P53 and bcl-2 in colorectal cancer arising in patients under 40 years of age: distribution and prognostic relevance.

Young people (40 years of age) with colorectal cancer (CRC) represent a distinct subgroup with more aggressive disease behaviour compared to older patients. We evaluate whether p53 and bcl-2 could be useful in identifying young patients at higher risk of tumour progression. We reviewed 1340 CRC patients with 58 patients 40 years (4.2%). They had more frequent moderately or poorly differentiated mucinous adenocarcinomas (26% versus 12.3%, p=0.03); higher advanced stage at diagnosis; shorter 5-year overall survival (49.8% versus 71%; p=0.02); more frequent p53 positive (89.8% versus 72.6%, p<0.05) and bcl-2 negative (88.0% versus 66.2%, p<0.05) tumours; no difference in DNA content or proliferation indexes. Moreover, p53+ and bcl-2- resulted in being independent predictors of survival with shorter survival for the p53+/bcl-2- patients. Combining p53 and bcl-2, we could identify young CRC patients at higher risk of progression, who probably require development of a more sophisticated therapeutic approach based on identification of predictive factors.

Malignant glucagonoma. New options of treatment.

Few cases of malignant glucagonomas have been described in the literature. In this paper we present a case of a 77-year-old woman with necrolytic migratory erythema and high plasma glucagon and chromogranin A levels caused by a neuroendocrine tumour. An abdominal CT scan suggested a pancreatic lesion and two liver metastases. The patient underwent pancreatic debulking and liver metastasectomy. Histological and immunohistochemical investigations revealed a well differentiated neuroendocrine tumour with vascular invasion and scattered immunopositivity for somatostatin receptors. The patient was treated with octreotide (20 mg i.m. every 28 days) for three years without side effects. Three months after surgery symptoms of disease recurred accompanied by hyperglucagonaemia and newly diagnosed liver lesions. The patient was treated with octreotide (30 mg i.m. every 28 days) and interferon-alpha (6 MU s.cc 3 times per week) plus three cycles of hepatic chemoembolisation. Symptoms resolved after the first month of therapy, hormone levels decreased compared to untreated levels and metastatic growth slowed as observed by radiographic evidence. The patient is now asymptomatic with persistent hepatic disease and normal serum glucagon levels forty months after primary treatment. So far, only few immunohistochemical studies are reported on malignant glucagonoma and combined treatment schedules. We demonstrated, for the first time, a scattered immunopositivity for somatostatin receptors in a malignant glucagonoma. For this reason, the somatostatin analogs therapy was instituted. A combined antiproliferative medical treatment and the hepatic chemoembolization have been able to control tumor growth and disease symptoms for a long time after surgery.

Second- and third-generation aromatase inhibitors as first-line endocrine therapy in postmenopausal metastatic breast cancer patients: a pooled analysis of the randomised trials.

The purpose of this study was to estimate in all randomised trials the relative risk of overall response rate (ORR), clinical benefit (CB), time to progression (TTP), overall survival (OS), and toxicity of aromatase inhibitors (AI), compared with tamoxifen (Tam) as first-line endocrine therapy in postmenopausal metastatic breast cancer (PMBC) women. Prospective randomised studies were searched through computerised queries of MEDLINE, EMBASE, and the American Society of Clinical Oncology (ASCO) abstract database. Relative risk, 95% confidence interval, and heterogeneity were derived according to the inverse variance and Mantel-Haenszel method and Q statistics. Six phase III prospective randomised trials including 2787 women were gathered. A significant advantage in ORR (P = 0.042), TTP (P = 0.007), and CB (P = 0.001) in favour of AI over Tam was detected at the fixed effects model. These results were not significant at the random effects model, owing to the significant heterogeneity. On the contrary, no difference was registered for OS (P = 0.743) with no significant heterogeneity. Regarding toxicity, Tam caused more frequently thromboembolic events (P = 0.005) and vaginal bleeding (P = 0.001) compared with AI. Aromatase inhibitors appear to be superior to Tam as first-line endocrine option in PMBC women. Owing to a component of variability between the six studies analysed, the random effects estimates differed from corresponding fixed ones. Investigators should assess heterogeneity of trial results before deriving summary estimates of treatment effect.

Darbepoetin alfa for the treatment of anemic patients with low- and intermediate-1-risk myelodysplastic syndromes.

