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Background: Abnormal expression of key proteins of the apoptotic pathway has been associated with poor prognosis, although there have been few studies of these correlations in patients with prostate carcinoma who are treated with radiotherapy. The current study examined the association between expression levels of Ki-67, bcl-2, bax, and bcl-x in pretreatment biopsy specimens and patient outcome after definitive radiotherapy alone., Methods: Archival pretreatment prostate biopsy tumor tissue was retrieved from 106 patients with Stage T1-T3 prostate carcinoma who were treated at the University of Texas M. D. Anderson Cancer Center with external beam radiotherapy between 1987 and 1993. Expression levels of Ki-67 (MIB-1 staining; n = 106 patients), bcl-2 (n = 77 patients), bax (n = 70 patients), and bcl-x (both long and short splice variants; n = 72 patients) were determined by immunohistochemical staining. The Ki-67 labeling index (Ki67-LI) was available for all patients and was derived from the percentage of Ki-67 positive cells. Biochemical failure after radiotherapy was defined as three consecutive rises in prostate specific antigen level on follow-up. The median follow-up was 62 months., Results: High Ki67-LI (> 3.5%) expression was observed in 33% of patients, overexpression of bcl-2 was observed in 16% of patients, altered bax expression was observed in 23% of patients, and altered bcl-x expression was observed in 53% of patients. There was no correlation found between the biomarkers. Kaplan-Meier survival estimates of freedom from biochemical failure (bNED) and the log-rank test revealed significantly lower rates in association with high Ki67-LI, positive bcl-2, and altered bax staining. No correlation was observed between bcl-x staining and bNED. Cox proportional hazards multivariate analysis confirmed that bcl-2 and bax were independent of pretreatment PSA level, Gleason score, disease stage, and Ki67-LI in predicting bNED., Conclusions: Abnormalities in the expression levels of bcl-2 and bax were associated with increased failure after patients were treated for prostate carcinoma with external beam radiotherapy. These biomarkers appeared to be useful in categorizing patient risk further, beyond Ki-67 staining and conventional clinical prognostic factors., (Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11230)

The delineation of target volume and organs at risk depends on the organs definition, and on the modalities for the CT-scan acquisition. Inter-observer variability in the delineation may be large, especially when patient's anatomy is unusual. During the two french multicentric studies of conformal radiotherapy for localized prostate cancer, it was made an effort to harmonize the delineation of the target volumes and organs at risk. Two cases were proposed for delineation during two workshops. In the first case, the mean prostate volume was 46.5 mL (extreme: 31.7-61.3), the mean prostate and seminal vesicles volume was 74.7 mL (extreme: 59.6-80.3), the rectal and bladder walls varied respectively in proportion from 1 to 1.45 and from 1 to 1.16; in the second case, the mean prostate volume was 53.1 mL (extreme: 40.8-73.1), the volume of prostate plus seminal vesicles was 65.1 mL (extreme: 53.2-89), the rectal wall varied proportionally from 1 to 1, 24 and the vesical wall varied from 1 to 1.67. For participating centers to the french studies of dose escalation, a quality control of contours was performed to decrease the inter-observer variability. The ways to reduce the discrepancies of volumes delineation, between different observers, are discussed. A better quality of the CT images, use of urethral opacification, and consensual definition of clinical target volumes and organs at risk may contribute to that improvement.

Purpose: To determine the significance of Ki-67/MIB1 staining as a marker of patient outcome for prostate cancer patients treated with radiotherapy., Experimental Design: Pretreatment archival prostate biopsy tumor tissue was available from 106 stage T1-T4 prostate cancer patients treated with external beam radiotherapy between 1987 and 1993 at M. D. Anderson Cancer Center. Diagnosis was made from prostate needle biopsy in 64 cases and from transurethral resection of the prostate (TURP) in 42 cases. All patients had a pretreatment prostate-specific antigen (PSA), and no patient had evidence of metastasis. Immunohistochemical staining for MIB1 was used to determine the percentage of Ki-67-positive tumor cells, the Ki-67 labeling index (Ki67-LI). Biochemical failure after radiotherapy was defined as three rises in PSA on follow-up. Median follow-up was 62 months., Results: The mean and median Ki67-LI for the entire cohort was 3.2 and 2.3. The mean and median Ki67-LIs for those diagnosed by needle biopsy were 3.2 and 2.3, and by TURP were 3.1 and 2.4. For all patients, mean Ki67-LI levels were significantly higher with stage T3/T4 disease, Gleason 7-10 disease, and in those that developed treatment failure. Similar relationships were observed when the Ki67-LI was dichotomized into low (< or =3.5%) and high (>3.5%) groups. Actuarial freedom from biochemical failure (bNED) when Ki67-LI was low and high was 76 and 33% at 5 years (P < 0.0001, log rank). Similar statistically significant differences were observed when the TURP and needle biopsy groups were analyzed separately. Cox proportional hazards regression showed that dichotomized Ki67-LI was an independent correlate of bNED, along with pretreatment PSA, Gleason score, and clinical stage., Conclusions: The Ki67-LI obtained from pretreatment prostate cancer tissue is a strong independent predictor of failure after radiotherapy using biochemical criteria. This prognostic factor was equally valuable for patients diagnosed by TURP or needle biopsy.

Purpose: The aim of this retrospective study was to evaluate the survival data and rates and patterns of complications and recurrences for patients who had early uterine cervix carcinoma and underwent brachytherapy and subsequent surgery., Methods and Materials: Between January 1990 and December 1997, 192 women with cervical carcinoma (Stages IA2 with vascular invasion [n = 28], IB1 [n = 144], and IIA [n = 20]) underwent brachytherapy, delivering 60 Gy and then hysterectomy with external iliac lymphadenectomy. Piver class I, II, and III hysterectomies were performed on 136, 38, and 18 patients, respectively. Adjuvant chemoradiotherapy was delivered to patients with positive lymph nodes., Results: The median follow-up time was 61 months. After brachytherapy, a pathologically complete response (CR) was observed in 137 (71.3%) of 192 women. The distribution of CRs according to tumor stage was as follows: Stage IA2, 24 (85.7%) of 28; Stage IB1, 105 (72.9%) of 144; and Stage IIA, 8 (40%) of 20. Patients with Stage IB1 cancer had 13 lymph node metastases (9%), as did 6 with Stage IIA disease (30%). Pelvic recurrences occurred in 9 (4.6%) of the 192 patients; in 3, local relapses were associated with relapses at distant sites. Ten patients had systemic relapses (5.2%). Recurrences at distant sites were more frequent (p < 0.02) in partial responders, and other recurrences were more frequent in patients with lymph node metastases (p < 0.04). The overall 5-year disease-free survival rate was 91.2% (96.2% for Stage IA2, 91% for Stage IB1, and 84.4% for Stage IIA cancers). The class of hysterectomy did not influence the outcome. Late complications occurred in 28 patients (Grade 1, 24 [12.5%]; Grade 2, 4 [2%]; and Grade 3, 1 [0.5%] of 192 patients)., Conclusions: Combined treatments resulted in high local control and low morbidity rates in patients with early-stage cervical carcinoma. Limited surgery seemed to be adequate after intracavitary therapy.

