Reduction of oral mucositis by palifermin (rHuKGF): dose-effect of rHuKGF

PURPOSE: The aim of the present study was to determine the dose effect of palifermin (recombinant human keratinocyte growth factor, rHuKGF) for reduction of the response of oral mucosa to fractionated radiotherapy in a mouse model. MATERIAL AND METHODS: Ulceration (confluent mucositis) of mouse tongue epithelium was analysed as the clinically relevant endpoint. Palifermin at doses from 1 - 30 mg/kg was administered before the onset (day -3), at the end of the first (day +4) or the second week of irradiation (day +11) with 5 x 3 Gy/week. Each protocol was terminated by graded radiation test (top-up) doses. In a further experiment, optimally effective doses were given on days -3 and +4, or -3, +4 and +11. RESULTS: Single dose irradiation of mouse mucosa yielded an ED50 (dose inducing ulcer in 50% of the mice) of 10.7 +/- 1.0 Gy. With fractionated irradiation for 1 week an ED50 for test irradiation (day +7) of 5.1 +/- 1.9 Gy was observed. After 2 weeks (day +14), the ED50 was 7.3 +/- 1.9 Gy. Palifermin significantly increased the ED50 values in all protocols tested. Maximally effective doses for single injections were 15.0 mg/kg (day -3, +11) or 22.5 mg/kg (day +4), which yielded ED50 values of 12.1 +/- 1.3 Gy, 13.7 +/- 1.5 Gy and 14.4 +/- 1.3 Gy, respectively. Higher palifermin doses did not further increase the ED50. Repeated injections on days -3 and +4 did not increase the ED50 beyond the value obtained with injections on day +4 alone. An additional injection on day +11 increased the ED50 further to 15.1 +/- 0.1 Gy. CONCLUSIONS: A significant palifermin dose-effect was seen at doses below 15 mg/kg. However, a significant increase in oral mucosal radiation tolerance by palifermin over untreated control tissue was observed already with low doses of 1 mg/kg. This indicates that in clinical studies with palifermin, the dose of the growth factor may be of minor relevance over a wide dose range.     

The results of radiotherapy of epicondylitis humeri using different dosages

In a prospective analysis the effectiveness of roentgen irradiation with minimal doses (daily single doses .03 Gy up to a total dose of 1.5 Gy) was investigated in 207 patients with an epicondylitis humeri. Compared with a group of 92 patients, who were irradiated with higher doses being in general use (weekly 2x single doses 1.0 Gy to a total dose of 4.0 Gy), the therapeutic results show no significant differences. After termination of the first irradiation series an improvement of complaints was seen in half of the patients (48.8% or 50.0%). A further increase of the quota in success to 74.9% or 70.6% was found 6 weeks after termination of irradiation. By reason of radiotherapeutic results, mainly attained in chronic states of epicondylitis humeri after primary conservative therapy without success for months and partly surgical pretreatment, the radiotherapy should be used more frequently than till now, especially in consideration of its slight side-effects and injuries of patients.     

Reduction of oral mucositis by palifermin (rHuKGF): Dose-effect of rHuKGF

Purpose: The aim of the present study was to determine the dose effect of palifermin (recombinant human keratinocyte growth factor, rHuKGF) for reduction of the response of oral mucosa to fractionated radiotherapy in a mouse model.

Material and methods: Ulceration (confluent mucositis) of mouse tongue epithelium was analysed as the clinically relevant endpoint. Palifermin at doses from 1 – 30 mg/kg was administered before the onset (day ?3), at the end of the first (day +4) or the second week of irradiation (day +11) with 5 × 3 Gy/week. Each protocol was terminated by graded radiation test (top-up) doses. In a further experiment, optimally effective doses were given on days ?3 and +4, or ?3, +4 and +11.

Results: Single dose irradiation of mouse mucosa yielded an ED50 (dose inducing ulcer in 50% of the mice) of 10.7 ± 1.0 Gy. With fractionated irradiation for 1 week an ED50 for test irradiation (day +7) of 5.1 ± 1.9 Gy was observed. After 2 weeks (day +14), the ED50 was 7.3 ± 1.9 Gy. Palifermin significantly increased the ED50 values in all protocols tested. Maximally effective doses for single injections were 15.0 mg/kg (day ?3, +11) or 22.5 mg/kg (day +4), which yielded ED50 values of 12.1 ± 1.3 Gy, 13.7 ± 1.5 Gy and 14.4 ± 1.3 Gy, respectively. Higher palifermin doses did not further increase the ED50. Repeated injections on days ?3 and +4 did not increase the ED50 beyond the value obtained with injections on day +4 alone. An additional injection on day +11 increased the ED50 further to 15.1 ± 0.1 Gy.

