-20717847

ABSTRACT

Single base substitutions can lead to missense mutations, silent mutations or intronic mutations, whose significance is uncertain. Aberrant splicing can occur due to mutations that disrupt or create canonical splice sites or splicing regulatory sequences. The assessment of their pathogenic role may be difficult, and is further complicated by the phenomenon of alternative splicing. We describe an HNPCC patient, with early-onset colorectal cancer and a strong family history of colorectal and breast tumors, who harbours a germ line MLH1 intronic variant (IVS9 c.790 +4A>T). The proband, together with 2 relatives affected by colorectal-cancer and 1 by breast cancer, have been investigated for microsatellite instability, immunohistochemical MMR protein staining, direct sequencing and Multiplex Ligation-dependent Probe Amplification. The effect of the intronic variant was analyzed both by splicing prediction software and by hybrid minigene splicing assay. In this family, we found a novel MLH1 germline intronic variant (IVS9 c.790 +4A>T) in intron 9, consisting of an A to T transversion, in position +4 of the splice donor site of MLH1. The mutation is associated with the lack of expression of the MLH1 protein and MSI in tumour tissues. Furthermore, our results suggest that this substitution leads to a complete skip of both exon 9 and 10 of the mutant allele. Our findings suggest that this intronic variant plays a pathogenic role.


Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Adenocarcinoma, Mucinous/genetics , Breast Neoplasms/genetics , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Introns/genetics , Mutation/genetics , Nuclear Proteins/genetics , Adaptor Proteins, Signal Transducing/metabolism , Adenocarcinoma, Mucinous/metabolism , Adenocarcinoma, Mucinous/pathology , Adult , Aged , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Colorectal Neoplasms, Hereditary Nonpolyposis/metabolism , Colorectal Neoplasms, Hereditary Nonpolyposis/pathology , DNA Mutational Analysis , DNA Primers/chemistry , DNA, Neoplasm/genetics , Female , Genotype , Humans , Immunoenzyme Techniques , Loss of Heterozygosity , Male , Microsatellite Instability , Middle Aged , MutL Protein Homolog 1 , Nuclear Proteins/metabolism , Pedigree , Polymerase Chain Reaction , Prognosis , Young Adult
2.
Curr Cancer Drug Targets ; 8(5): 359-66, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18690842

ABSTRACT

Gastrointestinal Stromal Tumors (GISTs) are the most common mesenchimal tumors of the gastrointestinal tract. Such tumors usually have activating mutations in either KIT (75-80%) or Platelet Derived Growth Factor Receptor alpha (PDGFRa) (5-10%) which lead to ligand-independent signal transduction. Targeting these activated proteins with Imatinib mesylate, a small-molecule kinase inhibitor, has proven useful in the treatment of recurrent or metastatic GISTs. However, more than half of patients develop resistance to Imatinib after about 2 years. Therefore, other targets have been studying in order to implement the therapeutical armamentarium for this disease. Sunitinib malate is an oral multikinase inhibitor that targets several receptor tyrosine kinases and has proved to prolong survival in Imatinib-resistant patients. Other molecules, such as Nilotinib, Sorafenib and Dasatinib were shown to be useful in Imatinib resistant mutant cell lines and the results of their activity in humans are being awaited. Recent evidence suggests that GIST cells acquire the capability to escape from the control of KIT and PDGFRa through the activation of alternative pathways. Therefore, further effort should be invested in the discovery of new signaling pathways, such as AXL, MET, IGF-R, which might be involved in the evolution of the disease. After a description of KIT and PDGFRa as known targets of anti-GIST treatments, we review other mechanisms and mediators that might be potential targets of new therapies, providing a comprehensive revision of the new molecular strategies under investigation.


Subject(s)
Antineoplastic Agents/therapeutic use , Gastrointestinal Stromal Tumors/drug therapy , Signal Transduction/drug effects , Gastrointestinal Stromal Tumors/genetics , Humans , Proto-Oncogene Proteins c-kit/chemistry , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/metabolism , Receptors, Platelet-Derived Growth Factor/antagonists & inhibitors , Receptors, Platelet-Derived Growth Factor/genetics , Receptors, Platelet-Derived Growth Factor/metabolism
3.
Ann Oncol ; 19(7): 1293-1298, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18372285