Objective: To study the safety of conformal radiotherapy dose escalation up to 80 Gy for curative treatment of prostate cancer., Material and Methods: A multicentre trial sponsored by the PHRC include 164 patients under the age of 75 years with stage T1b-T3 N0 M0 prostatic adenocarcinoma, between 1995 and 1998. The prostate was treated at 5 dose levels: 18 patients at 66 Gy, 28 at 70 Gy, 49 at 74 Gy, 48 at 78 Gy, 21 at 80 Gy. The acute and delayed toxicity was graded according to a multidisciplinary glossary. Quality of life was evaluated before and one year after treatment using the EORTC QLQ-C30 questionnaire and additional questions., Results: 89% and 55% of mild or moderate gastrointestinal and urinary adverse effects were observed during treatment, respectively. At long-term follow-up, of the 162 evaluable patients, 12.3% presented grade 2 adverse effects and 2.5% presented grade 3 adverse effects (1 case of haematuria, 2 urethral strictures, 1 bladder neck lesion) with no significant difference between the various dose levels. Two successive quality of life questionnaires were available for 119 patients: tiredness, pain and dyspnoea increased in parallel, but non-significantly in the groups receiving conventional doses or high doses. The proportion of patients reporting sexual activity without endocrine therapy decreased from 48% before treatment to 35% one year later. The proportion of patients with no clinical or laboratory signs of progression was higher in the high-dose group., Conclusion: No significant difference was observed between conventional dose levels and high dose levels in terms of toxicity or quality of life. As the adverse effects were acceptable, a randomized trial comparing 70 Gy and 80 Gy has been initiated.

Purpose/objective: The effect of adenoviral-mediated p53 transgene expression on the radiation response of two human prostate cancer cell lines, the p53(wild-type) LNCaP and p53(null) PC3 lines, was examined. The objective was to determine if this vector sensitizes cells to radiation independently of their p53 status., Methods and Materials: A recombinant adenovirus-5 vector (RPR/INGN 201, Introgen Therapeutics, Houston, TX) containing a CMV promoter and wild-type p53-cDNA (Ad5-p53) was used to facilitate p53 transgene expression. A multiplicity of infection (MOI) of 10-40 viral particles per cell was used, based on Ad5/CMV/lacz infection and staining for the beta-galactosidase reporter gene product. Clonogenic assays were performed to evaluate the degree of sensitization to radiation of viral-transduced cells compared with irradiated nontransduced controls. The relative efficacy of these treatments to induce apoptotic cell death was determined using the TUNEL assay., Results: The delivery of Ad5-p53 (10 MOI) reduced control plating efficiency from 36.5% to 0.86% in the LNCaP cell line and from 75.1% to 4.1% in the PC3 cell line. After correcting for the effect of Ad5-p53 on plating efficiency, the surviving fraction after 2 Gy (SF2) of gamma-irradiation was reduced over 2.5-fold, from 0.187 to 0.072, with transgene p53 expression in the LNCaP cell line. Surviving fraction after 4 Gy (SF4) was reduced over 4.5-fold, from 0.014 to 0.003, after Ad5-p53 treatment. In the PC3 cell line, Ad5-p53 (40 MOI) reduced SF2 over 1.9-fold from 0.708 to 0.367, and SF4 over 6-fold from 0.335 to 0.056. In both the LNCaP and PC3 cell lines, the combination of Ad5-p53 plus radiation (2 Gy) resulted in supra-additive apoptosis (approximately 20% for LNCaP and approximately 15% for PC3 at 50 MOI), above that seen from the addition of the controls; control vector Ad5-pA plus RT (0.15% for LNCaP and 1.44% for PC3), Ad5-p53 alone (28.6% for LNCaP and 21.7% for PC3), RT alone (0% for LNCaP and 0.23% for PC3), or Ad5-pA alone (0.1% for LNCaP and 0.29% for PC3)., Conclusion: The clonogenic survival and apoptosis data demonstrate that p53 transgene expression sensitizes human prostate adenocarcinoma cells in vitro to irradiation. As this effect was observed in both the p53(wild-type) LNCaP and p53(null) PC3 lines, radiosensitization was independent of p53 status.

An adenovirus 5 vector containing wild-type p53 cDNA (Ad5-p53) and a cytomegalovirus promoter was used to generate p53 transgene expression. Control vector (Ad5-pA) contained the poly-adenosine sequence. PC3 cells (2 x 10(6)) were injected s.c. into the legs of nude mice. Treatment with Ad5-p53 was initiated at a tumor volume of 200 mm3. Three intratumoral injections (days 1, 4, and 7) were given with 3 x 10(8) plaque-forming units, followed by 5 Gy pelvic irradiation (day 8) in one fraction using a cobalt-60 source. Tumor volume measurements were obtained every 2 days. LNCaP cells (2 x 10(6)) were injected orthotopically into the prostates of nude mice, and tumor weight was approximated using serum prostate-specific antigen (PSA) obtained from weekly tail vein bleedings. The target PSA for the start of the studies was 5 ng/ml. The intraprostatic injections of Ad5-p53 were done twice (days 1 and 2) and followed by 5 Gy pelvic irradiation on day 3. The PC3 tumor volume growth curves were log transformed and fitted using linear regression. The times (in days) for the tumors to reach 500 mm3 were calculated as 10.7 +/- 0.7 (+/- SE) for the saline control (no virus), 9.8 +/- 2.1 for Ad5-pA, 15.6 +/- 1.6 for Ad5-p53, 14.6 +/- 1.5 radiation therapy (RT; 5 Gy), 14.6 +/- 1.5 for Ad5-pA plus RT, and 31.4 +/- 5.3 for Ad5-p53 plus RT. The Ad5-p53 plus RT times were significantly different from the other groups. An enhancement factor of 3.4 was calculated, indicating supra-additivity. LNCaP tumor growth was determined via weekly serum PSA measurements. Treatment failure was determined using two PSA-based methods; a serum PSA of > 1.5 ng/ml or two rises in PSA during 6 weeks posttreatment. The results were similar using either end point. Treatment with Ad5-p53 plus 5 Gy resulted in significantly fewer PSA failures (<30%), as compared with Ad5-p53 alone (64-73%) and the other controls (approximately 80-100%) These results are also consistent with a supra-additive inhibition of tumor growth. Tumor growth in vivo was inhibited supra-additively when p53null and p53wildtype prostate tumors were treated with Ad5-p53 and 5 Gy radiation.

Purpose: To evaluate the feasibility of dose escalation in a multi-institutional study in prostate cancer patients., Methods and Materials: Between October 1995 and October 1998, 164 patients with localized adenocarcinoma of the prostate were treated with 3-dimensional conformal radiotherapy at one of five French institutions. The dose of radiation was escalated from 66 to 80 Gy (ICRU point). The maximum dose to the rectal wall was limited to 75 Gy., Results: Results were compared in two groups, one (group 1) receiving the standard dose (n = 46 patients; 66 to 70 Gy) and the other (group 2) receiving the escalated dose (n = 118 patients; 74 to 80 Gy). There was no difference in the characteristics of patients between the two groups. The mean follow-up time was 32 months in group 1 and 17.5 months in group 2. No statistical difference between the two groups was observed in the incidence of late gastrointestinal and urinary toxicities. The probability of achieving a posttreatment prostate-specific antigen nadir of

Purpose: To determine the outcome of patients with positive margins after lumpectomy for breast cancer and to address the issue of the relationship between local recurrences and distant metastasis in the absence of chemotherapy., Methods and Materials: Among 3697 patients with primary breast cancer, we retrospectively analyzed 152 patients who had undergone conservative surgery with axillary dissection, had infiltrating carcinomas with positive margins, were node-negative, and received radiotherapy without chemotherapy. One-third received hormonal therapy. Endpoints were local failure and distant metastasis. Median follow-up was 72 months., Results: Five- and 10-year recurrence-free survival were 0.80 and 0.71 respectively for local recurrences, and 0.85 and 0.73 respectively for metastasis. Infiltrating carcinoma on the margins was associated with early local relapse as opposed to intraductal carcinoma. Local and distant recurrences had similar patterns of yearly-event probabilities. Hazard of relapsing from metastasis was 2.5 times higher after a local recurrence. In the multivariate analysis, negative estrogen receptors (ER-)(p = 0.0012), histologic multifocality (p = 0.0028), and no hormonal therapy (p = 0.017) predicted local relapses, while ER- (p = 0.004) and pathologic grade (p = 0.009) predicted metastasis. Hormonal therapy did not prevent early local recurrences., Conclusion: In this population, reexcision is advisable for local purposes and because the data support the hypothesis that local and distant recurrences are tightly connected.