BACKGROUND: The hematological and quality of life (QoL) changes associated with darbepoetin alfa (DA) therapy were assessed in anemic patients with previously untreated low- and intermediate-1-risk myelodysplastic syndrome (MDS). PATIENTS AND METHODS: Fifty-three patients received DA administered subcutaneously once a week for 24 weeks. Treatment was initiated at 150 microg fixed dose and was doubled if after the first 12 weeks there was no or suboptimal erythroid response. RESULTS: The final response rate was 24/53 (45%), with 21 major and three minor responses. Most of the responses (21/24; 87.5%) were obtained at the dose of 150 microg. With a median follow-up of 9.4 months, 17 patients maintain their response. Treatment was well tolerated with no relevant side-effects. MDS progression was observed in one case. Increases in hemoglobin levels were positively correlated with improved QoL scores using both the linear analog scale assessment (energy level, r = 0.429, P = 0.036; daily activities, r = 0.653, P < 0.001; overall well-being, r = 0.457, P = 0.024) and the Functional Assessment of Cancer Therapy-Anemia questionnaire (r = 0.247, P = 0.025). In multivariate analysis, only low levels (<200 IU/l) of endogenous erythropoietin predicted response to DA therapy. CONCLUSIONS: DA is an active, safe and well tolerated treatment for anemia in a substantial proportion of patients with low- and intermediate-1-risk MDS, and has a positive impact on the patients' QoL.

Once-weekly dosing of recombinant human erythropoietin alpha in patients with myelodysplastic syndromes unresponsive to conventional dosing.

BACKGROUND: Once-weekly dosing of recombinant human erythropoietin (rhEPO) in patients with myelodysplastic syndromes (MDS) has not been investigated thoroughly. We performed a clinical trial to evaluate the effects of this new dosing regimen in patients with MDS who were unresponsive to the conventional three-times-weekly schedule. PATIENTS AND METHODS: Forty-eight patients with low- or intermediate-risk MDS were enrolled in a 12-week study. rhEPO alpha (rhEPOalpha) was administered once-weekly by subcutaneous injection with a starting dose of 40,000 U fixed dose. The drug dosage was increased to 60,000 U fixed dose if after 6 weeks there was no or suboptimal erythroid response. RESULTS: Clinically significant responses were seen in 13 (27%) patients, with 11 improving their response after dose escalation of rhEPOalpha. Only one patient (case 23) maintains a response after a follow-up period of 14 months. All other patients had responses lasting between 10 and 43 weeks, with a median time to relapse of 20 weeks. Treatment was well tolerated, with no relevant adverse events. Response to therapy was associated with significantly higher concentrations of circulating erythroid blast-forming units and a decrease of the bone marrow fraction of apoptic CD34+ cells. CONCLUSIONS: Once-weekly rhEPOalpha therapy results in an improvement of erythropoiesis in a subset of MDS patients who are unresponsive to conventional dosing, and may act by inhibiting apoptosis of erythroid precursors. These results warrant further investigation of this dosing regimen either alone or in combination with other agents.

Single-agent vinorelbine in pretreated breast cancer patients: comparison of two different schedules.

This retrospective study compared toxicity and activity of vinorelbine according to two schedules with different projected dose intensities in heavily pretreated breast cancer patients. Forty patients were assessable for toxicity and activity in each group; group A received vinorelbine 25 mg/m2 week + lenograstim (150 microg/m2 s.c. on day 3); group B received 25 mg/m2 on days 1 and 8 every 3 weeks. The projected dose intensity was 25 mg/m2/week and 16.6 mg/m2/week, and delivered dose intensity 95.2% and 94.5% in group A and B, respectively. Grade 3-4 afebrile neutropenia was recorded in 25% and 37.5% of patients in A and B, respectively. Overall response rate, 52.5% and 35%; no change, 35% and 40%; progression of disease, 12.5% and 25% in A and B, respectively. Median duration of the response was 10 months for group A and 7 months for B. Median time to progression: 9.0 months and 4.0 months for A and B, respectively. At a median follow-up of 45 months for group A and 19 months for group B, median overall survival was 19 months and 16, respectively. In conclusion the results of the study showed that dose intensity of vinorelbine could have an improvement in terms of time to progression in pretreated advanced breast cancer.

A randomized phase II study of combination, alternating and sequential regimens of doxorubicin and docetaxel as first-line chemotherapy for women with metastatic breast cancer.

