Phase I study of weekly topotecan combined to concurrent external cranial irradiation in adults with glioblastoma multiforme of the brain.

Although the standard of care for patients with glioblastoma multiforme (GM) remains postoperative radiotherapy (RT) in combination with chemotherapy (CT), the optimal regimen awaits verification. A phase I study was performed to determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) of topotecan (Hycamptin), given concurrently with RT, in patients with previously untreated glioblastoma multiforme (GM) of the brain. Thirty-six patients with histologically confirmed GM were enrolled. After surgery or stereotactic biopsy, patients received conventional external cranial RT (59.4 Gy/33 fractions in 6.6 weeks). Two cycles of topotecan were administered at days 1 and 4 of each week. Each cycle consisted of 30-min intravenous infusion 30-60 min before RT. The dose of topotecan was escalated in three dose increments from 1.0 to 1.25 and 1.5 mg/m(2) on a twice a week schedule among different patient groups. Three dose levels of topotecan were tested. Ten patients accrued to level 1 (topotecan dose 1 mg/m(2)/day, twice a week). No grade 4 toxicities were seen. Grade 2/3 hematologic toxicity was observed in 4 patients. Of the 11 patients included at level 2 (topotecan dose 1.25 mg/m(2)/day twice a week), 3 presented with grade 3 leucopenia and 2 with grade 3 thrombocytopenia. Of the 15 patients accrued to level 3 (topotecan dose 1.5 mg/m(2), twice a week), six had episodes of grade 4 leucopenia and two developed grade 4 thrombocytopenia. No other serious, early non-hematologic or late toxicities were seen at 21 months median follow-up time (range 6-36 months). From the cases included at level 2 and 3, five patients experienced episodes of grade 2/3 asthenia (13.8%), headache 9 (25%), confusion 5 (13.8%), seizure 4 (11%), and cutaneous erythema 3 (8.3%). The DLTs of topotecan given concurrently with RT were mainly hematological and the MTD was determined at the 1.25 mg/m(2)/day, twice a week dose level. A phase II chemoradiation study using the above recommended MTD dose of topotecan is ongoing, to establish the response rates, the local failures and the median survival of the above patients.

Treatment of benign diseases with megavoltage X-ray beams: is there a risk for gonadal damage?

AIMS: To measure the testicular and ovarian doses and to assess the risk for gonadal damage to patients treated with megavoltage X-ray beams for benign diseases. MATERIALS AND METHODS: Radiation therapy of benign diseases was simulated on an anthropomorphic phantom with a 6MV photon beam. The gonadal dose was calculated during the irradiation of heterotopic ossification, liver and vertebra haemangiomas, bone cysts, Graves' ophthalmopathy and gynaecomastia. Dose measurements were carried out using thermoluminescent dosimeters. For the radiotherapy of heterotopic ossification, the effect of using lead blocks to spare lymphatic drainage on the gonadal dose was determined. RESULTS: The ovarian and testicular total doses were found to be 2.00-680 and 2.0-39.0 mGy, respectively, depending on the gonadal location in respect to the treatment volume. The introduction of blocks into the primary beam resulted in an increase in gonadal dose up to a factor of 1.7. The radiation-induced risk of hereditary disorders in future generations was (1.0-40.8) x 10(-4) and (1.0-23.4) x 10(-4) for women and men, respectively. CONCLUSIONS: Radiation therapy of benign diseases always resulted in gonadal doses below 1 Gy and therefore there was no risk for permanent gonadal failure. The excess risk of radiation-induced hereditary disorders in offspring was low in comparison with the natural frequency of these effects. However, there was a considerable excess in risk after irradiation in the hip bone.

Therapeutic external irradiation in women of reproductive age: risk estimation of hereditary effects.