One hundred and sixty-two breast carcinomas treated by adjuvant chemotherapy were investigated in immunohistochemistry for expression of p53 and two wild-type p53-regulated induced proteins, mdm2 and p21/waf1. p21 and mdm2 were expression stongly correlated with Ki67 but not with survival. The p53+/p21+, p53+/p21- and p53+/mdm2- phenotypes were associated with the worst prognosis. The p53+/p21+/ mdm2+ tumors were associated with a better outcome than the other phenotypes, they may be tumors expressing wild-type p53 and p21, and a form of mdm2 that might lead to the stabilization of p53. It is suggested that p21/mdm2 expression should be investigated in all cases of p53 positive breast cancer.

We evaluated the feasibility of administering, in an out-patient setting, a sequential high dose alkylating regimen with hematopoietic growth factor (HGF) and stem cell support to patients with advanced breast cancer. Peripheral blood stem cells (PBSC) were previously collected after chemotherapy and HGF. Two consecutive cycles of alkylating agents were planned: Thiotepa (T) then, 15 days later, BCNU (B). Three dose levels of each agent were administered in cohorts of consecutive patients: 400, 500 and 600 mg/m2 respectively. HGF and reinfusion of PBSC followed both cycles. Toxicity and response were evaluated according to the WHO recommendations. From April 1996 to August 1988, 30 women were enrolled: 8 in the first, 12 in the second and 10 in the third dose level. In all cases, B was administered after T with a median delay of 25 days because of grade 3/4 hematological toxicity. 4 patients did not receive B because of previous lung radiotherapy, persistent tricytopenia or insufficient PBSC collection. 19 patients with measurable lesions were considered for response. The objective response rate was 48% (11% CR, 37% PR). We recommended T and B at a dose of 600 mg/m2 to conduct a phase II study in metastatic breast cancer and even to administer B before T.

Background: Shared decision-making is increasingly advocated as an ideal model. However, very few studies have tested the feasibility of giving patients the opportunity to participate in the choice of treatment., Patients and Methods: Women, with non-metastatic breast cancer, eligible for non-intensified adjuvant chemotherapy attending our hospital were proposed two administrations of chemotherapy and radiotherapy: a sequential and a concomitant one. Two patient-questionnaires were used to elicit motivations for their choice and their degree of comfort with the process of decision-making and one questionnaire to test physicians' ability to predict patients' choice., Results: Participation rate in the study was 75.3% (n = 64). Majority (64%) of patients chose the concomitant treatment. Multivariate analysis revealed that patients with a lower level of education, who discussed the choice with social circle, and who most feared side-effects were more likely to choose the sequential treatment. Physicians were able to predict patients' choice in 66% of cases. 89% of patients declared that they were fully satisfied with having participated in the choice of treatment and 79% supported shared decision-making., Conclusions: Results are in favour of promoting active participation of cancer-patients in medical decision-making. The adequate degree of such participation remains however to be elicited and tested for therapeutic choices implying more difficult trade-offs between quantity and quality of life.

Neutrinos represent a new "window" to the Universe, spanning a large range of energy. We discuss the science of neutrino astrophysics and focus on two energy regimes. At "lower" energies ( approximately 1 MeV), studies of neutrinos born inside the sun, or produced in interactions of cosmic rays with the atmosphere, have allowed the first incontrovertible evidence that neutrinos have mass. At energies typically one thousand to one million times higher, sources further than the sun (both within the Milky Way and beyond) are expected to produce a flux of particles that can be detected only through neutrinos.

Background: Our purpose was to evaluate the relationship of Ki-67 labeling index (Ki67-LI) to deoxyribonucleic acid (DNA) ploidy, S phase fraction (SPF), other clinical prognostic factors, and clinical outcome for patients with prostate cancer treated by external beam radiotherapy., Methods: Tissue was retrieved from 42 patients who underwent transurethral resection of the prostate before treatment with external beam radiotherapy between 1987-1993. DNA histogram profiles were classified as diploid (diploid + near-diploid) and nondiploid (tetraploid + aneuploid). Immunohistochemical staining of Ki-67 by the MIB-1 monoclonal antibody was used to calculate Ki67-LI. Median patient follow-up was 62 months. Treatment failure was defined as two consecutive rises in serum prostate-specific antigen (PSA) or clinical evidence of disease recurrence., Results: The mean and median Ki67-LIs were 3.1 and 2.4, respectively (range, 0-12.4). Mean Ki67-LI values were significantly associated with higher stage, Gleason score, and pretreatment PSA. Nondiploid tumors had significantly higher Ki67-LIs, as did patients who failed radiotherapy over the follow-up period. SPF was not significantly correlated with Ki67-LI. As a categorical variable, the most significant relationships were seen when Ki67-LI was subdivided into thirds around the median (Ki67-LI 1.5-3.5%, and Ki67-LI >3.5%). This trichotomous variable correlated significantly with pretreatment PSA (P = 0.0008), tumor stage (P = 0.016), Gleason score (P = 0.024), and treatment failure (P = 0.0015), but not with DNA-ploidy (P = 0.15). In actuarial univariate analyses, Ki67-LI appeared to be a more significant predictor of patient outcome (P = 0.003) than DNA-ploidy (P = 0.035)., Conclusions: The Ki67-LI correlated with known prognostic factors such as pretreatment PSA, tumor stage, and Gleason score, and was also weakly related to DNA-ploidy. In comparison to DNA-ploidy, Ki67 LI seems to be a better correlate of treatment outcome., (Copyright 1999 Wiley-Liss, Inc.)

Background: The current study was undertaken to evaluate the incidence and predictors of late toxicity in patients with localized prostate carcinoma treated with high dose three-dimensional conformal radiotherapy (3D-CRT)., Methods: A total of 743 patients with prostate carcinoma classified as T1c-T3 were treated with 3D-CRT that targeted the prostate and seminal vesicles. A minimum tumor dose of 64.8 gray (Gy) was given to 96 patients (13%), 70.2 Gy to 266 patients (365), 75.6 Gy to 320 patients (43%), and 81.0 Gy to 61 patients (8%). The median follow-up time was 42 months (range, 18-109 months). Late toxicity was graded according to the Radiation Therapy Oncology Group morbidity scoring scale., Results: Late gastrointestinal (GI) and urinary (GU) toxicities were absent or minimal (Grade 0 or 1) in 90% of patients. The 5-year actuarial likelihood of the development of Grade 2 and 3 late GI toxicities was 11% and 0.75%, respectively. A multivariate analysis identified doses > or =75.6 Gy (P<0.001), history of diabetes mellitus (P = 0.01), and the presence of acute GI symptoms during treatment (P = 0.02) as independent predictors of Grade > or =2 late GI toxicity. The 5-year actuarial likelihood of the development of Grade 2 and 3 late GU toxicities was 10% and 3%, respectively. Doses > or =75.6 Gy (P = 0.008) and acute GU symptoms (P<0.001) were independent predictors of Grade > or =2 late GU toxicity. Among 544 patients who were potent before treatment (73% of all patients), 211 (39%) became impotent after 3D-CRT. The 5-year actuarial risk of potency loss was 60%. Doses > or =75.6 Gy (P<0.001) and the use of neoadjuvant androgen deprivation (P = 0.01) were independent predictors of posttreatment erectile dysfunction., Conclusions: The incidence of severe late complications after high dose 3D-CRT was minimal. Radiation doses > or =75.6 Gy and the presence of acute treatment-related symptoms during 3D-CRT correlated with a higher incidence of Grade > or =2 late GI and GU toxicities. In addition to higher doses, the use of androgen deprivation therapy increased the likelihood of permanent impotence in these patients. Intensity-modulated radiotherapy, which makes it possible to enhance the conformality of the dose distribution, has recently been implemented in an attempt to reduce the incidence of moderate grade toxicities in patients receiving high dose 3D-CRT.

