Geriatric analysis from PRODIGE 20 randomized phase II trial evaluating bevacizumab + chemotherapy versus chemotherapy alone in older patients with untreated metastatic colorectal cancer.

BACKGROUND: Older patients have frailty characteristics that impair the transposition of treatment results found in younger patients. Predictive factors are needed to help with treatment choices for older patients. The PRODIGE 20 study is a randomized phase II study that evaluated chemotherapy associated with bevacizumab (BEV) or not (CT) in patients aged 75 years or older. PATIENTS AND METHODS: Patients underwent a geriatric assessment at randomization and at each evaluation. The predictive value of geriatric and oncologic factors was determined for the primary composite end-point assessing safety and efficacy of treatment (BEV or CT) simultaneously and also progression-free survival (PFS) and overall survival (OS). RESULTS: 102 patients were randomized (51 BEV and 51 CT; median age 80 years [range 75-91]). On multivariate analysis, baseline normal independent activity of daily living (IADL) score and no previous cardiovascular disease predicted the primary end-point. High (versus low) baseline Köhne score predicted short PFS and baseline Spitzer quality of life (QoL) score <8, albumin level ≤35 g/L, CA19.9 >2 LN levels above normal and high baseline Köhne score predicted short OS. Survival without deteriorated QoL and autonomy was similar with BEV and CT. On subgroup analyses, the benefit of bevacizumab seemed to be maintained in patients with baseline impaired IADL or nutritional status. CONCLUSION: Normal IADL score was associated with a good efficacy and safety of both BEV and CT. Köhne criteria may be relevant prognostic factors in older patients. Adding bevacizumab to chemotherapy does not impair patient autonomy or QoL.

Bevacizumab+chemotherapy versus chemotherapy alone in elderly patients with untreated metastatic colorectal cancer: a randomized phase II trial-PRODIGE 20 study results.

Background: Metastatic colorectal cancer frequently occurs in elderly patients. Bevacizumab in combination with front line chemotherapy (CT) is a standard treatment but some concern raised about tolerance of bevacizumab for these patients. The purpose of PRODIGE 20 was to evaluate tolerance and efficacy of bevacizumab according to specific end points in this population. Patients and methods: Patients aged 75 years and over were randomly assigned to bevacizumab + CT (BEV) versus CT. LV5FU2, FOLFOX and FOLFIRI regimen were prescribed according to investigator's choice. The composite co-primary end point, assessed 4 months after randomization, was based on efficacy (tumor control and absence of decrease of the Spitzer QoL index) and safety (absence of severe cardiovascular toxicities and unexpected hospitalization). For each arm, the treatment will be consider as inefficient if 20% or less of the patients met the efficacy criteria and not safe if 40% or less met the safety criteria. Results: About 102 patients were randomized (51 BEV and 51 CT), median age was 80 years (range 75-91). Primary end point was met for efficacy in 50% and 58% and for safety in 61% and 71% of patients in BEV and CT, respectively. Median progression-free survival was 9.7 months in BEV and 7.8 months in CT. Median overall survival was 21.7 months in BEV and 19.8 months in CT. The 36-month overall survival rate was 27% in BEV and 10.1% in CT. Severe toxicities grade 3/4 were mainly non-hematologic toxicities (80.4% in BEV, 63.3% in CT). Conclusion: Bevacizumab combined with CT was safe and efficient. Both arms met the primary safety and efficacy criteria.

Prophylaxis of catheter-related deep vein thrombosis in cancer patients with low-dose warfarin, low molecular weight heparin, or control: a randomized, controlled, phase III study.

PURPOSE: Whether an anticoagulant prophylaxis is needed for patients with cancer with a central venous catheter is a highly controversial subject. We designed a study to compare different prophylactic strategies over 3 months of treatment. METHODS: We performed a phase III prospective, open-label randomized trial. After the insertion of a central venous access device, consecutive patients with planned chemotherapy for cancer were randomized to no anticoagulant prophylaxis, low molecular weight heparin [low molecular weight heparin (LMWH); with isocoagulation doses], or warfarin 1 mg/day. Treatments were given over the first 3 months. Doppler ultrasound and venographies were performed on days 1 and 90, respectively, or sooner in case of clinical presumption of thrombosis. RESULTS: A total of 420 patients were randomized, and 407 were evaluable. Forty-two catheter-related deep vein thrombosis (DVT) occurred (10.3 %), 20 in those with no anticoagulation, 8 in those receiving warfarin, and 14 in those receiving LMWH. Nine additional non-related catheter deep vein thrombosis (CDVT) occurred. Anticoagulation significantly reduced the incidence of catheter-related DVT (p = 0.035) and catheter non-related DVT (p = 0.007), with no difference between warfarin and LMWH. Safety was good (3.4 % of attributable events) but compliance with randomized prophylaxis was lower than expected. CONCLUSIONS: Prophylaxis showed a benefit regarding catheter-related and non-catheter-related DVT with no increase in serious side effects.

