[Breast lesions of a metastatic melanoma on a radiotherapy territory: Treatment by vemurafenib and carcinologic surgery]. / Métastases cutanées d'un mélanome sur un territoire de radiothérapie au niveau du sein: traitement par vémurafénib et chirurgie d'exérèse large.

INTRODUCTION: This article describes the unique case of a female patient who presented distant melanoma metastasis on the breast while having irradiation therapy for breast cancer. This happened eight months after the initial treatment for a melanoma of the back (under the right scapula). Furthermore, this case report demonstrates the efficiency of Vemurafenib® as a treatment for late stage melanomas. CASE REPORT: The patient was a 47-year-old female that had a superficial spreading melanoma under the right scapula (Breslow 1.02mm) that was treated with 2cm skin excision and sentinel lymph node sampling that was negative. The melanoma was positive for the BRAF600E mutation. One month after this incident, the patient developed breast cancer that was treated with conservative surgery and radiotherapy. Three months after the end of the irradiation treatment, she developed multiple melanoma metastasis on the skin of the breast. Our multidisciplinary team decided to initiate a treatment with vemurafenib. The patient showed an excellent response, so the surgical team completed the treatment with a radical mastectomy and immediate reconstruction with a pedicled latissimus dorsi flap. The histologic report of the mastectomy specimen showed no sign of melanocytic proliferation, that demonstrates the efficacy of vemurafenib. The patient showed no relapse after two years of follow-up. DISCUSSION: The speed of development and location of cutaneous metastases in this case brought us to think about the effects of radiation therapy on the skin. Radiation therapy causes acute complications (radiodermatitis) by cellular and molecular mechanisms. Moreover, depressed immunity is found after irradiation. Association of these mecanisms could explain the appearance of these metastases in irradiation field. The efficiency of vemurafenib found in our case is consistent with what is described in literature, especially with the improvement in median overall survival. CONCLUSION: This case demonstrates a unique case of distant melanoma metastasis on the irradiation field of a breast cancer. It also demonstrates the efficacy of vemurafenib as well as the efficacy of a radical complementary surgical treatment in these patients.

A phase I study of UFT-oral vinorelbine in metastatic breast cancer.

BACKGROUND: Despite current treatment options, metastatic breast cancer (MBC) remains essentially incurable, requiring research on new drugs or combinations to improve survival and quality of life. PATIENTS AND METHODS: This phase I study was designed to define the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT) and recommended dose of all-oral tegafur-uracil (UFT)/folinic acid combined with vinorelbine as chemotherapy for MBC. Starting doses were 40 mg/m(2)/week of oral vinorelbine administered continuously and 250 mg/m(2)/day of UFT plus 90 mg/day of folinic acid from day 1 to day 28, followed by a 1-week rest period. RESULTS: Ten patients were included. Eight were evaluable for toxicity and antitumor response. The second dose level was shown to be the MTD. At this dose, 2 out of 5 patients receiving oral vinorelbine at 40 mg/m(2)/week and UFT at 300 mg/m(2)/day developed DLT consisting of grade 3 asthenia and grade 3 nausea despite standard prophylaxis. Other toxicities were grade 1 diarrhea and anemia. There were no treatment-related deaths. CONCLUSIONS: The recommended dose for this combination seems to be the first dose level. A stable response was observed for 6 patients (average 33 weeks). This combination appears to be well-tolerated and offers an alternative to intravenous chemotherapy.

[Second conservative radiosurgical treatment for ipsilateral breast cancer recurrence]. / Second traitement conservateur radiochirurgical dans les récidives locales du cancer du sein.

