Phase I/II study of irinotecan, 5-fluorouracil,and <Emphasis Type="Italic">l</Emphasis>-leucovorin combination therapy (modified Saltz regimen) in patients with metastatic colorectal cancer

Background A combination of irinotecan 125mg/m², 5-fluorouracil (5-FU) 500mg/m², and leucovorin (LV) 20mg/m² (Saltz regimen; treatment on days 1, 8, 15, and 22 every 6 weeks) is widely used for the treatment of metastatic colorectal cancer. A modified schedule with chemotherapy on days 1 and 8 of a 21-day cycle was recommended in 2001 because of early treatment-related mortality. We conducted a phase I/II study of this modified Saltz regimen as first-line therapy in Japanese patients with metastatic colorectal cancer to assess the maximum tolerated dose (MTD) and the recommended dose of 5-FU when given with fixed doses of l-LV and irinotecan, and to evaluate the efficacy and the feasibility of this regimen.Methods Irinotecan, 5-FU, and l-LV were administered on days 1 and 8 of a 21-day cycle. Irinotecan 100mg/m² was given intravenously over the course of 90min on day 1, followed by l-LV 10mg/m², and then 5-FU. The dose of 5-FU was escalated from 400mg/m² (level 1) to 500mg/m² (level 2). If neither level met the criteria for the MTD, the recommended dose was defined as level 2, and dose escalation was discontinued, because the maximum approved weekly dose of irinotecan alone in Japan is 100mg/m² and the dose of 5-FU in the original Saltz regimen was 500mg/m².Results One patient had grade 4 neutropenia with fever at level 1, and four patients had grade 3 neutropenia at level 2. There was no treatment-related death. Level 2 did not meet the criteria for the MTD. The relative dose intensities of the first five cycles were 91% for both 5-FU and irinotecan at level 1 and 86% for 5-FU and 93% for irinotecan at level 2. The response rates were 58% for all patients, and 69% for patients at level 2.Conclusion Our results confirm that the modified Saltz regimen is safe and efficacious for Japanese patients. The recommended doses for phase II studies are irinotecan 100mg/m², 5-FU 500mg/m², and l-LV 10mg/m².     

Biweekly administration regimen of docetaxel combined with CPT-11 in patients with inoperable or recurrent gastric cancer

Background. Both docetaxel (TXT) and irinotecan (CPT-11) are active chemotherapeutic agents for gastric cancer. We designed a biweekly administration regimen of TXT combined with CPT-11 for 4 weeks as one cycle in patients with inoperable or recurrent gastric cancer, and conducted a dose-escalation study. Methods. Patients with histologically confirmed gastric cancer were treated with the regimen. The dosage levels of TXT and CPT-11 were as follows: level 1, 30mg/m² and 50mg/m²; level 2, 35 and 50mg/m²; level 3, 40 and 50mg/m²; level 4, 40 and 60mg/m²; and level 5, 50 and 60mg/m². The dose escalation was based on the dose-limiting toxicity (DLT) observed during the first cycle. Results. Grade 4 neutropenia was observed at level 3, but no other DLT was observed at less than level 4 during the first cycle. However, three patients at level 3 could not continue treatment without a decrease in the dosage after the second cycle. Based on these results, level 2 was considered to be the clinically recommended dosages. Conclusion. Biweekly TXT and CPT-11 was well tolerated. The recommended dosages of TXT and CPT-11 for a phase II trial are 35mg/m² and 50mg/m², respectively.     

Organochlorines, p53 mutations in relation to breast cancer risk and survival. A Danish cohort-nested case-controls study