The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response.

DNA repair is essential in maintaining genome integrity and defects in different steps of the process have been linked to cancer and aging. It is a long lasting question how DNA repair is spatially and temporarily organized in the highly compartmentalized nucleus and whether the diverse nuclear compartments regulate differently the efficiency of repair. Increasing evidence suggest the involvement of nuclear pore complexes in repair of double-strand breaks (DSBs) in yeast. Here, we show that the human nucleoporin 153 (NUP153) has a role in repair of DSBs and in the activation of DNA damage checkpoints. We explore the mechanism of action of NUP153 and we propose its potential as a novel therapeutic target in cancers.

[Adrenal metastasis: survival following surgical resection]. / Métastase surranélienne: survie après chirurgie d'exérèse.

GOAL: This study aims to determine the post-surgical survival after resection of adrenal metastasis from extra-adrenal primary cancers. PATIENTS AND METHODS: A retrospective study of sixteen patients undergoing surgery for adrenal metastasis between 1995 and 2005 analyzed age, type of primary cancer, interval to detection of adrenal metastasis, type of surgery performed, and survival (Kaplan-Meier curve). RESULTS: The study included 10 men and 6 women with a mean age of 55.5 years (25-74). Adrenal metastasis causes no clinical signs or symptoms. Diagnosis was made on the basis of CT scan in 12 cases and PET scan in 4 cases. The primary cancer site was lung (6), kidney (3), melanoma (2), colorectum (2), esophagus (1), pancreas (1), and B-cell lymphoma (1). Metastasis was confined to the adrenal in 7 cases and associated with other-site metastasis in 9. The interval from diagnosis of the primary cancer to detection of the adrenal metastasis ranged from 9 months to 11 years. Surgery consisted of radical resection in 5 cases, metastasectomy in 10 cases, and biopsy in one case. The overall survival was 12 months (range 2-120 months); when the diagnosis of the metastasis was synchronous with that of the primary, survival was just 8 months. CONCLUSION: The survival after surgery for adrenal metastasis is poor; it is even more dismal when the metastasis is diagnosed synchronously with the primary tumor. Surgical management depends on the primary neoplasm and the extent of metastases.

Concomitant intensive chemoradiotherapy induction in non-metastatic inflammatory breast cancer: long-term follow-up.

The aim of this study was to evaluate with a long follow-up the efficacy of concomitant chemoradiotherapy in non-metastatic inflammatory breast cancer (IBC) and to evaluate the breast conservation rate. Between 1990 and 2000, 66 non-metastatic patients with IBC were treated with chemotherapy and concomitant irradiation. The induction chemotherapy consisted of epirubicine, cyclophosphamide and vindesine, in association with split-course bi-fractionated irradiation to a total dose of 65 Gy with concomitant cisplatin and 5-fluorouracil. Maintenance chemotherapy consisted of high-dose methotrexate and six cycles of epirubicine, cyclophosphamide and fluorouracil. Hormonal treatment was given if indicated. Mastectomy was not systemic. Among 65 evaluable patients, 57 (87.6%) achieved a complete clinical response and had a breast conservation. Only six loco regional relapses were noted in six patients with a delay of 20 months and with concomitant metastatic dissemination in four cases. Median disease-free survival (DFS) was 28 months. Median overall survival (OS) was 63 months and median follow-up was 55.5 months. Induction chemotherapy and concomitant irradiation is feasible in patients with IBC, permitting a breast conservation with a high rate of local control with an OS comparable to that of the best recent series.

Randomized phase II study of docetaxel plus estramustine and single-agent docetaxel in patients with metastatic hormone-refractory prostate cancer.

