Edmond P. Malaise

Relation between the pathological nature and the growth rate of human tumors

Abstract An analysis of 530 cases reported in the literature over the past 14 years has demonstrated differences in the mean growth rate of various pathological types. This analysis shows that the various types of tumors may be ranked with respect to their increasing D.T.: embryonal carcinomas, lymphomas, malignant mesenchymal tumors, squamous cell carcinomas and adenocarcinomas.

Potential doubling time and clinical outcome in head and neck squamous cell carcinoma treated with 70 GY in 7 weeks

PURPOSE To study the predictive value of pretreatment potential doubling time and labeling index, as measured by flow cytometry in patients with head and neck squamous cell carcinoma treated with conventional radiotherapy. METHODS AND MATERIALS 70 patients with a squamous cell carcinoma of the oropharynx and 4 patients with another involved head and neck site were entered in this prospective study. The duration of the S phase (TS), the labeling index (LI), and the potential doubling time (Tpot) were obtained by flow cytometry measurements of a tumor biopsy obtained after i.v. injection of 200 mg bromodeoxyuridine to the patient. The treatment consisted of 70 Gy in 7 weeks, 2 Gy per fraction and five fractions per week. RESULTS The mean and median LI were 7.7% (standard deviation, SD: 5.0) and 6.3%, respectively. The mean and median TS were 9.3 h (SD: 3.6) and 8.3 h, respectively. The mean and median Tpot were 5.6 days (SD: 5.4) and 4.6 days, respectively. No significant relationship was found between the Tpot or LI and the tumor stage (T), nodal status (N), histological grade, and the site of the primary within the oropharynx. The only parameter significantly associated with an increased risk of local relapse was the tumor stage (p < 0.001). The mean Tpot for the group of tumors that relapsed locally was 5.3 days (SD: 3.3), compared to 6.1 days (SD: 4.08) for those who did not relapse locally (NS). Two parameters were significantly associated with a decrease in disease-free (DFS) and overall survival, namely the tumor stage (p < 0.005, and p < 0.001, respectively, for DFS and overall survival) and nodal involvement (p = 0.02 and (p < 0.005, respectively, for DFS and overall survival). The TS, LI, DNA index, and Tpot were not significantly associated with local relapse, DFS, and survival, either in the univariate or in the multivariate analysis. CONCLUSIONS The method used to evaluate tumor cell kinetics did not provide clinically relevant kinetic parameters for this type of cancer. The classic prognostic factors (tumor stage and nodal status) were strongly associated with clinical outcome.

Radiation-induced DNA double-strand breaks and the radiosensitivity of human cells: a closer look.

A large number of reports suggest that DNA double-strand breaks (DSB) play a major role in the radiation-induced killing of mammalian cells. However, the arguments supporting the relationship between DSB and radiosensitivity are generally indirect. Furthermore, care must be taken to allow for the possible impact of the techniques and of the experimental protocols on the relationship between DSB and cell death. The recent data on DSB induction, repair and misrepair in human cell lines and their correlation with intrinsic radiosensitivity are reviewed.

Relationship between the growth rate of human metastases, survival and pathological type

Abstract Data have been collected for 203 patients on the growth rate of pulmonary metastasis and survival, defined as delay between the diagnosis of the primary tumour and death. These cancers when found to be disseminated were not treated. The distribution of the survival times was found to be log-normal. The survival of the patient increased as the doubling time (D.T.) of the tumour increased. This group of patients was subdivided according to five histological types. A similar correlation between survival and doubling time was found in the five sub groups. As previously shown, the histologic subgroups have different mean D.T., but it was found that the increase of mean survival from one subgroup to another is shorter that what would be expected from the increase of D.T. Furthermore, for the same D.T., survival is longer for patients with a cancer of the histologic type with the shortest mean D.T. Assuming the growth rate of the tumours remain constant, it is possible to calculate the number of times the volume of the tumour doubles during the survival time. When comparing the various histological subgroups, this mean number increases as the mean growth rate becomes more rapid.

Very accelerated radiation therapy: Preliminary results in locally unresectable head and neck carcinomas

PURPOSE To report preliminary results of a very accelerated radiation therapy Phase I/II trial in locally advanced head and squamous cell carcinomas (HNSCC). METHODS AND MATERIALS Between 01/92 and 06/93, 35 patients with an unresectable HNSCC were entered in this study. Thirty-two (91%) had Stage IV, and 3 had Stage III disease. The mean nodal diameter, in patients with clinically involved nodes (83%), was 6.3 cm. The median Karnovsky performance status was 70. The treatment consisted of a twice daily schedule (BID) giving 62 Gy in 20 days. RESULTS In all cases, confluent mucositis was observed, which started about day 15 and resolved within 6 to 10 weeks. Eighty percent of patients had enteral nutritional support. The nasogastric tube or gastrostomy was maintained in these patients for a mean duration of 51.8 days. Eighteen patients (53%) were hospitalized during the course of treatment due to a poor medical status or because they lived far from the center (mean 25 days). Nineteen patients (56%) (some of whom were initially in-patients) were hospitalized posttreatment for toxicity (mean 13 days). Five patients (15%) were never hospitalized. During the follow-up period, 12 local and/or regional failures were observed. The actuarial 18-month loco-regional control rate was 59% (95% confidence interval, 45-73%). CONCLUSIONS The dramatic shortening of radiation therapy compared to conventional schedules in our series of very advanced HNSCC resulted in: (a) severe acute mucosal toxicity, which was manageable but required intensive nutritional support in all cases; and (b) high loco-regional response rates, strongly suggesting that the time factor is likely to be critical for tumor control in this type of cancer.