Conclusions: A significant palifermin dose-effect was seen at doses below 15 mg/kg. However, a significant increase in oral mucosal radiation tolerance by palifermin over untreated control tissue was observed already with low doses of 1 mg/kg. This indicates that in clinical studies with palifermin, the dose of the growth factor may be of minor relevance over a wide dose range.     

Effect of EGFR-inhibition on the radiation response of oral mucosa: experimental studies in mouse tongue epithelium

The aim was to quantify the effect of selective inhibition of the epidermal growth factor receptor (EGFR) on the radiation response of mouse oral mucosa to daily fractionated irradiation. Irradiation comprised graded single doses of 25 kV X-rays to the lower tongue surface or fractionated doses of 5 x 3 Gy week(-1) (200 kV X-rays) over 1 or 2 weeks, followed by graded local doses, to generate full dose-effect curves. For selective inhibition of EGFR, BIBX1382BS, a tyrosine kinase inhibitor, was administered orally at a dose of 50 mg kg(-1), for the entire overall treatment time. The ED50 (the dose expected to induce ulcer in 50% of the mice) for untreated mucosa was 11.9 +/- 1.2 Gy. Fractionated irradiation administered over 1 or 2 weeks yielded ED50 values for the concluding test irradiation of 6.7 +/- 2.1 and 6.5 +/- 1.9 Gy, respectively. Administration of BIBX1382BS resulted in a non-significant increase of the top-up ED50 to 8.3 +/- 1.6 Gy (p = 0.1197) after 1 week and to 7.6 +/- 1.6 Gy (p = 0.2263) after 2 weeks. EGFR inhibition does not alter the radiation response of oral mucosa to fractionated irradiation or interfere with mucosal repopulation processes. This indicates that the regulation of mucosal repopulation is largely independent of EGFR activation.     

Amelioration of Early Radiation Effects in Oral Mucosa (Mouse) by Intravenous or Subcutaneous Administration of Amifostine

PURPOSE: To quantify the reduction of radiation-induced oral mucositis by amifostine as a function of administration route. MATERIAL AND METHODS: Mucosal ulceration of lower mouse tongue epithelium was analyzed. Amifostine was injected at 1.8 mg/injection subcutaneously (s.c.) or intravenously (i.v.), 45 min or 10 min prior to irradiation. With single-dose irradiation, a single amifostine injection was given. During daily fractionated irradiation (5 x 3 Gy) for 1 week, amifostine was administered s.c. or i.v. twice (days 0, 3), or s.c. on all irradiation days (days 0-4). With ten fractions over 2 weeks, five s.c. injections were given in week 1 (days 0-4) or week 2 (days 7-11), or both. Two i.v. injections were given either in week 1 (days 0, 3) or week 2 (days 7, 10). All fractionation protocols were terminated by graded test doses to generate full dose-effect curves. RESULTS: In a single-dose control experiment, the ED(50) (dose after which ulcer induction is expected in 50% of the mice) was 11.7 +/- 1.4 Gy. Intravenous application of amifostine increased the ED(50) to 14.0 +/- 1.4 Gy (p = 0.024), while s.c. administration had no significant effect. The ED(50) for test irradiation after 5 x 3 Gy was 5.8 +/- 1.4 Gy. Two s.c. or i.v. amifostine injections yielded ED(50) values of 7.2 +/- 1.1 Gy (p = 0.0984) or 7.6 +/- 1.2 Gy (p = 0.0334); five s.c. injections increased the ED(50) to 8.2 +/- 0.9 Gy (p = 0.0039). The ED(50) after 10 x 3 Gy/2 weeks was 6.6 +/- 1.8 Gy. Subcutaneous or intravenous administration of amifostine in week 1 yielded a significant increase in ED(50) to 9.4 +/- 2.5 Gy (p = 0.0099) and 10.0 +/- 2.2 Gy (p = 0.0014). By contrast, amifostine administration in week 2 had no significant effect. Administration in weeks 1 and 2 resulted in an ED(50) of 10.8 +/- 3.6 Gy (p = 0.0053). CONCLUSION: Amifostine during daily fractionated irradiation is effective only if administered in the initial treatment phase, i.e., week 1 in the mouse. The differences in the effect in weeks 1 and 2 suggest mechanisms of action other than radical scavenging.     