Epidemiological studies integrating genetic susceptibility with biological measurements of organochlorine exposure may provide new clues regarding these substances influence on breast cancer etiology. Initial attempts pursuing this avenue has dealt with polymorphisms in the carcinogen-metabolizing enzymes cytochrome P450 (CYPlAl). This study examined if mutations in the tumor suppressor gene p53 affected organochlorine exposure related breast cancer risk and survival. The material consisted of 162 breast cancer cases and 316 matched controls, who had participated, in the Copenhagen City Heart Study (CCHS) between 1976 and 1978. Cases diagnosed between study initiation and 1993 were identified by linkage to the Danish Cancer Registry. The case group served as a cohort in the survival analyses. Information on known and suspected breast cancer risk factors was obtained from CCHS, and the Danish Breast Cancer Cooperative Group provided information on tumor characteristics. Lipid adjusted serum concentrations of selected organochlorines were compared between cases and controls while stratifing by p53 mutation status. A non-significant increased risk of breast cancer was observed in the highest exposure level of dieldrin and polychlorinated biphenyls among women who developed a tumor with mutant p53 (odds ratio (OR)=3.53, 95% confidence interval (CI)=0.79–15.79 and OR=3.00, 95% CI=0.66–13.62). There was no clear difference in overall survival between breast cancer cases with 'wild-type' and mutant p53, although a significant dose-response relationship appeared for dieldrin exposure in tumors with 'wild-type' p53. These preliminary results suggest that p53 mutations may have a modifying effect on at least the breast cancer risk associated with exposures to organochlorines.     

Phase I trial of combined chemotherapy with docetaxel, cisplatin, and 5-fluorouracil for patients with locally advanced squamous cell carcinoma of the head and neck

Background This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicities of combination chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (5-FU) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN).Methods Patients received two cycles of chemotherapy repeated every 4 weeks. Starting doses (dose level 0) were: docetaxel 60mg/m², cisplatin 60mg/m², and 5-day continuous infusion 5-FU 600mg/m² per day. At least three patients were examined at each dose level before advancing to the next level.Results Nineteen male patients (median age, 59.5 years) were enrolled. Eighteen patients had previously untreated stage III or IV SCCHN and 1 had local relapse, rT4. In the 19 patients, the regimen was well tolerated, with neutropenia as the most common toxicity (grade 3; n = 11; grade 4; n = 1). Dose-limiting toxicity (DLT) was observed at the fifth dose level (docetaxel 70mg/m², cisplatin 70mg/m², 5-FU 750mg/m² per day), when 1 patient developed grade 2 renal toxicity during the first course; another 2 patients had persistent neutropenia. These doses were thus deemed the MTD for the regimen. In the 18 assessable patients, the overall clinical response rate was 94% (17/18 patients) and primary-site complete response (CR) occurred in 4 (22%) patients.Conclusion The MTD of this regimen was docetaxel 70mg/m² on day 1, cisplatin 70mg/m² on day 4, and 5-FU 750mg/m² per day for 5 days. The regimen was safe and generally well-tolerated and demonstrated good efficacy in patients with locally advanced SCCHN.     

Phase II study of cisplatin and 5‐fluorouracil in previously treated metastatic breast cancer: an Eastern Cooperative Oncology Group study (PA 185)

Purpose: The present study was conducted to investigate the efficacy and toxicity of a cisplatin and 5fluorouracil (5FU) combination in previously treated advanced breast cancer.Methods: Thirtysix women with recurrent metastatic breast cancer were entered on a phase II study of 5FU 1000mg/m²/day given intravenously as a continuous infusion on days 1–3 and cisplatin 30mg/m²/day given intravenously over 1h on days 2–4, repeated every 21 days. All subjects had received one previous chemotherapy regimen for metastatic disease and either progressed during treatment or relapsed after responding to previous chemotherapy. Fourteen patients had also received previous adjuvant chemotherapy, 17 patients had previous radiation therapy, and 29 patients had previous hormonal therapy.Results: Among 32 responseevaluable patients, there were 10 partial remissions (31%) and 1 complete remission (3%), with an overall objective response rate of 34%. Median duration of response was 4 months. Median survival was 10.5 months for responders and 9.5 months for the entire group. Toxicity was mild to moderate in most patients. Overall twelve patients experienced grade 3 toxicity (10 hematologic, 1 mucositis, and 2 nausea). There were no grade 4 or 5 toxicities.Conclusion: Infusional cisplatin and 5FU is a well tolerated and active regimen in women with previously treated advanced breast cancer.     