Exposure of women of childbearing age to ionizing radiation may result in induction of genetic disorders in future generations. This study aims to estimate the risk of hereditary effects attributable to therapeutic external irradiation in women. An anthropomorphic phantom was used to simulate radiotherapy in female patients and ovarian dose was measured for irradiation of brain, breast and lung cancer, and for treatment of Hodgkin's disease. These malignancies are among the most common tumours presenting in women of reproductive age. Dose measurements were undertaken using thermoluminescent dosemeters and all exposures were made with 6 MV X-ray beams. The dose to ovaries was found to be 2-3 cGy, 8-11 cGy and 11-15 cGy depending on the distance from the primary irradiation field during radiotherapy of brain, breast and lung cancer, respectively. The corresponding ovarian dose resulting from treatment of supradiaphragmatic and infradiaphragmatic Hodgkin's disease was 18-25 cGy and 128-356 cGy, respectively. A small excess risk of genetic diseases of (1-15) x 10(-4) was estimated for radiotherapy above the diaphragm. Pelvic irradiation resulted in an increased risk of hereditary effects of (77-214) x 10(-4).

Pegulated liposomal doxorubicin and cisplatin given concurrently with conventional radiotherapy: a phase I dose-escalation trial for patients with squamous cell carcinoma of head and neck and lung.

This is a phase I study of concurrent chemoradiation with pegulated liposomal doxorubicin (PLDH) and cisplatin for patients with squamous non-small cell lung cancer (NSCLC) and head and neck carcinoma (SCCHN). Nine patients with NSCLC and 9 with SCCHN were recruited in two phase I dose-escalation trials. The starting dose of PLDH was 7 mg/m2 once a week and was increased by 5 mg/m2 dose increments for every 3 patients. The standard dose of cisplatin was 20 mg/m2 once a week for 6.5-7 weeks of conventional external irradiation. The total tumor dose was 64 and 70 Gy for NSCLC and SCCHN patients respectively. The maximum tolerated dose of PLDH was 12 mg/m2 for the two cohorts of patients. Grade 3 mucositis was the dose limiting toxicity for NSCLC and SCCHN patients, at the 17 mg/m2 dose level. Three chemoradiation delays of 7 days were confirmed. The median time of follow-up was 17.9 months (range 3-36 months). Four patients died due to local-regional failure combined with distant metastases (3 patients) and pericardial effusion (1 patient). In total, there were 6/18 (33%) CRs (95% confidence interval, 11-55%), and 10/18 (55%), PRs (95% confidence interval, 32-78%). The recommended phase II PLDH dose combined to cisplatin and external irradiation is 12 mg/m2/week. The incorporation of PLDH in concomitant chemoradiation regimens for future treatment of squamous cell carcinoma of the lung and head and neck is warranted.

A phase I trial of weekly docetaxel and cisplatinum combined to concurrent hyperfractionated radiotherapy for non-small cell lung cancer and squamous cell carcinoma of head and neck.

We conducted a phase I study to evaluate the activity and tolerability of concurrent docetaxel and cisplatinum radiosensitization with hyperfractionated irradiation, in patients with advanced non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN). Nine patients (5 stage III(A) and 4 III(B)) with NSCLC, and 15 with SCCHN (10 stage III and 5 IV) were treated with a b.i.d. hyperfractionated (HF) radiotherapy schedule. The normalized total dose for alpha/beta ratio = 10 Gy was 69.6 Gy for NSCLC and 80.5 Gy for SCCHN patients. The standard dose of cisplatin (10 mg/m(2)) was given combined to docetaxel on a weekly basis. The docetaxel starting dose level was 10 mg/m(2)/week and was escalated by 3 mg/m(2) increments in cohorts of 8 patients (5 SCCHN and 3 NSCLC). DLT (grade 3 malaise) was observed in 4 out of 8 patients treated at the 16 mg/m(2)/week docetaxel dose level. The 13 mg/m(2)/week docetaxel dose level was defined as the MTD causing grade 3 mucositis in 4 out of 8 patients. In total 4 (17%) patients developed grade 3 neutropenia. G-CSF support was given in 1/8, 4/8, and 5/8 patients treated at the 10, 13 and 16 mg/m(2) docetaxel dose levels respectively. Fatigue was the most common adverse event (5/24: 21%) and was responsible for more than 1 week treatment delay in 4 out of 8 patients treated at the 16 mg/m(2)/week docetaxel dose level. Nine (3 NSCLC and 6 SCCHN patients: 37.5%) had treatment delay of 1 week, while 7 (3 NSCLC and 4 SCCHN: 29%) had delays of 2 weeks for combined chemoradiation sequelae. Acute hypersensitivity reactions occurred in 3 (12.5%) patients, and grade 3 mucositis in 2/8, 5/8 and 6/8 patients, treated at 10, 13 and 16 mg/m(2)/week docetaxel dose levels respectively. The overall response rate was 79% (CI = 63-96%) with 33% and 53% CRs for NSCLC and SCCHN patients respectively. There were 3 deaths among 9 NSCLC and 4 among 15 SCCHN patients. Local and/or distant disease recurrences were shown in 4 NSCLC and in 6 SCCHN patients; 5 NSCLC and 9 SCCHN patients are alive with no evidence of tumor progression at 8.5 months mean follow-up time. Radiosensitization with docetaxel and cisplatin given concurrently with HF (b.i.d.) radiotherapy on a weekly basis is a promising approach and the recommended dose for further phase II studies is 10 mg/m(2)/week for both drugs. The antitumor activity shown was significant in both types of tumors. The incorporation of docetaxel in chemoradiotherapy regimens for future treatment of squamous cell carcinoma of the lung and head and neck, merits evaluation in phase II and III trials.