Effects of Systemic or Topical Administration of Sodium Selenite on Early Radiation Effects in Mouse Oral Mucosa

PURPOSE: To quantify the effect of sodium selenite (selenium) on radiation-induced oral mucositis (mouse) after subcutaneous or topical administration. MATERIAL AND METHODS: Mucosal ulceration of the lower epithelium of mouse tongue was analyzed. Selenium (5 mug) was applied subcutaneously (s.c.) or locally, 60 min or 30 min prior to irradiation, respectively. In combination with single-dose irradiation, a single selenium application was given. With daily fractionated irradiation (3 Gy/fraction) for 1 week (days 0-4), selenium was administered at all 5 days of irradiation. With ten fractions over 2 weeks, selenium was applied in week 1, week 2, or both. All fractionation protocols were terminated by graded test doses to generate full dose-effect curves. RESULTS: In a single-dose control experiment, the ED(50) (dose after which ulcer induction is expected in 50% of the mice) was 12.9 +/- 1.6 Gy. Selenium increased the ED(50) to 17.7 +/- 2.6 Gy (s.c.; p = 0.0003) and 16.3 +/- 3.0 Gy (local; p = 0.0104). The ED(50) for test irradiation after 5 x 3 Gy was 7.4 +/- 2.2 Gy. Subcutaneous administration of selenium resulted in an ED(50) of 11.5 +/- 2.0 Gy (p = 0.0015), local application yielded an ED(50) of 10.0 +/- 2.1 Gy (p = 0.0284). The ED(50) for test irradiation after 10 x 3 Gy/2 weeks was 8.0 +/- 1.7 Gy. Subcutaneous or local administration of selenium in week 1 yielded a significant increase in ED(50) to 10.5 +/- 1.0 Gy (p = 0.0069) and 10.7 +/- 1.0 Gy (p = 0.0039), respectively. By clear contrast, selenium administration in week 2 had no significant effect. Administration in both weeks resulted in an ED(50) of 9.1 +/- 2.0 Gy (s.c.; p = 0.2747) and 9.7 +/- 1.4 Gy (local; p = 0.0541). CONCLUSION: Administration of sodium selenite during clinically relevant fractionated irradiation protocols has a significant effect during the initial treatment phase, i.e., week 1 in the mouse. Therefore, in clinical radiotherapy, the latent time to manifestation of confluent mucositis may be significantly prolonged, and hence the burden for the patient clearly reduced by selenium.     

Esophageal Cancer

PURPOSE: To present the results of a prospective phase II study in esophageal carcinoma. PATIENTS AND METHODS: Patients received single doses of 1.8 Gy up to 27 Gy, then concomitant boost to a total of 50.4 Gy (PTV2 [planning target volume], single dose 1.8 Gy) and 64.8 Gy (PTV1, single dose 1.2 Gy in the morning and 1.8 Gy in the afternoon) concurrently with 800 mg/m(2)/d 5-fluorouracil and 20 mg/m(2)/d cisplatin (weeks 1 and 5). High-dose-rate brachytherapy (2-3 x 6 Gy) on Fridays of weeks 4-6 used a customized applicator facilitating central placement and circumferential dose homogeneity. RESULTS: 50 patients with squamous cell carcinoma (90%) or adenocarcinoma and mostly advanced tumor stage were treated (82% T3/T4 and 70% N1). Median overall survival (median OS 16 months; 1-year-OS 61%; 2-year OS 29%) was significantly longer for patients without nodal disease (35 vs. 11 months; p = 0.01). Hematotoxicity was grade 3 in 11/50, and grade 4 in 1/50 patients. Four percent of higher-grade nausea or vomiting occurred. Esophageal late toxicity was grade 3 in 9/50 patients, and grade 4 in 2/50 patients. CONCLUSION: Survival was excellent especially for patients without nodal disease in this dose-intensified schedule with acceptable tolerability.     

