[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.

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.

Establishment, characterization, chemosensitivity, and radiosensitivity of two different cell lines derived from a human breast cancer biopsy.

In vitro culture of a human breast cancer biopsy fragment gave rise to two permanent cell lines, CAL 18 A and CAL 18 B, which were differentiated by both morphological and ultrastructural analysis. The karyotypic and growth properties of these two cell lines also differed, providing further evidence of cell heterogeneity within a given tumor. Both cell lines lost their hormone receptors in vitro. CAL 18 A cells grew in agar and were tumorigenic after inoculation into nude mice; neither of these properties was observed in CAL 18 B cells. The chemosensitivity of 12 antineoplastic drugs was assessed by a short-term assay, using inhibition of tritiated thymidine incorporation by the cells after contact with the drugs as the end point. Only a few drugs were active at moderate concentrations. The overall responses of both cell lines were similar. The cell survival curves, established by the colony method following a single dose of radiation, were also very similar, despite the greater heterogeneity of CAL 18 B cells. The two cell lines appear to be interrelated, since CAL 18 B cells were occasionally observed to emerge from CAL 18 A clones, suggesting that malignant cell redifferentiation may occur spontaneously in vitro.

Epidermal growth factor receptor and labeling index are independent prognostic factors in glial tumor outcome.

The aim of this study was to perform a multivariate analysis including clinical and biological prognostic factors on glial tumor outcome. Seventy-nine patients were analyzed (48 men and 31 women; mean age = 56 years, range = 16-77 years): 7 had a benign glial tumor (grades 1 and 2), 21 had an anaplastic glial tumor (grade 3), and 51 had a glioblastoma (grade 4). Median follow-up was 17.9 months for patients who survived (50 patients died). Biopsies were obtained at time of diagnosis (complete tumor resection in 62 patients and stereotaxic biopsies in 17 patients). Epidermal growth factor receptor (EGFR) was measured by a binding assay, and labeling index (LI) was measured by tritiated thymidine incorporation. EGFR varied from 4 to 73,110 fmol/mg protein (mean = 3912 fmol/mg protein; median = 374 fmol/mg protein; n = 79). LI varied between 0.1 and 16.5% (mean = 6.2%; median = 5.2%; n = 40). Log10 EGFR was significantly and positively correlated with patient age. LI was significantly different according to tumor histology. Univariate Cox analysis (end point was cancer death) showed that age (P = 0.027), log10 EGFR (P = 0.025), and LI (P = 0.0019) were significant continuous variables, the survival being shortened when the covariable increased; tumor resection (P = 0.015, relative risk = 0.45) and histology (P = 0.0009) were significant categorical factors. A multivariate Cox analysis (forward selection) including age, histology, tumor resection, log10 EGFR, and LI revealed that log10 EGFR, LI, and tumor resection were the only independent significant predictors of survival. This multivariate approach reveals that the clinical prognostic factors of glial tumors, namely age and tumor histology, disappear, to the benefit of intrinsic characteristics of the tumor, i.e., EGFR expression and LI, suggesting that coupled EGFR and LI determination could be a useful tool for better evaluation of glial tumor outcome.

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.

Alternate day treatment and late effects: the concept of an effective dose per fraction.

Although most institutions treat all fields each day, some radiotherapists continue to adopt an alternate day schedule. The resulting daily variations of the dose per fraction in laterally located targets have been analyzed using the linear-quadratic model. Patients with breast carcinoma treated with definitive radiotherapy in 1974-1975 with one field a day were studied. An effective dose per fraction was derived, with a value higher than the average dose per fraction received by the reference point. The greater the fluctuations between the doses per fraction on successive days, the higher the effective dose per fraction. The corresponding cell survival due to alternate treatment as compared to survival with daily treatment depends on the alpha/beta ratio. For a late effect with low alpha/beta ratio, an alternate treatment may lead to almost 10-fold increase in cell kill in these lateral targets such as those responsible for subcutaneous sclerosis as compared to daily treatment of all fields with the same total dose. Taking the average effective dose per fraction in our series, the increase in cell kill was 4-fold. Acute effects would suffer less damage due to alternate treatment because of a high alpha/beta ratio. Treatment on an alternate schedule should be restricted to palliative radiotherapy.