ABSTRACT

BACKGROUND: The expression of the insulin-like growth factor (IGF) system has never been studied in gastrointestinal stromal tumors (GISTs). PATIENTS AND METHODS: We studied the immunohistochemical expression of IGF1 receptor (IGFR-I), IGF1 and IGF2 in 94 samples of GISTs. IGF1 and IGF2 expression was scored in three classes: negative (N), moderate (M) and strong (S), according to staining intensity and extent. RESULTS: IGFR-I was overexpressed in all cases. IGF1 and IGF2 expression was absent in 25 and 48 cases, moderate in 29 and 16 cases and strong in 40 and 30 cases, respectively. Strong IGF1 expression significantly correlated with higher mitotic index (P = 0.0001), larger (P = 0.01), higher risk (P = 0.0002), metastatic (P = 0.0001) and relapsed (P = 0.04) GISTs. Strong IGF2 expression correlated with higher mitotic index (P = 0.05) and higher risk GISTs (P = 0.001). The Kaplan-Meier analysis (N versus M versus S) showed a significant worsening of the disease-free survival (DFS) with the increase of IGF1 (P = 0.02) and IGF2 (P = 0.02) expression. In the subgroup of patients with operated high-risk GISTs, there was a better trend in DFS for patients affected by GISTs with negative IGF1 and IGF2. CONCLUSIONS: The expression of IGF1 and IGF2 seems to predict relapse in GIST patients.


Subject(s)
Gastrointestinal Stromal Tumors/metabolism , Insulin-Like Growth Factor II/metabolism , Insulin-Like Growth Factor I/metabolism , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Fluorescent Antibody Technique , Gastrointestinal Stromal Tumors/genetics , Gastrointestinal Stromal Tumors/pathology , Gene Expression , Humans , Immunohistochemistry , Insulin-Like Growth Factor I/genetics , Insulin-Like Growth Factor II/genetics , Kaplan-Meier Estimate , Male , Middle Aged , Proto-Oncogene Proteins c-kit/metabolism , Receptor, IGF Type 1/metabolism , Recurrence , Tumor Burden
4.
Ann Oncol ; 19(4): 706-10, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18187489

ABSTRACT

BACKGROUND: The prognostic significance of KIT or platelet-derived growth factor receptor alpha (PDGFRalpha) mutations in gastrointestinal stromal tumors (GISTs) is still controversial. PATIENTS AND METHODS: In all, 104 patients were diagnosed with GISTs by KIT immunoreactivity; tumor DNA was sequenced for the presence of mutations in KIT exons 9, 11, 13 and 17 and in PDGFRalpha exons 12 and 18. Disease-free survival (DFS) was analyzed in 85 radically resected patients. RESULTS: KIT mutations occurred in exon 11 (69), in exon 9 (11) and in exon 17 (1). PDGFRalpha mutations were detected in exon 18 (10) and in exon 12 (3). Ten GISTs were wild type. Exon 11 mutations were as follows: deletions in 42 cases and point mutations in 20 cases and insertions and duplications, respectively, in 2 and 5 cases. A better trend in DFS was evident for duplicated and point-mutated exon 11 KIT GISTs. There was a significant association between PDGFRalpha mutations, gastric location and lower mitotic index. Moreover, PDGFRalpha-mutated GISTs seemed to have a better outcome. CONCLUSIONS: Point mutations and duplications in KIT exon 11 are associated with a better clinical trend in DFS. PDGFRalpha-mutated GISTs are preferentially localized in the stomach and seem to have a favorable clinical behavior.


Subject(s)
Gastrointestinal Stromal Tumors/genetics , Gene Duplication , Point Mutation , Proto-Oncogene Proteins c-kit/genetics , Receptor, Platelet-Derived Growth Factor alpha/genetics , Adult , Aged , Aged, 80 and over , Disease-Free Survival , Female , Gastrointestinal Stromal Tumors/mortality , Gastrointestinal Stromal Tumors/pathology , Humans , Male , Middle Aged , Mitotic Index
5.
Support Care Cancer ; 16(8): 869-77, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18224349