Modelling hematological parameters after total body irradiation

Abstract

Purpose: The time- and dose-dependent reconstitution of hematopoiesis after radiation exposure is strongly related to the stem cell population and can be used to predict hematological parameters. These parameters allow further insight into the hematopoietic system and might lead to the development of novel stem cell transplantation models.

Materials and methods: CD4-/- C57Bl/6 mice, transgenic for human CD4 and HLA-DR3, were irradiated in a single (3, 6, 8 and 12 Gy) and fractionated (6 × 1 Gy, 6 × 1.5 Gy, 6 × 2 Gy; twice daily) dose regimen. Blood was analyzed weekly for red blood cells (RBC), hemoglobin concentration (Hb), hematocrit (HCT) and white blood cells (WBC). Organ and tissue damage after irradiation were examined by histopathology.

Results: The recovery curves for RBC, Hb, HCT and WBC showed the same velocity (< 1 week) for all radiation doses (3–12 Gy) starting at different, dose-dependent times. The only dose-dependent parameter was defined by the beginning of the recovery process (dose-dependent shift) and higher doses were related to a later recovery of the hematopoietic system. The RBC, Hb and HCT recovery was followed by a saturation curve reaching a final concentration independent of the radiation dose. Histological analysis of the bone marrow in the single dose cohort showed a dose-dependent reduction of the cellularity in the bone marrow cavities. The fractioned radiation dose cohort resulted in a regeneration of all bone marrow cavities.

Conclusion: Specific functions were developed to describe the reconstitution of hematological parameters after total body irradiation.     

Phase I Trial of Radiochemotherapy with Bendamustine in Patients with Recurrent Squamous Cell Carcinoma of the Head and Neck

BACKGROUND AND PURPOSE: After initial radiochemotherapy of head-and-neck cancers, therapeutic options are often limited for patients with progressive disease. Reirradiation, with or without chemotherapy, appears to be the most potential treatment option. The aim of this study was to determine the maximum tolerated dose of bendamustine in combination with reirradiation for these patients. PATIENTS AND METHODS: 13 patients with recurrent squamous cell carcinoma of the head-and-neck region after initial radiochemotherapy were treated. Reirradiation of the recurrent region under protection of the spinal cord consisted of 1.8 Gy given five times per week, up to 30.6 Gy. Simultaneous bendamustine was administered on days 1 and 2 at increasing dose levels (80, 100, and 120 mg/m(2) bendamustine). The regimen was administered every 4 weeks. A minimum of three patients were enrolled at each dose level. RESULTS: The therapy was well tolerated. Patients received one to six cycles of bendamustine (median: three). Hematologic toxicities observed were leukocytopenia, thrombocytopenia, or anemia. At dose level II (100 mg/m(2) bendamustine), grade 3/4 hematologic toxicity was seen in one patient so that this level was filled up to six patients. There was no grade 3/4 toxicity seen in the other twelve patients. The most frequent nonhematologic toxicities (grade 1 or 2) were infections (in most cases C-reactive protein elevations without other clinical signs of infection) and nausea. CONCLUSION: The reapplication of radiochemotherapy with bendamustine is well tolerated. The recommended dose for phase II studies was established at dose level III (bendamustine 120 mg/m(2)).     

Effects of dexpanthenol with or without Aloe vera extract on radiation-induced oral mucositis: preclinical studies

PURPOSE: To define the effect of dexpanthenol with or without Aloe vera extract on radiation-induced oral mucositis. MATERIALS AND METHODS: Mouse tongue mucosal ulceration was analysed as the clinically relevant endpoint. Graded single or fractionated dose irradiation (10 x 3 Gy/2 weeks, graded test doses on day 14) were combined with topical administration of dexpanthenol or a base, with or without Aloe vera extract. The formulations were applied for 14 days (single dose) or 24 days after the first fraction. RESULTS: Single dose irradiation resulted in an ED50 (dose at which a positive mucosal response was expected in 50% of the animals irradiated) of 11.9+/-1.2 Gy. None of the formulations yielded a significant change in incidence or time course of ulceration. Test irradiation after 10 x 3 Gy gave an ED50 of 9.0+/-0.1 Gy. Base treatment increased the ED50-values to 10.5+/-0.8 Gy (p = 0.0095) and 9.9+/-0.7 Gy (p = 0.0445) without or with Aloe vera. Dexpanthenol resulted in ED50 values of 9.5+/-0.1 Gy without Aloe vera (p > 0.05), and of 10.9+/-0.9 Gy (p = 0.0035) with Aloe vera. The latent time to ulceration was prolonged, compared to the control (6.3 days) without Aloe vera (8.0-8.2 days, p < 0.001) and with dexpanthenol and Aloe vera (7.3 days, p = 0.0239). CONCLUSIONS: With single dose irradiation, neither dexpanthenol nor Aloe vera extract significantly changed the oral mucosal radiation response. With fractionated irradiation, drug administration significantly increased the isoeffective radiation doses, independent of dexpanthenol or Aloe vera content. Neither dexpanthenol nor Aloe vera display a prophylactic potential.     