Results of proton therapy of uveal melanomas treated in Nice.

PURPOSE: To present the first results of uveal melanomas treated with the Medicyc Cyclotron 65 MeV proton beam facility in Nice, analyzing the factors that affect the cause-specific survival (CSS), metastatic rate, and reporting the visual outcome. METHODS AND MATERIALS: This study concerns 538 patients referred by French institutions between June 1991 and December 1996. The eye and tumor parameters were measured using ultrasonography and angiography. Since 1994, CT scans were performed in most patients to help determine the axial length and the shape of the ocular globe. Tantalum clips were inserted around the tumor by the referring ophthalmologist. There were 349 posterior pole tumors (64.9%), 130 equatorial tumors (24.1%), and 59 ciliary body tumors (11%). Two hundred four patients (37.9%) had T1 or T2 tumors, and 334 patients (62.1%) had T3 or T4 tumors. The median tumor diameter was 14.6 mm, and the median tumor height was 5.1 mm. All patients received 52 Gy (57.20 Gy Co-equivalent dose) on 4 consecutive days. The data were analyzed by December 1997. RESULTS: The CSS was 77.4% at 78 months, the overall survival was 73.8% and the local control was 89.0%. The CSS was not influenced by the patient age or the site of the tumor. It was 81.5% for T1 and T2 tumors, versus 75% for T3 and T4 tumors (P = 0.035). It was found that the tumor diameter, rather than the height, was the most important parameter affecting outcome. The metastatic rate was 8%. It depended on the T stage, tumor diameter and thickness, but not the tumor site. Thirty-eight enucleations were performed, most of them due to tumor progression and/or glaucoma. One-third of the patients in whom visual acuity was adequately scored before and after treatment had a stable, if not improved vision, and half the patients retained useful vision after treatment. CONCLUSION: The outcome of patients suffering from uveal melanoma and treated with high-energy protons compares favorably with other techniques of treatment. The tumor dimensions affected CSS and metastatic rate. Even though two-thirds of patients had posterior pole tumors, half of them retained useful vision.

Concomitant b.i.d. radiotherapy and chemotherapy with cisplatin and 5-fluorouracil in unresectable squamous-cell carcinoma of the pharynx: clinical and pharmacological data of a French multicenter phase II study.

PURPOSE: The aim of this phase II study conducted on unresectable squamous cell carcinoma (USCC) of the oro- and hypopharynx was to associate twice-a-day (b.i.d.) continuous nonaccelerated radiotherapy with concomitant cisplatin (CP)-5-fluorouracil (5-FU) chemotherapy, both given at full dose. Feasibility, efficacy, survival, and pharmacokinetic-pharmacodynamic relationships were analyzed. METHODS AND MATERIALS: Fifty-four consecutive patients with strictly USCC of oro- and/or hypopharynx received continuous b.i.d. radiotherapy (RT) (2 daily fractions of 1.2 Gy, 5 days a week, with a 6-h minimal interval between fractions). Total RT dose was 80.4 Gy on the oropharynx and 75.6 Gy on the hypopharynx. Three chemotherapy (CT) courses of CP-5-FU were given during RT at 21-day intervals (third not delivered after the end of RT). CP dose was 100 mg/m2 (day 1) and 5-FU was given as 5-day continuous infusion (day 2-day 6: 750 mg/m2/day cycle 1, 750 mg total dose/day cycle 2 and 3). Pharmacokinetics was performed for 5-FU (105 h follow-up) and CP (single sample at 16 h). Special attention was paid to supportive care. RESULTS: Good feasibility of RT was observed (85.2% of patients with total dose > 75 Gy). Five patients received 1 CT cycle, 34: 2 cycles, and 15: 3 cycles. The most frequent and severe acute toxicities were mucositis with grade 3-4 occurring in 28% at cycle 1 and 86% at cycle 2, as well as neutropenia (43% at cycle 2). Locoregional control at 6 months was observed in 66.7% of patients. No late toxicity above grade 2 RTOG was noticed. CP dose and 5-FU AUC(0-105h) were significantly linked to grade 3-4 neutropenia (cycle 2). Cumulative total platinum (Pt) concentration and Karnofsky index were the only independent predictors of locoregional control at 6 months. Finally, total RT dose and total Pt concentration were the only independent predictors of specific survival. CONCLUSION: This protocol showed good locoregional response with an acceptable toxicity profile. Pharmacokinetic survey is probably an effective approach to further reduce toxicity and improve efficacy. A multicentric randomized phase III study, now underway, should confirm these encouraging results.

