Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients' risk of fluoropyrimidine-related severe toxicity. METHODS: The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg's False Discovery Rate (FDR) procedure was used. RESULTS: FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia. CONCLUSIONS: This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

Effectiveness of bevacizumab added to standard chemotherapy in metastatic colorectal cancer: final results for first-line treatment from the ITACa randomized clinical trial.

BACKGROUND: We report the results from a first-line phase III randomized clinical trial on metastatic colorectal cancer (mCRC) aimed at evaluating the effectiveness of adding bevacizumab (B) to standard first-line chemotherapy (CT). PATIENTS AND METHODS: mCRC patients were randomized to receive first-line CT (FOLFIRI or FOLFOX4) plus B (arm A) or CT only (arm B). The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (ORR) and safety. Three hundred and fifty patients and 310 events were required to have an 80% statistical power to detect a difference in PFS between the groups. RESULTS: Between November 2007 and March 2012, 376 patients were randomized. About 60% of patients received FOLFOX4 and 40% FOLFIRI. After a median follow-up of 36 months, 343 progressions and 275 deaths had been observed in the overall population. The median PFS was 9.6 [95% confidence interval (CI) 8.2-10.3] and 8.4 (95% CI 7.2-9.0) months for arms A and B, respectively, with a hazard ratio of 0.86 (95% CI 0.70-1.07; P = 0.182). No statistically significant differences in OS or ORR were observed. B-containing regimens were associated with more frequent hypertension, bleeding, proteinuria and asthenia. CONCLUSIONS: The addition of B to standard first-line CT for mCRC did not provide a benefit in terms of PFS, OS or ORR. Further research is warranted to better identify the target population. CLINICAL TRIAL NUMBER: NCT01878422.

Intermittent versus continuous chemotherapy in advanced colorectal cancer: a randomised 'GISCAD' trial.

BACKGROUND: In advanced colorectal cancer, chemotherapy is usually administered without pauses and until progression but patients can experience cumulative toxicity and cannot tolerate a heavy therapeutic charge. AIM: The aim of the present trial was to evaluate whether an intermittent chemotherapy with levo-leucovorin + 5-fluorouracil (5-FU) + irinotecan (CPT-11) was at least as effective as the same regimen given continuously, both administered until progression, in patients affected with advanced colorectal cancer and not previously exposed to chemotherapy for metastatic disease. PATIENTS, MATERIALS AND METHODS: A total of 337 patients from 27 institutions were randomised between levo-leucovorin, 100/mg/m(2) i.v. + 5-FU; 400 mg/m(2) i.v. bolus + 5-FU; 600 mg/m(2) 22-h continuous infusion, days 1 and 2 + CPT-11; 180 mg/m(2) day 1, administered every 2 weeks 2 months on and 2 months off (arm A) and the same regimen administered continuously (arm B), until progression in both arms. The main end point was overall survival (OS), the secondary progression-free survival (PFS) and toxicity. RESULTS: At a median follow-up of 41 months, OS was 18 months in arm A and 17 months in arm B [hazard ratio (HR), 0.88]. Also PFS was comparable in the two groups (6 months in both, with HR, 1.03), and even grades 3-4 toxicity (mainly myelosuppression, fever and diarrhoea) was similar. Second-line oxaliplatin-based treatment was administered in a similar percentage (66%) in the two arms. The median chemotherapy-free period (drug holiday) in arm A was 3.5 months. CONCLUSION: Reducing the charge of therapy in this population did not diminish the efficacy of treatment. Further studies with this strategy, including biologicals, are warranted.

A randomized study comparing filgrastim versus lenograstim versus molgramostim plus chemotherapy for peripheral blood progenitor cell mobilization.

