Bone marrow and sentinel lymph node biopsy in patients with breast cancer: from staging to ultrastaging?

Bone marrow (BM) biopsy has been suggested as an independent prognostic tool to improve staging in patients with breast cancer. Two hundred and ten consecutive patients operated for breast cancer from June 2000 to June 2005 who signed an informed consent were enrolled in this protocol. Patients underwent SLN biopsy, and lymph nodes were analysed with serial sections and stained with hematossilin-eosin and immunohistochemistry. At the end of the procedure a BM aspirate from the iliac crest was obtained and 5-10 cc of blood collected. A CEA specific nested reverse transcriptase (RT) polymerase chain reaction (PCR) assay was used to examine BM samples. Results were blinded to both patients and clinicians. The median age of the patients was 56 years (range 34-80), and the median tumor diameter 1,5 cm (range 0.2-4.5). BM aspirates were unsuccessful in ten patients, and RT-PCR was not technically feasible in seventeen women, leaving 183 patients available for analysis of results and follow up. SLN biopsy allowed diagnoses of occult metastases (micrometastases and isolated tumor cells) in 16% of patients (29/183). 25% of T1N0 patients (23/92), 35% of T2N0 patients (6/17), and 44% of N1-2 patients (32/72) were BM+ (p = 0.03). At a median follow up of 35 months 5/122 in the BM- group and 6/61 in the BM+ group have relapsed (p = 0.2), while 1/122 and 4/61 have died of disease (p = 0.04) In conclusion, ultrastaging of breast cancer patients may identify a substantial subgroup of patients N-/BM- who may not require adjuvant chemotherapy, as well as a subgroup N-/BM+ with a decreased survival who may need more aggressive therapies. Further follow-up is needed to confirm this hypothesis, and several studies are under way.

[Towards the standardization of sentinel lymph node analysis in women with breast cancer]. / Verso una standardizzazione dell'analisi del linfonodo sentinella in donne con cancro della mammella.

Sentinel lymph node biopsy allows enhanced pathology through serial sections and immunohistochemical analysis of the retrieved node, with detection of micrometastases and isolated tumor cells not otherwise recognized. We present our experience with a simple, effective, pathology protocol requiring six couples of sections at three different sentinel lymph node levels. Additional micrometastases or ITC were diagnosed in 51/416 patients (14.6%).

[Does incidence of sentinel lymph node metastasis increase after diagnostic manipulation in women with breast cancer?]. / Aumenta l'incidenza di metastasi nel linfonodo sentinella dopo manipolazione diagnostica in donne con cancro della mammella?

503 patients were retrospectively evaluated to assess whether a previous needle or core biopsy, or surgical surgical excision of the primary tumor are associated with passive dislodgment of tumor cells in the sentinel lymph node, as reported in recent publications. We could not identify any increased incidence of sentinel lymph node micrometastases or isolated tumor cells after diagnostic manipulation of the primary tumor.

[Extemporaneous examination of the sentinel lymph node in breast cancer: is the glass half full or half empty?]. / L'esame estemporaneo del linfonodo sentinella nel cancro della mammella: il bicchiere è mezzo pieno o mezzo vuoto?

Intra-operative examination of sentinel LN is controversial. Concordance with definitive exam of SLN in this series was 81%, though only 54% of positive cases were diagnosed. Micrometastases and ITC were usually lost intraoperatively, accounting for 14% of cases. Frozen section and touch prep of the SLN were approximately equivalent. The latter has the advantage of preserving tissue for step-analysis of SLN. The ultimate method of intraoperative analysis of SLN which can combine cost-effectiveness and accuracy needs to be determined.

Combined 5-fluorouracil infusion with fractionated epirubicin and cyclophosphamide in advanced breast cancer.