PURPOSE: Currently, radical mastectomy represents the gold standard for ipsilateral breast cancer recurrence. However, we already showed that a second conservative treatment was feasible combining lumpectomy plus low-dose rate interstitial brachytherapy. In this study, we reported the preliminary results of a second conservative treatment using a high-dose rate brachytherapy. PATIENTS AND METHODS: From June 2005 to July 2009, 42 patients presenting with an ipsilateral breast cancer recurrence underwent a second conservative treatment. Plastic tubes were implanted intra-operatively at the time of the lumpectomy. After a post-implant CT scan, a total dose of 34 Gy in 10 fractions over 5 consecutive days was delivered through an ambulatory procedure. The toxicity evaluation used the Common Terminology Criteria for Adverse Events v3.0. RESULTS: The median follow-up was 21 months (6-50 months), median age at the time of the local recurrence was 65 years (30-85 years). The median delay between the primary and the recurrence was 11 years (1-35 years). The location of the recurrence was in the tumor bed for 22 patients (52.4%), in the same quadrant for 14 patients (33.3%) and unknown for six patients (14.3%). The median tumor size of the recurrence was 12 mm (2-30 mm). The median number of plastic tubes and plans were nine (5-12) and two (1-3) respectively. The median CTV was 68 cm(3) (31.2-146 cm(3)). The rate of second local control was 97%. Twenty-two patients (60%) experienced complications. The most frequent side effect consisted in cutaneous and sub-cutaneous fibrosis (72% of all the observed complications). CONCLUSION: A second conservative treatment for ipsilateral breast cancer recurrence using high-dose rate brachytherapy appears feasible leading to encouraging results in terms of second local control with an acceptable toxicity. Considering that a non-inferiority randomized trial comparing mastectomy versus second conservative treatment could be difficult to perform, what proof level will be necessary to achieve in order to change the medical procedures?

[Normal tissue tolerance to external beam radiation therapy: skin]. / Dose de tolérance des tissus sains: la peau et les phanères.

Acute skin toxicity is frequent during radiation therapy and can lead to temporary arrest of the treatment. Chronic toxicity can occur and conduct to cosmetic problems. Alopecia is the most frequent toxicity concerning hair and is most of the time reversible. Several factors linked to patients influence skin toxicity, such as undernutrition, old age, obesity, smoking, skin diseases, autoimmune diseases, failure of DNA reparation. Skin, hair and nail toxicities depend also on radiation schedule. Acute toxicity is greater when dose per fraction increases. Chronic and acute toxicities are more often when total dose increases. Under 45 Gy, the risk of severe skin toxicity is low, and begins above 50 Gy. Skin toxicity depends also on the duration of radiotherapy and split course schedules are associated with less toxicities. Irradiation surface seems to influence skin toxicity but interaction is more complex. Reirradiation is often feasible in case of cancer recurrence but with a risk of grade 3-4 toxicity above all in head and neck cancer. The benefit/risk ratio has to be always precisely evaluated. Permanent alopecia is correlated with the follicle dose. Modern techniques of radiation therapy allow to spare skin.

[Second primitive malignant neoplasm after radiotherapy]. / Deuxième cancer primitif survenant après radiothérapie.

Since the prolongation of survival for patients treated by radiotherapy second primary cancers are not rare. Cumulative incidence of second primary malignancy after radiotherapy (SPMAR) 40 years after treatment can reach 20 % when patients were 40 years old at treatment time. Among SPMAR some of them can be promoted by irradiation. Relative risk (RR) analysis is the most common method used to estimate the proportion of such second cancers. Most of studies reported a RR around 1.1 in adult patients. In young patients RR is about 6, meaning that SPMAR attributable to irradiation is more elevated in this subgroup. Quantification of these events, biomolecular mechanisms, risk factors are complex and not yet fully understood. Information given to patients must be adapted and the cost/benefit ratio has to be justified regarding SPMAR risk. Irradiation technique optimisation is an important point especially in young patient and adults, in order to reduce at maximum the volume of organ at risk exposed while not compromising optimal dose given to the tumour volume, although no standard rules of irradiation are definitively established at the present time.

[Spinals and paraspinals tumors treated by CyberKnife: feasibility and efficacy]. / Tumeurs spinales et paraspinales traitées par irradiation stéréotaxique par CyberKnife((R)) au centre Antoine-Lacassagne de Nice.