ABSTRACT

GOALS OF WORK: The way to inform cancer patients varies widely among different countries. In most Mediterranean countries, the traditional approach has been of partial disclosure of the truth. The intent of our work was to find if the attitude in Italy has changed in recent years and if differences still exist among different geographical regions in our country. Both patients' and physicians' attitudes vary in Italy depending on geographical area. In the South, the focus is on traditional values and full involvement of patients' family, with limited communication to (and limited autonomy of) the patient. Such attitude is less pronounced in Central Italy, whereas the North is more oriented to open communication and full decisional autonomy of the patient. MATERIALS AND METHODS: Approximately 600 consecutive patients in three different centres in Northern, Central and Southern Italy (respectively, Udine, Ancona and Catanzaro) were asked to answer a 26-item questionnaire on communication aspects to investigate the quality of the information given and potential differences between geographical areas. RESULTS: Questionnaires were completed by 587 patients (median age 60 years, 57% women), mainly with gastrointestinal (32%) or breast cancer (30%). About 370 patients (63%) had active disease at time of interview. A high proportion of patients were correctly informed on diagnosis (86%) and therapy (84%). On the contrary, patients fully aware of their prognosis were only about 43%. Nevertheless, most patients (60%) stated they were completely satisfied with the information received. There were differences between geographical areas on various information aspects, with patients from Southern Italy being, in general, less informed. CONCLUSIONS: In Italy, the cultural attitude towards communication in oncology is changing on both the physician and the patient side. There are still significant geographical differences, but there is a general trend suggesting improved awareness about diagnosis and treatment, with the notable exception of prognosis.


Subject(s)
Access to Information , Neoplasms , Patient Education as Topic , Cancer Care Facilities , Communication , Cultural Characteristics , Female , Humans , Italy , Male , Middle Aged , Patient Satisfaction , Physician-Patient Relations , Prognosis , Surveys and Questionnaires
6.
Clin Genet ; 71(2): 158-64, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17250665

ABSTRACT

Subjects affected by hereditary non-polyposis colorectal cancer exhibit a high susceptibility to colon and extracolonic tumours, due to MMR gene defects. Revised Bethesda criteria are used to select patients as candidates for genetic tests. Recently, the CRCAPRO model has been developed, based on family history of colorectal and endometrial cancers. Our study aims to evaluate the reliability of CRCAPRO in identifying mutation carriers. We used the CRCAPRO program to evaluate carrier probability risk in 99 patients fulfilling Amsterdam or Bethesda guidelines. MLH1 and MSH2 were studied by direct sequencing in all the 99 patients, and the study of microsatellite instability and of MMR proteins expression was performed. Nine MLH1 and nine MSH2 germline mutations were identified. Five out of the nine patients with MLH1 mutation showed a CRCAPRO risk evaluation of less than 20%. The same happened for four out of nine patients with MSH2 mutation. Of the 17 patients with an estimated risk of more than 80%, only four harboured a mutation, all in the MSH2 gene. The highest risk calculated by the CRCAPRO system in the nine carriers of a MLH1 mutation has been 31.7%. In our experience, the CRCAPRO program sensitivity and specificity appears to be low but needs to be further evaluated in larger samples.


Subject(s)
Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , Software , Adaptor Proteins, Signal Transducing , Adult , Aged , Carrier Proteins/genetics , Carrier Proteins/metabolism , Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis , Colorectal Neoplasms, Hereditary Nonpolyposis/metabolism , DNA Mismatch Repair , DNA Mutational Analysis , Diagnosis, Computer-Assisted , Female , Genetic Testing/statistics & numerical data , Humans , Male , Microsatellite Instability , Middle Aged , MutL Protein Homolog 1 , MutS Homolog 2 Protein/genetics , MutS Homolog 2 Protein/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism
7.
Int J Gynecol Cancer ; 16(3): 1419-23, 2006.
Article in English | MEDLINE | ID: mdl-16803540

ABSTRACT

Hereditary nonpolyposis colorectal cancer (HNPCC) is an inherited syndrome of cancer susceptibility caused by germ line mutations of genes participating in mismatch repair (MMR). Carriers of MMR gene mutations have an increased risk of colorectal cancers and cancer of other organs. Tumors of the endometrium represent the most frequent extracolonic malignancies in HNPCC. It has been suggested that women harboring MMR gene mutations have a higher risk of endometrial cancer than of colon cancer. Here, we describe an HNPCC patient with early-onset endometrial cancer and a strong familial history of endometrial tumors who harbored a germ line MSH2 splice site mutation (IVS9_2A>G). This mutation was responsible for abnormal messenger RNA processing, leading to the introduction of a premature stop signal and to the expression of a truncated MSH2 protein. In addition, the same mutation was associated with loss of MSH2 protein expression, high microsatellite instability, and PTEN inactivation. Although a direct relationship between the endometrial cancer susceptibility and the MSH2 mutation we found cannot be established, our observations, consistent with the work of other authors, suggest the involvement of germ line MSH2 abnormalities in endometrial tumor development and support the case for endometrial cancer screening in women from HNPCC families.