5-Fluorouracil (5-FU) given by continuous infusion (c.i.) allows higher dose delivery, causes less myelosuppression, and may interfere with repair of DNA damage caused by epirubicin and cyclophosphamide. With this rationale, we conducted a phase II study to test the activity and toxicity of 5-FU c.i., epirubicin, and cyclophosphamide in patients with metastatic breast cancer (MBC). Twenty-eight patients with MBC were entered in the trial. 5-FU (200 mg/m(2)) was administered by c.i. from day 1 to day 20. Epirubicin (35 mg/m(2)) and cyclophosphamide (400 mg/m(2)) were administered from day 2 to day 4, every 4 weeks. All patients were evaluable for response and toxicity. A total of 125 courses of chemotherapy were administered, with a median of 4 per patient (range: 2--6). Toxicity, assessed using World Health Organization criteria, was as follows: nausea and vomiting grade III--IV occurred in 36%, alopecia (grade III) in 86%, neutropenia (grade III--IV) in 50%, and cardiac toxicity grade I--II in 11% of patients. Five patients (17.9%) had a complete response to therapy, and 16 (57.1%) had a partial response (response rate 75%, 95% CI 55--89%). Disease stability and progression occurred in 4 (14.3%) and 3 (10.7%) patients, respectively. Median time to progression was 13.1 months (range: 3.4--66.9+), and median survival time was 27.7 months (range: 5.4--67.1+). Outpatient treatment with combined 5-FU c.i., epirubicin, and cyclophosphamide shows high activity in advanced breast cancer and gives prolonged remission with acceptable toxicity.

Phase II study of epirubicin, mitomycin C, and 5-fluorouracil in hormone-refractory prostatic carcinoma.

Management of metastatic prostatic carcinoma when it becomes refractory to hormonal therapy is controversial, and no standard treatment exists. Nevertheless, chemotherapy for hormone-refractory prostatic carcinoma (HRPC) has shown some advantages compared with the best supportive care. In a prospective phase II study, we evaluated the combination of epirubicin (E), mitomycin C (MMC), and 5-fluorouracil (5-FU) in patients with HRPC. Twenty-eight patients with HRPC were treated with a combination of E (30 mg/m2), 5-FU (750 mg/m2), and MMC (5 mg/m2) day 1 and 2, every 4 weeks. Treatment was continued until evidence of disease progression or excessive toxicity. Patients were monitored with serial measurements of prostate-specific antigen (PSA). Forty-seven percent of the patients exhibited a reduction of serum PSA concentration and an objective response; 38% exhibited disease stability, and 15% had disease progression. Toxicity was substantial. The median time to progression was 7.3 months (range, 1.7-16.8 months) and median survival was 14.5 months (range, 1.6-38.4 months). Performance status improved in 80% of patients, and bone pain was relieved in 70%. Thus the combination of E, MMC, and 5-FU shows activity in the treatment of HRPC, giving substantial palliation of symptoms. In one patient, PSA values remained low even when the tumor had progressed.

Cisplatin, vindesine, mitomycin-C and 13-cis retinoic acid in the treatment of advanced non small cell lung cancer. A phase II pilot study.

BACKGROUND: Thirteen-cis retinoic acid (RA) has been shown to have growth-inhibitory and differentiative activity on non-small cell lung cancer (NSCLC) cells in vitro. This promoted the rationale for combining RA with three active drugs, cisplatin (CDDP) vindesine (VDS) and mitomycin-c (MMC) in the treatment of advanced NSCLC. PATIENTS AND METHODS: Patients with a histologically confirmed non-resectable NSCLC, measurable lesion, performance status < or = 3, and informed consent were enrolled. The chemotherapy schedule included cisplatin 60 mg/m2 and mitomycin-c 10 mg/m2 day 1 and vindesine 3 mg/m2 on days 1 and 5, every 4 weeks. RA was administered orally, at a dose of 0.5 mg/kg, 5 days per week, during chemotherapeutic intervals and to responding patients until disease progression was observed. RESULTS: Thirty patients, receiving a total of 163 chemotherapy courses, were evaluated for response and toxicity. Objective responses included complete response in 2 patients (7%), partial response in 10 patients (33%), stable disease in 9 patients (30%) and progressive disease in 9 patients (30%), (response rate 40%: Confidence interval 95% 22.7% to 59.4%). Median time to progression was 8.6 months (range 3.9-45+). Median overall survival was 11.3 months (range 1-45+). The 1-year survival rate was 47%. Toxicity (WHO) included nausea and vomiting grade 2 in 6 patients, transient ileus in 3 patients and grade 3-4 leukopenia in 5 patients. Two patients underwent surgical resection of residual disease and remain in CR. CONCLUSIONS: The addition of RA to cisplatin, vindesine and mitomycin-c is feasible and shows some activity in the treatment of NSCLC, with manageable toxicity.