BACKGROUND: Docetaxel (Taxotere)-based regimens are the new standard therapy in advanced hormone-refractory prostate cancer (HRPC). A synergistic activity has been shown with docetaxel in combination with estramustine in vitro; however, the benefit of this combination remains controversial in clinical practice. We assessed the activity and safety of docetaxel alone and docetaxel-estramustine in HRPC. PATIENTS AND METHODS: Patients (n = 92) with metastatic HRPC and rising prostate-specific antigen (PSA) while receiving androgen suppression were randomized to 3-weekly treatment with either docetaxel 75 mg/m(2), day 1 (D), or docetaxel 70 mg/m(2), day 2, plus oral estramustine 280 mg twice daily, days 1-5 (DE). RESULTS: Ninety-one patients were treated (DE 47, D 44). A PSA response occurred in 68% (primary endpoint met) and 30% of patients, respectively. Median PSA response duration was 6.0 months in both groups. Median time to progression was 5.7 and 2.9 months, and median survival was 19.3 and 17.8 months in the DE and D arms, respectively. Hematologic and non-hematologic toxic effects were mild and similar in both arms. One patient in each group withdrew due to toxicity. Quality of life was similar in both groups. CONCLUSION: Combining estramustine with docetaxel in this schedule is an active and well-tolerated treatment option in HRPC.

[MRI evaluation of primary chemotherapy response in breast cancer]. / Evaluation par IRM de la réponse à la chimiothérapie d'induction dans les cancers du sein.

The aim of this work was to evaluate the value of contrast enhanced MRI for determination of response to neoadjuvant chemotherapy (type FEC) in breast cancer according to two parameters: size of the enhancing tumor and the maximum relative enhancement curve (MRC) in the same tumor area. Twenty women with breast cancer (15 invasive ductal carcinomas and 5 invasive lobular carcinomas) T2 (n = 8) or T3 (n = 12) were evaluated by physical examination and MRI after a minimal of three courses of FEC and prior to surgery. Data from physical examination and imaging studies were compared to histopathological findings. Physical examination estimated correctly the residual tumor size in 45% of cases and MRI in 60% with 3 false negative cases. Among evaluated patients with MRI measurable residual tumor, tumor size was underestimated in 69% of the cases and overestimated in 31% of the cases. A MRC flattening was observed in 5 cases among the patients with a partial response or clinical stable disease correlated with a poor cellular density in the microscopic findings. MRI monitoring of chemotherapy response can be useful for guiding surgery. Therefore, underestimation of the residual tumor size and false negative rate are remaining problems.

[Induction chemotherapy and laryngeal preservation in pharyngolaryngeal carcinomas. Study of a 124 serie's patients and patient's follow up with laryngeal preservation]. / Chimiothérapie d'induction et préservation laryngée dans les cancers du pharyngolarynx. Etude d'une série de 124 patients et suivi des patients en préservation laryngée.

OBJECTIVE: To try and determine the value of chemotherapy and its subsequent effect on laryngeal preservation in patients presenting with laryngeal and pharyngeal carcinomas. One group was initially treated with surgery and radiotherapy. The second group was treated with chemotherapy and subsequent salvage surgery and/or radiotherapy. Their survival rates and laryngeal preservation rates were compared. PATIENTS AND METHODS: From 251 patients the authors have retrospectively studied 124 patients with induction chemotherapy. The survival rate has been compared with a control group of 127 patients who was treated by initial surgery and radiotherapy. RESULTS: The survival rate at 5 years for the patients initially treated by surgery and radiotherapy was 64.1%. The survival for patients with a total clinical response following chemotherapy was 49.8% at 5 years. Survival with no total clinical response following chemotherapy treated by secondary radiotherapy was 25.7% at 3 years. The initial rate of laryngeal preservation is 32.2% but this rate fell to 22% after local recurrencies. CONCLUSION: The group with total clinical response after induction chemotherapy with laryngeal preservation have a non significantly difference in their survival compared with the group initially treated by surgery and radiotherapy. In contrary patients with non complete clinical response have a survival of 25.7% at 3 years. The rate of local recurrency of patients with laryngeal preservation is 32.5% and gives a finally rate of laryngeal preservation of 21%. These recurrencies decrease the survival rate.

Pre-irradiation chemotherapy for newly diagnosed high grade astrocytoma.