The use of radiotherapy in advanced stages of Hodgkin's disease remains controversial. The rationale for its use is based on efficacy at all stages of the disease as well as in patients with recurrent disease, but also on the topography of the recurrences after exclusive chemotherapy (which occur at non irradiated sites in 75% of cases), and on its ability to improve relapse rates as shown in many randomized trials. Unfortunately, this improvement does not translate into higher survival rates because of the increased late morbidity and an inadequate selection of patients who might benefit from irradiation. The benefits of radiotherapy are probably the highest in stage III rather than IV, in patients with scleronodular disease, and in those with mediastinal involvement experiencing a complete response to radiotherapy. A better survival should be observed with the shift towards a decrease of the doses delivered, an improvement of the quality of the irradiation, and a better definition of the volumes to be treated in association with the use of optimal chemotherapies.

Background: The prognostic value of peritumoral vascular invasion (PVI) in node negative breast cancer (N-) is a controversial issue. Considerable debate has focused on how PVI should be defined, and the techniques used to detect them have differed considerably from one study to another., Material and Methods: In our study, 167 cases of N- breast cancers were reviewed, with a view to determining whether or not PVI, as defined in the recently published European recommendations, were present., Results: Based on the results of the subsequent statistical study, the presence of PVI was not found to constitute a reliable prognostic index to the outcome of N- breast cancer., Conclusion: Referring each case to the data available in the literature, the difficulties encountered when searching for PVI of this kind are described, the results of various studies on the topic are reviewed and whether it is worth pursuing studies along these lines is discussed.

Aims of the Study: To determine the risk factors for local and distant failure in node-negative breast cancer treated with breast-conservative surgery and radiotherapy and to determine the relationship between these two events., Material and Methods: We retrospectively selected 908 patients who received conservative surgery and radiotherapy but no chemotherapy between 1980 and 1995, for a node-negative breast cancer. Patients were divided in two groups according to the status of the margins of resection. All pathology specimens were reviewed., Results: In case of negative margins, the risk factors for local recurrences picked up by the Cox model were histologic multifocality (P = 0.0076), peritumoral vessel invasion (P = 0.021) and age < or = 40 years (P = 0.024), and in case of involved margins, negative oestrogen receptors (P = 0.0012), histologic multifocality (P = 0.0028), and absence of hormonal therapy (P = 0.017). The 10-year local recurrence rate was 18% in case of negative margins and 29% in case of involved margins, although in the latter case patients received high-dose adjuvant radiotherapy. Accordingly, the 10-year distant failure rates were 16% and 27%, respectively. Many arguments suggest that local and distant failures are closely related., Conclusion: Patients with histologic multifocality or positive margins are at high risk of local failure and then of distant failure, and require a more aggressive initial treatment.

Purpose: To determine the risk factors associated with recurrence after breast-conserving treatments, and the relationship between occurrence of a local recurrence and subsequent distant metastases., Methods and Materials: Among the 3697 patients with primary breast cancer treated at Institut Paoli-Calmettes Cancer Center, Marseille, between 1980 and 1995, we retrospectively analyzed 756 patients who had been treated with conservative surgery with uninvolved margins of excision, were node-negative, and had received uniform radiotherapy and no chemotherapy. One third of the patients received hormonal therapy via tamoxifen or surgical castration. The endpoints considered were local failures and distant metastases. All tumors were reviewed by our pathologists. The median follow-up for the 700 survivors was 62 months., Results: In the multivariate analysis, histological multifocality (p = 0.0076), peritumoral vessel invasion (p = 0.0215), and young age (p = 0.0245) were associated with an increased risk of local recurrences, whereas tumor size (p = 0.0013), young age (p = 0.003), and histological multifocality (p = 0.0414) were associated with an increased risk of distant metastases. Local recurrences and distant metastases had similar yearly-event probabilities. Median time to distant metastases was shorter after a local recurrence. Early timing of local recurrences did not mark a higher risk of distant metastases. Hazard of relapsing from distant metastases was 4.4 times higher after a local recurrence., Conclusion: our results support the hypothesis that, in this subset of patients, local recurrences favor further dissemination of cancer cells. We are unable to clearly identify a group who would benefit from more aggressive local therapy.

Purpose: To evaluate late myocardial damage after adjuvant radiotherapy using a mixed-beam (photons plus electrons) technique to treat the internal mammary lymph nodes in left-side breast cancer., Methods and Materials: A bicycle ergometer stress test coupled with thallium-201 perfusion scintigraphy and analysis by single-photon computed tomography (CT) was performed on 19 patients treated with left-side breast/chest wall and internal mammary radiation for breast cancer between 1987 and 1993. To be sure that we would evaluate late toxicity caused by the irradiation, patients had to fulfill the following eligibility criteria: left-side breast cancer, treatment between 1987 and 1993 and no recurrence during follow-up, age < or = 75 years, no known risk for coronary artery disease, no previous chemotherapy, internal mammary field treated with an association of photons and electrons, and CT scan-based treatment planning., Results: Median age at scintigraphy was 59 years. Two patients did not reach optimal exercise level and were not evaluable. Among the 17 evaluable patients representing 91.6 patient years of follow-up, there were no perfusion defects by visual or quantitative analysis., Conclusion: The mixed-beam technique seemed to spare the heart from harmful irradiation and to protect the myocardium. Results need to be confirmed on the long-term use of this technique.

Thymomas are rare, slow-growing neoplasms that are considered to be malignant because of their potential invasiveness. The most widely used staging system is that of Masaoka and colleagues, which takes into account the extent of clinical and histopathologically determined disease involvement. However, recent data suggest that the staging system of the French Study Group on Thymic Tumors (GETT system), which is based on the surgical and pathologic features of the tumor, may be superior to the Masaoka system. Total resection followed by radiation therapy is the treatment of choice for all thymomas, except stage IA tumors, which can be treated with surgery alone. Chemotherapy can improve the outcome of invasive Masaoka stage III and IV thymomas or recurrent thymomas. Only platinum-containing regimens show consistent efficacy.