Carboplatin, vindesine, 5-fluorouracil-leucovorin and 13-cis retinoic acid in the treatment of advanced non-small cell lung cancer. A phase II study.

PURPOSE: Carboplatin, vindesine and 5-fluorouracil/leucovorin are drugs active in the treatment of non-small cell lung cancer (NSCLC) and they can be administered in an outpatient setting. Retinoids, which are widely used agents in chemoprevention, have been reported to exert (in vitro models) growth inhibitory effects of synergistic type with chemotherapy, and differentiating effects on NSCLC cells. PATIENTS AND METHODS: 28 patients with advanced NSCLC with measurable disease were entered into the trial. Eligibility criteria included performance status < or = 3 and adequate renal and liver function. Patients with brain metastases were not excluded. Treatment was as follows: Carboplatin (CBCDA) 300 mg/m2 day 1, Vindesine (VDS) 3 mg/m2 days 1 and 5, leucovorin (L) 100 mg/m2, 5-fluorouracil (5-FU) 370 mg/m2 for 5 days and 13-cis retinoic acid (R) 1 mg/kg, administered between chemotherapy courses. After 6 courses of chemotherapy responders were maintained with R, until progression. RESULTS: 120 courses of chemotherapy have been delivered (median 4 courses per patient, range 1 to 6). All patients were evaluable for response and toxicity. Objective responses: 2 complete responses (CR) (7%), 9 partial responses (PR) (32%), 9 stable disease (SD) (32%), 8 progressive disease (PD) (29%). (Response rate 39%, 95% CI: 22% to 60%). Median time to progression was 7.7 months (range 3.4-22) and median survival was 9.7 months (range 0.5-27) with 40% of patients alive after one year. Toxicity WHO: hematological grade 3-4 in 46% of patients, grade 2 diarrhea in 21% of patients, ileus in 14% of patients, Neurologic grade 2 in 11% of patients. CONCLUSIONS: The addition of RA to CBDCA, VDS, FU, L, R represents an effective treatment in NSCLC, with manageable toxicity.

Chemo-immunotherapy in advanced head and neck cancer.

BACKGROUND: Patients with advanced squamous cell carcinoma of the head and neck (SCC) have a depressed immune system whose function is worsened by chemotherapy. In a pilot phase II study, in order to improve the immune function during chemotherapy, we combined to cisplatin (CDDP) and 5-fluorouracil (5-FU) two biological response modifiers, retinyl palmitate (R) and Thymopentin (TP-5) for the treatment of SCC. PATIENTS AND METHODS: Fifty patients with recurrent or metastatic SCC of the head and neck were treated with Cisplatin 24 mg/m2 from day 1 to 5 and 5-FU 1,000 mg/m2 by a 120 hour continuous infusion. Retinyl palmitate was administered orally 50,000 i.u. b.i.d and Thymopentin 50 mg subcutaneously 3 times a week. RESULTS: Chemotherapy treatment was well tolerated with G3 hematological toxicity in 30% of patients and G2 gastrointestinal toxicity in 20% of patients. 16 patients (32%) had a complete response (CR), 13 patients had partial response (PR) (26%), (response rate 58%, 95% c.i. 43%-72%); stable disease (SD) was observed in 7 patients (14%), while 14 patients progressed (PD) (28%). Median time to progression was 12 months (range 2.8-94.5). Median overall survival was 13.5 months (range 2-104). CONCLUSIONS: The association of CDDP and 5-FU with Retinyl Palmitate and TP5 has a major activity in the treatment of advanced head and neck cancer and a relatively well tolerated toxicity.

Ifosfamide, vinorelbine and gemcitabine in advanced non-small cell lung cancer. A phase I study.