We conducted a prospective randomized clinical trial to assess the mobilizing efficacy of filgrastim, lenograstim and molgramostim following a disease-specific chemotherapy regimen. Mobilization consisted of high-dose cyclophosphamide in 45 cases (44%), and cisplatin/ifosfamide/etoposide or vinblastine in 22 (21%), followed by randomization to either filgrastim or lenograstim or molgramostim at 5 microg/kg/day. One hundred and three patients were randomized, and 82 (79%) performed apheresis. Forty-four (43%) patients were chemonaive, whereas 59 (57%) were pretreated. A median number of one apheresis per patient (range, 1-3) was performed. The median number of CD34+ cells obtained after mobilization was 8.4 x 10(6)/kg in the filgrastim arm versus 5.8 x 10(6)/kg in the lenograstim arm versus 4.0 x 10(6)/kg in the molgramostim arm (P=0.1). A statistically significant difference was observed for the median number of days of growth factor administration in favor of lenograstim (12 days) versus filgrastim (13 days) and molgramostim (14 days) (P<0.0001) and for the subgroup of chemonaive patients (12 days) versus pretreated patients (14 days) (P<0.001). In conclusion, all three growth factors were efficacious in mobilizing peripheral blood progenitor cells with no statistically significant difference between CD34+ cell yield and the different regimens, and the time to apheresis is likely confounded by the different mobilization regimens.

Peripheral blood progenitor cell (PBPC) mobilization in heavily pretreated patients with germ cell tumors: a report of 34 cases.

The aim of the study was to evaluate peripheral blood progenitor cell mobilization by disease-specific chemotherapy in heavily pretreated patients with germ cell tumor (GCT), scheduled for high-dose chemotherapy. Thirty-four consecutive patients, 29 males and five females, with advanced GCT referred to our department for high-dose chemotherapy were evaluated retrospectively. Sixteen patients were mobilized by vinblastine 0.11 mg/kg on days 1 and 2, ifosfamide 1200 mg/m2 days 1-5 and cisplatin 20 mg/m2 days 1-5 (VeIP). In 10 patients, etoposide 75 mg/m2 days 1-5 was used instead of vinblastine (VIP), while in eight patients the mobilization was attempted by administering 7 g/m2 of cyclophosphamide. The choice of either etoposide or vinblastine was predicated upon which of these two drugs was associated with best results during premobilization chemotherapy. Cyclophosphamide was selected in patients refractory to previous cisplatin-based salvage chemotherapy. Twenty-five out of 34 patients underwent a successful PBPC collection. In 17 of them one leukapheresis procedure was sufficient to collect the target number of CD34+ cells, while in eight patients a double procedure was necessary. Altogether 33 aphereses were performed in 25 patients. In nine patients leukapheresis was not attempted. This was due to the fact that the chemotherapy failed to mobilize the target number of CD34+ cells in eight of them, treated with the VeIP mobilizing regimen, while one patient treated with high-dose cyclophosphamide rapidly progressed during therapy and for this reason leukapheresis was not undertaken. In conclusion, in heavily pretreated patients with GCT, PBPC mobilization is feasible by a further course of salvage chemotherapy. The choice of either etoposide (VIP) or vinblastine (VeIP) can be predicated upon which of these two drugs was associated with best results during premobilization chemotherapy. In our hands, VeIP seems to be less satisfactory as mobilizing treatment than VIP, possibly due to a superior number of premobilization courses of chemo therapy in some patients. Moreover, high-dose cyclophosphamide remains a good alternative for mobilizing patients refractory to salvage chemotherapy.

An Italian experience of high-dose chemotherapy and autologous bone marrow transplantation (ABMT) in germ cell tumours. Suggestions for future direction.

In this paper an Italian cooperative trial investigates the role of a high-dose regimen with carboplatin, etoposide and ifosfamide in germ cell tumours. Twenty-eight patients underwent one or two transplants. Seventeen with progressive disease. Nine in sensitive relapse and two with stable disease after salvage therapy. Toxicity was generally moderate: two deaths occurred at day 15 from ABMT (one from VOD and one from tumour growth). Five patients are alive and disease free at least 10 months follow-up. In highly pre-treated patients this high-dose combination seems to give an option of cure for relapsed patients. Early transplantation is suggested.

A sequential chemo-radiotherapeutic treatment for patients with malignant gliomas: a phase II pilot study.