PURPOSE: Stereotactic radiotherapy using the CyberKnife has become a key treatment in the multidisciplinary management of secondary tumours, as well as primary benign or malignant tumours located within or adjacent to vertebral bodies and the spinal cord. The aim of this treatment is to improve local control and clinical response, including previously irradiated cases. PATIENTS AND METHODS: In this study, we present the first patients treated with CyberKnife between December 2006 and December 2007 for spinal or paraspinal tumours. The primary aim was to assess the feasibility and tolerance of stereotactic radiotherapy using the CyberKnife. Secondary aims were to establish the short-term local control, to calculate the local progression-free survival and overall survival. Clinical examination and imaging procedures were performed every three months. Response was assessed according to RECIST criteria. RESULTS: During that period, 16 patients were treated with CyberKnife. Thirteen patients had been pre-treated, three of whom had received spinal cord doses considered to be maximal. Three patients did not receive previous irradiation. The median age was 59 (36-74). The most frequent symptoms were pain (n = 8) and motor weakness (n = 4). The median dose was 30 Gy (16-50). The median number of fractions was 3 (1-5). No patient developed acute myelitis. Three patients developed acute reaction. Overall survival at 18 months was 72.4%, with a mean survival of 18.2 months (95% CI: 15.4-20.9). Local progression-free survival at 18 months was 58.4%, with a mean value of 16.9 months (95% CI: 13.6-20.2). CONCLUSION: The use of stereotactic radiotherapy with CyberKnife represents a major progress in the management of paraspinal tumours. The main advantages are better sparing of the spinal cord and the possibility of increasing the dose to the tumour target volume.

Local recurrence after breast cancer affects specific survival differently according to patient age.

PURPOSE: Young age is known to be an independent factor for developing local recurrence (LR) in breast cancer patients. It has also been shown that the occurrence of LR negatively affects patient outcome, especially if LR occurs within 3 years after treatment of the primary tumour. The question whether the impact of LR on patient outcome differs according to the patient's age has not been addressed before. The purpose of the present study is to investigate cancer-specific survival (CSS) as well as overall survival after LR in young patients (<50 years old) and to compare it to older patients. The age cut-off level was taken as 50 to avoid strong imbalance in patient numbers between the 2 groups. PATIENTS AND METHODS: Between 1974 and 2003, 2,130 breast cancer patients were treated with conservative surgery and axillary dissection. All of them received post-operative radiotherapy. Adjuvant chemo- and/or hormonal therapy was given according to the prognostic factors and the treatment policy at the time of diagnosis. Only biopsy-confirmed ipsilateral LRs were taken into account. Early LRs were those observed within 36 months after surgery, and late LRs were those which occurred thereafter. The median follow-up was 100 months. Survival analysis was conducted with the Kaplan-Meier method. RESULTS: The median age was 59 years. There were 472 patients aged <50 years versus 1,658 older patients. Pathological tumour size, hormone receptor status and lymph node involvement were evenly distributed in the 2 groups. The 5- and 10-year CSS was 92.3 and 83.9% in young patients, and 94.4 and 87.6% in older patients (p = 0.061), respectively. Overall, 200 LRs were observed; 52 of them (26%) were early LRs. The rate of LR was significantly higher in young patients: at 5 years, it was 10.5 versus 3.7% in patients ≥50 years; the respective rates at 10 years were 17.8 and 8.8% (p < 0.0001). The 5- and 10-year CSS in patients who developed LR was 86.8 and 76.0%, versus 94.7 and 88.2% in patients who did not develop LR (p < 0.0001). The 5-year CSS after LR in young and older patients was 77.6 and 65.7%, respectively (p = 0.028). CONCLUSION: Although young patients experience more LR than older ones, once LR occurs, young patients have a better outcome than the others. Possible hypotheses are: (1) more aggressive treatment in young patients after LR; (2) the treatment is better sustained in young patients; (3) biological differences in the characteristics of LR.

[CyberKnife and neoadjuvant chemotherapy for breast tumors: preliminary results]. / CyberKnife et chimiothérapie néoadjuvante pour les tumeurs du sein localement évoluées : résultats préliminaires.

PURPOSE: CyberKnife((R)) (CK) allows stereotaxic irradiation for thoracic tumor thanks to a tracking system which potential is known for lung tumors. This technique has never been used to treat breast tumors but may have a real potential. PATIENTS AND METHOD: In order to define the interest of treating breast tumors with CK, we have conducted a phase I study with a dose escalation, adding CK to neoadjuvant chemotherapy in view of allowing conservative treatment for patients that will not have surgery in first intent. Neoadjuvant chemotherapy includes six cures, including three of docetaxel and three of FEC. CK treatment is made during the second cure of chemotherapy. Two dose levels are delivered in three fractions: 19.5 and 22.5Gy. Surgery is performed six to eight weeks after the last cure. The primary objective is to define tolerance of stereotactic irradiation concomitant with neoadjuvant chemotherapy for breast tumors. Skin toxicity is the limiting criterion of the study. The secondary objectives are both histological response and quality of surgery. Here, we are presenting the preliminary results of the 2-dose level. This study participates in the French national grant called Programme hospitalier de recherche clinique (PHRC). RESULTS: No skin toxicity of grade I or more have been find. Surgery was performed as conventional and there was no complication. Pathology exams found one complete response, one lymphangitis and one partial response. CONCLUSION: These preliminary results seem to be promising but need to be confirmed. We carry on the dose escalation study.