Risk estimation of radiation-induced thyroid cancer from treatment of brain tumors in adults and children.

The purpose of this study was to estimate the risk of thyroid cancer induction attributable to brain radiation therapy in adult and pediatric patients. An anthropomorphic phantom was used to simulate treatment of brain tumors with two lateral opposed fields. Thyroid dose was measured using thermoluminescent dosimeters. Phantom measurements were performed for all possible field sizes that may be applied during brain radiotherapy in adults and children. The dependence of the thyroid dose on the distance from the irradiation field and on the presence of beam modifiers in the primary beam was investigated. All phantom exposures were generated with a 6 MV photon beam. Thyroid dose was found to vary from 9.6 to 89.4 cGy and from 8.0 to 194.0 cGy depending upon the field size used and the thyroid location in respect to the field edge for adults and children respectively. The excess relative risk of thyroid cancer induction for exposed children was estimated to be 0.6-14.9. The corresponding excess relative risk for adults was 0.1-1.1. The introduction of lead blocks or wedges into the primary beam may result in a considerable increase of the risk of thyroid cancer due to the increase of the thyroid dose. This study shows that brain radiotherapy during childhood may be associated with an increased risk of secondary thyroid cancer while the risk in adult patients is much smaller.

Embryo/fetus radiation dose and risk from dual X-ray absorptiometry examinations.

The aim of the current study was to estimate the embryo/fetus radiation doses and risks associated with spinal and hip dual X-ray absorptiometry (DXA) scans performed on the pregnant mother. The results were compared with the embryo/fetus dose from a thoracolumbar radiograph and pelvic radiograph. Posteroanterior (PA) lumbar spine and proximal femur scans during the first, second and third trimesters were performed on a phantom simulating pregnancy at the three trimesters of gestation. All scans were carried out using a Hologic 1000/W pencil beam DXA unit. Moreover, embryo/fetus doses from a (a) thoracolumbar radiograph and (b) pelvic radiograph were estimated for all periods of gestation using the same phantom. Radiation doses were measured using thermoluminescent dosimeters. The dose reduction achievable by shielding the embryo/fetus with a protective apron during DXA scans was studied for all trimesters of gestation. The embryo/fetus doses during the first trimester were measured to be 1.7 mGy and 2.7 mGy for the PA spine and femur DXA scan, respectively, for an embryo/fetus located 8.5 cm from the anterior maternal surface. The risk of excess fatal cancer was 0.2 per million unborn children irradiated in utero for measurements of the spine and 0.3 per million unborn children for measurements of the femur. The embryo/fetus doses during the second and third trimesters were 2.7 mGy and 4.9 mGy respectively for the scans of the lumbar spine. The risk of childhood fatal cancer was 0.3 per million for the second trimester and 0.5 per million for the third trimester. The embryo/fetus radiation doses during the second and third trimesters were estimated as 1.4 mGy and 1.0 mGy respectively for the examinations of the proximal femur. The risk of childhood fatal cancer was 0.1 per million for both trimesters. The use of the apron resulted in a very small change in the dose absorbed by the embryo/fetus. The embryo/fetus dose associated with both DXA modes investigated in the current study is at least 700 times lower in comparison with embryo/fetus dose from a thoracolumbar or pelvic radiograph in all periods of gestation. In conclusion, the embryo/fetus dose in bone density measurements of spine and femur using pencil beam DXA is lower than the average daily natural background in the United States of 8 mGy. The health provider can decide whether a DXA scanning is beneficial to a pregnant woman, taking into account the potential radiation risks to the embryo/fetus presented in the current study.