BACKGROUND: The purpose of our study was to evaluate the activity and toxicity of a sequential chemo-radiotherapeutic treatment on the basis of an earlier report by The Johns Hopkins Oncology Center. MATERIALS AND METHODS: Eighteen patients with histologically diagnosed malignant gliomas entered the study. Fifteen patients had glioblastoma multiforme (83%). BCNU (40 mg/sqm/die) and Cisplatin (40 mg/sqm/die) were administered concurrently for 3 days every 3-4 weeks. Radiotherapy consisted of 45 Gy whole cranial irradiation plus a 15 Gy boost on the preoperative volume. RESULTS: Thirteen patients had measurable disease and were evaluable for response. After chemotherapy we obtained 3 CRs (complete remission) and 4 PRs (partial remission) (RR (response rate 54%). Three PRs were converted to CRs after radiotherapy, for a complete remission rate of 46% (6/13). The median duration of response was 10 months. The median survival of the entire patients population was 9 months with 33% survival rates at 1 year. Hematological toxicity grade 4 in one patient and grade 3 in two patients were the major complications due to chemotherapy. CONCLUSIONS: Our sequential chemo-radiotherapeutic regimen appears to have significant activity in adults with newly diagnosed high-grade gliomas.

Global approach to hepatic metastases from colorectal cancer: indication and outcome of intra-arterial chemotherapy and other hepatic-directed treatments.

Liver metastases of colorectal cancer is present in more than 20% of new diagnosed patients and in 40-60% of relapsed patients. It is a life-threatening prognostic aspect. Hepatic resection, when possible, is the best therapeutic modality, although the overall survival rate is still low (30%). Angiography and intraoperative ultrasonography are useful for resection. The number of hepatic metastases and the surgical margin are probably the most significant prognostic factors. Colorectal cancer may spread predominantly to the liver making regional treatment strategies viable options. Subtotal hepatic resections and segmentectomies are potentially curable procedures for single or small numbers of hepatic metastases without other sites of disease. However, there have been no prospective randomized trials comparing patients with unresected liver metastases and resected metastases. Regional chemotherapy with floxuridine seems usefull combined with hepatic resection or as palliative therapy. Gastric ulcer and biliary sclerosis are the main related toxicities. Patients with localized, unresectable hepatic metastases or concomitant bad medical condition may be candidates for radiation, percutaneous ethanol injection, cryosurgery, percutaneous radiofrequency, hypoxic flow-stop perfusions with bioreductive alkylating agents, hepatic arterial ligation, embolization and chemoembolization. These new hepatic-directed modalities of treatment are being investigated and may offer new approaches to providing palliation and prolonging survival. This review will report the possibilities of intra-arterial chemotherapy and other novel hepatic-directed approaches to the treatment of liver metastases from colorectal cancer.

Immunoscintigraphy of adenocarcinomas by means of 111In-labelled F(ab')2 fragments of anti-CEA monoclonal antibody F023C5.

F(ab')2 fragments of F023C5, an anti-CEA monoclonal antibody, were conjugated to diethylenetriamine pentaacetic acid (DTPA) and converted into a ready to use reagent for instant 111In-labelling. The resulting 111In radiopharmaceutical (2-3 mCi/0.5 mg of F(ab')2 fragments) was administered intravenously and tested for its ability to image (at 48-72 h after administration) 31 primary and 85 metastatic carcinoma lesions in 70 adenocarcinoma patients (26 gastrointestinal, 18 breast and 26 lung tumor patients) whose serum CEA was elevated in 43 cases and normal in the other 27. The results were as follows: no adverse reactions or evidence of toxicity were observed in any of the patients. positive immunoscintigraphy results were obtained in 78% CEA-seropositive and in 64% seronegative patients. the fraction of documented lesions which was imaged was 69% in CEA-seropositive patients and 39% in seronegative patients. several 'unexpected' radiolocalizations were imaged; 30/34 were confirmed as (previously occult) tumour lesions in follow-up studies. In 6 patients, the immunoscintigraphic demonstration of previously occult lesions contributed to the early detection of tumour recurrences. the major limitation of the method is the non-specific radioactivity accumulation in the liver, which prevents the detection of liver metastases. in CEA-seropositive patients the fraction of imaged extra-hepatic tumour lesions is over 80%. the major cause of negative immunoscintigraphy results is lack of CEA in the tumour lesion, as demonstrated by immunohistochemistry of surgically removed tumours.

Locoregional therapy for liver metastases from colorectal cancer: the possibilities of intraarterial chemotherapy, and new hepatic-directed modalities.