The objective of this phase I study was to identify the maximum tolerated dose (MTD) and toxicity of a three drug, platinum-free regimen, including gemcitabine, ifosfamide and vinorelbine, in the treatment of patients with advanced non-small cell lung cancer (NSCLC). 33 chemotherapy-naïve patients with histologically confirmed, unresectable NSCLC, received fixed doses of ifosfamide (1500 mg/m2 days 1-3 with mesna) and vinorelbine (25 mg/m2 days 3 and 8). The gemcitabine dose was escalated from 500 to 1200 mg/m2 on days 3 and 8 every third week. The escalation was stopped at dose level 4 (gemcitabine 1200 mg/m2) since all 3 patients of this cohort showed dose-limiting thrombocytopenia and/or neutropenia at treatment cycle 1. The dose recommended for phase II trials is: gemcitabine 1000 mg/m2 and vinorelbine 25 mg/m2 given on days 3 and 8 plus ifosfamide 1500 mg/m2 on days 1-3. An encouraging response rate of 50% (95% confidence interval (CI): 32-68%) was observed in 32 patients evaluated. Our results show that ifosfamide, vinorelbine and gemcitabine can be safely administered as outpatient chemotherapy for NSCLC. Myelosuppression is the dose-limiting toxicity (DLT) of this regimen with no major subjective side-effects observed.

[Importance of a multidisciplinary approach to metastatic cancer of the rectum]. / Intérêt d'une approache multidisciplinaire des cancers du rectum initialement métastatiques.

Management of rectal cancers with synchronous metastasis is difficult. We evaluated in 23 patients a combination of pelvic radiotherapy at the dose of 45 Gy in 5 weeks and 25 fractions with chemotherapy by 5-fluorouracil (350 mg/m2/day) and folinic acid (20 mg/m2/day) for 5 days at the time of the first and the fifth week of the irradiation. Surgery was indicated firstly in cases of stricture or secondarily for resection of the primary location and, when possible, of the metastasis. General state of health of the patients improved in 35%, symptomatology in 86% and comfort in 72% of the cases. Response rates for the primary tumor were 41% of partial response and 50% of stable disease. For the metastatic lesions, they were 9% and 59% respectively. Sixty-one per cent of patients were secondarily operated with resection of the primary tumor in 12 cases and of hepatic metastases in 2 cases. The median survival and the median survival without progression were respectively 13 and 9 months. Radiochemotherapy combination as the first treatment was beneficial in 4/5 of the patients presenting a rectal cancer with synchronous metastasis and allowed us to select those that would secondarily benefit from a surgical resection.

Beta-interferon, retinoids and tamoxifen as maintenance therapy in metastatic breast cancer. A pilot study.

BACKGROUND: Chemotherapy (CT), fundamental for the treatment of metastatic breast cancer (MBC), rarely cures, due to the presence of minimal residual disease (MRD). Based on the synergistic antiproliferative effect of interferon, retinoids and tamoxifen on breast cancer cell lines, we designed a pilot study to test if a combination of beta-interferon (beta-IFN), retinoids and tamoxifen could improve the progression free survival and overall survival in patients (PTS) treated with CT for MBC. METHODS: Thirty-six patients, with stage IV carcinoma of the breast, were treated with a combination of Cyclophosfamide, 5-fluorouracil, 4-epidoxorubicin, vincristine and prednisone every 3 weeks for six courses (FECPV), followed by two courses of methotrexate, mitomycin-c and mitoxantrone (MMM). Treatment was continued, in response, with low dose beta-interferon, retynil palmitate and tamoxifen until disease relapse. RESULTS: Among 36 evaluable PTS, 23 achieved a clinical response (64%) (95% c. i. 48 x 80%), 7 had disease stability (19%), and 6 (17%) progressed. Leukopenia occurred in 15 patients, thrombocytopenia in six, and anemia in 11. 16 patients had nausea/vomiting; stomatitis was observed in nine patients and diarrhea in three. Toxicity of maintenance therapy was mild and mainly hepatic. Median response duration was 31 months (range 5-75+). Median overall survival was 32 months (9-83+). CONCLUSIONS: Our study shows that this regimen is feasible and shows activity in MBC with an acceptable toxicity.