Fotemustine Combined with Procarbazine in Recurrent Malignant Gliomas: A Phase I Study with Evaluation of Lymphocyte O6-alkylguanine–DNA Alkyltransferase Activity

The aims of this phase I study in patients with recurrent malignant gliomas were to determine the maximum tolerated dose (MTD) and toxicity profile of fotemustine when combined with a fixed dose of procarbazine (PCZ), and to evaluate the extent of O ⁶-alkylguanine–DNA alkyltransferase (ATase) depletion in circulating lymphocytes during treatment. Sixteen patients received an induction cycle consisting of 100mg/day oral PCZ for 12 consecutive days and a 1-h intravenous infusion of fotemustine given 4h after PCZ on days 5 and 12 at escalated doses (50, 75, 100 and 125mg/m²/day). After a 6-week rest period, a maximum of 4 maintenance cycles (PCZ 300mg/day, 4 days; fotemustine, day 4) was given every 4 weeks. ATase activity was measured on days 1, 5 and 12 over 4h after PCZ intake. Fifteen patients had previously received at least one nitrosourea-based chemotherapy, associated with PCZ in 12 cases. The MTD of fotemustine was 125mg/m² (days 5 and 12) with myelosuppression as the dose limiting toxicity (DLT). At this dose level, half of patients experienced grade 3 anemia, neutropenia or thrombopenia. No extra-hematological DLT was observed. No significant depletion of ATase activity by PCZ was evidenced. One partial response and 7 stable diseases were obtained leading to a disease control rate of 50%. The median times to progression and survival were 2.6 and 9.7 months, respectively. This combined regimen of PCZ and fotemustine was well tolerated with a good disease control rate in heavily pretreated glioma patients and merits further investigation in phase II studies.     

Inflammatory Breast Carcinoma: Pathological or Clinical Entity?

Inflammatory breast carcinoma (IBC) diagnosis is usually based in the presence of typical clinical symptoms (redness and edema in more than 2/3 of the breast), which are not always associated with pathologic characteristics (subdermal lymphatics involvement). Whether exclusively pathologic findings without clinical symptoms are sufficient for IBC diagnosis remains controversial. A retrospective analysis of 163 clinically diagnosed IBC (CIC) either with dermal lymphatics invasion or not, was compared with another group of 99 patients with dermal lymphatics invasion without clinical symptoms (occult inflammatory carcinoma) (OIC). The following clinical and pathological characteristics have been analyzed and compared: age, menopausal status, clinical axillar node involvement, symptoms duration before diagnosis, grade, estrogen receptors, presence of metastases at diagnosis, local recurrence, metastasic dissemination, disease-free (DFS) and overall survival (OS). Median age was younger in CIC (52.3 vs. 63.8 years; p<0.001). Symptom duration before diagnosis were significantly shorter in CIC (3.4 vs. 6.8 months; p<0.0001). Visceral (36.2% vs. 17.2%; p=0.001) and brain metastases (7.4% vs. 1%; p=0.02) was significantly more frequent in CIC. Negative estrogen receptors were more frequent in CIC (34.9% vs. 65.1%; p<0.004). Five-years DFS (25.6 vs. 51.6%; p<0.0001) and OS (28.6 vs. 40%; p<0.05) were shorter in CIC. CIC (regardless of subdermal lymphatics involvement) must be clearly differentiated from OIC. Prognosis of CIC patients is poorer, so this two entities should be clearly differentiated when therepeutic results are reported.     

A Critical Examination of the Results from the Harvard-MIT NCT Program Phase I Clinical Trial of Neutron Capture Therapy for Intracranial Disease

