High rate of extra-haematological toxicity compromises dose-dense sequential adjuvant chemotherapy for breast cancer.

BACKGROUND: A dose-dense strategy has been considered to improve results of adjuvant chemotherapy for breast cancer. This randomised phase II trial investigated the feasibility of this approach with sequential anthracyclines and taxanes-based chemotherapy. METHODS: Patients with high-risk node-positive breast cancer were treated with three cycles of fluorouracil 500 mg m(-2), epirubicin 100 mg m(-2), cyclophosphamide 500 mg m(-2) (FEC 100) followed by three cycles of docetaxel 100 mg m(-2) delivered at 2-weekly intervals supported by primary prophylaxis with filgrastim. All patients were randomised to either uninterrupted treatment (arm A) or to have a 2-week additional period of rest between the FEC and docetaxel (arm B). The primary endpoint was the rate of success of chemotherapy delivery. Using a two-stage Fleming design, 120 patients were required with one interim analysis. RESULTS: In March 2005, enrolment was stopped into arm A after the observation of severe skin toxicities. Following the planned interim analysis, the study was closed because of the high rate of grade 3/4 skin toxicities in both arms (arm A: 32.4% and arm B: 18.9%). CONCLUSION: Sequential dose-dense FEC 100 followed by docetaxel 100 mg m(-2) is not feasible. Feasibility still depends largely on several factors including the choice of drugs, dosage and sequence of administration.

A prospective, observational study describing the haematological response in patients undergoing chemotherapy treated by tri-weekly darbepoetin alfa for anaemia.

OBJECTIVE: This prospective, observational study investigated the haematological response to darbepoetin alfa (DA) administered every three weeks for the treatment of anaemia. Response was also assessed according to baseline characteristics including iron, folate and vitamin B12 status. RESEARCH DESIGN AND METHODS: Anaemic adult patients with malignant non-myeloid cancer, starting or having already undergone chemotherapy received DA on day of inclusionand were followed up for up to 24 weeks. Concentration of haemoglobin (Hb), as well as iron, vitamin B12 and folate status where available, were recorded at inclusion, after a treatment period of 9 weeks and up to a maximum of 24 weeks or cessation of DA treatment, whichever was sooner. MAIN OUTCOME MEASURES: The main outcome measure assessed in this study was the percentage of patients reaching a Hb concentration of at least 11 g/dL at least once at any time during the study. RESULTS: A total of 2912 patients were included. The mean Hb concentration increased from 10.0 g/dL at inclusion to 11.4 g/dL at 9 weeks and 11.8 g/dL at 24 weeks. In 74.6% of patients the target Hb level of 11.0 g/dL or above was reached. After initiation of DA treatment, 9.5% of patients required a blood transfusion by week 9, and 5.6% thereafter. Vitamin B12 and folate status were unknown for 80.3% of patients and the iron status for 73.2% of patients. Compared with patients who remained untreated for vitamin B12 or folate deficiency, a higher percentage of patients with vitamin status within normal limits achieved the target Hb concentration. However, achievement of target Hb level appeared not to be affected by iron status. CONCLUSIONS: In this study, the mean Hb level increased in anaemic cancer patients treated with DA and the majority of patients achieved the target Hb level. In contrast to the recommendations of guidelines (EORTC) encouraging the measurement of iron and vitamin levels, the present study demonstrated that data were not routinely collected for these factors.

[Prognostic factors for malignant uveal melanoma. Retrospective study on 2,241 patients and recent contribution of monosomy-3 research]. / Facteurs pronostiques du mélanome malin de l'uvée. Etude rétrospective sur 2,241 patients et apport récent de la recherche de la monosomie 3.