Prognostic factors in 1,038 women with metastatic breast cancer.

BACKGROUND: Treatment of metastatic breast cancer (MBC) remains palliative. Patients with MBC represent a heterogeneous group whose prognosis and outcome may be dependent on host factors. The purpose of the present study was dual: first, to draw up a list of factors easily available in everyday clinical practice requiring no sophisticated or costly methods and second, to provide results from a large cohort of women who underwent diagnostic and treatment at a single institution. PATIENTS AND METHODS: From 1975 to 2005, a total of 1,038 women with MBC during their follow-up were included in this retrospective analysis. Patients were subsequently assigned to five groups according to the period of metastatic diagnosis. RESULTS: It is shown that age at initial diagnosis, hormonal receptor status and site of metastasis are the most relevant prognostic factors for predicting survival from the time of metastastic occurrence. It is also shown that a metastasis-free interval is an easily and immediately available multifactorial prognostic index reflecting the multiparametric variability of the disease. CONCLUSION: These fundamental observations may assist physicians in evaluating the survival potential of patients and in directing them toward the appropriate therapeutic decision.

[Tolerance of the association sucralfate / Cu-Zn salts in radiation dermatitis]. / Tolérance de l'association de sucralfate / sels de Cu-Zn dans les radiodermites.

The aim of this study was to evaluate the tolerance of topical application of the combination sucralfate / copper zinc salts in radiation dermatitis in women suffering from breast cancer and treated by radiotherapy. 47 patients (average age : 57,5 years) that have to be treated by radiation therapy on non lesional areas, were included into this open multicentric study. They had to apply Cicalfate cream twice a day, from the fi rst radiation therapy session and during 10 weeks. Patients were treated by photon- or electrontherapy (72 % et 28 %, respectively; cumulated total dose : 58,6Gy). Tolerance was considered to be excellent. The radiation dermatitis (score NCIC > or = 2) was noted at the 3rd week of radiotherapy only in 5 % of the subjects and in 53 % of the subjects, the last week of treatment. Pruritus was significantly increased at D21. Pain and discomfort were increased at D28, but remained low intensity. The soothing effect of the combination of sucralfate/ copper zinc salts were considered satisfying or very satisfying by investigators and patients during the study, varying from 94 to 100 % of satisfaction. The impact of radiation therapy on the patients'quality of life, assessed by DLQI, evaluated at the end of the study was not statistically different from the score calculated at D7 (DLQI=0,8 et D7 versus DLQI=1 at D70). Thus, topical application of the combination sucralfate / copper zinc salts can be used in the indication radiation dermatitis.

EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update.