Purpose: In patients with early cervix carcinoma, both radiotherapy and surgery or combined modalities provide effective therapies. In the two last modalities, recommended surgery is radical hysterectomy. The purpose of this prospective study was to assess the value of a limited vaginal hysterectomy after brachytherapy in patients without any unfavorable prognostic factor., Patients and Methods: Twenty-two patients (stage Ia2 with vascular invasion: three patients, stage Ib 1:19 patients) with 1 cm median maximal tumor size and with previous negative laparoscopic lymphadenectomy (median number of lymph nodes: 12) underwent a limited vaginal hysterectomy 6 weeks after utero-vaginal brachytherapy., Results: Two mild intra-operative complications were noted. Venous hemorrhage (100 mL) occurred in one patient during lymphadenectomy and another patient presented bladder injury during hysterectomy. These two complications were successfully controlled with no need for laparotomy. Only one late complication was observed: bladder grade G2 (b). With a 29 months follow-up (20-48 months), no recurrence was reported., Conclusion: These results appear promising in patients with very early cervix carcinoma but remain to be confirmed on a larger scale.

The aim of this study was to evaluate the clinical and economic benefit of filgrastim given with intensive sequential chemotherapy. Women with poor-prognosis breast cancer received four cycles of high-dose cyclophosphamide (3 g/m2) and doxorubicin (75 mg/m2), followed by filgrastim 5 microg/kg/dy, stem cell collection after the cycle 1, and stem cell infusion after cycle 3 and cycle 4. The first cohort received filgrastim after the fourth cycle but the second cohort did not.Thirty three patients were included in the first cohort and 13 in the second. The results indicate that the duration of grade IV neutropenia was shorter in the group given filgrastim as was the median time to recover an absolute neutrophil count (ANC) > 1.0 x 10(9)/L. The rate and duration of the rehospitalizations were higher in the group not receiving filgrastim. We found that costs such as drugs and hospitalizations were significantly higher (p = 0.032 and p = 0.049) in the non-filgrastim-treated group. Using ANC > 1.0 x 10(9)/L as an intermediary efficiency criterion it was more cost effective to give filgrastim. It can be concluded from this study that filgrastim can decrease the duration of grade IV neutropenia in patients receiving intensive sequential chemotherapy. This, in turn, reduces the cost of hospitalization. However, in our study, this reduction of neutropenia did not have any impact on further therapy.

Inflammatory breast cancer still has a poor prognosis despite improvements related to the introduction of neoadjuvant chemotherapy. The purpose of this study was to evaluate pathologic response rate and outcome of patients receiving high-dose chemotherapy with haematopoietic stem cell support for IBC. Seventeen consecutive patients with IBC received an association of mitoxantrone (36 mg/m2), cyclophosphamide (120 mg/kg), melphalan (140 mg/m2), with stem cell transplantation (SCT) following four to five cycles of cyclophosphamide (1000 mg/m2), doxorubicin (75 mg/m2) and 5FU (500 mg/m2). Mastectomy was performed a median of 2 months (range 1.5-45) after high-dose chemotherapy and was followed by radiotherapy. Macroscopic and microscopic pathologic complete response rates were respectively 56 and 39%. With a median follow-up of 36 months (range 17-52) 10 patients remain alive free of disease and seven patients have relapsed. Two relapses occurred in the group of patients with pathologic CR and five in the group with residual tumour. These results show that high-dose chemotherapy (HDC) with alkylating agents followed by SCT allows a very high tumour eradication in inflammatory breast cancer, suggesting a possible global benefit in progression-free survival and survival which remains to be demonstrated prospectively.

Electron beam intraoperative radiation therapy (EB-IORT) and intraoperative low-dose rate brachytherapy (IOLB) seem able to improve the local control of advanced or recurrent pelvic tumours (ARPT). We report the usefulness, technical considerations and potential advantages of employing post-operative high-dose rate brachytherapy (POHB) as a treatment for ARPT. From February 1995 to February 1997, 14 patients underwent POHB for ARPT. The mean age was 58 years (range: 37-74). Six patients presented with recurrent rectal carcinoma, three with cervix carcinoma (one primary T3; two recurrences), two with bladder carcinoma (one primary T4; one recurrence), one with prostate carcinoma, one with recurrent pre-sacral lymphoma and one with undifferentiated carcinoma. At the time of resection, blind-end HDR catheters were implanted in a single plan in the tumour bed and stabilized by absorbable sutures. Eight days later, POHB delivered 20Gy in 5 fractions or 40Gy in 10 fractions for advanced and recurrent tumours, respectively. To decrease the incidence of late side-effects, a change was made after the tenth patient to deliver 2 Gy per fraction twice a day, with an interval of 6 h between each fraction. With a median follow-up of 8 months (range: 1-22), local control was achieved in all cases. Six patients developed metastatic disease. One patient presented a perineal wound dehiscence requiring surgery 2 months after POHB. POHB is feasible for patients with recurrent or advanced pelvic diseases, and appears more cost-effective than EB-IORT for dosimetric and radiobiological considerations. Compared with IOLB, POHB allows the total radioprotection of the medical staff, and, in the context of cost reduction, a reduction of the overall time of hospitalization.

Headache is a common emergency department complaint and has a broad differential diagnosis. Most commonly the headache is without serious underlying cause, but occasionally can be the manifestation of a more catastrophic illness. History may be the most important aspect in the evaluation of headache patients and careful attention to historical clues or atypical symptoms may point to a diagnosis. We present a patient with a first-time headache, which was ultimately found to be secondary to a carotid cavernous fistula. Historical features that require a more aggressive work-up of headache are discussed.

Despite important initial chemosensitivity, advanced ovarian cancer has a bad prognosis with a median survival of 20 to 30 months. These results might be better with intensive chemotherapy. We analysed 67 patients treated by intensive chemotherapy with autologous stem cell transplantation for advanced ovarian cancer at Institute Paoli-Calmettes between 1980 and 1994. Population was divided in two groups: salvage group (n = 30) for initial chemotherapy-refractory patients and consolidation group (n = 37) for sensitive patients. Several successive conditioning regimens were used, all based on alkylating agents. Principal toxicities were severe aplasia and mucositis. Four patients died from toxicity related to infection during strong immunosuppression. In salvage group, 9 out of 21 evaluable patients responded (43%), but duration of responses was short (median range of 5 months) and 2-year overall survival rate was 8% after transplantation. In consolidation group, 19 patients are alive and 15 are without disease progression with a median follow-up of 42 months (17, 161) after diagnosis. Five-year disease-free survival rate is 28% (median range of 35 months) and 5-year overall survival rate is 48% (median range of 41 months). Intensification does not seem to be long term beneficial for initial chemotherapy refractory patients, despite objective responses rate better than classical treatment. On the other hand, results seem better than conventional treatments in case of chemosensitive disease and should be confirmed prospectively in larger cohort of patients. Moreover, other research directions are open like intensification supported by hematopoietic growth-factors and peripheral stem cells, definition of best conditioning regimen, use of taxanes, and intensification in first line chemotherapy after initial surgery.

The importance of dose-intensity has been suggested in breast cancer. The aim of this study was to evaluate the feasibility of a high-dose intensity doxorubicin-cyclophosphamide regimen with supporting G-CSF and blood stem cells. Twenty-five patients with non-metastatic breast cancer received four cycles of doxorubicin (75 mg/m2) and cyclophosphamide (3000 mg/m2) at 3 week intervals. Apheresis was performed after the first cycle and if necessary after the second cycle. Stem cells were reinfused after the third and fourth cycles. G-CSF was started on day 3 of each cycle (5 microg/kg/day) and was stopped the day before the last apheresis or when absolute neutrophil count was above 0.5 x 10(9)/l. Median received dose-intensity was respectively 25 mg/m2/week (range 22-26) and 1000 mg/m2/week (range 904-1065) for doxorubicin and cyclophosphamide. Grade IV thrombocytopenia occurred in 8% of cycles. Two patients needed platelets and 12 red cell transfusion. Fifteen patients were readmitted for a median duration of 4 days (range 1-7). We have established a safe, outpatient, high-dose intensity doxorubicin-cyclophosphamide regimen with supporting G-CSF and blood stem cells which can be submitted for comparison with the current standards.