Subject(s)
Adenocarcinoma/genetics , Endometrial Neoplasms/genetics , MutS Homolog 2 Protein/genetics , Point Mutation , RNA Splice Sites/genetics , Adenocarcinoma/complications , Adenocarcinoma/metabolism , Adult , Base Sequence , Colorectal Neoplasms, Hereditary Nonpolyposis/complications , Colorectal Neoplasms, Hereditary Nonpolyposis/genetics , DNA Mutational Analysis/methods , Endometrial Neoplasms/complications , Endometrial Neoplasms/metabolism , Female , Genomic Instability , Humans , Immunohistochemistry , Molecular Sequence Data , MutS Homolog 2 Protein/metabolism , Pedigree , RNA Processing, Post-Transcriptional
9.
Br J Cancer ; 90(10): 1898-904, 2004 May 17.
Article in English | MEDLINE | ID: mdl-15138469

ABSTRACT

The aim of this study was to assess the activity and toxicity of a platinum-based treatment on a group of patients with unknown primary tumours (UPTs). Patients with a diagnosis of UPT underwent a standard diagnostic procedure. Treatment was started within 2 weeks from diagnosis and consisted of carboplatin 400 mg m(-2) day 1, doxorubicin 50 mg m(-2) day 1, etoposide 100 mg m(-2) days 1-3, every 21 days. Response was evaluated after three courses and treatment continued in case of objective response (OR) or symptom control. A total of 102 patients were eligible. The median age was 59 years, sex male/female 54/48, histology was mainly adenocarcinoma or poorly differentiated carcinoma. Nodes, bone, liver and lung were the most frequently involved sites. In all, 79 patients received at least three courses of treatment; 26 patients received six courses or more. Six complete responses and 21 partial responses were observed, for a total of 27 of 102 ORs or 26.5% (95% confidence interval 18.2-36.1%). The median survival was 9 months and median progression-free survival was 4 months. Toxicity was moderate to severe, with 57.8% of patients experiencing grade III-IV haematological toxicity, mainly leucopenia. The regimen employed has shown activity in tumours of unknown primary site, but was associated with significant toxicity. Such toxicity may be considered unjustified, given the large proportion of patients with tumours not likely to respond. Efforts should therefore be addressed to identify predictors of response to chemotherapy, thus limiting aggressive treatment to those patients who could benefit from it.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasms, Unknown Primary/drug therapy , Adult , Aged , Carboplatin/administration & dosage , Doxorubicin/administration & dosage , Etoposide/administration & dosage , Female , Humans , Infusions, Intravenous , Leukopenia/chemically induced , Male , Middle Aged , Treatment Outcome
10.
Oncology ; 65(3): 198-203, 2003.
Article in English | MEDLINE | ID: mdl-14657592

ABSTRACT

OBJECTIVES: The incidence of non-small cell lung cancer (NSCLC) is increasing among the elderly. We studied the toxicity and efficacy of a weekly schedule of gemcitabine and cisplatin in elderly patients with advanced NSCLC. METHODS: Patients aged 70 years or above with advanced NSCLC were treated in a phase II prospective trial with gemcitabine 1,000 mg/m(2) and cisplatin 35 mg/m(2) on days 1, 8 and 15 every 28 days. RESULTS: Forty-eight patients with a median age of 74 years (range 70-78) participated in the study. We observed 14 cases with partial response, 14 with stable disease and 16 with progressive disease, whilst 4 patients were not evaluable. By intention-to-treat analysis, partial response rate was 31.8% whilst progressive disease was 33.3%. Median survival was 9 months; 1-year survival probability was 34.4% and median time to progression was 4 months. Grade III-IV leukopenia was observed in 5/48 patients (10.4%), 20/48 patients (41.7%) had grade III-IV thrombocytopenia and 7/48 patients (14.6%) had grade III-IV anemia. One patient experienced grade III emesis and 2 patients had grade III-IV fatigue. CONCLUSIONS: At this dose and schedule the combination of gemcitabine and cisplatin appears to be an active and well-tolerated regimen for elderly patients with advanced NSCLC.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Deoxycytidine/analogs & derivatives , Lung Neoplasms/drug therapy , Adenocarcinoma/drug therapy , Adenocarcinoma/pathology , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Squamous Cell/drug therapy , Carcinoma, Squamous Cell/pathology , Cisplatin/administration & dosage , Deoxycytidine/administration & dosage , Dose-Response Relationship, Drug , Female , Humans , Lung Neoplasms/pathology , Male , Maximum Tolerated Dose , Neoplasm Staging , Prognosis , Prospective Studies , Treatment Outcome , Gemcitabine
11.
Cancer Invest ; 21(5): 701-7, 2003.
Article in English | MEDLINE | ID: mdl-14628428