BACKGROUND: This randomized phase II study was conducted to evaluate the efficacy of doxorubicin and docetaxel (DOC) administered either as a combination, an alternating or a sequential regimen in women with metastatic breast cancer. Secondary objectives included overall response, time to progression, survival and safety. PATIENTS AND METHODS: Patients with breast cancer (n=123) were randomized to receive doxorubicin and DOC either in combination (60 mg/m2 of each drug), or by alternated or sequential schedule (100 mg/m2 DOC and 75 mg/m2 doxorubicin) every 3 weeks for a maximum of eight cycles as first chemotherapy for stage IV disease. A second randomization allocated patients from each arm to receive prophylactic oral ciprofloxacin or no therapy to prevent febrile neutropenia. RESULTS: Patients received a median of eight cycles. In an intention-to-treat analysis, the overall response was 63%, 52% and 61% in the combination, alternating and sequential schedules, respectively. Corresponding rates of complete response were 15%, 14% and 11%. Grade 4 neutropenia was common in all arms (81%) and, together with febrile neutropenia, was significantly more frequent with the combination. Prophylaxis with ciprofloxacin did not reduce the incidence of febrile neutropenia or infection. Other frequent non-hematological adverse events included alopecia, nausea, vomiting, stomatitis and asthenia. Congestive heart failure only occurred in the combination arm (10%). CONCLUSION: All three schedules are feasible and endowed of good therapeutic activity. In view of the more pronounced toxicity and the risk of cardiac events because of the higher exposure to doxorubicin, the combination should be least favored when treating women with metastatic breast cancer. Prophylaxis with ciprofloxacin was ineffective and is not recommended.

A phase II study of irinotecan plus chronomodulated oxaliplatin, 5-fluorouracil and folinic acid in advanced colorectal cancer patients.

The combination of irinotecan (CPT-11), oxaliplatin (L-OHP), 5-fluorouracil (5-FU) and folinic acid (FA) is one of the possibilities to overcome chemoresistance in advanced colorectal cancer (ACRC) patients. The aim of this study was to determine the tolerability and activity of CPT-11 plus chronomodulated infusion of L-OHP, 5-FU and FA in ACRC patients. A total of 35 patients (91% pretreated, 77% with CPT-11, 54% with L-OHP, 42% with both) were treated every 3 weeks with CPT-11, 180 mg m(-2) day 1 i.v., plus L-OHP, 20 mg m(-2) day(-1), 5-FU, 700 mg m(-2) day(-1) and FA, 150 mg m(-2) day(-1), all three drugs from day 2 to day 5 by chronomodulated infusion. The patients' (pt) data were as follows: male/female 21/14; median age 58 years (range: 38-70); PS 0: 26 pts (74%), PS 1: 8 pts (23%), PS 2: 1 pt (3%); primary tumour colon/rectum 26/9; involved organs: 1, 14 pts (40%); 2, 17 pts (48%); >or=3: 4 pts (11%); previous chemotherapy lines 1: 12 pts (34%), 2: 10 pts (28%), >or=3: 10 pts (28%). A total of 221 courses (c) were performed; no grade 4 toxicity was observed with only one grade 3 (G3) neutropenia and thrombocytopenia (3%) in one out of 221 courses (<1%). Maximal toxicity (G3) was nausea and diarrhoea in 10 pts (28%), occurring in 14 out of 221 c (6%) and 12 out of 221 c (5%) respectively. Seven patients achieved a partial response (20%, confidence interval (c.i.) 6.8-33.3) and one patient a complete response (2.9%, c.i. 0-8.4), for a total overall response rate of 22.9% (c.i. 9-36.8); 15 out of 35 (42.9%, c.i. 26.5-59.3) had stable disease and 12 out of 35 (34.3%, c.i. 18.6-50) patients underwent a progression. In conclusion, this four-drug regimen is feasible in advanced pretreated ACRC patients with no significant haematological toxicity and acceptable diarrhoea. The activity of this combination is currently studied in EORTC 05011 study.

Circadian optimisation of irinotecan and oxaliplatin efficacy in mice with Glasgow osteosarcoma.