A phase I trial was designed to evaluate normal tissue tolerance to neutron capture therapy (NCT); tumor response was also followed as a secondary endpoint. Between July 1996 and May 1999, 24 subjects were entered into a phase I trial evaluating cranial NCT in subjects with primary or metastatic brain tumors. Two subjects were excluded due to a decline in their performance status and 22 subjects were irradiated at the MIT Nuclear Reactor Laboratory. The median age was 56 years (range 24–78). All subjects had a pathologically confirmed diagnosis of either glioblastoma (20) or melanoma (2) and a Karnofsky of 70 or higher. Neutron irradiation was delivered with a 15cm diameter epithermal beam. Treatment plans varied from 1 to 3 fields depending upon the size and location of the tumor. The ¹⁰B carrier, L-p-boronophenylalanine-fructose (BPA-f), was infused through a central venous catheter at doses of 250mgkg^–1 over 1h (10 subjects), 300mgkg^–1 over 1.5h (two subjects), or 350mgkg^–1 over 1.5–2h (10 subjects). The pharmacokinetic profile of ¹⁰B in blood was very reproducible and permitted a predictive model to be developed. Cranial NCT can be delivered at doses high enough to exhibit a clinical response with an acceptable level of toxicity. Acute toxicity was primarily associated with increased intracranial pressure; late pulmonary effects were seen in two subjects. Factors such as average brain dose, tumor volume, and skin, mucosa, and lung dose may have a greater impact on tolerance than peak dose alone. Two subjects exhibited a complete radiographic response and 13 of 17 evaluable subjects had a measurable reduction in enhanced tumor volume following NCT.     

Is salvage chemotherapy for metastatic breast cancer always effective and well tolerated? A phase II randomized trial of vinorelbine versus 5-fluorouracil plus leucovorin versus combination of mitoxantrone, 5-fluorouracil plus leucovorin

Metastatic breast cancer remains an incurable disease and the median overall survival has not significantly improved over the past two decades. Aims of the present randomized phase II trial were to analyse activity and toxicity of chemotherapies with single agent or with combination regimens in previously treated patients with advanced breast cancer. Ninety-nine eligible patients were randomized to receive the following chemotherapies: Arm A – 30mg/m² i.v. weekly; Arm B – leucovorin 100mg/m² i.v. followed by 5-fluorouracil 370mg/m² i.v. days 15, q 28days; Arm C – mitoxantrone 12mg/m² i.v. only day 1+leucovorin 100mg/m² i.v. followed by 5-fluorouracil 370mg/m² i.v. days 13, q 28days. Patients characteristics are comparable in the three groups. The median number of chemotherapy courses administered was 7, 6 and 5 in arm A, B and C, respectively. Objective responses were 24%, 30% and 21% and the median duration of responses were 2, 2.5 and 5.5 months in the arm A, B and C, respectively. Median overall survivals were 9.5, 9 and 9 months in the three arms. No difference was noted comparing the survivals of responding or non responding patients. General toxicity was not mild, with 27.5% of patients experiencing WHO grade 3–4 toxicities.Our results are similar in the three groups of patients and comparable to those reported by other authors. Chemotherapy applied to patients with second or subsequent recurrence allow objective responses in a small percentage of patients. Moreover responders have a negligible prolongation of survival.     

Irofulven Induces Apoptosis in Breast Cancer Cells Regardless of Caspase-3 Status*

Caspase-3 deficiency can limit the efficiency of pro-apoptotic anticancer treatments. Irofulven (hydroxymethylacylfulvene, HMAF, MGI 114, NSC 683863) is an antitumor drug, currently in a Phase III and multiple Phase II trials, which can differentiate between tumor and normal cells in apoptosis induction. This study investigated whether apoptosis induced by irofulven requires caspase-3. Irofulven action was compared in breast cancer cells differing in caspase-3 status: deficient MCF-7 cells and proficient MDA-MB-231 cells and in normal human mammary epithelial cells, HMEC. Irofulven induces significant, concentration and time-dependent apoptotic DNA fragmentation in breast cancer cell lines, regardless of caspase-3 status. After 12, 24 and 48h incubation at 1M irofulven ( 3×GI₅₀), fragmented DNA comprised 3.7, 14.1 and 34.6% and 8.4, 12.6 and 20.3% of total DNA in MCF-7 and MDA-MB-231 cells, respectively. Cell viability (trypan blue exclusion) remained largely unaffected during the first 24h but decreased markedly after 48h, indicating secondary necrosis. Net losses in cell numbers were apparent at 48h. Normal HMEC cells were refractory to 1M drug with only 3–9% fragmented DNA after 12–48h, although apoptosis was observed at drug levels >3M. The broad-spectrum caspase inhibitor Z-VAD-fmk inhibited irofulven-induced apoptosis of all cell lines at 20M with nearly complete abrogation of apoptosis at 100M. Irofulven treatment resulted in marginal caspase-3 processing in MDA-MB-231 and HMEC cells. These results indicate that whereas the caspase cascade mediates irofulven- induced apoptosis, caspase-3 is dispensable (supported by NIH CA70091 and CA78706).     