ABSTRACT

Adjuvant 5-fluorouracil (5FU) and levamisole (Lev) have been considered standard treatment for stage III colon cancer patients. However, the uncertain contribution of Lev to the efficacy of treatment has led many oncologists to prefer the 5FU/leucovorin combination. To establish the role of Lev, we conducted a randomized trial comparing the 5FU/Lev combination with 5FU alone in patients with Dukes' C colon cancer. Patients with stage III colon cancer were randomized to receive 5FU alone (450 mg/m2 i.v. bolus daily for 5 days and then, beginning at day 28, weekly for 48 weeks) or the same plus Lev (50 mg orally three times/day for 3 days, repeated every 2 weeks for 1 year). From December 1994 to March 1998, 92 patients were assigned to receive 5FU/Lev, and 93 were assigned to receive 5FU alone. Leukopenia and hepatic toxicity were more frequent in patients receiving 5FU/Lev as compared with those receiving 5FU (respectively, p = 0.003 and p = 0.039), whereas other toxicities were equivalent and mild in both arms. After a median follow-up time of 48 months, 80 patients have had recurrences (40 in each arm) and no advantages in terms of disease-free survival and overall survival could be demonstrated for the combination arm. The addition of Lev to 5FU does not seem to be relevant for the clinical activity of this adjuvant regimen, whereas toxicity related to Lev should be considered when an adjuvant treatment for stage III colon cancer patients is proposed.


Subject(s)
Antimetabolites, Antineoplastic/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colonic Neoplasms/drug therapy , Fluorouracil/pharmacology , Administration, Oral , Adult , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/administration & dosage , Chemotherapy, Adjuvant , Colonic Neoplasms/pathology , Colonic Neoplasms/surgery , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Humans , Injections, Intravenous , Levamisole/administration & dosage , Levamisole/pharmacology , Male , Middle Aged , Treatment Outcome
12.
J Exp Clin Cancer Res ; 22(2): 329-32, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12866585

ABSTRACT

Mucocele-like (ML) lesions of the breast are rare tumours and were reported as benign lesions that histologically resembled colloid carcinoma of the breast when first described about sixteen years ago. Only subsequent reports identified ML lesions associated with ductal hyperplasia or carcinoma. The Authors report an additional case of ML tumour of the breast and review the available medical literature. A young asymptomatic woman, without family history of breast cancer, presented with a palpable breast mass. As the radiological aspect was not typical of a simple cyst, the patient underwent a fine needle aspiration biopsy which showed a doubtful pathological pattern compatible with fibroadenoma. The patient underwent surgery and the gross examination of the surgically removed mass revealed multiple aggregated cysts containing mucinous material. Microscopic examination showed a ML tumour of the breast, with aspects of cribriform ductal hyperplasia.


Subject(s)
Breast Neoplasms/pathology , Mucocele/pathology , Adolescent , Biopsy, Needle , Breast Neoplasms/diagnosis , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/surgery , Female , Humans , Hyperplasia , Mucins/metabolism , Mucocele/diagnosis , Mucocele/surgery , Ultrasonography, Mammary
13.
Eur J Cancer ; 39(8): 1144-9, 2003 May.
Article in English | MEDLINE | ID: mdl-12736115

ABSTRACT

Pre-clinical data suggest a relationship between DNA MisMatch Repair (MMR) system failure, particularly the inactivation of genes hMLH1 and hMSH2, and resistance to drugs like cisplatin and carboplatin. We studied the correlation between loss of hMLH1 expression in tumour cells and clinical outcome in 38 patients with ovarian cancer, who underwent cisplatin-based chemotherapy. 19 patients (56%) showed loss of hMLH1 expression (Group A) while 15 patients (44%) showed normal hMLH1 expression (Group B). 4 patients were not evaluable for hMLH1 expression. The 2 groups of patients were similar for clinical characteristics, response to chemotherapy and time to progression. Group A patients showed a median survival of 55 months whereas Group B patients had a median survival of 12 months (P=0.014). Loss of hMLH1 expression was the only independent predictor of survival in the multivariate analysis. Our observations suggest a relationship between loss of hMLH1 and improved survival in advanced ovarian cancer.