Purpose: To evaluate the efficiency of Helium-Neon (He-Ne) laser in the prevention of oral mucositis induced by high dose chemoradiotherapy before autologous bone marrow transplantation (BMT)., Methods and Materials: Between 1993 and 1995, 30 consecutive patients receiving an autologous peripheral stem-cell or bone marrow transplant (BMT) after high dose chemoradiotherapy were randomized to possibly receive prophylactic laser to the oral mucosa after giving informed consent. Chemotherapy consisted of cyclophosphamide, 60 mg/kg intravenously (I.V.) on day (d)-5 and d-4 in 27 cases, or melphalan 140 mg/kg I.V. on d-4 in three cases. Total body irradiation (TBI) consisted of 12 Gy midplane dose in six fractions (4 Gy/day for three days). He-Ne laser (632.8 nm wavelength, power 60 mW) applications were performed daily from d-5 to d-1 on five anatomic sites of the oral mucosa. Oral examination was performed daily from d0 to d + 20. Mucositis was scored according to an oral exam guide with a 16 item scale of which four were assessed by the patients themselves. Mean daily self assessment scores for oral pain, ability to swallow and oral dryness were measured. A daily mucositis index (DMI) and a cumulative oral mucositis score (COMS) were established. Requirement for narcotics and parenteral nutrition was recorded., Results: The COMS was significantly reduced among laser treated (L+) patients (p = 0.04). The improvement of DMI in L+ patients was also statistically significant (p < 0.05) from d + 2 to d + 7. Occurrence and duration of grade III oral mucositis were reduced in L+ patients (p = 0.01). Laser applications reduced oral pain as assessed by patients (p = 0.05) and L+ patients required less morphine (p = 0.05). Xerostomia and ability to swallow were improved among the L+ patients (p = 0.005 and p = 0.01, respectively). Requirement for parenteral nutrition was not reduced (p = NS)., Conclusion: Helium-Neon laser treatment was well tolerated, feasible in all cases, and reduced high dose chemoradiotherapy-induced oral mucositis. Optimal laser treatment schedules still needs to be defined.

Background and Purpose: Symptoms of acute radiation enteritis (ARE), dominated by diarrhea, occur in more than 70% of patients receiving pelvic irradiation. Eicosanoids and free radicals release have been implicated in the pathogenesis. Mesalazine (5-ASA) is a potent inhibitor of their synthesis in the mucosa and could therefore be of some interest in preventing ARE., Patients and Methods: The study was performed in six radiotherapy units in France who agreed on standardized irradiation procedures. One hundred and fifty-three patients planned for external beam radiotherapy to the pelvis > or = 45 Gy for prostate (n = 97) or uterus (n = 54) cancer were randomized on a double blind basis to receive prophylactic 5-ASA (4 g/day Pentasa) or placebo. Patients with concomitant chemotherapy were excluded. Prostate and uterus cancers were chosen since these centropelvic tumors require a similar radiotherapy protocol during the first step of treatment and involve a comparable volume of small intestine. The symptoms of ARE and their severity were assessed every week during irradiation, and 1 and 3 months after its end. All patients followed a low fiber and low lactose diet. End points were diarrhea, use of antidiarrheal agents, abdominal pain, and body weight. Effficacy was evaluated using intention to treat., Results: (means +/- SD) Groups did not differ for age (mean 64 +/- 9 years), sex, tumor site, or irradiation procedure. During irradiation, diarrhea occurred in 69% and 66% of the 5-ASA and placebo groups, respectively (chi2, P = 0.22). Curves of survival without diarrhea did not differ between groups (logrank P = 0.09). Severity of diarrhea did not differ between groups except at d15 where it was significantly more severe in the 5-ASA group (ANOVA P = 0.006). Duration of diarrhea did not differ (22 +/- 15 days in both groups, P = 0.88). Abdominal pain was less frequently reported in the 5-ASA group at d28 (34% vs. 51%, P = 0.048). Use of antidiarrheal agents and body weight did not differ between groups., Conclusion: Mesalazine 4 g/day did not decrease the symptoms of ARE.

The chemotherapy side-effects are insufficiently documented while they strongly condition patients' quality of life. The aim of the study was to assess by means of a self-administered questionnaire the somatic symptoms experienced by breast cancer patients during their NCF (mitoxantrone + cyclophosphamide + 5-fluorouracil) chemotherapy and to demonstrate the interest of this self-report by comparing the frequency of side-effects assessed by the patients to that noted by the physicians in medical records. The study was carried out among 44 patients receiving their chemotherapy + radiotherapy at the Paoli-Calmettes Institute (marseille) between July 1994 and May 1995. The questionnaire comprized of 17 symptoms evaluated in terms of frequency, duration/severity and distress. The most frequent symptoms are: hair loss and nausea (75%), hot flush (57%), lack of appetite and headache (46%) associated with distress in 67 to 100% of cases. Their frequency was underestimated by the physicians in medical records. This study showed a large discordance patient-physician in the assessment of chemotherapy side-effects. The type of tool presented in this study could complement the usual scales of toxicity that do not provide an estimation of true patients' experience.

Purpose: Splenomegaly occurs frequently in patients with myelofibrosis (MF) or chronic myelogenous leukemia (CML), indicating significant splenic metaplasia. Symptomatic radiation therapy can be delivered, but the best irradiation scheme is still unknown. Results of splenic irradiation in patients with myelofibrosis or chronic leukemia were retrospectively analyzed., Patients and Methods: There were 24 patients: 15 presented with MF and 9 with CML. Median irradiation doses were 9.8 and 7.7 Gy, respectively. The hematologic toxicity was moderate (except for platelets in the acute phase of the disease)., Results: No toxicity was observed. Various factors predictive of the response to radiation therapy are described. While high (around 14 Gy) radiation therapy dose appears necessary for MF and should be started before the increase in transfusion need, huge splenomegalies should be excluded in regard to CML. As for other cases, the optimal dose is still unclear, but should probably be high enough, ie, around 10 Gy., Conclusion: To further study and better understand biological mechanisms underlying response to radiotherapy in patients with MF, prospective radio-chemotherapy phase II trials should be conducted in both CML and MF patients.

Acute oral complications are serious and disabling secondary effects for patients undergoing cancer therapy. Therefore, the authors wanted to develop a sensitive and specific method to measure oral mucosal changes associated with autologous with autologous bone marrow transplantation. 14 patients, all volunteers, 18-56 years old, receiving conditioning regimens of cyclophosphamide and total body irradiation were included. The clinical changes of the oral mucosa and functional modifications were scored daily, over 21 days with a 16 item scale, ranging from 0 to 3. A daily index of mucositis (DIM) was established by adding the scores obtained for the 16 items and a cumulative score of oral mucositis was obtained by the addition of the 21 DIM for assessing the severity of oral mucositis throughout its duration. The internal consistency measures (Chronbach alpha) were strong (range 0.80-0.97). A scale of equivalence, pre-established in comparison with pre-existing general mucositis rating scales, permitted a day by day simple classification in a 4-grade scale, to be obtained. Support for the validity of the suggested scale is presented. This scale may help to improve the study of oral complications of cancer therapy.