Phase II of doxorubicin/taxol in metastatic breast cancer

Purpose. To assess the response rate, survival, and toxicity of Taxol®(paclitaxel) as 1h infusion plus doxorubicin as firstline treatment for patients with metastatic breast cancer (MBC).Patients and methods. Seventysix patients with untreated MBC were recruited. All of them had measurable disease and were evaluable for toxicity. Fiftyfive percent of the patients had visceral involvement. The dose of doxorubicin was fixed at 50mg/m² as a short intravenous infusion, followed by 200mg/m² of Taxol as a 1h intravenous infusion. Doxorubicin was administered during the first seven cycles, continuing with Taxol only up to a maximum of ten cycles.Results. Neutropenia was the most important toxicity: 30% grade 3 and 18% grade 4. Only 2 patients showed a decrease in the left ventricular ejection fraction (LVEF) which caused discontinuing the treatment. No clinical congestive heart failure (CHF) was observed. Seventyfour patients were eligible for response evaluation: 10 (14%) achieved complete response (CR) and 46 (62%) achieved partial response (PR). The mean duration of response was 13.47± 1.35 months (95% confidence interval (CI): 10.82; 16.12) and the mean survival was 21.50± 1.42 months (95% CI: 18.72; 24.29).Conclusion. The overall response (OR) rate was 76%. No CHF was assessed and 2 patients stopped treatment due to LVEF decrease. Although doxorubicin 50mg/m² followed by Taxol 200mg/m² in 1h intravenous infusion presents a toxicity profile which demands a close followup, it represents a convenient outpatient schedule with similar activity rate compared to longer Taxol infusions.     

Combined Treatment Modality for Anaplastic Oligodendroglioma: A Phase II Study

Purpose: To investigate feasibility, toxicity and antitumor activity of combined surgery, postoperative radiation therapy (RT) and adjuvant chemotherapy (CHT) in adult patients with pure anaplastic oligodendroglioma (PAO) or mixed anaplastic oligoastrocytoma (MAO).Methods: Between January 1988, and June 1993, 23 patients entered into a phase II study. After surgery, post-operative RT was administered with 60Gy in 30 daily fractions in 30 treatment days in 6 weeks. Two weeks after RT, adjuvant modified PCV (mPCV) (Procarbazine, 60mg/m², days 1–14; CCNU, 100mg/m², day 1; and vincristine, 1.4mg/m² (max. 2mg), days 1 and 8) was administered every six weeks up to six cycles or until progression occurred.Results: Median survival time is not attained yet, while 1–5 year survival rates are 100%, 100%, 78%, 61%, and 52%, respectively. Median time to tumor progression is not attained yet, while 1–5 year progression-free survival rates are 100%, 100%, 70%, 52%, and 52%, respectively. On univariate analysis of potential prognostic factors, sex, tumor location (frontal versus other), and histology (pure versus mixed anaplastic oligodendroglioma) were not found to influence survival. Age of <50 years carried improved prognosis as well as Karnofsky performance status (KPS) 90–100 when compared to KPS of 70–80. Patients having tumors 4cm did better than those with tumors >4cm as well as those with total tumor resection when compared to those with subtotal tumor resection or biopsy only. Acute high-grade (3) CHT-related toxicity was mainly hematological with only 3 (13%) patients experiencing acute grade 4 toxicity.Conclusions: Combined treatment modality consisting of surgery, postoperative high-dose RT and mPCV chemotherapy for patients with anaplastic oligodendroglioma was effective with acceptable toxicity. Further studies are needed with more patients and longer follow-up to verify these results in this rare disease.     