Peripheral primitive neuroectodermal tumour during pregnancy.

The case of a 25-year-old primipara in the second trimester of pregnancy, suffering from a peripheral primitive neuroectodermal tumour (pPNET) diagnosed by bone biopsy, is described. External irradiation was initially performed because of Jacksonian seizures due to a lesion in the right cerebral hemisphere. Appropriate shielding was used to reduce fetal exposure during brain radiotherapy. Caesarian delivery at the 27th week of gestation was performed because of tumour progression. The neonate had no evidence of disease and survived for 1 month. However, the placenta and ovaries showed metastases from the maternal pPNET. The patient died 14 months after initial diagnosis owing to the aggressiveness of the tumour, the rapid and extensive semination (bone marrow, lung, liver, craniospinal axis involvement) and the inability to adequately treat the patient with appropriate doses of chemotherapy.

Image segmentation in treatment planning for prostate cancer using the region growing technique.

The purpose of this study was to evaluate the performance of a region growing technique for segmenting prostate, bladder and rectum in CT images of prostate cancer patients. Prostate, bladder and rectum were segmented in all CT images of 10 patients using the region growing technique and manual tracing. Volumes of the above organs computed with the region growing technique were compared with those from manually traced images on a slice-by-slice basis. Measurement reproducibility of both segmentation techniques was evaluated using the data obtained from four independent observers. The region growing technique was 1.5 times faster than manual tracing. There was no statistical difference between the slice volumes of prostate, bladder and rectum obtained by the two segmentation techniques (p > 0.05, paired Student's t-test). Correlation between slice volumes of all organs of interest provided both by region growing and by manual tracing was very good (prostate r2 = 0.84; bladder r2 = 0.93; rectum r2 = 0.85). An overall reasonable agreement was found between the two segmentation techniques. The intraobserver and interobserver variations for prostate, bladder and rectum volume segmentation were found to be lower with the region growing technique than with manual tracing. The suggested semi-automatic technique allows the possibility of generating accurate and reproducible segmentation of prostate, bladder and rectum from CT data with great saving in labour.

Brain radiotherapy during pregnancy: an analysis of conceptus dose using anthropomorphic phantoms.

The aims of this study were: (a) to determine conceptus dose resulting from brain radiotherapy; (b) to investigate the necessity of using shielding devices over patient's abdomen during treatment; and (c) to estimate the components of conceptus dose. Radiation doses received by conceptus were measured using anthropomorphic phantoms simulating pregnancy at 4, 12 and 24 weeks gestation and thermoluminescent dosemeters. All irradiations were performed with two lateral and opposed fields approximating the minimum, medium and maximum field size used during treatment of brain malignancies. For a treatment course delivering 65 Gy to tumour without using shielding equipment, conceptus dose never exceeded 100 mGy. Appropriate positioning of 5.1 cm of lead over the phantom's abdomen provided reduction of conceptus dose from 26% to 71%, depending upon gestational age, field size and distance from the field isocentre. The contribution of scatter arising from within the phantom to the conceptus dose was small compared with that from head leakage and collimator scatter. Our dosimetric results indicate that the construction of special shielding equipment is not a prerequisite for treating brain malignancies during pregnancy. However, based on the concept that exposures in women of childbearing age should be kept as low as reasonably achievable, we suggest that shielding devices should be used whenever possible.

A method of estimating fetal dose during brain radiation therapy.

PURPOSE: To develop a simple method of estimating fetal dose during brain radiation therapy. METHODS AND MATERIALS: An anthropomorphic phantom was modified to simulate pregnancy at 12 and 24 weeks of gestation. Fetal dose measurements were carried out using thermoluminescent dosimeters. Brain radiation therapy was performed with two lateral and opposed fields using 6 MV photons. Three sheets of lead, 5.1-cm-thick, were positioned over the phantom's abdomen to reduce fetal exposure. Linear and nonlinear regression analysis was used to investigate the dependence of radiation dose to an unshielded and/or shielded fetus upon field size and distance from field isocenter. RESULTS: Formulas describing the exponential decrease of radiation dose to an unshielded and/or shielded fetus with distance from the field isocenter are presented. All fitted parameters of the above formulas can be easily derived using a set of graphs showing their correlation with field size. CONCLUSION: This study describes a method of estimating fetal dose during brain radiotherapy, accounting for the effects of gestational age, field size and distance from field isocenter. Accurate knowledge of absorbed dose to the fetus before treatment course allows for the selection of the proper irradiation technique in order to achieve the maximum patient benefit with the least risk to the fetus.