INTRODUCTION: We conducted a retrospective study on the clinical factors influencing the local and general prognosis of patients treated for uveal melanoma with a preliminary analysis of the prognostic value of monosomy 3. PATIENTS: and method: The patients sent to Curie Institute for uveal melanoma have a complete initial clinical evaluation, conservative management by radiotherapy or enucleation, and local and general long-term follow-up. Over the last 5 years, the status of chromosome 3 has been assessed by FISH in the tumors of enucleated patients. Findings concerning the initial workup, treatment, and follow-up are recorded prospectively. We conducted a retrospective study with multivariate analysis of the clinical factors influencing local recurrence, ocular conservation metastasis, and survival and studied the effect of monosomy 3. RESULTS: A total of 2241 patients were registered with a median follow-up of 72 months. Of these patients, 92.8% had conservative management with iodine 125 brachytherapy or proton beam therapy and 7.2% of the patients had enucleation (n=160). Tumors from 120 patients were studied for the status of chromosome 3 by FISH. The overall survival rate was 76.3% and the metastatic rate was 19.5%. The clinical factors influencing survival were the size and location of the tumor, age of the patient, gender, and initial treatment. The factors influencing the metastatic risk were the same plus retinal detachment and local recurrence. Monosomy 3 was a significant risk factor for metastatic disease. DISCUSSION: This study found the usual risk factors with the difference that location on the equator seems to be of worse prognosis than ciliary body involvement for survival and metastasis. In addition, the initial retinal detachment appears to be a risk factor for local recurrence and metastasis. At present, the evaluation of chromosome 3 is available for enucleated tumors but it could probably be done on needle biopsy performed during conservative management as well. CONCLUSION: This study confirms previous results on the prognostic factors of uveal melanoma and on the value of monosomy 3. The increasingly precise identification of a group of high-risk patients should allow us to propose adjuvant therapy and to adapt follow-up.

Combined proton beam radiotherapy and transpupillary thermotherapy for large uveal melanomas: a randomized study of 151 patients.

INTRODUCTION: Exudation from the tumour scar and glaucoma can be major problems after proton beam irradiation of uveal melanoma and can sometimes lead to secondary enucleation. We conducted a randomized study to determine whether systematic transpupillary thermotherapy (TTT) after proton beam radiotherapy could have a beneficial effect. PATIENTS AND METHOD: Between February 1999 and April 2003, all the patients treated by proton beam radiotherapy for uveal melanomas >/=7 mm thick or >/=15 mm in diameter were included in this study after giving their informed consent. One half of the patients received proton beam radiotherapy alone (60 Gy in 4 fractions) and the other half received the same dose of proton beam radiotherapy followed by TTT at 1, 6 and 12 months. All the information concerning the initial tumour parameters, treatments and follow-up was recorded and a statistical analysis was performed. RESULTS: We randomized 151 patients. The median follow-up was 38 months. The 2 groups of patients were similar in terms of age, gender and tumour characteristics. The patients treated with TTT showed a greater reduction of tumour thickness (p = 0.06), less retinal detachment at the latest follow-up (p = 0.14) and a lower secondary enucleation rate (p = 0.02). DISCUSSION: The present study is the first randomized analysis to demonstrate a significant decrease in the secondary enucleation rate in patients treated with TTT after proton beam radiotherapy. Further studies should be performed to determine whether TTT could be beneficial to smaller tumours and to define its optimal dose.

[Diode laser thermotherapy and chemothermotherapy in the treatment of retinoblastoma]. / Thermothérapie et thermochimiothérapie au laser diode dans le traitement du rétinoblastome.