Increased risk of second cancers following breast cancer: Role of the initial treatment

Objectives and methods.The risk of second primary malignancies (SMN) was studied in a cohort of 4,416 one-year survivors of a breast cancer. The role of the menopausal status and of the initial treatment modalities (surgery, radiotherapy, and chemotherapy) was investigated. Results.Excluding second primary breast cancer and non-melanoma skin cancer, a total of 193 (4.4%) patients developed a SMN between 1973 and 1992, compared with 136 expected (Standardised Incidence Ratio, SIR=1.4, 95% CI (1.2–1.6)). No trend towards either an increase or a decrease was noted in the SIR with time after treatment (p=0.2). The greatest increase in the relative risk concerned soft tissue cancers (SIR=13.0, 95% CI: 6.8–22.3), followed by leukaemia (SIR=3.1, 95% CI: 1.7–5.0), melanoma (SIR = 2.7, 95% CI: 1.4–4.8), kidney (SIR=2.5, 95% CI: 1.2–4.5), ovary (SIR=2.0, 95% CI: 1.2–3.1) and uterine tumours (SIR=1.9, 95% CI: 1.4–2.5). The SIR was 3.0 (95% CI 1.8–4.7) in women under 40 at the time of the breast cancer, 1.9 (95% CI : 1.4 – 2.4) in those aged 40–49 and 1.2 (95% CI 1.0–1.4) in those aged 50 or more. In the 2,514 women who had received radiotherapy as initial treatment without chemotherapy, the SIR for all SMN was 1.6 (95% CI: 1.1–2.3) fold higher than in those who had not received radiotherapy as initial treatment. Conclusion.In conclusion, this study confirms the increased risk of second malignancies in women treated for a breast cancer, and particularly in those who were younger at the time of treatment for breast cancer. Our results also suggest that radiotherapy may play a role in the onset of these second lesions.     

Treatment of advanced breast cancer with gemcitabine and vinorelbine plus human granulocyte colony‐stimulating factor

Purpose. A phase II trial was performed to investigate the efficacy and tolerance of gemcitabine, vinorelbine, and recombinant human granulocyte colonystimulating factor (GCSF) in advanced breast cancer. Patients and methods. Between April 96 and August 97, 60 patients entered this trial. Fortyfive patients were previously untreated and 15 patients had failed previous palliative chemotherapy with (n = 10) or without anthracyclines (n = 5). Therapy consisted of gemcitabine 1000mg/m² on days 1 + 15 + 21 and vinorelbine 40mg/m² on days 1 + 21, both diluted in 250ml saline and infused over 30min. GCSF was administered at 5g/kg/day subcutaneously from days 2–6 and 22–26. Courses were repeated every 5 weeks. Treatment was continued in case of response or stable disease until a total of six courses. Results. The overall response rate was 55.5% for patients who had not received prior palliative chemotherapy (95% confidence interval, 40%–70.3%), including 5 CR (11.1%) and 20 PR (44.4%) 12 patients (27%) had stable disease (SD), and 8 (18%) progressed. Secondline treatment with this regimen resulted in 6/15 (40%) objective remissions, 5 had SD, and 4 PD. The median time to progression was 9.5 months (range, 1.5–28) in previously untreated patients, and 7.0 months (range, 2–23) in those who had failed prior chemotherapy. After a median followup time of 15 months, 44 patients (73%) are still alive with metastatic disease. Myelosuppression was commonly observed, though WHO 3 and 4 neutropenia occured in only 9 (l5%) and 2 patients (3%), and was never complicated by septicaemia; grade 3 anemia was noted in 2 patients. Severe (WHO grade 3) nonhematologic toxicity was rarely observed, and included nausea/emesis in 3 and constipation in 2 patients. Conclusions. Our data suggest that gemcitabine and vinorelbine plus GCSF is an effective and tolerable first as well as secondline combination regimen for treatment of advanced breast cancer.     