Subject(s)
Neoplasm Proteins/genetics , Ovarian Neoplasms/genetics , Adaptor Proteins, Signal Transducing , Adult , Aged , Antineoplastic Agents/therapeutic use , Carrier Proteins , Cisplatin/therapeutic use , Disease Progression , Drug Resistance, Neoplasm , Female , Gene Expression Regulation, Neoplastic , Humans , Middle Aged , MutL Protein Homolog 1 , Nuclear Proteins , Ovarian Neoplasms/drug therapy , Regression Analysis , Survival Analysis
14.
Tumori ; 87(4): 219-22, 2001.
Article in English | MEDLINE | ID: mdl-11693798

ABSTRACT

AIMS AND BACKGROUND: This trial evaluated the feasibility and tolerability of an immunochemotherapeutic approach that uses cisplatin, vindesine, and dacarbazine (DTIC), or only DTIC, in combination with interferon alpha-2a (IFN-alpha), in patients with metastatic melanoma, considering the significant toxicity of several different regimens used up to now. METHODS: Between May 1995 and September 1997, 51 melanoma patients (50 of whom were assessable) entered a multicentric trial and were randomized to receive cisplatin (30 mg/m2 daily for 3 days) + vindesine (2.5 mg/m2 only day 1) + DTIC (250 mg/m2 daily for 3 consecutive days) + IFN-alpha (3 MIU i.m. 3x/wk continuously) (CVD arm) versus DTIC (800 mg/m2 day 1) + IFN-alpha (3 MIU i.m. 3x/wk continuously) (DTIC arm). The chemotherapy was recycled every 21 days. Patient reevaluation was performed every two cycles, and the treatment was continued in case of objective response or stabilization of disease. RESULTS: We observed 3 complete responses, 2 partial responses and 5 stable diseases in the CVD arm, and 2 partial responses and 4 stabilizations of disease in the DTIC arm. CONCLUSIONS: We conclude that these chemotherapeutic regimens are well tolerated regimens with modest toxicity. Future trials will be conducted associating the CVD regimen with biological response modifiers (IFN, IL-2) in order to improve the results.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Interferon-alpha/therapeutic use , Melanoma/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cisplatin/administration & dosage , Combined Modality Therapy , Dacarbazine/administration & dosage , Feasibility Studies , Female , Humans , Immunotherapy , Interferon-alpha/adverse effects , Male , Melanoma/pathology , Melanoma/therapy , Middle Aged , Neoplasm Metastasis , Treatment Outcome , Vindesine/administration & dosage
16.
Minerva Med ; 91(3-4): 53-7, 2000.
Article in English | MEDLINE | ID: mdl-11037630

ABSTRACT

BACKGROUND: The frequency of advanced non-small cell lung cancer (NSCLC) increases with age and more effective and less toxic chemotherapy schedules are needed in elderly patients. Cisplatin-based regimens are considered the best treatment for advanced NSCLC, although they produce only a modest advantage in overall survival with considerable toxicity. METHODS: In the present study the activity and toxicity of a weekly gemcitabine and cisplatin schedule was evaluated in a small group of advanced NSCLC patients aged 68 years or more. Treatment consisted of gemcitabine 1000 mg/m2 i.v. and cisplatin 35 mg/m2 i.v., both given weekly on days 1, 8, 15 followed by 1 week of rest. RESULTS: Fifteen previously untreated patients entered the study; their median age was 72 years (range 68-76). One hundred and sixteen weekly administrations were delivered. The median dose-intensity was 614.5 mg/m2 per week for gemcitabine (82%) and 21 mg/m2 per week for cisplatin (80%). All the 15 patients were evaluable for response and toxicity. The overall response rate was 40% [95% CI = 16-68%]. The main toxicity was WHO grade III-IV thrombocytopenia that was recorded in 6 patients (40%). Other major toxicities were very low and no treatment-related deaths were reported. CONCLUSIONS: This schedule appears to be active, to have a favourable toxicity profile and can be considered in advanced NSCLC elderly patients. Of interest, the patients enrolled received high dose intensities of both drugs.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin/administration & dosage , Deoxycytidine/analogs & derivatives , Lung Neoplasms/drug therapy , Aged , Carcinoma, Non-Small-Cell Lung/mortality , Deoxycytidine/administration & dosage , Female , Humans , Lung Neoplasms/mortality , Male , Pilot Projects , Survival Rate , Gemcitabine
17.
J Exp Clin Cancer Res ; 19(1): 13-6, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10840930