INTRODUCTION: The use of transpupillary thermotherapy alone or associated with systemic chemotherapy is a therapeutic modality of ocular retinoblastoma that allows ocular preservation without external beam irradiation of the eye. We present our experience with thermotherapy in the treatment of selected cases of retinoblastoma. MATERIAL AND METHODS: This paper reports a retrospective case series of patients treated for retinoblastoma by thermotherapy or chemothermotherapy (carboplatin IV followed by thermotherapy) in a single institution from October 1994 to December 2000. Data collected include general characteristics of the treated children, tumor characteristics, and the results of the treatments on local tumor control. Transpupillar thermotherapy was delivered with a diode laser through an operating microscope. Each tumor was treated separately and laser intensity, spot size, and duration were adapted to the size of the tumor and the clinical response. Chemothermotherapy consisted in thermotherapy delivered shortly after an intravenous injection of carboplatin (560 mg/m(2)) at day 1, followed by thermotherapy alone at day 8 if the lesion was 6mm or more in diameter. This cycle was administered every 28 days. The choice between thermotherapy and chemothermotherapy depended on the initial size of the lesions. Thermotherapy was used when the lesion measured 3mm or less. Lesions measuring more than 15 mm, or associated with substantial vitreous seeding, retinal detachment, or optic nerve head involvement are not suitable for these techniques. RESULTS: During the study period, 239 children were treated in our institution and 109 of them (147 eyes, 372 tumors) could be treated conservatively without external beam radiation. The median tumor diameter at the moment of thermotherapy or chemothermotherapy was 2mm (range, 0.2-15.0mm). One hundred and ninety-four tumors were treated by chemothermotherapy and 18 by thermotherapy alone. In 75% of the cases, the treatment was administered after two courses of chemotherapy (etoposide and carboplatin). After a mean follow-up of 55 months (range, 16-89 months), tumor control was obtained in 87.1% of lesions after chemothermotherapy and 77.8% after thermotherapy. Salvage enucleation was necessary for seven lesions (seven eyes) but none in the cases where thermotherapy was used alone. No severe systemic side effects were noted. DISCUSSION: Diode laser delivers hyperthermia on the tumor bed and its use alone or in association with systemic administration of carboplatin makes it possible to preserve the eye without external beam irradiation, with few side effects and less cumulative doses of chemotherapy. CONCLUSION: Thermotherapy and chemothermotherapy provide excellent local tumor control and eye preservation in selected cases of retinoblastoma.

Thymidine kinase as a proliferative marker: clinical relevance in 1,692 primary breast cancer patients.

PURPOSE: To assess the prognostic value of thymidine kinase (TK), an enzyme involved in the DNA synthesis salvage pathway, relative to other prognostic factors in primary breast cancer. PATIENTS AND METHODS: This retrospective study involved 1,692 patients with operable breast cancer treated in six institutions (median follow-up, 82 months). Among the 857 node-negative patients, 135 received adjuvant chemotherapy (fluorouracil, doxorubicin, cyclophosphamide [FAC] or fluorouracil, etoposide, and cisplatin [FEC]). TK was assayed in cytosol with a quantitative radioenzymatic technique. Disease-specific survival (DSS), local recurrence-free interval (LRI), and distant-relapse-free interval (DRI) were investigated. RESULTS: High TK levels were associated with large tumor size, high histologic grade, and steroid hormone receptor negativity. Univariate analysis of the entire data set showed that high TK levels were related to shorter DSS (P < 10(-5)), LRI (P < 10(-3)), and DRI (P < 10(-5)). In time-dependent Cox models, high TK levels remained an independent predictor of the three outcomes, both in the overall population and in node-negative patients, although its prognostic value decreased over time. In node-negative patients, the introduction of an interaction term in multivariate analysis suggested that chemotherapy was more efficacious for patients who had tumors with high TK contents. In node-positive patients, high TK levels were related only to an increased risk of LRI. CONCLUSION: High TK values are an important risk factor in node-negative patients and seem to be associated with a beneficial effect of adjuvant FAC or FEC in patients who received adjuvant chemotherapy. The rationale of chemotherapy for patients with slowly proliferating tumors has to be discussed from a risk-benefit point of view.

Role of chemotherapy alone or in combination with hyperthermia in the primary treatment of intraocular retinoblastoma: preliminary results.