Liver metastasis of colorectal cancer is a life-threatening prognostic factor. Hepatic resection, when possible, is the best therapeutic modality, although the overall survival rate is still low (30%). The diagnosis has been carried out by clinical examination, abnormal alkaline phosphatase, lactic acid dehydrogenase and tumor markers, abdominal liver echography and computed tomography scan. Angiography and intraoperative echography are useful for resection. The number of hepatic metastases and the surgical margin are probably the most significant prognostic factors. Colorectal cancer may spread predominantly to the liver making regional treatment strategies viable options. Subtotal hepatic resections and segmentectomies are potentially curable procedures for single or small numbers of hepatic metastases without other sites of disease. However, there have been no prospective randomized trials comparing patients with unresected liver metastases and resected metastases. Regional chemotherapy with floxuridine seems useful combined with hepatic resection or as palliative therapy. Gastric ulcer and biliary sclerosis are the main related toxicities. Patients with localized, unresectable hepatic metastases or concomitant bad medical condition may be candidates for radiation, percutaneous ethanol injection, cryosurgery, radiofrequency, hypoxic flow-stop perfusions with bioreductive alkylating agents, hepatic arterial ligation, embolization and chemoembolization. These new hepatic-directed modalities of treatment are being investigated and may offer new approaches to providing palliation and prolonging survival. This review reports the possibilities of intraarterial chemotherapy and other novel hepatic directed approaches to the treatment of liver metastases from this common disease.

[Adjuvant concomitant chemotherapy in pancreatic cancer]. / La chemioterapia adiuvante concomitante del carcinoma pancreatico.

Pancreatic cancer is a leading cause of cancer death. Despite improvement in diagnosis and treatment in the last 15 years, mortality rates essentially equal the incidence of the disease. Combination treatment with chemoradiation yields up to now better results than chemotherapy or radiotherapy given alone in consideration of substantial radio and chemoresistance of the cancer cells. This study will review the most important literature data about combination adjuvant treatment and preoperative (primary) chemoradiation in pancreatic cancer. Some other reports will be given on locoregional chemotherapy and finally a brief view on a possible perspective for promising future treatments coming from data of molecular pathology. Adjuvant chemoradiation after surgery has been shown to be superior to operation alone in potentially resectable pancreatic cancer in many studies, in terms both of local control and median overall survival. Unfortunately, a consistent percentage of patients cannot receive adjuvant treatment since late recovery after surgery or post-operative morbidity. Owing to this last reason, many authors prefer primary chemoradiation in potentially resectable pancreatic cancer; neoadjuvant treatment find out its background in other relevant biological and clinical evaluations. Some studies report encouraging results with primary chemoradiation using 5-fluorouracil. Other experiences with relatively new drugs, with potent radiosensiting effect, such as gemcitabine or taxol are going on; many of these are phase I studies. Clinical research in the field of preoperative treatment is up to now emerging in some important Oncological Institutions. The principal actual aim seems to be that of forsee periods of treatment which will be brief and use the dose of chemotherapy that is active, giving acceptable toxicity. Ongoing trials will give, in the next years, the answer about the improvement of efficacy of treatments largely expected by all researchers.

Mitoxantrone (M) and vinblastine (V) in the treatment of advanced breast cancer.

Twenty-four patients with metastatic breast cancer, all but 1 pretreated with one or more chemotherapeutic regimens, were entered in a pilot study to assess toxicity and efficacy of the combination mitoxantrone and vinblastine. Dominant sites of metastases were viscera in 9 patients, bone in 10 and soft tissues in 5. All patients received mitoxantrone 10 mg/m2 i.v. on day 1 and vinblastine 1.7 mg/m2 by 4 hour infusion on days 3, 4 and 5, every 3-4 weeks. Objective responses (1 CR, 7 PR) were observed in 8 (38%) of the 21 evaluable patients. Median duration of response was 10.5 months. Of 12 patients pretreated with an anthracycline containing regimen, 4 responded (1 CR and 3 PR). Major toxicity was myelosuppression, grade 4 in 2 cases and grade 3 in 2 others. No evident alopecia was observed and only 1 case of grade 1 cardiac toxicity. In conclusion, mitoxantrone followed by vinblastine is an effective regimen in metastatic breast cancer also in pretreated patients, and previous anthracycline administration does not seem to reduce the percentage of response. Moreover, toxicity is generally mild.

Metastases to the submaxillary gland from breast cancer: case report.