Cell proliferation kinetics in human solid tumors: relation to probability of metastatic dissemination and long-term survival.

A large number of studies have investigated the relationship between the long-term survival and the percentage of tumor cells in S phase assessed by autoradiography after tritiated thymidine labelling, image cytometry, flow cytometry or labelling with an halogenated analog of thymidine, in various types of human solid tumors. The survey of the results clearly shows that the S-phase fraction (SPF) is of high prognostic significance in several types of cancers, in particular in breast cancers, non-Hodgkin lymphomas, ovarian cancers, neuroblastoma, bladder cancers and lung cancers. SPF was found of high independent significance in 10 of the 11 studies in which multivariate analyses of prognostic factors had been carried out. Proliferation appears generally to be of higher prognostic significance than ploidy. In view of the wide differences in the biological characteristics of the tumors studied, it is likely that the association between a high proliferation rate and the degree of tumor aggressiveness is a general feature of human solid tumors. However, high proliferative rate of tumor cells is probably not the cause of tumor biological aggressiveness but a variable associated with it. The extent to which cells escape from the regulatory systems which control their proliferation appears to be a good index of tumor progression.

Inherent radiosensitivity and split-dose recovery in plateau-phase cultures of 10 human tumour cell lines.

The radiation response of 10 human tumour cell lines, eight of them established in our Institute, was analysed. Single dose acute survival curves were constructed and fitted with the linear-quadratic (LQ) model. The mean inactivation dose (D) was also calculated, together with D(o) and n. In order to measure both split-dose recovery and delayed plating recovery of plateau-phase cells, confluent cultures were subjected to two doses of 2 Gy 24 h apart, and plated 24 h later, simulating clinical fractionation. Survival of these cells (S2 x 2) was compared to that following 4 Gy given to cells plated at low density and an overall recovery factor (RF) was derived, including both types of recovery. S2 x 2 and RF were compared to the intrinsic radiosensitivity parameters. The three melanoma cell lines differed in radiation response, and the three squamous cell carcinoma cell lines were rather radioresistant. The neuroblastoma cell line was highly sensitive, yet it expressed the highest beta and the highest RF. Using a non-parametric correlation test, S2 x 2 was found to be related to D, whereas RF was not related to the radiosensitivity parameters. However, the two cell lines with the lowest D and the lowest S2 expressed the highest RF. These results suggest that radiosensitive cell lines may have a considerable capacity to recover if confluent cultures are exposed to fractionated irradiation. The overall recovery factor (RF) used here is proposed as a useful measure of cellular recovery.

Micronucleus induction in 10 human tumour cells after high- and low-dose radiation.

A number of data measuring survival of animal or human cells to low LET ionizing radiation have demonstrated that these cells may be hypersensitive to doses below 1 Gy, possibly due to the absence of an inducible repair mechanism, which is observed at higher doses. The production of micronuclei (MN) in cells exposed to ionizing radiation reflects genotoxic damage. Moreover, the micronucleus assay is sensitive to low radiation doses. We have exposed 10 human tumour cell lines to doses ranging between 0.12 and 4 Gy. Using cytochalasin B to block the cells in a binucleate phase, we have scored the fraction of binucleate cells (BNC) expressing MN, as well as the number of MN per BNC, as a function of gamma-ray dose. Experimental points were fitted with a binomial equation. Doses from 1 to 4 Gy were fitted separately from those below 1 Gy, and the initial slopes after both fits were compared. Taken together, the initial slopes of MN induction after low-dose (LD) irradiation were not different from those after high-dose (HD) irradiation. Only in one cell line was a significant increase in MN production detected after LD irradiation. This cell line had the shallowest linear term after HD irradiation. It appeared that the likeliness of expressing hypersensitivity at LD was correlated with the quadratic term of MN induction at HD, which does not contradict an inducible repair hypothesis. However, the failure of observation of a significant hypersensitivity at LD for nine cell lines, and the high variability of response at LD suggests that this occasional effect may be influenced by other factors as well.