BACKGROUND: The efficacy of the etoposide-carboplatin combination in extraocular retinoblastoma is well known. This drug combination is therefore used in intraocular retinoblastoma, as primary reduction chemotherapy, before local treatment. The use of carboplatin in combination with diode laser hyperthermia as local treatment (thermochemotherapy) has been recently described as a conservative approach avoiding external beam radiotherapy in posterior pole tumours. METHODS: All patients were reviewed, who were treated for retinoblastoma at the Institut Curie between June 1994 and October 1995, in whom treatment included either reduction chemotherapy or thermochemotherapy or both modalities successively. 23 patients presenting with unilateral (three) or bilateral (20) intraocular retinoblastoma received neoadjuvant chemotherapy consisting of two courses of etoposide 150 mg/m2/day and carboplatin 200 mg/m2/day for 3 days. 15 patients (17 eyes), eight of whom had already received neoadjuvant chemotherapy, were treated by thermochemotherapy. RESULTS: Neoadjuvant chemotherapy: overall, seven eyes in seven patients could be treated conservatively, avoiding external beam irradiation, with a median follow up of 14 months. Thermochemotherapy: external beam irradiation was avoided for 14 of the 17 eyes treated. CONCLUSION: Integration of neoadjuvant chemotherapy and combined treatment with carboplatin and diode laser, into the therapeutic armamentarium for retinoblastoma allows use of more aggressive treatments such as enucleation and external beam radiation.

Meningeal carcinomatosis in patients with breast carcinoma. Clinical features, prognostic factors, and results of a high-dose intrathecal methotrexate regimen.

BACKGROUND: This retrospective study evaluates the results of a regimen of high-dose intrathecal methotrexate and the prognostic factors for the response in patients with meningeal from breast carcinoma. METHODS: From 1979 to 1994, 68 breast carcinoma patients were diagnosed with meningeal carcinomatosis at a mean age of 52 years. All but two had previous metastatic involvement. The proportion of lobular and ductal carcinomas was balanced. Malignant cells were present in cerebrospinal fluid (CSF) samples from 61 patients, whereas the 7 remaining patients had increased CSF protein associated with computerized tomographic scan evidence of meningeal metastases. From 1989, 41 of the patients received a regimen of high-dose intrathecal methotrexate with systemic folinic acid rescue (HD-MTX+FA): intrathecal MTX, 15 mg daily x 5 days, repeated every 2 weeks, and intrathecal hydrocortisone acetate, 125 mg on Day 1, and folinic acid, 10 mg intramuscularly 12 hours after each MTX injection. Systemic treatment and radiation therapy were usually associated. Patients treated before 1988 received intrathecal MTX in conventional doses (15 mg once a week). RESULTS: Clinical objective response, defined as a neurological improvement for at least one month, was achieved in 17 patients (41%) and stabilization in 14 (34%) treated with the HD-MTX+FA regimen. The response rate was significantly higher compared with that of the group treated with the conventional doses (P = 0.03). Median survival was 14 weeks for patients treated with the HD-MTX+FA regimen, compared with 7 weeks for patients who received conventional doses of MTX (P = 0.01). Grade 3 or 4 neutropenia was the main toxicity that occurred in 16 16 patients (39%) treated with the HD-MTX+FA regimen, and in 7 patients (33%) treated with conventional doses of MTX. In a univariate analysis, three parameters were singled out as having a favorable prognostic value for response to therapy; controlled systemic disease at diagnosis (P < 0.05), low initial CSF protein level (P < 0.05), and concomitant systemic chemotherapy during intrathecal therapy (P < 0.02). Multivariate analysis was not performed because the sample size was too small. CONCLUSIONS: Although this study was retrospective, the intrathecal HD-MTX+FA regimen appears to be a more efficient strategy than conventional doses of MTX to induce neurologic improvement and perhaps better survival. It should be recommended in combination with systemic chemotherapy for selected patients with meningeal carcinomatosis from breast carcinoma who are likely to benefit from intensive therapy, i.e., patients with a CSF protein level less than 5 g/L and in whom systemic disease has been controlled.

Breast tumour response to primary chemotherapy predicts local and distant control as well as survival.