The purpose of this work was to determine the response rate and toxicity of a combination of Carmustine and Cisplatin administered before radiation in patients with newly diagnosed high grade astrocytoma. A good response rate has been published with this association in primary cerebral high grade tumor. This protocol was administered in a homogeneous population of 37 adult patients with measurable tumor on magnetic resonance imaging (MRI) or CT scan. After biopsy or subtotal resection, the patients received BCNU 40 mg/m2/d and CODP 40 mg/m2/d, for 3 days every 28 days for 3 cycles. Evaluation was performed before each cycle. Radiation therapy began 4 weeks after completing the chemotherapy or immediately if there was evidence of tumor progression on chemotherapy. Seven out of 37 (19%) demonstrated tumor regression with a median duration to progression of 11 months. Median survival was 6 months. Myelosuppression was the predominant but manageable toxicity. This work indicated that the first chemotherapy protocol gave poor results in a homogeneous group of patients, with bad prognosis.

Thrombotic microangiopathy and digital necrosis: two unrecognized toxicities of gemcitabine.

We report one new case of hemolytic-uremic syndrome (HUS) and one case of digital necrosis after treatment with gemcitabine (Gemzar). Case 1, a 34-year-old man, was given first-line metastatic treatment with gemcitabine for a adenocarcinoma of the pancreas. After a cumulative dose of 10 000 mg/m2 gemcitabine, the onset of subacute renal failure associated with hemolytic anemia of mechanical origin was observed. A diagnosis of probable gemcitabine-induced thrombotic microangiopathy was arrived at. Symptoms resolved after stopping the chemotherapy, in spite of the progression of the disease. Case 2, a 61-year-old man, was administered a combination of gemcitabine and a platinum salt as first-line metastatic treatment for carcinoma of the bladder urothelium. Following a cumulative dose of 10 000 mg/m2 of gemcitabine, the patient suffered from bilateral peripheral vascular disease of somewhat acute onset with hemorrhagic lesions of the finger pads that became necrotic. The work-up was negative and a causal relationship was attributed to gemcitabine. The patient made good progress when given an i.v. infusion of Ilomedine (iloprost trometamol) and chemotherapy was withdrawn. We conclude that gemcitabine must be added to the list of drugs that cause HUS and necrotizing vasculitis.

[Caring for stage IB cancer of the cervix. Proposal for a protocol based on a review of the literature]. / Prise en charge du cancer du col utérin au stade IB. Proposition d'un protocole fondé sur une revue de la littérature.

A review of the literarure indicates that there are two essential prognostic factors in stage Ib cancer of the cervix: the size of the tumour (determined by a physical examination and MRI) and invasion of the lymph nodes (determined by lymphadenectomy). Of the available means of treatment, many workers use surgery at stage Ib1 and a combination of chemotherapy and radiotherapy at stage Ib2. Hence, our pre-therapeutic assessment usually includes a physical examination under general anaesthesia, MRI of the abdomen and pelvis, and laparoscopic pelvic lymphadenectomy for stage Ib1 and laparoscopic lumbo-aortic lymphadenectomy for stage Ib2. For stage Ib1 < 2 cm, if extemporaneous examination of the pelvic lymph nodes is positive, we perform lymphadenectomy of the lumbo-aortic lymph nodes and initiate treatment with chemotherapy and radiotherapy. If pelvic lymphadenectomy gives negative results in a woman who does not wish to remain fertile, we carry out radical vaginal hysterectomy (Schauta-Stoeckel) rather than radical hysterectomy (Piver 2) by laparotomy or laparoscopy. If the margins are healthy and devoid of vascular or lymphatic involvement, no further treatment is given. If this is not the case, we suggest a postoperative radio-chemotherapy. For patients who wish to retain their fertility, we carry out radical cervicectomy. For tumours measuring between 2 and 4 cm, and if pelvic lymphadenectomy is positive, we propose radio-chemotherapy, or radical hysterectomy as for small tumours. For Ib2 tumours, and if no lumbar adenopathy is seen at MRI, we perform a lumbo-aortic lymphadenectomy, followed by a radio-chemotherapy. If invasion of lumbar lymph nodes is suspected at MRI, we perform a biopsy on the left scalenic lymph nodes; if invasion is present at this level, we give palliative treatment with simple pelvic radiotherapy. If lumbo-aortic lymphadenectomy reveals invasion, radiotherapy is directed at these nodes. If, at the end of combined chemotherapy and radiotherapy, some remaining tumour is discovered at the MRI assessment, we carry out extrafacial hysterectomy.

Impact of screening on breast cancer detection. Retrospective comparative study of two periods ten years apart.