Role of ethanolic extract of Morus alba leaves on some biochemical and hematological alterations in irradiated male rats

Purpose: The present study aimed to evaluate the protective role of “Morus alba Linn (Family: Moraceae) commonly known as mulberry” leaves extract against hazardous effects of gamma rays in male rats.

Materials and methods: Thirty six male albino rats were divided into six groups (six rats/group); (1) control group received 1?ml distilled water, (2) low dose of extract (100?mg/kg) group treated daily with low oral dose of ethanolic extract of mulberry leaves (100?mg/kg body weight (b.wt.)) for 21 consecutive days, (3) high dose of extract (200?mg/kg) group treated daily with high oral dose of ethanolic extract of mulberry leaves (200?mg/kg b.wt.) for the same period, (4) irradiated group rats were subjected to whole body gamma irradiation at a shot dose of 7?Gy, (5) low dose of extract?+?irradiated group treated daily with low oral dose of ethanolic extract of mulberry leaves (100?mg/kg b.wt.) for 21 consecutive days then rats were exposed to gamma irradiation at a single dose of 7?Gy, (6) high dose of extract?+?irradiation group treated daily with high oral dose of ethanolic extract of mulberry leaves (200?mg/kg b.wt.) for 21 consecutive days then rats were exposed to gamma irradiation at a single dose of 7?Gy. Rats were sacrificed 1, 7, 15 days post gamma irradiation in all groups. Blood samples were taken at three intervals time in the six groups.

Results: The results showed that whole body irradiation of rats induced significant decrease (p?p?Conclusions: Mulberry leaves extract prior to exposure to gamma irradiation has radio protector against hazardous effect of irradiation in male rats.     

Combined radiotherapy with cis- or carboplatin in advanced head and neck tumors

This report reviews the treatment results of 111 patients with stage T3-4, N0-3, M0, biopsy proven squamous cell carcinoma of the oropharynx and oral cavity. All patients were treated by primary irradiation with 1.8 to 2 Gy per day for five days a week up to a target volume dose of 39.6 or 40 Gy. Simultaneously 20 mg/m2 cisplatin was given under hyperhydration and mannitol diuresis on days 1 to 5. In case of partial tumour regression radiotherapy was continued up to 70 Gy with another course of cisplatin. In case of minor response surgery was interposed followed by subsequent irradiation with 30 Gy and a second course of cisplatin. 67% of the patients showed an initial complete tumour involution and 27% a partial response. The five year actuarial survival rate with a minimum follow-up of two years is 47.6%. More than 96% of the long term survivors showed a complete response after the end of treatment. The results demonstrate that concomitant radiation and chemotherapy with cisplatin is a highly effective treatment in advanced head and neck carcinoma with tolerable toxicity. Carboplatin (CBDCA) is a second generation platinum analog and has shown comparable antitumour activity but less nephro- and neurotoxicity than cisplatin in head and neck cancer. In order to determine the feasibility and efficacy of simultaneous application of CBDCA and radiotherapy a phase I-II study is going on. Between September 1987 and March 1988 30 patients with advanced squamous carcinoma of the head and neck (T3-4, N0-3) have entered this trial. Patients were separated into three groups which received 60 mg/m2. 70 mg/m2 and 80 mg/m2 CBDCA from days 1 to 5 and 28 to 32. Radiotherapy was administered up to a target absorbed dose of 70 Gy. 5 X 2 Gy/week in shrinking field technique. The group which received 80 mg/m2 CBDCA reached the myelotoxicity limit so that subsequent patients were treated with 70 mg/m2. Among 30 patients who completed the treatment, 22 showed a complete (CR) and eight a partial remission (PR). Despite the short follow-up period the preliminary results appear to be comparable with those achieved after combined radiotherapy and cis-DDP application without any limitations for patients with renal or cardiovascular disorders.     