Anaemia is frequently diagnosed in patients with cancer, and may have a detrimental effect on quality of life (QoL). We previously conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer.[Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer. Eur J Cancer 2004;40:2201-2216.] We report here an update to these guidelines, including literature published through to November 2005. The results of this updated systematic literature review have enabled us to refine our guidelines based on the full body of data currently available. Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, and in patients undergoing cancer surgery. The addition of further Level I studies confirms our recommendation that in cancer patients receiving chemotherapy and/or radiotherapy, treatment with erythropoietic proteins should be initiated at a Hb level of 9-11 g/dL based on anaemia-related symptoms rather than a fixed Hb concentration. Early intervention with erythropoietic proteins may be considered in asymptomatic anaemic patients with Hb levels 11.9 g/dL provided that individual factors like intensity and expected duration of chemotherapy are considered. Patients whose Hb level is below 9 g/dL should primarily be evaluated for need of transfusions potentially followed by the application of erythropoietic proteins. We do not recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients undergoing chemotherapy or radiotherapy who have normal Hb levels at the start of treatment, as the literature has not shown a benefit with this approach. The addition of further supporting studies confirms our recommendation that the target Hb concentration following treatment with erythropoietic proteins should be 12-13 g/dL. Once this level is achieved, maintenance doses should be titrated individually. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia, with studies supporting the use of epoetin alfa and epoetin beta weekly and darbepoetin alfa given every week or every 3 weeks. We do not recommend the use of higher than standard initial doses of erythropoietic proteins with the aim of producing higher haematological responses, due to the limited body of evidence available. There is Level I evidence that, within reasonable limits of body weight, fixed doses of erythropoietic proteins can be used to treat patients with chemotherapy-induced anaemia. This analysis confirms that there are no baseline predictive factors of response to erythropoietic proteins that can be routinely used in clinical practice if functional iron deficiency or vitamin deficiency is ruled out; a low serum erythropoietin (EPO) level (only in haematological malignancies) appears to be the only predictive factor to be verified in Level I studies. Further studies are needed to investigate the value of hepcidin, c-reactive protein, and other measures as predictive factors. In these updated guidelines, we explored a new question of whether oral or intravenous iron supplementation increases the response rate to erythropoietic proteins. We found no evidence of increased response with the addition of oral iron supplementation, but there is Level II evidence of improved response to erythropoietic proteins with the addition of intravenous iron. However, the doses and schedules for intravenous iron supplementation are not yet well defined, and further studies in this area are warranted. The two major goals of erythropoietic protein therapy are prevention or elimination of transfusions and improvement of QoL. The total body of evidence shows that red blood cell (RBC) transfusion requirements are reduced following treatment with erythropoietic proteins. This analysis also confirms that QoL is significantly improved in patients with chemotherapy-induced anaemia and in those with anaemia of chronic disease following erythropoietic protein therapy, with more robust evidence now available that QoL was improved in studies investigating early intervention in cases of chemotherapy- or radiotherapy-induced anaemia. There is only indirect evidence that patients with chemotherapy-induced anaemia or anaemia of chronic disease initially classified as non-responders to standard doses proceed to respond to treatment following a dose increase. None of the studies addressed the question in a prospective, randomised fashion, and so the Taskforce does not recommend dose escalation as a general approach in all patients who are not responding. There is still insufficient data to determine the effect on survival following treatment with erythropoietic proteins in conjunction with chemotherapy or radiotherapy. Our analysis of survival endpoints in studies involving patients receiving radio(chemo)therapy found that most studies were inconclusive, with no clear link between the use of erythropoietic proteins and survival. Likewise, we found no clear link between erythropoietic therapy and other endpoints such as local tumour control, time to progression, and progression-free survival. There is no evidence that pure red cell aplasia occurs in cancer patients following treatment with erythropoietic proteins, and the fear of this condition developing should not lead to erythropoietic proteins being withheld in patients with cancer. There is Level I evidence that the risk of thromboembolic events and hypertension are slightly elevated in patients with chemotherapy-induced anaemia receiving erythropoietic proteins. Additional trials are warranted, especially to define the optimal doses and schedules of intravenous iron supplementation during erythropoietic therapy. While our review did not address cost benefit evaluations in detail, the consensus is that studies taking into account all real determinants of cost and benefit need to be performed prospectively.

Early versus late local recurrences after conservative treatment of breast carcinoma: differences in primary tumor characteristics and patient outcome.