ABSTRACT

We report the long-term results of a series of patients affected by advanced epithelial ovarian cancer treated with the PEC combination (cisplatin 60 mg/m2, epirubicin 60 mg/m2 and cyclophosphamide 750 mg/m2, all at day 1, every 21 days). Response was evaluated after three cycles, and treatment continued in responsive patients. A total of 80 patients with a median follow-up of 55 months were studied. Fifty-eight patients with stage III ovarian cancer and 22 patients with stage IV received PEC as primary treatment (41 patients), or for residual disease after surgery (37 patients), or for relapsed disease after primary surgery (2 patients). The overall response rate was 67.5% (20.0% complete response, 47.5% partial response), with 22.5% stable disease and 3.7% progressive disease. Median progression free survival was 13.0 months, and median survival was 25 months. Grade III-IV toxicity was moderate: leukopenia 20.0% of patients, thrombocytopenia 5.0%, anemia 16.2%. No cardiac toxicity was observed. In conclusion, the PEC combination, an anthracycline-containing platinum-based regimen, proved to be effective in advanced ovarian cancer, in terms of response rate and overall survival. The regimen was devoid of significant toxicity and in particular of cardiac toxicity.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Cisplatin/administration & dosage , Cyclophosphamide/administration & dosage , Epirubicin/administration & dosage , Ovarian Neoplasms/drug therapy , Adult , Aged , Combined Modality Therapy , Female , Humans , Middle Aged , Neoplasm, Residual/drug therapy , Ovarian Neoplasms/pathology , Ovarian Neoplasms/surgery , Recurrence , Retrospective Studies , Survival Analysis
18.
Cancer ; 89(12): 2630-6, 2000 Dec 15.
Article in English | MEDLINE | ID: mdl-11135225

ABSTRACT

BACKGROUND: In a previous study, the authors tested the combination of fotemustine (FM) 100 mg/m(2) intravenously (i.v.) on Day 1, dacarbazine (DTIC) 250 mg/m(2) i.v. on Days 2-5, and interferon alpha (IFNalpha) 3 MIU intramuscularly three times per week in 43 patients with advanced melanoma. An overall response rate of 40% and a median survival of 40 weeks were obtained. To evaluate whether the addition of cisplatin (CDDP) to this regimen could improve these results, the authors conducted a preliminary Phase I study and concluded that CDDP 25 mg/m(2) i.v. for 2 days can be combined safely with DTIC, FM, and IFNalpha. Herein, the authors report the results of a Phase II trial with this regimen. METHODS: From June 1996 to February 1999, 64 patients with metastatic melanoma who were not amenable to surgery were enrolled in this study. Sixty eligible patients (32 males and 28 females; median age, 53 years) were treated with a combination of FM 100 mg/m(2) i.v. on Day 1, DTIC 300 mg/m(2) i.v. on Days 2-4, and CDDP 25 mg/m(2) i.v. on Days 3 and 4 recycled every 3 weeks. IFN alpha2b was administered at a dose of 3 MIU intramuscularly 3 times per week until disease progression. RESULTS: A total of 189 courses were administered, with a median number of 3 courses per patient (range, 1-8 courses per patient). Eleven complete responses and 12 partial responses were observed, for an overall response rate of 38.3% (95% exact confidence interval, 26.1-51.8%). The median survival was 36 weeks. Neutropenia and thrombocytopenia affected 85% of patients and 68% patients and was World Health Organization Grade 3-4 in 40% and 50%, respectively. The side effects attributable to IFN alpha2b were mild and manageable. The other side effects were moderate and well controlled by supportive therapy. CONCLUSIONS: The schedule used in this study demonstrated significant activity in patients with advanced, untreated melanoma. The addition of CDDP in the management of the patients in this series seemed to increase significantly both the proportion of patients who achieved a complete response and the probability of long term survival compared with a previous series of patients who were treated by the authors. However, considering the currently available therapies, this regimen does not seem to offer a special advantage in the treatment of patients with this disease. New agents and new protocols are needed.