A case of metastases to the submaxillary gland from breast carcinoma is reported. The patient, a 68-year-old female, had been operated for a stage II N+ breast carcinoma 4 years before. She then received six courses of CMF adjuvant program. A literature review is presented concerning the 8 well-documented cases reported.

Cyclophosphamide, methotrexate,5-fluorouracil, alternating with adriamycin and mitomycin C in metastatic breast cancer: a pilot study.

To explore the clinical applicability of the Goldie and Coldman hypothesis, we treated 28 patients with metastatic breast cancer with alternating non-cross-resistant chemotherapy. The patients received cyclophosphamide, 600 mg/m2, 5-fluorouracil, 600 mg/m2, methotrexate, 40 mg/m2, alternated every three weeks with adriamycin, 60 mg/m2, and mitomycin C, 10 mg/m2. Only one patient had previously received palliative chemotherapy. Six patients had received adjuvant CMF, and 17 patients had been pretreated with endocrine therapy (13 for advanced disease, 4 as adjuvant). Fourteen patients had bone involvement, and 10 had visceral metastases. A mean of 12 cycles was given to 24 evaluable patients. The objective response rate was 67%: 11 patients (46%) achieved complete and 5 (21%) partial remission. Response rate in soft tissues was 83.3%, in bone 50%, in liver 100%, and in lung 80%. The median duration of response was 14 months, with 7 patients still in remission. No life-threatening toxicity was observed. Our preliminary results support the validity of this approach and the efficacy of this combination chemotherapy. A large-scale randomized study is warranted.

[High-dose chemotherapy and peripheral hemtopoietic cells (PBPC) in solid tumors]. / Chemioterapia ad alte dosi e cellule progenitrici periferiche (PBPC) nei tumori solidi.

High-dose chemotherapy is a policy which is increasing in the field of solid tumors both in Europe and in North America. Hundreds of patients undergo ABMT or PBPCT in Europe every year especially for breast carcinoma. Waiting for the results of several ongoing trials, high-dose chemotherapy has shown to be of extreme interest in the adjuvant setting of patients with high risk breast cancer in phase II trials. The best results had been reported by Peters and Gianni; with a minimum follow-up of 5 years 65 and 56% of their patients with ten or more axillary lymph nodes are alive disease free. These results are better than any others with standard doses. The only one published trial (from South Africa) on advanced disease clearly favours high-doses of cyclophosphamide, mitoxantrone and etoposide versus standard doses of cyclophosphamide, mitoxantrone and vincristine in terms of overall survival and time to relapse. The use of PBPC replacing ABMT has allowed an easier tolerability of the procedure and a reduction of the costs. There is a clear reduction of the toxic death rate to 1% in 1995 for breast cancer patients compared with 20% of fifteen years ago. Germ cell tumors in responding relapse after salvage chemotherapy seem to be ideal candidates for ABMT/PBPC programs with an expected 40% disease free survival. The clinical impact of the PBPC contamination by tumor cells is still nowadays a matter of debate at least for breast carcinoma and neuroblastoma. This review will focus on the present situation of high-dose chemotherapy for solid tumors with some insights to new technologies and their applications.

The use of granulocyte colony-stimulating factors following peripheral blood progenitor cell rescue after high-dose chemotherapy for advanced breast cancer: a prospective study.

The use of high-dose chemotherapy followed by hematopoietic rescue is increasing worldwide for solid tumors. Several studies have suggested that the period of absolute neutrophil count (ANC, < 500/ml) may be shortened in patients who receive peripheral blood progenitor cells (PBPC). To estimate the clinical value of granulocyte-colony-stimulating factor, we examined a cohort of 26 consecutive patients with advanced breast cancer who received one or two cycles of high-dose chemotherapy with PBPC rescue with or without filgrastim. Thirty-five courses of high-dose ICE (ifosfamide, carboplatin, etoposide) chemotherapy were administered and evaluated. All patients received PBPC rescue. Sixteen patients (21 courses) received subcutaneous filgrastim (5 mg/kg) following PBPC infusion. Recovery to > or = 500 ANC occurred at a median time of 7 days post PBPC infusion among patients who received filgrastim versus 10 days among patients who received standard support care only (P < 0.01). The administration of filgrastim was not associated with a reduction in the duration of hospitalization, in the total number of days on nonprophylactic antibiotics, number of red blood cell transfusions, time to platelet engraftment, or number of febrile days. This could be the consequence of the high hematopoietic cell dose administered in the study. Therefore, any effect of filgrastim was probably masked by the use of a large number of PBPC. Larger prospective randomized studies, specifically focused on the utility of the administration of growth factors following high-dose chemotherapy and PBPC rescue, may be warranted to know whether the administration of filgrastim after PBPC transplantation is really necessary.