A long-term effect of X rays on thermal sensitivity of the mouse ear

The response of the mouse ear to hyperthermia was investigated after single doses of X rays. A dose of 15 Gy, which alone caused no visible effect, increased thermal sensitivity at 1-2 weeks after irradiation. There was a slight recovery at 4-6 weeks but thermal sensitivity was still increased at 6 months. When heat treatment was given at 1 week or 24 weeks after X-ray doses ranging from 9-18 Gy, it was found that thermal sensitivity increased as the dose was increased above 10 Gy. Although there are reports which indicate that prior radiotherapy given more than two months earlier does not affect normal tissue response to the mild hyperthermia currently being used to treat patients, more aggressive heat therapy may produce unexpected responses at previously irradiated sites.     

Simultane Radiochemotherapie mit intraluminaler HDR-Brachytherapie des Ösophaguskarzinoms

PURPOSE: To study efficacy and toxicity of radiochemotherapy in esophageal cancer including initial endoluminal high-dose-rate brachytherapy (HDR-BT). PATIENTS AND METHODS: Between 01/1995 and 06/2005, 61 patients with esophageal cancer were treated preoperatively with definitive and palliative intent. Treatment started with intraluminal HDR-BT for recanalization of the esophagus (single fraction size of 8 Gy in 0.5 cm depth, three times, q7d) followed by external-beam radiation therapy (50 Gy total dose, 5 x 2 Gy/week, 25 fractions in 5 weeks). Chemotherapy was started simultaneously with external irradiation (three courses of cisplatin and 5-fluorouracil, q21d). RESULTS: Swallowing function improved in 55/61 patients (dysphagia classification according to the RTOG), and worsened in 6/61 patients, respectively. Median duration of symptomatic improvement was 11 months, median follow-up 12 months (range 3-68 months). Following simultaneous radiochemotherapy, tumor resectability was achieved in 7/25 patients of the neoadjuvant group, and the histological specimen showed complete remission in 6/7 patients. CONCLUSION: These results indicate a favorable effect of simultaneous radiochemotherapy starting with endoluminal HDR-afterloading-( AL-)BT in esophageal cancer.     

Results of whole lung irradiation and chemotherapy in comparison with partial lung irradiation in metastasizing, undifferentiated soft tissue sarcomas

The poor prognosis of patients with unresectable pulmonary metastases of soft tissue sarcoma is well known. In order to evaluate the beneficial effect of radiotherapy, we have treated 44 patients with pulmonary metastases of grade 3 soft tissue sarcoma from 1980 to 1986. In 36 patients the treatment volume was restricted to the single metastases up to a dose of 50 to 60 (9 to 10 Gy/week). The survival rate at one year was 18% and at two years 6%. Eight patients were treated with a combined regimen, consisting of cisplatin and ifosfamide with simultaneous whole lung irradiation. Irradiation was performed with 8 or 16 MV photons at a hyperfractionation of 2 x 0.8 Gy/day (8 Gy/week). After a dose of 12 Gy, the single metastases were boosted up to 50 to 60 Gy, with a second course of chemotherapy. In six of eight patients complete remissions were achieved, one patient showed a partial remission. The survival rate at 27 months was 50%. The patients with partial remission died from pulmonary progression at 23 months. One patient died after twelve months from a loco-regional recurrence in the tonsillar fossa without evidence of pulmonary disease. Side effects included alopecia and moderate bone marrow suppression approximately twelve days after each chemotherapy cycle. Pulmonary fibrosis was observed only at the high dose volume without impairment of respiratory function. From these observations the conclusion is drawn that whole lung irradiation simultaneously with cisplatin and ifosfamide chemotherapy provides good palliative results without relevant morbidity in patients with high grade unresectable pulmonary metastases of soft tissue sarcomas.     