Bladder and rectum volume estimations using CT and stereology.

Twelve prostate cancer patients underwent a treatment planning CT prior to radiotherapy. Stereologic method based on Cavalieri principle was applied to CT images. Systematic and random sampling of CT slices were performed with alternative ways for assessing the volumes of bladder and rectum. The contribution of point counting to the precision of the obtained volume estimations was analysed. It was found that 100-150 test points counted on only 5-7 systematically sampled slices through bladder or rectum suffice for reliable volume estimations of the above organs. Also, the superiority of systematic vs random sampling was confirmed. The suggested volumetric method gives the possibility of generating unbiased and efficient bladder and rectum volume assessments directly from CT data with great saving in labour.

A pilot study on concurrent platinum chemotherapy and intracavitary brachytherapy for locally advanced cancer of the uterine cervix.

This study aims to evaluate the feasibility, toxicity and efficacy of concurrent chemotherapy with platinum compounds and brachytherapy, for locally advanced carcinoma of the cervix (Stages IIA/B, IIIA). The hypothesis was that synchronous chemo-brachytherapy may be sufficient to cause down-staging of the tumour, to render it operable, and hopefully improve the prognosis. 36 women with locally advanced cervical cancer were treated with concomitant brachytherapy and chemotherapy before surgery and/or definitive external radiotherapy. All patients received two caesium-137 Selectron MDR applications, 1 week apart. The dose calculated to point A for each implant was 20-25 Gy. Chemotherapy consisting of continuous cisplatin infusion (50 mg m2) and of carboplatin (300 mg m-2) was given simultaneously with intracavitary irradiation during the first and second application, respectively. The combined therapy was followed when feasible by radical hysterectomy, pelvic lymphadenectomy and pelvic radiotherapy. Patients deemed ineligible for surgery because of poor response were given full dose external radiotherapy. 31/36 patients were treated by Wertheim hysterectomy of whom 10 had negative lymph nodes and resection margins. Definitive external radiotherapy was given in the remaining five patients. Overall, 83% were disease free at 2.8 years mean follow-up. The most frequent acute side-effects of chemobrachytherapy were nausea and vomiting. No renal toxicity was observed. Thrombocytopenia was seen in five patients and was responsible for delayed surgery in four patients. Concerning late effects, two patients developed grade 2 intestinal sequelae, two mild frequency and two vaginal stenosis. One rectovaginal and one vesicovaginal fistula developed in two patients; and a third patient had a fistula associated with tumour recurrence. Concurrent brachytherapy and chemotherapy with platinum compounds is well tolerated and effective in reducing tumour bulk before definitive local treatment (surgery or external radiotherapy), in patients with locally advanced carcinoma of the uterine cervix.

Concurrent platinum and docetaxel chemotherapy and external radical radiotherapy in patients with invasive transitional cell bladder carcinoma. A preliminary report of tolerance and local control.