The purpose of the present paper was to evaluate correlations between clinical response to chemotherapy and outcome in a subgroup analysis of premenopausal patients with tumours considered too large for breast conserving surgery, treated with primary chemotherapy (n = 200) from a previously published trial (Scholl S.M., Fourquet A., Asselain B, et al. Eur J Cancer 1994, 30A, 645-652). Objective response rates amounted to 65% following four courses. In a multivariate Cox regression analysis, comparing seven parameters, the following variables were associated with poor survival: clinically involved nodes [N1b:RR: 2.7 (95% CI 1.3-5.3)], the failure to respond to chemotherapy [D:RR: 2.62 (95% CI 1.3-5)] and a raised S phase fraction [SPF > 5%: RR: 2.4 (95% CI 1.2-5)]. Parameters associated with increased metastatic recurrence rates, by order of entry in the model, were: young age [< 35: RR: 2.46 (95% CI 1.2-5)], large clinical tumour size [T3: RR: 2.02 (95% CI 1.2-3.4)], poor histological grade (SBR III: RR: 1.93 (95% CI 1.1-3.3)] and the failure to respond to chemotherapy [D: RR: 1.91 (95% CI 1-3.4)]. The assessment of both tumour cell proliferation rates as well as possibly drug resistance markers (although not available in the present study) should be helpful in selecting patients likely to benefit from intensified chemotherapy regimens. The most accurate predictor of response in the present study appeared to be the response to chemotherapy treatment itself.

Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6.

The aim of this study was to assess a potential advantage in survival by neoadjuvant as compared to adjuvant chemotherapy. 414 premenopausal patients with T2-T3 N0-N1 M0 breast cancer were randomised to receive either four cycles of neoadjuvant chemotherapy (cyclophosphamide, doxorubicin, 5-fluorouracil), followed by local-regional treatment (group I) or four cycles of adjuvant chemotherapy after primary irradiation +/- surgery (group II). Surgery was limited to those patients with a persisting mass after irradiation, and aimed to be as conservative as possible. 390 patients were evaluable. With a median follow-up of 54 months, we observed a statistically significant difference (P = 0.039) in survival in favour of the neoadjuvant chemotherapy group. A similar trend was seen when the time to metastatic recurrence was evaluated (P = 0.09). At this stage, no difference in disease-free interval or local recurrence between these two groups could be observed. The mean total dose of chemotherapy administered was similar in both groups. On average, group I had more intensive chemotherapy regimes (doxorubicin P = 0.02) but fewer treatment courses (P = 0.008) as compared to the treated patients in group II. Haematological tolerance was reduced when chemotherapy succeeded to exclusive irradiation. Breast conservation was identical for both groups at the end of primary treatment (82 and 77% for groups I and II, respectively). Of the 191 evaluable patients in the neoadjuvant treatment arm, 65% had an objective response (> 50% regression) following four cycles of chemotherapy. The objective response rate to primary irradiation (55 Gy) was 85%. Improved survival figures in the neoadjuvant treatment arm could be the result of the early initiation of chemotherapy, but we cannot exclude that this difference might be attributable to a slightly more aggressive treatment. So far, the trend in favour of decreased metastases was not statistically significant. The local control appeared similar in both subgroups.

Neoadjuvant chemotherapy in operable breast cancer.

Primary chemotherapy in localised breast cancer may prevent tumour spread during surgical treatment and reduce proliferation of micrometastases. A randomised clinical trial, in 196 premenopausal and postmenopausal patients with operable (T2-3, N0-1b) breast cancer, was started in November 1983 at the Institut Curie to compare neoadjuvant and adjuvant regimens of chemotherapy with radiotherapy with or without surgery. The patients have been followed up for 35-70 months (median 54). A neoadjuvant group received two monthly cycles of intravenous doxorubicin/cyclophosphamide/5-fluorouracil before locoregional therapy and four cycles subsequently. Six monthly cycles following locoregional therapy were administered to the adjuvant group. Because of inclusion of postmenopausal and/or node-negative patients, compliance was less than optimal in 39 patients who were analysed separately according to actual dose received. Tumour response, evaluated after two cycles of neoadjuvant chemotherapy, was significantly associated with dose (P = 0.003). Survival showed a slight non-significant advantage for the neoadjuvant group. Survival plotted by actual dose was also similar. Neoadjuvant chemotherapy was safe and at least as effective as the adjuvant regimen. Patients have been accrued to a subsequent larger trial of chemotherapy as first-line treatment.