Phase I/II Trial of External Irradiation plus Medium-Dose Brachytherapy Given Concurrently to Liposomal Doxorubicin and Cisplatin for Advanced Uterine Cervix Carcinoma

BACKGROUND AND PURPOSE: Although the standard of care for patients with locally advanced uterine cervix carcinoma is cisplatin-(CDDP-)based chemotherapy and irradiation (RT), the optimal regimen remains to be elucidated. A phase I/II study was conducted to evaluate the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) of liposomal doxorubicin (Caelyx) combined with CDDP and RT for cervical cancer. PATIENTS AND METHODS: 24 patients with stage IIB-IVA were enrolled (Table 1). They all received external RT (up to 50.4 Gy) and two medium-dose rate (MDR) brachytherapy implants (20 Gy each at point A). The Caelyx starting dose of 7 mg/m2/week was increased in 5-mg/m2 increments to two levels. The standard dose of CDDP was 20-25 mg/m2/week. RESULTS: Concurrent chemoradiation (CCRT) sequelae and the DLTs (grade 3 myelotoxicity and grade 3 proctitis in five patients treated at the 17 mg/m2/week Caelyx dose level) are shown in Tables 2, 3, 4, and 5. After a median follow-up time of 17.2 months (range 4-36 months), four patients had died, 15 showed no evidence of progressive disease, and five (20.8%, 95% confidence interval [CI]: 12.5-29.1%) were alive with relapse (Figure 1). There were seven complete (29.1%, 95% CI: 19.8-38.4%) and 17 partial clinical responses (95% CI: 61.1-80.1%). The median progression-free survival was 10.4 months. Causes of death were local regional failure with or without paraaortic node relapse combined with distant metastases (Table 6). CONCLUSION: Conclusion: The MTD of Caelyx given concurrently with CDDP and RT was determined at the 12 mg/m2/week dose level. The above CCRT schema is a well-tolerated regimen, easy to administer in ambulatory patients, and results appear promising.     

Low-dose hyperradiosensitivity of human glioblastoma cell lines in vitro does not translate into improved outcome of ultrafractionated radiotherapy in vivo

PURPOSE: Low dose hyperradiosensitivity (HRS) has been observed in HGL21- and T98G human glioblastoma cells in vitro. The present study investigates whether these effects translate into improved outcome of ultrafractionated irradiation (UF) in vivo. MATERIAL AND METHODS: T98G or HGL21 were transplanted on the hind leg of nude mice. Tumours were irradiated with UF (3 fractions of 0.4 Gy per day, interval 4 h, 7 days per week) or with conventional fractionation (CF; 1 fraction of 1.68 Gy per day, 5 days per week) over 2 or 4 weeks in HGL21 and 2,4 or 6 weeks in T98G. In HGL21, graded top-up doses under clamped hypoxia were applied after 4 weeks of fractionated irradiation. Additional groups of animals were irradiated with single doses under clamp hypoxic conditions with or without whole body irradiation (WBI) before tumour transplantation. Experimental endpoints were growth delay (time to 5-fold starting volume, GD(V5)) and local tumour control. RESULTS: In T98G tumours median relative GD(V5) was 1.2 [95% C.I. 0.96; 8] in the CF and 0.8 [0.7; 1.02] in the UF arm (p = 0.009) indicating that ultrafractionation is less efficient than conventional fractionation. The TCD50 value of 33.5 Gy [22; 45] after UF was higher than TCD50 of 23.6 Gy [16; 31] after CF (p = 0.15). In HGL21 the median relative GD(V5) was not significantly different between CF and UF. The top-up TCD50 value of 16.1 Gy [95% C.I. 9; 23 Gy] after CF was significantly lower than the corresponding value of 33.2 Gy [23; 44] after UF irradiation (p = 0.007), indicating a higher efficacy of CF compared to UF. CONCLUSION: The results on human T98G and HGL21 glioblastoma do not support the hypothesis that HRS in vitro translates into improved outcome of ultrafractionated irradiation in vivo.     

Protective effects of systemic dermatan sulfate treatment in a preclinical model of radiation-induced oral mucositis

Purpose

Oral mucositis is a frequent, dose-limiting side effect of radio(chemo)therapy of head-and-neck malignancies. The epithelial radiation response is based on multiple tissue changes, which could offer targets for a biologically tailored treatment. The potential of dermatan sulfate (DS) to modulate radiation-induced oral mucositis was tested in an established preclinical mucositis model.