This single arm, open labeled, non randomized study was aimed to evaluate the toxicity of 3 cycles of MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) with rhG-CSF (5 micrograms/kg/day from day 3 to day 14), on 14 patients with previously untreated infiltrating bladder carcinoma, 42 cycles were administered. Chemotherapy toxicity was very low, with 7% of neutropenia grade 3 or 4.4% of thrombocytopenia grade 2, no mucositis above grade 2 and no nadir sepsis. Bone pain related to rhG-CSF occurred in 14% of cycles. 88% of the cycles were given at full dose without any delay and mean relative dose intensity was 96.4% (RDI was 100% for 9 patients). One patient achieved a complete pathological response (cystectomy: 1) and 6 clinical responses with negative transurethral resection. Addition of rhG-CSF to MVAC chemotherapy allows a high dose intensity of MVAC with very low toxicity over 3 cycles. This association should be compared to standard MVAC or intensified regimens to evaluate efficacy, toxicity, and cost effectiveness.

Antisense oligonucleotides were used to determine the role of the BCR-ABL gene in the proliferation of chronic myeloid leukaemia (CML) clonogenic cells. Peripheral blood Philadelphia chromosome positive cells were obtained from eight CML patients at diagnosis (chronic phase = 7; accelerated phase = 1). Mononuclear cells were incubated with synthetic antisense 18-mer oligonucleotides complementary to the two different junctions b2a2 or b3a2. The type of junction (b2a2 or b3a2) was previously determined by RT-PCR techniques. Cells incubated for 12 to 14 hours with or without sense oligonucleotides served as controls. After incubation with oligonucleotides, the cell DNA synthesis was analysed by flow cytometry using the BrdUrd/DNA method and the cell plating efficiency in methylcellulose was determined. In six of the seven patients in chronic phase, there was a significant inhibition of CFU-GM production which was only 68.4 +/- 19%; (p < .01) of that found in controls. The S phase index, which depends upon the percentage of S phase cells as well as the fluorescence intensity, was 48 +/- 29% (p < .01) of the control values for the seven patients in chronic phase. Interestingly, for the only CML patient in accelerated phase, antisense oligomers had no inhibitory effect on either the production of CFU-GM or the number of S phase cells. In improving the specificity of oligomers, it might be useful for gene-targeted anti-leukemic therapy and/or bone marrow purging.

Purpose: To evaluate the importance of fractionating total body irradiation (TBI) in patients receiving an allogenic bone marrow transplant (BMT) for an acute myeloblastic leukemia (AML) in first complete remission (CR1)., Methods and Materials: Between 1983 and 1990, 171 consecutive patients received either single dose TBI (STBI) (n = 65) or fractionated TBI (FTBI) (n = 106) after being conditioned with cyclophosphamide and before receiving a non-T-depleted Human Leucocyte Antigen (HLA)-identical marrow. Both groups were comparable except for date of BMT and diagnosis-to-BMT interval (D-BMT)., Results: After 63 months median follow-up, transplant-related mortality (TRM), probability of relapse, and 5-year disease-free survival (DFS) were 0.38 and 0.27 (p = 0.04), 0.29 and 0.26 (p = 0.22), 0.43 and 0.56 (p = 0.06), respectively, for STBI and FTBI. The supposed influence of the schedule of TBI disappeared in the multivariate analysis: TRM was enhanced by severe acute graft vs. host disease (p = 0.0002), early years of transplant (before January 1, 1987) (p = 0.0003), and longer D-BMT intervals (p = 0.038). Relapse was linked to early years of transplant (p < 0.00001), and the absence of chronic GVHD (p = 0.007). Longer DFSs were observed for later years of transplant (after January 1, 1987 and later) (p = 0.001), milder acute GVHD (p = 0.005), and shorter D-BMT intervals (p = 0.045). Important improvements of the results were made during the 7-year observation period: TRM, probability of relapse, and DFS were, respectively, 0.36, 0.28, and 0.46 for patients transplanted before January 1, 1987 vs. 0.21, 0.15, and 0.67 after that date., Conclusion: Our data strongly suggest that allogenic BMT is the best postremission treatment for AML in CR1, and the results are better when BMT shortly follows the achievement of remission. The schedule of TBI was of little importance compared with the improvements made in the management of patients undergoing BMT during the 1980s, and, therefore, reports concerning data prior to 1985 should be interpreted cautiously.

Between 1979 and 1990, 149 patients with non-metastatic thymomas were treated in ten French cancer centers. Patients were staged according to the 'GETT' classification, derived from that of Masaoka. There were 13 stage I patients, 46 stage II, 58 stage III and 32 stage IVA. Gross total resections were performed in 63 cases, subtotal resections in 31 cases and in 55 cases a biopsy alone was performed. All patients received radiotherapy and 74 were given post-operative chemotherapy. Median follow-up was 7.7 years. Local control was achieved in 117 cases (78.5%) and was influenced by the stage of the disease (p < 0.01) and the extent of surgery (p < 0.01). Twenty-six patients developed metastatis after a median period of 9 months. Five- and ten-year disease-free survival rates were 59.5% (51-67%) and 49.5% (39-60%), respectively, and were influenced by the stage of the disease (p < 0.01), the extent of surgery (p < 0.001) and a mediastinal compression on presentation (p = 5 x 10(-6)). Four factors could predict a worse overall survival in the multivariate analysis: mediastinal compression on presentation (p < 0.001), absence of chemotherapy (p < 0.001), biopsy alone (p = 0.003), and young age (p = 0.013). A worse DFS was predicted by mediastinal compression on presentation (p < 0.001), absence of chemotherapy (p < 0.001), young age (p = 0.006), and stages III-IVA (p = 0.04). Future therapeutic strategies are discussed and the literature is reviewed.

Purpose: To evaluate the radiosensitivity of self-renewing progenitor cells in acute myeloblastic leukemia (AML), we have compared the radiosensitivity of the cells grown either in methylcellulose alone for 7 days, or first in suspension culture for 7 days before being plated in methylcellulose. Methylcellulose selects for terminal-dividing cells and suspension cultures have been developed because they allow self-renewal to occur: The exponential growth of the progenitors of AML cultured in suspension is due to self-renewal., Methods and Materials: Cells were harvested from previously untreated leukemic human bone marrows. The myeloblastic lineage of the colonies was assessed by morphological, cytochemical, and immunophenotypic analysis, and by the use of growth factors that did not stimulate the growth of T-lymphocytes. The cell-cycle distribution of the blasts was analyzed by flow cytometry and was comparable for all samples. The irradiation was performed with gamma-photons at a dose-rate of 0.05 Gy/min, similar to the clinical conditions used in our institution for total body irradiation (TBI)., Results: The culture methods selected aggressive leukemias. There were large variations of the individual radiosensitivity whatever culture method was used. The progenitor cells capable of self-renewal were more radiosensitive than terminal dividing cells. In two cases, a shoulder was found in the initial part of the cell-survival curves of cells capable of self-renewal. In these two cases, the best fit for the data was the linear quadratic model (survival = e-alpha D-beta D2) with alpha/beta values of 1.49 Gy and 3.12 Gy, respectively., Conclusion: The very low values of alpha/beta suggest a reduced antileukemic effect in case of fractionated TBI, and may lead to more reliable screening methods to determine the most appropriate technique for radiation ablation of bone marrow prior to bone marrow transplantation (BMT).