The relevance of circadian rhythms in irinotecan and oxaliplatin tolerability was investigated with regard to antitumour activity. Mice bearing Glasgow osteosarcoma (GOS) received single agent irinotecan (50 or 60 mg kg(-1) per day) or oxaliplatin (4 or 5.25 mg kg(-1) per day) at one of six dosing times expressed in hours after light onset (3, 7, 11, 15, 19 or 23 hours after light onset). Irinotecan (50 mg kg(-1) per day) and oxaliplatin (4 or 5.25 mg kg(-1) per day) were given 1 min apart at 7 or 15 hours after light onset, or at their respective times of best tolerability (7 hours after light onset for irinotecan and 15 hours after light onset for oxaliplatin) or worst tolerability (15 hours after light onset for irinotecan and 7 hours after light onset for oxaliplatin). Tumour growth rate was nearly halved and per cent increase in estimated life span (% ILS) was - doubled in the mice receiving irinotecan at 7 hours after light onset as compared to 15 hours after light onset (P<0.05). Results of similar magnitude were obtained with oxaliplatin for both endpoints, yet with 7 hours after light onset corresponding to least efficacy and 15 hours after light onset to best efficacy (P<0.05). Irinotecan addition to oxaliplatin proved therapeutic benefit only if the schedule consisted of irinotecan administration at 7 hours after light onset and oxaliplatin delivery at 15 hours after light onset, i.e. when both drugs were given near their respective "best" circadian times. These would correspond to the middle of the night for irinotecan and the middle of the day for oxaliplatin in humans.

Quality of life and chronotherapy.

The importance of evaluating patient's quality of life (QoL) in clinical practice and research is recognized clearly in oncology. In the advanced phase of disease such an evaluation represents an endpoint as important as survival. Quality of life is both a subjective and multidimensional concept evaluated mainly by validated questionnaires. In colorectal trials involving advanced stage disease the effects of different chemotherapy treatments on QoL were evaluated. Almost all the studies found no deterioration in QoL during chemotherapy. The European Organization for the Research and Treatment of Cancer (EORTC) Chronotherapy Study Group utilized three different approaches to assess QoL. The first centered on the stability of QoL during a 6mon treatment period in patients undergoing chronotherapy. The second centered on research of the biological and clinical determinants of QoL involving features of the circadian activity rhythm and patient survival and the relationship between QoL and patient performance status, response to therapy, and psychosocial variables as well as drug-induced toxicity. The third centered on the clinical effectiveness of psychological intervention on patients undergoing chronotherapy to improve psychosocial status during treatment. This papers reviews the results of EORTC Chronotherapy Group studies on QoL.

Single-agent oxaliplatin in pretreated advanced breast cancer patients: a phase II study.

PURPOSE: Oxaliplatin (L-OHP), a new platinum analogue, is an active drug in colorectal and ovarian cancer. In this phase II study we explored tolerability and activity of oxaliplatin as a single agent in metastatic breast carcinoma patients. PATIENTS AND METHODS: Fourteen anthracycline pretreated advanced breast cancer patients were enrolled. Oxaliplatin was given at 130 mg/m2 on day 1 and repeated every three weeks. Analysis of toxicity, response rate and survival was performed. RESULTS: The median number of courses per patient was four (range 2 6). The median administered dose-intensity was 43.3 mg/m2/week (range 32.5-43.3) which represents 100% of projected dose-intensity. No severe toxicity was encountered. Three patients developed acute transient laryngeal symptoms. Three patients displayed a partial response (21%), (95% confidence interval (CI): 0%-43%), two stable disease (14%) and nine progressed (64%). Response lasted five, four and five months respectively. Median survival was 12 months. CONCLUSIONS: In this limited experience, oxaliplatin appeared to be well tolerated and moderately active in advanced anthracycline-pretreated breast cancer patients. Combination chemotherapy with other active drugs such as 5-fluorouracil (5-FU), anthracyclines and taxanes should represent the next step of development of this new drug.

Irinotecan and chronomodulated infusion of 5-fluorouracil and folinic acid in the treatment of patients with advanced colorectal carcinoma: a phase I study.