Dose-rate effect on induction and repair rate of radiation-induced DNA double-strand breaks in a normal and an ataxia telangiectasia human fibroblast cell line

Using pulsed-field gel electrophoresis (PGFE), we measured DNA double-strand breaks (DSB) in a normal human fibroblast and in a cell line derived from a patient suffering from ataxia telangiectasia (AT), a syndrome associated with a hypersensitivity to ionizing radiation. Initial DSB levels assessed after irradiation at 4 degrees C are similar in both cell lines. The DSB repair rate was measured after 30 Gy delivered at 4 degrees C and followed by an incubation at 37 degrees C for 24 h. In AT cells, the DSB repair rate is faster between 0.5 and 9 h and slower between 9 and 24 h. In addition, the DSB levels were measured after irradiation at 37 degrees C at 0.01 Gy min-1 (5-40 Gy). The shape of the curves was curvilinear and a plateau was reached at 10 Gy in the control. After an irradiation at 37 degrees C, DSB levels were significantly higher in AT cells than in the normal fibroblast cells. A model was developed assuming that DSB induction is independent of temperature and that DSB repair rate is independent of dose-rate and dose. This model was used to predict the 37 degrees C DSB data on the basis of the 4 degrees C data. Experimental data and predictions are in agreement, thus validating the above assumptions. It is suggested that, even for extreme situations such as 30 Gy delivered at 4 degrees C or 30 Gy delivered at 37 degrees C at 0.01 Gy min-1, DSB induction and repair are identical. Our results could be interpreted assuming an heterogeneity of DSB. A small fraction of DSB is slowly repaired. This fraction is lower in control than in AT cells. By protracting repair time, the 37 degrees C low-dose rate experiments permit a cleaner distinction between AT and control cells.

Changes in labeling indices of human tumors after irradiation

Abstract The time courses of the in vitro labeling index (LI) and of the tumor cell density (CD) were studied in 53 patients after one or several sessions of irradiation. Prior to irradiation, a significant positive correlation was observed between LI and CD. In these tumors the depression in LI was greater and of longer duration than in experimental tumors, it increased progressively during the course of fractionated irradiation. The histologic type and the site of the tumor appeared to influence the course of LI and CD. A temporary increase of LI was observed in only 7 of 31 patients irradiated in one or two sessions and in only 2 of 22 patients who were followed during a fractionated course of radiotherapy. In the 9 patients whose LI increased after irradiation, the pretreatment LI and CD were significantly lower than in the other patients. No relationship was observed between pretreatment LI or CD values and either tumor regression with radiotherapy or 5-year survival. However, a significant fall in LI after irradiation was generally observed in patients who had no noticeable tumor regression and in those who did not survive 5 years; no significant or a less significant fall in LI was observed in tumors which regressed after radiotherapy and in patients who survived at 5 years.

The influence of cell proliferation in tumours and normal tissues during fractionated radiotherapy

Abstract Proliferation rates of human tumours and normal tissues can be derived from clinical observations. They are in agreement with experimental data obtained on animals. The proliferation rates do not remain constant after an irradiation or during the course of fractionated irradiation. Thus the usual regular fractionation does not seem optimally adapted to the kinetics of the cell populations. However, there is no evidence for any superiority of few and large fractions.

A comparison of early effects with two dose rates in brachytherapy of cervix carcinoma in a prospective randomised trial

This phase III randomised trial examined the early effects of two low dose rates (0.38 and 0.73 Gy/h) in brachytherapy of stage I and IIp cervical cancer patients. A total of 204 patients were included between January 1985 and September 1988. Since the main analysis of this paper concerned surgical difficulties, only the 155 patients (76%) on whom surgery was performed at the Institut Gustave-Roussy were retained in this analysis. Treatment consisted of uterovaginal 137Cs irradiation followed by immediate or deferred surgery. The two groups were similar for pretreatment characteristics except for endocervix involvement. Their brachytherapy parameters were also similar (60 Gy pear dimensions, doses to critical organs, total kerma, etc.). The factors with a poor prognosis were, for surgical difficulties, older age, stage II and a small irradiated pear volume; for difficulties with haemostasis, immediate surgery, stage II and previous surgery; and for difficulties in dissection, lymph node involvement. The dose rate significantly influenced surgical difficulties for the stage IIp patients operated on by deferred surgery. Those treated with the higher dose rate showed a 2-fold increase in surgical difficulties compared to those irradiated at the lower dose rate (P = 0.03). The independent prognostic factors for sterilisation of the surgical specimen were small tumour size and absence of lymph node involvement. An inverse dose rate effect was observed for medium size tumours, with significantly more sterilisations observed in stage IIp patients in the lower dose rate group (P < 0.01).

The influence of allogeneic inhibition and tumour age on the kinetics of L1210 leukaemia in vivo

Abstract We have confirmed that the cells of a leukaemia, grown as an ascites, undergoes a lengthening of cell-cycle time and diminishing growth fraction. In isologous mice, the initial growth phase of the L 1210 leukaemia is truly exponential and the duration of the cell cycle closely corresponds to the doubling time. The slow increase of cell cycle time, at least in the isologous mice, does not seem to be able to be explained as an immune phenomenon. Allogeneic inhibition has been demonstrated, both by an equivalent increase of the doubling time and the duration of the cell cycle, which occurs during the initial phases of tumour growth.