Inflammatory Breast Cancer Survival: The Role of Obesity and Menopausal Status at Diagnosis

No previous studies have evaluated the effect of body size and menopausal status at diagnosis on survival from inflammatory breast cancer (IBC). We evaluated whether obesity and menopausal status had an impact on IBC survival in a cohort of 177 female IBC patients seen from 1974 to 1993 at The University of Texas MD Anderson Cancer Center. Survival time was defined as time from diagnosis until death or censorship at last date of contact. We categorized women by body size by using the National Institutes of Health/National Heart, Lung, and Blood Institute's definitions of obesity as body mass index ((BMI)=weight in kg/(height in m)²)30, overweight as 25BMI <30kg/m², and normal/lean as BMI <25kg/m². Cox proportional hazards analysis, adjusting for axillary lymph node involvement and chemotherapy protocol, revealed a modifying effect of menopausal status at diagnosis on the association between obesity and IBC survival (P=0.02). Relative to postmenopausal women, premenopausal women had significantly worse survival (hazard ratio (HR)=1.51, 95% confidence interval (CI)=1.03–2.22). After stratifying by menopausal status, premenopausal obese women had non-significantly better survival than their leaner premenopausal counterparts (HR=0.63, 95% CI=0.34–1.15) while postmenopausal obese women had significantly worse survival than their leaner counterparts (HR=1.86, 95% CI=1.02–3.40). These findings suggest that factors associated with larger body size at diagnosis may contribute to shorter IBC survival among postmenopausal women but not premenopausal women, who were found to have poorer survival regardless of body size.     

Tolerance of the Normal Canine Brain to Epithermal Neutron Irradiation in the Presence of p-boronophenylalanine

Twelve normal dogs underwent brain irradiation in a mixed-radiation, mainly epithermal neutron field at the Brookhaven Medical Research Reactor following intravenous infusion of 950mg of ¹⁰B-enriched BPA/kg as its fructose complex. The 5 × 10cm irradiation aperture was centered over the left hemisphere. For a subgroup of dogs reported previously, we now present more detailed analyses including dose–volume relationships, longer follow-ups, MRIs, and histopathological observations. Peak doses (delivered to 1cm³ of brain at the depth of maximum thermal neutron flux) ranged from 7.6Gy (photon-equivalent dose: 11.8Gy-Eq) to 11.6Gy (17.5Gy-Eq). The average dose to the brain ranged from 3.0Gy (4.5Gy-Eq) to 8.1Gy (11.9Gy-Eq) and to the left hemisphere, 6.6Gy (10.1Gy-Eq) to 10.0Gy (15.0Gy-Eq). Maximum tolerated threshold doses were 6.7Gy (9.8Gy-Eq) to the whole brain and 8.2Gy (12.3Gy-Eq) to one hemisphere. The threshold peak brain dose was 9.5Gy (14.3Gy-Eq). At doses below threshold, some dogs developed subclinical MRI changes. Above threshold, all dogs developed dose-dependent MRI changes, neurological deficits, and focal brain necrosis.     

Accuracy of mammography and echography versus clinical palpation in the assessment of response to primary chemotherapy in breast cancer patients with operable disease

The response to primary chemotherapy is an important prognostic factor in patients with non metastatic breast cancer. In this study we compared the assessment of response performed by clinical palpation to that performed by echography and mammography in 141 out of 157 consecutive breast cancer patients (T2-4, N0-1, M0) submitted to primary chemotherapy. A low relationship was recorded between tumor size assessed clinically and that evaluated by either mammography: Spearman R=0.38 or echography: R=0.24, while a greater correlation was found between the tumor dimension obtained by the two imaging techniques (R=0.62). According to the WHO criteria, the grade of response of breast cancer to primary chemotherapy, showed by mammography and echography, was less marked than the grade of response seen at clinical examination. Residual tumor size assessed clinically depicted a stronger correlation with pathological findings (R=0.68) than the residual disease assessed by echography (R=0.29) and mammography (R=0.33). Post-chemotherapy histology evaluation revealed pathological complete response in three cases (2.1%). Two of these cases were judged as complete responders by clinical palpation but only one was recognized by mammography, and none by echography. Clinical response, but not the response obtained by the two imaging techniques, was a significant predictor for longer disease free survival (p=0.04). To conclude, physical examination measurements remain the method of choice in evaluating preoperatively the disease response in trials of primary chemotherapy. Prediction of pathological outcome is not improved by echography and mammography.     