Over a 10 year period, we transplanted 63 patients with acute lymphoblastic leukaemia (ALL) who had achieved first complete remission (CR). All were > 15 years old and 45 (71%) had at least one poor prognostic factor. Twenty-nine patients with a suitable sibling underwent autologous bone marrow transplantation (BMT). Beginning in 1984, patients without a donor received an allogeneic BMT (34 patients). Preparation consisted of cyclophosphamide (CY)/TBI (78%) or melphalan (Mel)/TBI (22%); marrow was treated in vitro in 31 patients (allogeneic: 7; autologous: 24). Kaplan-Meier estimates of the probability at 6 years of relapse, survival and DFS were 41% (allogeneic: 10%, autologous: 65%, p < 0.05), 44% (allogeneic: 62%, autologous: 26%, p = NS) and 42% (allogeneic: 62%, autologous: 27%, p < 0.06), respectively. This report confirms that allogeneic BMT permits long-term remissions giving high levels of survival when performed shortly after entering first CR while autologous BMT, when performed in the same setting, is less successful at preventing relapse. This study also confirms the high sensitivity of ALL to the graft-versus-leukemia effect provided by allogeneic BMT. Chemoradiotherapy dose intensification delivered at autologous BMT is not sufficient to prevent relapses. Autologous BMT must therefore be augmented by other approaches of which immunotherapy may be one.

In patients with locally advanced cervical cancer, most of the treatment failures occur within the pelvis. In an attempt to improve local control, 40 patients with bulky tumors (stage IB > 5 cm, stage IIB with distal parametrial invasion, and stage III-IVA) were treated between 1988 and 1992 with concurrent chemoradiation (CCR). The whole pelvis received a midplane dose of 45 Gy over 33 days. Daily radiation dose was 1.8 Gy, with twice-daily fractionation in the last 20 patients. Chemotherapy was administered on the 1st and 21st days of radiation therapy (RT) consisting of cisplatin (60 mg/m2), followed by 5-fluorouracil (600 mg/m2/day continuous i.v. infusion) over 96 hr (and decreased to 40 and 400 mg/m2, respectively, in the last 23 patients). CCR was first followed by a single intracavitary application and then by a parametrial boost in stage IIB-III patients and in stage IVA patients with disease reaching the pelvis side wall. Then surgery (colpohysterectomy with lymphadenectomy or pelvic exenteration) was performed in 35 patients. Median follow-up time was 2.6 years (0.6-5.6 years). Acute toxicity (WHO grade 3-4 diarrhea) in 13 patients led to 6 RT interruptions and 4 incomplete RTs. One patient died of a septic episode without leukopenia after completion of CCR. Five postexenteration complications required a second surgical procedure, of which one patient died with tumor and small bowel fistula. One patient developed small bowel late complication and another patient developed urinary late complications. No postoperative or late complications were observed in patients treated with twice-daily fractionation. Pelvic control was achieved in 32 of 40 patients (81 and 74% in stage IB-IIB and stage III-IVA, respectively). Sites of failure were the pelvis (6 cases), metastases (7 cases), and both (2 cases). Two-year survival and DFS rates were 61 and 66%, respectively, in stage IB-IIB and 77 and 65% in stage III-IVA. High SCC-TA4 values significantly worsened DFS rates. In patients with stage III-IVA tumors, additional surgery could be an important component of this treatment strategy and may be compatible with CCR using twice-daily fractionation radiotherapy. However, these results must be confirmed by a large-scale prospective study.

In our institution, total body irradiation (TBI) is performed by means of a sweeping beam technique. Toxicity of the procedure was evaluated according to the only grading system designed for high dose chemoradiotherapy. One hundred patients undergoing TBI and conditioned with a standard cyclophosphamide regimen before BMT were evaluated. Regimen-related toxicity was graded according to the Seattle transplantation toxicity system, from 0 to IV (fatal toxicity), in eight organs on days 0, 7, 14, 28 and 100 for lungs. Eighteen patients did not develop any toxicity. Grades III, IV toxicities were uncommon (9%) and were not influenced by dose of TBI, GVHD prophylaxis, disease status and allogenicity although no grade IV toxicity was observed among autologous marrow recipients. However, grade II toxicity was more common in patients receiving allogeneic vs autologous grafts (p < 0.01) because of increased mucosal (p = 0.002) and liver (p = 0.12) toxicities. Renal toxicity was unevaluable. When cumulative toxicity was equal or higher than 4, day 100 survival was worse (p = 0.05). These data confirm the safety of our TBI procedure and the validity of the grading system except for renal toxicity. We suggest that a more aggressive conditioning regimen may be tolerated by patients receiving autologous grafts.

To evaluate the impact of teaching during hospital training in an adult cancer ward, 107 consecutive students were asked to freely select the chart of a patient representative of their course and to write comments on it, at the end of their course. Students selected charts of young patients rather than older ones (P less than 0.0001). Most of the patients had a poor prognosis (69%). Students frequently emphasized psychosocial aspects of cancer and patient's information (patient-student relationship: 50%; diagnosis acceptance: 36%; information: 19%), but rarely considered post-treatment sequelae of cured patients (4%), palliative care (9%), and truth (10%). The selection of a large majority of poor prognosis patients led us to invite them to attend consultations to meet patients who are cured or in fair condition. Other topics must be emphasized (palliative care, truth, and post-treatment morbidity). Finally, such an evaluation provides good information on the course of the students and is easily performed and analysed.

Between 1975 and 1985, we have treated 157 patients with carcinoma of the cervix T1. The size of the tumor was always equal or less than 30 mm. Our patient underwent Cesium 137 brachytherapy with Fletchers applicators followed by a modified radical hysterectomy and pelvic lymphadenectomy 4 to 6 weeks later. Intracavitary brachytherapy was performed within three days (low dose rate 0.8-1 Gy/h). The median 60 Gy Isodose was: 65 mm height, 58 mm width and 29 mm thickness. At surgical time we mentioned that vaginal cut out was 2-3 cm and pelvic lymphadenectomy limited to external iliac nodes. The 5 and 10 disease Free Survival was respectively 91.6 and 89.4%. We observed 14 relapses, five were distant metastases only. The tumor size and pelvic node involvement were the main prognostic factors in our data. The sterilization of the cervix wasn't of prognostic value. Complications occurred in 22 patients, 2 (1.3%) were severe urinary injury.

From 1970 to 1985, 299 patients with lip cancer were examined, treated and followed-up at the Bergonié Foundation. In most cases, interstitial radiotherapy was used and the local control rate reached 94%. Local recurrences could usually be treated again, so that the final local control rate was 99%. However, the management of neck nodes remains controversial in some cases: 5.6% only of T1-2 N0 stages developed neck nodes, which were successfully controlled in 78.9% of cases and it was therefore considered that the preferred option should be to maintain the patients under close follow-up. For T3 N0 cases, of which 17.6% would evolve, it was considered that a sub-mental and sub-maxillary neck node dissection was advisable when performance status was satisfactory and when a close follow-up was difficult. The recurrence rate was 40% for patients with palpable neck nodes who were often submitted to a combined radio-surgical treatment. In such cases, recurrences were controlled in 22% of patients who died 7 times out of nine.

From 1970 to 1985, 299 patients with carcinoma of the lip were entirely managed at the Bergonié Foundation. Interstitial radiotherapy was most commonly used. It resulted in a successful local control in 96% of cases (238/248), while cosmetic and functional results seemed better than those of surgery. However, surgery seemed more performant for in situ carcinomas, late aggressive T3 carcinomas, local recurrences, as for T4 lesions associated with other techniques. After reviewing the case history of patients with local recurrences, we found technical faults in one half of those managed by interstitial radiotherapy. Local control rates after surgical salvage of recurrences was 99%. Treatment of neck nodes was not discussed in this publication.