The role of cetuximab in pre-treated refractory patients with metastatic colorectal cancer: outcome study in clinical practice.

We carried out a multicentric retrospective study on cetuximab + chemotherapy in pre-treated refractory patients outside clinical protocols, by registering the main clinical and pathological parameters. We evaluated 144 pre-treated patients. Cetuximab was administered usually in combination with irinotecan (93.8%). A 45% disease control rate (complete plus partial responses plus stable disease) was obtained in 55 patients and was related to absence of weight loss (p<0.0001) and high grade (> or =2) skin toxicity (p<0.0001). Median time to progression (TTP) was 4 months (95%CI 2.7-5.3) and median overall survival (OS) was 11.8 months (95%CI 8.5-15.1). Performance status << or =1, no weight loss and high grade (>or =22) skin toxicity were related both to a longer TTP (p=0.035, p=0.035, p=0.0017) and OS (p<0.0001, p<0.0001, p=0.006). According to multivariate analysis, the absence of weight loss was related to longer TTP (HR 0.331, p=0.004) and OS (HR 0.176, p<0.0001), and EGFR over-expression (3+) to longer TTP (HR 0.402, p=0.020).

The evaluation of effect of radiotherapy on T and B lymphocytes with standard methods and monoclonal antibodies: results at 30 months.

We examined and evaluated the immunologic status of 15 patients suffering from neoplastic, not ematologic, diseases, who underwent external beam radiation therapy. We determined the total lymphocyte count, the percentage of E and EAC rosettes, surface membrane immunoglobulins, the lymphocyte reactivity to PWM and PHA, and T-lymphocyte subpopulations by means of monoclonal antibodies (OKT3-OKT4-OKT8). Besides we evaluated the percentage of LEU7 and OKM1 cells and lymphocytes response to MLR. Blastogenesis tests (PHA and MLR), after 18 months, were performed with and without monocytes. We found out that the amount of T and B lymphocyte subpopulations, which was extremely variable during and after radiotherapy, gradually returned to initial value. After 30 months, the functional impairment seems to be almost completely recovered. At 18 months from the beginning of radiation treatment, the mixed lymphocyte reaction was normal. The presence of monocytes doesn't change either MLR or PHA responses. LEU7+ cells are normal, while OKM1+ cells increased.

Modulated chemo-hormonotherapy in advanced breast cancer. A pilot study.

Twenty-two patients with advanced breast cancer have been treated with sequential chemo-hormonotherapy consisting of tamoxifen 20 mg/day orally for 14 consecutive days, followed by no therapy for ten days, then estrogen 0.625 mg/day orally for three days; the next day methotrexate 200 mg/m2 i.v. and cyclophosphamide 600 mg/m2 i.v.; after 24 hours folinic acid 200 mg/m2 i.v. and 5-fluorouracil 600 mg/m2 i.v. Fifteen patients were evaluable for response, 22 were evaluable for toxicity. All but one were heavily pretreated with chemo and/or hormonotherapy. Nine of 15 had previously received palliative CMF (cyclophosphamide, methotrexate, 5-fluorouracil) (mean 9 cycles), and one patient 12 cycles adjuvant CMF. Thirteen of 15 previously received tamoxifen (median treatment of 18 months). Six patients had multiple metastatic disease, while five had visceral involvement. They were all postmenopausal, with median age 57 years, and median disease-free interval 31 months. ER status was not known and the median ECOG performance status was 1. Overall response rate was 20%. Only one patient attained complete remission; 46.6% were stable disease and 33.3% progressive disease. Accepting that the response rate is very low in pretreated patients, this 20% can be significant. Ninety cycles were administered to 22 patients and the treatment was very well tolerated: both hematologic and nonhematologic toxicities were mild.