Subject(s)
Antigens, CD , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Melanoma/drug therapy , Membrane Glycoproteins , Neural Cell Adhesion Molecules , Adult , Aged , Anemia/chemically induced , Antigens, Neoplasm , Antigens, Surface/genetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , CD146 Antigen , Cisplatin/administration & dosage , Cisplatin/adverse effects , Dacarbazine/administration & dosage , Dacarbazine/adverse effects , Female , Fever/chemically induced , Follow-Up Studies , Humans , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , MART-1 Antigen , Male , Melanoma/genetics , Melanoma-Specific Antigens , Middle Aged , Monophenol Monooxygenase/genetics , Nausea/chemically induced , Neoplasm Proteins/genetics , Neutropenia/chemically induced , Nitrosourea Compounds/administration & dosage , Nitrosourea Compounds/adverse effects , Organophosphorus Compounds/administration & dosage , Organophosphorus Compounds/adverse effects , RNA, Messenger/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Survival Analysis , Thrombocytopenia/chemically induced , Treatment Outcome , Vomiting/chemically induced
19.
Br J Cancer ; 80(10): 1595-8, 1999 Jul.
Article in English | MEDLINE | ID: mdl-10408405

ABSTRACT

In a randomized clinical trial, gemcitabine (GEM) was more effective than 5-fluorouracil (5-FU) in advanced pancreatic cancer patients. GEM and 5-FU have different mechanisms of action and their combination, from a theoretical point of view, could result in a higher activity. To test activity and feasibility of such a combination, a multi-institutional phase II study was initiated in November 1996 by the Italian Group for the study of Digestive Tract Cancer (GISCAD). Primary objectives of this study were to determine the activity in terms of response rate and clinical benefit, while the secondary objective was toxicity. According to the optimal two-stage phase II design, 54 patients were enrolled. Schedule was: GEM 1000 mg m(-2) intravenous (i.v.), and 5-FU 600 mg m(-2) bolus i.v. weekly for 3 weeks out of every 4. All the 54 patients were symptomatic (pain, weight loss, dyspepsia). A clinical benefit was obtained in 28 patients (51%) (95% confidence interval (CI) 38-64%). Two patients achieved a partial response and 34 a stable disease. Median survival for all the patients was 7 months. Side-effects were mild: no gastrointestinal or haematological grade 3-4 toxicity (WHO) were recorded. We observed only six episodes of grade 2 (WHO) leukopenia and seven episodes of thrombocytopenia. Although the non-randomized design of this study suggests caution in the interpretation of these data, in consideration of the low incidence of toxicity and the favourable results obtained in terms of clinical benefit, it may be worthwhile to test more active schedules of 5-FU (continuous infusion) in combination with gemcitabine.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Pancreatic Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Female , Fluorouracil/administration & dosage , Humans , Male , Middle Aged , Treatment Outcome , Gemcitabine
20.
Ann Oncol ; 10(2): 217-21, 1999 Feb.
Article in English | MEDLINE | ID: mdl-10093692

ABSTRACT

BACKGROUND: The combination of gemcitabine and cisplatin has proven effective in the treatment of advanced non-small-cell lung cancer (NSCLC). However, the optimal schedule for administration of the two drugs has not yet been determined. In this study we evaluated the activity and toxicity of a weekly gemcitabine and cisplatin schedule. PATIENTS AND METHODS: Thirty-six untreated patients with stage IIIB IV NSCLC entered the study. Treatment consisted of gemcitabine 1000 mg/m2 i.v. and cisplatin 35 mg/m2 i.v., both given weekly on day 1,8, and 15, followed by one week of rest. RESULTS: Ninety-seven courses (273 weekly administrations) were delivered. The median dose-intensity was 612 mg/m2 per week for gemcitabine (82%) and 21 mg/m2 per week for cisplatin (80%). All 36 of the patients were evaluable for toxicity, and 30 for response. Partial remissions were observed in 12 patients, for an overall response rate of 40% (95% confidence interval (95% CI): 22.5%-57.5%). Most of the partial remissions were seen in IIIB patients (54% of the stage IIIB and 22% of the stage IV patients responded). According to the intent-to-treat principle, the response rate was 33.3% (12 of 36 patients). The median response duration was 9.9 months (range 4-23) and the median survival time 11.8 months (range 1-24). World Health Organization (WHO) grade 3-4 myelotoxicity was: thrombocytopenia in nine patients (25%), neutropenia in six (16.6%) and anemia in six (16.6%); there was very little additional major toxicity. CONCLUSIONS: This regimen appears to be active and to have a favourable toxicity profile.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Cisplatin/administration & dosage , Deoxycytidine/analogs & derivatives , Lung Neoplasms/drug therapy , Adult , Aged , Carcinoma, Non-Small-Cell Lung/mortality , Cisplatin/adverse effects , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Female , Humans , Lung Neoplasms/mortality , Male , Middle Aged , Gemcitabine
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