Methods

Irradiation was either applied alone or in combination with daily DS treatment (4?mg/kg, subcutaneously) over varying time intervals. Irradiation comprised single dose irradiation with graded doses to the lower tongue surface or daily fractionated irradiation of the whole tongue. Fractionation protocols (5?×?3?Gy/week) over one (days 0–4) or two weeks (days 0–4, 7–11) were terminated by an additional local single dose irradiation to a defined treatment field on the lower tongue surface to induce the mucosal radiation response. The additional single dose irradiation (top-up) on day 7 (after one week of fractionation) or day 14 (after 2 weeks of fractionation) comprised graded doses in order to generate full dose–effect curves. Ulceration of the epithelium of the lower tongue, corresponding to confluent mucositis, was analysed as clinically relevant endpoint. Additionally, the time course parameters, latent time and ulcer duration were analysed.

Results

DS treatment significantly reduced the incidence of ulcerations. DS application over longer time intervals resulted in a more pronounced reduction of ulcer frequency, increased latent times and reduced ulcer duration.

Conclusion

DS has a significant mucositis-ameliorating activity with pronounced effects on mucositis frequency as well as on time course parameters.

     

Attenuation of radiation-induced gastrointestinal damage by epidermal growth factor and bone marrow transplantation in mice

Purpose: We examined the effect of epidermal growth factor (EGF) and bone marrow transplantation (BMT) on gastrointestinal damage after high-dose irradiation of mice.

Material and methods: C57Black/6 mice were used. Two survival experiments were performed (12 and 13 Gy; ⁶⁰Co, 0.59–0.57 Gy/min). To evaluate BMT and EGF action, five groups were established – 0 Gy, 13 Gy, 13 Gy + EGF (at 2 mg/kg, first dose 24 h after irradiation and then every 48 h), 13 Gy + BMT (5 × 10⁶ cells from green fluorescent protein [GFP] syngenic mice, 4 h after irradiation), and 13 Gy + BMT + EGF. Survival data, blood cell counts, gastrointestine and liver parameters and GFP positive cell migration were measured.

Results: BMT and EGF (three doses, at 2 mg/kg, administered 1, 3 and 5 days after irradiation) significantly increased survival (13 Gy). In blood, progressive cytopenia was observed with BMT, EGF or their combination having no improving effect early after irradiation. In gastrointestinal system, BMT, EGF and their combination attenuated radiation-induced atrophy and increased regeneration during first week after irradiation with the combination being most effective. Signs of systemic inflammatory reaction were observed 30 days after irradiation.

Conclusions: Our data indicate that BMT together with EGF is a promising strategy in the treatment of high-dose whole-body irradiation damage.     

Recall-Dermatitis durch Docetaxel-Reexposition nach Gehirnbestrahlung Fallbeobachtung und Literaturübersicht

BACKGROUND: Together with radiation therapy the taxanes Paclitaxel and Docetaxel are more and more integrated into multimodal therapy regimens concerning breast- and lung cancer as well as squamous cell carcinoma of the head and neck. Especially in palliative situations we have to be aware of increasing side effects caused by interaction of the different treatment components. Therefore we report on a severe recall dermatitis that occurred in two breast-cancer patients following irradiation of the brain and reexposition to Docetaxel. PATIENTS AND METHOD: From January until March 1999 two female patients suffering from metastatic breast cancer and newly diagnosed cerebral metastases respectively carcinomatous meningitis underwent irradiation of the whole brain (2 Gy 5 days/week up to a reference dose of 50 Gy) in our department. Both patients had several courses of Docetaxel (Taxotere) 30 mg/m2 BSA weekly respectively 100 mg/m2 BSA/month since October and November 1998. After completion of radiotherapy chemotherapy with Docetaxel was continued. RESULTS: Both patients tolerated Docetaxel well before and during radiotherapy. However, after having finished irradiation of the brain and receiving Docetaxel again a severe erythema of the irradiated skin and large areas of moist epitheliolysis with crust occurred (CTC grade IV). CONCLUSION: The dermatitis related to irradiation and reexposition to Docetaxel observed in our two cases is interpreted as a recall reaction. The basic initiating pathologic mechanism has not been solved completely. Further investigation is needed to find out how the taxanes can be used in combination radiochemotherapy regimens without causing severe toxicity to the irradiated skin or mucosa.