PURPOSE: The present study aims to evaluate the feasibility, toxicity, and efficacy of concurrent chemotherapy with cisplatinum and docetaxel, and external radical radiotherapy for transitional cell carcinoma of urinary bladder. MATERIALS AND METHODS: 42 patients (34 men, 8 females) with invasive bladder carcinoma (clinical stages T1-4) were treated after transurethral biopsy with chemotherapy and concomitant external radiotherapy. Chemotherapy consisting of cisplatin infusion (30 mg/m2) and Docetaxel (40 mg/m2) was given twice a week simultaneously with-irradiation during the whole treatment period (6-8 weeks) as follows: Cisplatin (D1,D8,D15,D22, D25,D36,D43,D50) and Docetaxel (D4, D11, D18, D25, D32, D39, D46, D53). An external irradiation scheme 1.8 to 2.0 Gy per fraction, 5 days a week was used up to 68-74 Gy (6MeV photons) total tumor dose. RESULTS: All but S patients completed the planned chemoradiation protocol. The complete response rate (CR-rate) assessed at 3 months after completion of combined treatment was 100%, 63.6%, 46.15% and 95% for clinical stage (c) cT1 (9/9), cT2 (7/11), cT3 (6/13) and cT4 (1/4) cases respectively. None of 9 patients with T1 tumors had any local failure at 36.1 months mean follow-up time. In total, 9 of 37 patients (24.32%) relapsed locally and/or distantly and were followed for 25.04 months (mean time), 50% of the relapses occurred at a mean time of 7.25 months. The mortality rate was 10.81% (4/37). All these patients died with a mean time of 11 months. 32 cases remain alive 19-46 months after treatment; 27 of those are with no evidence of disease with a mean follow-up time of 32.24 months. In total, there was a 78.50% (30/37) and a 75.67%, (28/37) rate of overall survival and pelvic control respectively at 25.04 months mean follow-up time. Chemotherapy was discontinued in 2 cases due to acute gastrointestinal toxicity and in 3 more, due to patient compliance. There was 1 toxic death 2 months after treatment completion due to ureteral obstruction and impaired renal function. The acute toxicity was estimated as moderate to severe and caused the interruption of treatment for 5 to 10 days in 8 of 37 patients (21.62%). Myelotoxicity appeared in 22/37 patients but febrile grade III and IV neutropenia was observed in 3 patients (8.10%) and thrombocytopenia (Grade I-III) in 8 (21.62%). Concerning late effects a sigmoid stricture, a transient small bowel obstruction, 4 patients with contracted bladder and 1 case with renal failure were found. Grade I to III hypersensitivity reactions appeared in 8/37 patients (21.62%) while stomatitis (grade I-II) and grade II skin toxicity appeared in 3 and 4 patients respectively. These and other symptoms (Grade I to II peripheral edema, transient myalgias and arthralgias in 7/37 cases), paresthesias or numbness (3/37) and peripheral motor dysfunction (1/37) were responsible for early reduction of docetaxel dose from 40 mg/m2 to 20 mg/m2. CONCLUSION: This preliminary analysis suggest that the radiosensitizing effect of cisplatin and docetaxel to megavoltage irradiation yielded a high CR-rate in transitional cell bladder carcinoma patients with medium to severe early and late side effects. The value of such a combined treatment as far as the tumor eradication is concerned requires further evaluation, because of the small number of patients, the short follow-up, and the absence of other studies using docetaxel as a radiosensitizer in urothelial cell cancer.

CT-based radiotherapy treatment planning for cancer of the nasopharynx.

We analysed 32 cases of nasopharyngeal carcinoma (NPC) treated with radiotherapy trying to define the role of CT scan during radiotherapy planning, as well as radiation treatment and the follow-up of the patients. CT scan was found to help 15 cases with low-parapharyngeal involvement and/or bone erosion. Persistent abnormal CT findings at 2 mo after the end of radiation treatment were related to a 30% local recurrence rate. This rate went up to 100% in case of skull-base destruction.

Prophylactic administration of indomethacin for irradiation esophagitis.

This is a double-blind study in which 14 randomly selected patients treated for lung cancer by irradiation, were receiving indomethacin, while 14 patients treated also by irradiation served as controls. The purpose of the study was to investigate a possible protective effect of the drug in irradiation esophagitis. The esophagus was included in the irradiation field in all patients. Histologic findings of esophagitis were not different in the two groups. However, endoscopic esophagitis and symptomatology were milder in the patients who received indomethacin.

Seasonal variations in the frequency distribution of breast cancer in Greek women according to the month of their birth.

The frequency distribution of patients with breast cancer according to the month of their birth was examined in 1,165 women comprising the total number of patients recorded in our cancer registry from 1975 until the end of 1982. Statistical evaluation of this material using an exact chi 2 for simple null hypothesis demonstrated the existence of two high frequency peaks corresponding to March and April in the spring and September in the autumn. These frequencies were significantly higher (P less than 0.001) than those of the remaining months. Confirmation of this finding would imply the introduction of a new variant in breast cancer epidemiology.