OBJECTIVES: To investigate whether some aspects of patient or tumor characteristics influence the timing of local recurrence (LR) in breast cancer treated conservatively, and to assess the impact of the timing of LR on patient outcome. METHODS: A retrospective analysis was conducted on patients treated with conservative breast surgery followed by radiotherapy for breast carcinoma who developed LR. Out of 2,008 cases treated in our Institute between 1977 and 2002, 180 ipsilateral LR were observed. Of these, 46 LR were observed within 36 months after treatment, called early local recurrence (ELR), 44 developed between 37 and 60 months, called medium local recurrence (MLR), and 90 occurred after 60 months, called late local recurrence (LLR). Patient and tumor characteristics were analyzed in the 2 groups and compared. RESULTS: Primary tumors >20 mm were more frequently found in patients with ELR (31%) than in patients with LLR (17%, p = 0.047). Grade 3 tumors were more often encountered in patients with ELR than in patients with LLR (27 versus 7%, p = 0.0002). Patients with ELR more frequently had tumors with negative estrogen receptors than patients with LLR (37% versus 6%, p < 0.0001). There was no statistically significant difference in the axillary lymph node (LN) status between patients with ELR and those with LLR (35 and 23% of positive LN, respectively, p = 0.24). Tumor size, grade, LN status, hormone receptors and the timing of LR affected the specific survival (SS) from initial surgery. On multivariate analysis, only LN status and the timing of LR retained an independent prognostic value, with an odds ratio of 6.7 for ELR. After LR, the SS was also influenced by all of the above factors, and on multivariate analysis, LN status, hormone receptors and the timing of LR were independent predictors with an odds ratio of SS of 2.50 in case of ELR (p = 0.006). The 5-year SS after LR for ELR, MLR and LLR were 55.8, 74.8 and 79.5%, respectively. CONCLUSIONS: Unfavorable tumor characteristics such as big size, high grade, lack of hormone receptors, but not LN status, were associated with ELR. These findings suggest that patients with such aggressive tumor characteristics who do not recur early will have a lower risk of LLR than patients with more favorable factors.

EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer.

Anaemia is frequently diagnosed in patients with cancer, yet it is difficult to identify a single cause due to its multifactorial aetiology. We conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer (see ). Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, in patients undergoing cancer surgery and following allogeneic bone marrow transplantation. The Hb level at which erythropoietic protein therapy should be initiated is difficult to determine as it varied between studies; a large number of Level I studies in patients with chemotherapy-induced anaemia or anaemia of chronic disease enrolled patients with a Hb concentration /=90 g/L) impact upon the response to erythropoietic proteins when used to treat chemotherapy-induced anaemia or prevent cancer anaemia. Evidence indicates that endogenous EPO concentration impacts on response in patients with lymphoproliferative malignancies, but is not a valid parameter in patients with solid tumours. There is Level I evidence that fixed doses of erythropoietic proteins can be used at the start of therapy to treat patients with chemotherapy-induced anaemia, but maintenance doses should be titrated individually. There is no evidence that pure red cell aplasia (PRCA) occurs following treatment with erythropoietic proteins in patients with chemotherapy-induced anaemia or when used prophylactically in patients with cancer. There is Level I evidence that the risk of thromboembolic events and hypertension are slightly elevated in patients with chemotherapy-induced anaemia receiving erythropoietic proteins. Level I evidence supports the effectiveness of erythropoietic proteins to prevenroteins to prevent anaemia in non-anaemic cancer patients receiving chemotherapy or radiotherapy or in those undergoing cancer surgery. However, these are non-licensed indications and we do not currently recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients who have normal Hb values at the start of treatment. Additional trials are warranted, especially on the issues of iron replacement and cost-effectiveness of erythropoietic protein therapy, as well as on tumour response/progression and survival.

[Neoadjuvant chemotherapy for symptomatic non operable grade II fibrillary astrocytoma in adults]. / Chimiothérapie néoadjuvante dans les astrocytomes fibrillaires de grade II symptomatiques non opérables de l'adulte.

We collected 6 case-reports of symptomatric non removable low grade fibrillary astrocytoma of adults treated with a procarbazine-CCNU-vincristine chemotherapy regimen. All patients had drug-resistant epilepsy but brain imaging was stable. Total gross resection was rejected because of Volume or tumor location. After 4 to 7 cycles of chemotherapy, 2 patients had partial response and one minor response on brain MRI. All of them were seizure-free. Progression free survival was not reached at 5 Years. Up-front chemotherapy for low-grade astrocytomas may be useful and has to be prospectively evaluated.

Breast cancer in elderly women: is partial breast irradiation a good alternative?