OBJECTIVE: The aim of this study was to evaluate changes in the mode of discovery of breast cancer in the last 15 years. We compared two periods separated by a 10-year interval, during which a mass mammographic screening programme was established in our department. MATERIALS AND METHOD: We made a retrospective comparison of the records of female patients with breast cancer diagnosed in our hospital over the period 1986-1989 (first period) and 1997-1999 (second period). The mass screening programme for breast cancer began in 1995. RESULTS: We collected 372 patients in the first period and 341 in the second. We found a significant change in the mode of the discovery of breast cancer between the two periods: 80.2% versus 51.9%, respectively, of the cases of breast cancer were discovered by breast self-examination, 10.2% versus 13.7% were discovered by a physician, and 4.8% versus 29.1% were discovered by routine mammography as part of an individual or mass screening programme. The mean size of the tumours decreased significantly (2.6 cm versus 2.3 cm: p = 0.019), and the number of tumours with initial metastases or lymph node involvement decreased, almost attaining the level of significance (p = 0.06). It is difficult to compare the survival and disease-free survival curves because of the short follow-up in the second period (median follow-up = 10 months). However, a marked difference appears to be developing (p < 0.0001): patients diagnosed by mammography are showing better survival and disease-free survival compared with the others. DISCUSSION: We observed that more widespread use of mammography screening for breast cancer led to smaller tumours being discovered during the second period, with less lymph node involvement and less initial metastasis. Breast cancer screening is one of the most intensively evaluated health care practices with eight completed randomized trials yet its net benefit has remained controversial. It has been shown that, at least for patients aged 50 to 70, properly organized mass screening for breast cancer led to a reduction in mortality rate. However, individual breast self-exam, physician and mammographic screening can interfere with assessment of mass screening programmes in terms of individual benefit. In addition, introducing a mass screening programme may induce opportunistic screening in non-invited age groups and influence health behaviour in the target and non target populations. A retrospective study was performed to evaluate the mode of discovery, the diagnostic presentation, and prognostic factors in breast cancer in a French department before and after initiation of a mass-screening programme (MSP).

Chemotherapy and concomitant irradiation in inflammatory breast cancer.

The purpose of this study was to evaluate the efficacy of concurrent chemotherapy and irradiation in inflammatory breast cancer (IBC). Between January 1990 and December 1998, forty-eight non-metastatic patients with clinical or occult IBC were treated with chemotherapy and irradiation. The induction chemotherapy consisted of epirubicin, cyclophosphamide and vindesin, in association with split-course bi-fractionated irradiation to a total dose of 65 Gy with concomitant cisplatin and fluorouracil. Maintenance chemotherapy consisted of high-dose methotrexate and 6 cycles of epirubicin, cyclophosphamide and fluorouracil Hormonal treatment was given routinely but mastectomies were not routinely performed. A high rate of locoregional control was obtained in 47 evaluable patients of whom 93.6 % achieved a complete clinical response. Three patients had locoregional relapses, always with concomitant metastatic dissemination. In 47 patients, 21 developed metastatic dissemination with a median delay of 23 months. Median disease-free survival (DFS) was 45 months. Median overall survival (OS) has not yet been reached after a median follow-up of 44.5 months. The 3-year DFS rate was 53 % and the 3-year OS rate was 71 %. Toxicity was mainly hematological. During the induction therapy, grade 3 or 4 neutropenia occurred in 54 % of patients, grade 3 or 4 thrombocytopenia in 23 % and grade 3 or 4 anemia in 8 %. The administration of induction chemotherapy and concomitant irradiation is feasible in patients with IBC. The hematological toxicity of this treatment approach is significant but nevertheless, the treatment achieves a high degree of locoregional control and improved survivaL

Sensitive determination of vinorelbine and its metabolites in human serum using liquid chromatography-electrospray mass spectrometry.

A liquid chromatography-electrospray mass spectrometry method was developed for the quantitation of vinorelbine (VNB) and two metabolites, vinorelbine N-oxide (VNO) and deacetyl vinorelbine (DAV) in human serum. The limits of quantitation (LOQ) reached 0.5 ng/ml for both VNB and VNO and 1 ng/ml for DAV. The method was proved linear in the range of LOQs up to 1000 ng/ml, and extraction recovery was 80% on average for the three compounds. It was applied to the pharmacokinetic monitoring of vinorelbine and, for the first time, to the detection of VNO in the serum of patients suffering from non-small-cell lung cancer.