Weekly docetaxel for patients with platinum/paclitaxel/irinotecan-resistant relapsed ovarian cancer: a phase I study

Background This study was designed to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended dose (RD) of weekly docetaxel treatment in patients with relapsed ovarian cancer after the administration of platinum/paclitaxel/irinotecan.Methods Patients were enrolled on the basis of inclusion and exclusion criteria. Docetaxel was administered intravenously over a 60-min period on days 1, 8, and 15. Four dosage levels, 30, 35, 40, and 45mg/m², were employed, and the dosage was escalated from level 1 to level 4. DLT criteria were established, and the DLT was used as the criterion for deciding the MTD and RD.Results Twelve patients were enrolled. No grade 3/4 hematological toxicities were manifested at any dosage level. Grade 3/4 nonhematologic toxicities were manifested at level 4, consisting of fatigue/asthenia in 2 patients and neuropathy/sensory toxicity in 1 patient. Level 4 (45mg/m²) was thus judged to be the MTD, and the RD was concluded to be one level lower, i.e., level 3 (40mg/m²).Conclusions It was concluded that the RD for weekly docetaxel therapy is 40mg/m² per week in patients with relapsed ovarian cancer after the administration of platinum/paclitaxel/irinotecan.     

Prognostic significance of acute presentation with emergency complications of gastric cancer

Background Although acute complications necessitating emergency hospital admission are well documented in patients with carcinoma of the colon, comparable data for patients with gastric carcinoma is thin. The aim of this study, therefore, was to examine the outcomes of patients presenting to hospital as acute admissions with emergency complications of previously undiagnosed gastric cancer.Methods Three hundred consecutive patients with gastric adenocarcinoma were studied prospectively, and subdivided into two groups according to whether the patients were referred as acute emergencies (n = 116) or as outpatients (n = 184).Resuslts The commonest emergency complications were: abdominal pain (57%), vomiting (41%), gastrointestinal bleeding (37%), dysphagia (26%), and a palpable mass (18%). Stages of disease were significantly more advanced in patients presenting acutely (I:II:III:IV = 7:11:27:71) compared with patients referred via outpatients (20:23:50:91, ² = 3.955; DF, 1; P = 0.047). R0 gastrectomy was significantly less likely after acute presentation (23 patients; 20%) compared with patients referred via outpatients (70 patients; 38%; ² = 11.037; DF, 1; P = 0.001). Cumulative 5-year survival for patients referred acutely was 9%, compared with 22% after outpatient referral (² = 9.11; DF, 1; P = 0.0025). Multivariate analysis revealed two factors to be significantly and independently associated with durations of survival: stage of disease (hazard ratio [HR], 1.742; 95% confidence interval [CI], 1.493–2.034; P = 0.0001) and presentation with acute complications (HR, 1.561; 95% CI, 1.151–2.117; P = 0.004).Conclusion Emergency complications of gastric cancer are a significant and independent prognostic marker of poor outcome.Presented at: British Society of Gastroenterology, Birmingham 2003, and 5th International Gastric Cancer Congress, Rome 2003.     

Clinicopathological characteristics of breast carcinomas with allelic loss in the p73

p73, a new member of the p53 family, has been mapped to chromosome 1p36, a region where loss of heterozygosity (LOH) is frequently observed in primary human tumors. Allelic loss studies involving the 1parm in breast carcinomas offer rates ranging from 13% to 75%, depending on the genetic interval being studied. We investigated LOH in an intragenic microsatellite marker, and those centromerically flanking the p73 gene, at 1p36, and their correlations with patient age and 10 pathologic parameters in a series of 193 breast carcinomas. The LOH analysis was performed by amplifying DNA by PCR, using five markers of the 1p36 region (p73P1, D1S2694, D1S214, D1S2666 and D1S450). LOH was found in at least one of these markers in 27% of tumors. When we established the comparison between tumors with and without LOH and the distribution of the 10 pathologic parameters considered, we observed statistically significant differences in association with higher histologic grade (p=0.02), more advanced pathological stage (p=0.02), peritumoral vessel involvement (p=0.04) and poorly differentiated carcinomas (p=0.01), as well as in tumors that concomitantly exhibited lymph node metastases, peritumoral vessel involvement and absence of steroid receptors (p=0.02). These data suggest that LOH in the p73 region could be pathogenically related to breast cancer and possibly to a poor tumor prognosis.