BACKGROUND: Approximately half of all breast cancer occurs after age 65. Several aspects for the treatment of early breast cancer may be influenced by patient age, including postoperative radiation therapy (RT), in order to prevent the risk of local recurrence (LR). Postoperative adjuvant RT, improving the chances of local control, is not always completed because of comorbidity-associated factors. Does an alternative exist between a 5-week radiotherapy regime and no irradiation after breast conservative surgery without burdening the overall therapeutic management? METHODS: The authors review the literature regarding age-specific issues in the irradiation of breast cancer and the potential role of a partial breast irradiation (PBI) to prevent LR in the ipsilateral breast. RESULTS: Phase II and III trials have been analyzed for feasibility, efficacy and toxicity. PBI may be delivered with low or high dose rate brachytherapy and intra operative, or external beam radiation therapy. PBI satisfies the control quality criteria. The majority of the teams provide PBI recurrence rates lower than 5% (0-4.4%) with a median follow-up varying between 8 and 72 months, associated with cosmetic results comparable to those achieved with conventional external beam. CONCLUSIONS: Breast cancer in elderly women represents a medical and economical problem. The recommended conservative treatment includes RT for 50 Gy over 5 weeks. Some subgroups of patients did not receive radiotherapy because of comorbidity-associated factors or more favorable tumor biology. PBI seems to be an acceptable alternative to adjuvant RT over 5 weeks and no irradiation. The evaluation of toxicity and efficacy, especially in terms of local control, is necessary and large multicentric phase III trials comparing the two irradiation approaches are needed, including quality of life, economic considerations and longer follow-up.

Prognostic value of S-phase fraction in 920 breast cancer patients: focus on T1N0 status.

The aim of this study was to reexamine the prognostic role of tumor cell kinetics measured by S-phase fraction (SPF) and to establish its clinically relevant threshold values. SPF was determined by flow cytometry in a group of 920 consecutive breast cancer patients, all followed at our institute for 10 years (1988 to 1998). Mean age was 60.5 years (27-89 years). Median follow-up was 63 months (3-150 months). All patients had initial surgical treatment. SPF quartiles were: Q1=3.08%, median value = 5.98%, Q3=10.22%. A significant difference in overall specific survival was obtained between two populations divided by a cutoff at Q1 (p < 0.0001). A multifactorial analysis including SPF and known prognostic factors such as tumor size, node status, histological grade, ER and PR status was performed using the Cox model in a population of 719 patients: univariate analysis showed that each of these factors had significant influence on overall survival. Multivariate analysis selected three of them, ranked by decreasing order of hazard ratio (HR) value: SPF (HR: 3.88, p < 0.001), tumor size (HR: 2.49, p < 0.001) and nodal status (HR: 2.28, p < 0.001). In addition, when tumors were stratified according to SPF quartile values, there were statistically different overall survival curves in patients with small tumors (< 2 cm) and in axillary node-negative patients.

[Concomitant bifractionated radiotherapy and chemotherapy with cisplatin and 5-fluorouracil in locally progressive, non-resectable epidermoid carcinomas of the pharynx: ten years experience at the Antoine Lacassagne center]. / Radiothérapie bifractionnée et chimiothérapie par cisplatine et 5-fluoro-uracile concomitantes dans les carcinomes épidermoïdes localement évolués non résécables du pharynx: dix ans d'expérience au centre Antoine Lacassagne.

PURPOSE: Patients suffering from locally advanced unresectable squamous cell carcinoma of the oropharynx and hypopharynx treated with radiotherapy alone have a poor prognosis. More than 70% of patients die within 5 years mainly due to local recurrences. The aim of this study was to evaluate retrospectively the Antoine Lacassagne Cancer Center's experience in a treatment by concomitant bid radiotherapy and chemotherapy. Evaluation was based on analysis of the toxicity, the response rates, the survival, and the clinical prognostic factors. PATIENTS AND METHODS: From 1992 to 2000, 92 consecutive patients were treated in our single institution. All of them had stage IV, unresectable squamous cell carcinoma of the pharynx and they received continuous bid radiotherapy (two daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal interval between fractions). Total radiotherapy dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Two or three chemotherapy courses of cisplatin (CP)-5-fluorouracil (5FU) were given during radiotherapy at 21-day intervals (third not delivered after the end of the radiotherapy). CP dose was 100 mg/m2 (day 1) and 5-FU was given as 5-day continuous infusion (750 mg/m2/day at 1st course; 430 mg/m2/day at 2nd and 3rd courses). Special attention was paid to supportive care, particularly in terms of enteral nutrition and mucositis prevention by low-level laser energy. RESULTS: Acute toxicity was marked and included WHO grade III/IV mucositis (89%, 16% of them being grade IV), WHO grade III dermatitis (72%) and grade III/IV neutropenia (61%). This toxicity was significant but manageable with optimised supportive care, and never led to interruption of treatment for more than 1 week, although there were two toxic deaths. Complete global response rate at 6 months was 74%. Overall global survival at 1 and 2 years was 72% and 50% respectively, with a median follow-up of 17 months. Prognostic factors for overall survival were the Karnofsky index (71% survival at 3 years for patients with a Karnofsky index of 90-100% versus 30% for patients with a Karnofsky index of 80% versus 0% for patients with a Karnofsky index of 60-70%, p = 0.0001) and tumor location (55% at 3 years for oropharynx versus 37% for panpharynx versus 28% for hypopharynx, p = 0.009). CONCLUSION: These results confirm the efficacy of concomitant bid radiotherapy and chemotherapy in advanced unresectable tumor of the pharynx. The improvement in results will essentially depend on our capacity to restore in a good nutritional status the patients before beginning this heavy treatment.