BACKGROUND: Irinotecan (CPT-11) is an active drug in the treatment of patients with advanced colorectal carcinoma. The infusion of 5-fluorouracil (5-FU) according to circadian rhythms was used previously to decrease toxicity and to increase its therapeutic efficacy. The objective of this study was to establish the maximum tolerated dose (MTD) of CPT-11 together with a chronomodulated infusion of 5-FU and the l-form of folinic acid (FA). Secondary end points were the assessment of activity and quality of life (QoL). METHODS: Twenty-six patients with advanced colorectal carcinoma who had received previous treatment with 5-FU were entered on this Phase I study. At least three patients were recruited at each dose level. The CPT-11 starting dose was 175 mg/m(2) on Day 1 with an increase of 50 mg/m2 per dose level. A daily administration of chronomodulated 5-FU (900 mg/m2; peak delivery rate at 04:00) and FA (175 mg/m2; peak delivery rate at 04:00) for 5 days every 3 weeks was given with CPT-11. After the first three patients, the 5-FU dose was reduced to 700 mg/m2 per day due to toxicity. No intrapatient dose escalation was allowed. RESULTS: One hundred sixty-one courses were delivered. Dose-limiting toxicity was observed during the first course in seven patients (27%). Four patients developed neutropenia, with one patient reporting febrile neutropenia, two patients reporting severe stomatitis, and six patients reporting severe diarrhea. CPT-11 MTD was reached at 350 mg/m2 when a toxic death was observed with a recommended dose of 325 mg/m2. Six partial responses were observed (23%). The median duration of response and the progression free and overall survival rates were 199 days, 175 days, and 359 days, respectively. QoL was not affected by the treatment. CONCLUSIONS: The recommended dose for Phase II trials is 325 mg/m2 CPT-11 on Day 1, which is similar to the dose given as a single agent, together with a 5-day chronomodulated infusion of 700 mg/m2 5-FU and 175 mg/m2 FA. Intensification of this schedule every 2 weeks should be achievable.

Overcoming resistance to chronomodulated 5-fluorouracil and folinic acid by the addition of chronomodulated oxaliplatin in advanced colorectal cancer patients.

The addition of oxaliplatin (L-OHP) to a 5-fluorouracil (5-FU)/ leucovorin (FA) regimen was retrospectively evaluated in 35 consecutive advanced colorectal cancer patients after progression of disease. L-OHP, 25 mg/m2/day, was infused from 10.00-22.00 with a peak flow at 16.00 while 5-FU, 700 mg/m2/day and FA, 150 mg/m2/day of the I-form or 300 mg/m2/day of the racemic form, from 22.00 to 10.00 with a nocturnal peak at 4.00, for 5 days every 3 weeks in 24 patients and for 4 days every 2 weeks in the other 11. Diarrhea and sensitive neuropathy were the most relevant types of toxicity (17% of patients). An objective response was achieved in 8/35 patients (23%) [95% CL 9-37], stabilization in 15 patients (43%) which included five minor responses, and progression in 12. There was no relevant difference in quality of life assessed with the EORTC QLQ C30+3 questionnaire before and after treatment. Median duration of response and median progression-free survival were 6 months; median overall survival was 11 months. This retrospective study showed that it is possible to reverse resistance to chronomodulated 5-FU by adding chronomodulated L-OHP to the previous regimen; comparison with different schedules of this combination should be performed in order to identify the best tolerated and active regimen as second-line treatment of advanced colorectal cancer.

Weekly schedule of vinorelbine in pretreated breast cancer patients.

PURPOSE: In this phase II study, we explored tolerability and activity of vinorelbine administered according to a dose-dense weekly schedule with hematopoietic growth factor support in pretreated, advanced breast cancer patients. PATIENTS AND METHODS: From January 1994 to March 1996, 40 patients with metastatic breast cancer, pretreated with at least one prior anthracycline-containing regimen, were entered into the study. PATIENT CHARACTERISTICS: median age 53 years (range 32-70); ECOG performance status 0-1: 34 patients, 2: 6 patients; dominant visceral metastatic disease: 15 patients, dominant non-visceral: 25; anthracycline-refractory/resistant: 2 patients, sensitive: 38 patients. Six patients were treated as first-line therapy for metastatic disease and 34 in second- or subsequent lines. All patients received vinorelbine at the dose of 25 mg/m2/week as a short intravenous infusion, together with routine antiemetic medication. Granulocyte-colony stimulating factor (Lenograstim) at the dose of 150 microg/m2 subcutaneously on day 3 was included in the treatment schedule. RESULTS: The median number of treatment weeks was 23 (range: 4-24), with a delivered dose-intensity (DDI) of 23.8 mg/m2/week (range: 18.7-25, 95.2% of projected dose-intensity). Toxicity was mild, with non-complicated neutropenia being the main toxicity observed (grade 3-4 in 25% of the patients but only 2% of treatment weeks). Overall response rate was 52.5%, with complete responses in 12.5% of patients. Median duration of the response and median time to progression were 10 and 9 months, respectively. Median overall survival was 19 months. CONCLUSION: Dose-dense weekly vinorelbine is safe and effective with minimal toxicity in pretreated advanced breast cancer patients.