The labelling index: a prognostic factor in head and neck carcinoma.

The thymidine labelling index (LI), representing the percentage of cells in the DNA-synthesis phase, was measured in vitro prior to therapy in 87 patients with squamous cell carcinoma of the head and neck, who were treated between 1977 and 1982. The LI was not related to patient age, site of the tumour, clinical stage or histological grade. Overall survival was 44.5%. Univariate analysis demonstrated that survival was affected by the following factors: (1) age: patients older than 55 had a better outcome (p = 0.03); (2) site of the tumour (p = 0.005): laryngeal tumours had the best survival; (3) clinical stage (p = 0.05). Histological grade did not influence the survival (p = 0.41). Patients having a tumour LI higher than 15.5% (mean + 1 S.D.) had a significantly lower survival than patients with lower tumour LI (p = 0.008). A multivariate analysis using the Cox model showed that clinical stage and LI kept their prognostic impact with regard to survival. Finally, survival after relapse was lower in patients with a high tumour LI. These results demonstrate that a high tumour proliferation rate is an additional factor influencing the disease outcome in head and neck carcinoma. Patients with bad prognosis defined by this parameter could be offered a more energetic treatment.

Mean inactivation dose: a useful concept for intercomparison of human cell survival curves.

The mean inactivation dose (D) is calculated for published in vitro survival curves obtained from cell lines of both normal and neoplastic human tissues. Cells belonging to different histological categories (melanomas, carcinomas, etc.) are shown to be characterized by distinct values of D which are related to the clinical radiosensitivity of tumors from these categories. Compared to other ways of representing in vitro radiosensitivity, e.g., by the multitarget parameters D0 and n, the parameter D has several specific advantages: (i) D is representative for the whole cell population rather than for a fraction of it; (ii) it minimizes the fluctuations of the survival curves of a given cell line investigated by different authors; (iii) there is low variability of D within each histological category; (iv) significant differences in radiosensitivity between the categories emerge when using D. D appears to be a useful concept for specifying intrinsic radiosensitivity of human cell lines.

Pharmacokinetics of cisplatin given at a daily low dose as a radiosensitiser.

A total of 25 patients with inoperable cervical cancer were treated by daily radiotherapy (2 Gy); sensitisation was obtained by administration of 5 mg cisplatin 30 min before each irradiation session. The total cumulative dose of cisplatin varied between 50 and 150 mg. A complete kinetic profile (0-24 h) of platinum (Pt) was established after the first dose and at the end of treatment for 22 patients. Pt was quantified by atomic absorption spectrophotometry using Zeeman-effect background correction for trace analysis. The total Pt AUC0-24h increased from 1.53 +/- 0.77 to 7 +/- 3.55 micrograms.h.ml-1 between the start and the end of treatment (P less than 0.001). Ultrafilterable Pt (Pt UF) rose from 0.079 +/- 0.038 to 0.138 +/- 0.095 microgram.h.ml-1 (P less than 0.01). Elimination half-lives were unchanged for total Pt but rose for Pt UF; these kinetic modifications in Pt UF did not correlate with any significant change in individual serum creatinine levels. No clear correlation was found between the cumulative cisplatin dose and tumor levels measured in 13 patients, and the tumor cisplatin dose did not correlate with response to treatment. Patients with hematological toxicity were characterised by an increase in their residual Pt UF level during treatment. Overall, our findings strengthen the notion of Pt UF kinetic variability during repeated treatment.