Radio-prevention of micrometastases.

In developed countries, the cancer incidence is about 150,000 cases per year and half of people with cancer may die from the extension of the primary tumour in secondary deposits. This disaster costs more than 2 billion euro per year. People with cancer are often treated with surgery and/or radiotherapy of localized primary tumour and chemo-prevention of occult disseminated micrometastases. Since chemotherapy essentially targets cycling tumour cells, quiescent micrometastases which may contain only one cell may escape. We previously reported that human melanoma clones with high metastatic potential and low gangliosides content appeared very radiosensitive to low-dose ionizing radiation both in culture and in immunosuppressed animals. This exquisite radiosensitivity was observed with the highly metastatic single cells which were resting at the time of irradiation. These data are consistent with the dose-response relationship for the radiotherapy of secondary deposits which appears linear with no threshold. Highly metastatic cells at an early stage of growth also appear very sensitive to chemicals and activated immune cells. We propose the medical hypothesis according to which the spread of resting micrometastases should be prevented by a single fraction of total-body irradiation delivered at a dose sufficiently low (below 0.2 Gy) to avoid normal tissue radiotoxicity. Radio-prevention may complement standard treatments for patients with metastases and may be delivered even for patients in whom no distant metastases were detected on tumour diagnosis (M0 stage).

Radiobiological studies on the 65 MeV therapeutic proton beam at Nice using human tumour cells.

PURPOSE: To determine the relative biological effectiveness (RBE) for initial and delayed inactivation of cells by a modulated proton beam suitable for the treatment of tumours of the eye, within the spread-out Bragg peak and in its distal declining edge. MATERIALS AND METHODS: Human tumour SCC25 cells were irradiated with the 65 MeV proton beam at the Cyclotron Medicyc in Nice. Perspex plates of different thickness were used to simulate five positions along the beam line: 2mm corresponding to the entrance beam; 15.6 and 25 mm in the spread-out Bragg peak; 27.2 and 27.8mm for the distal edge. At each position clonogenic survival of the irradiated cells and of their progeny were determined at various dose values. 60Co gamma-rays were used as reference radiation. RESULTS: RBE values evaluated at the survival level given by 2 Gy of gamma-rays increased with increasing depth from close to 1.0 at the proximal to about 1.2 at the distal part of the peak. Within the declining edge it reached the value of about 1.4 at 27.2 and about 2 at 27.8 mm. For the progeny of irradiated cells, the RBE value ranged from 1.0 to 1.1 within the spread-out Bragg peak and then increased up to a value of 2.0 at the last position. The dose-effect curves for the progeny always had a larger shoulder than for the irradiated progenitors, their alpha parameters being lower by a factor of about 4 and their beta parameters always being higher. The alpha/beta ratio was about 50 Gy for the progenitors and about 6 Gy for their progeny. The incidence of delayed effects increased with dose and with the depth within the beam. CONCLUSIONS: RBE values for the inactivation of cells irradiated in the spread-out Bragg peak are compatible with the value currently assumed in clinical applications. In the distal declining edge of the beam, the RBE values increased significantly to an extent that may be of concern when the region of the treatment volume is close to sensitive tissues. The yield of delayed reproductive cell death was significant at each position along the beam line.