Intraoperative radiotherapy during awake craniotomies: preliminary results of a single-center case series.

Awake craniotomies are performed to avoid postoperative neurological deficits when resecting lesions in the eloquent cortex, especially the speech area. Intraoperative radiotherapy (IORT) has recently focused on optimizing the oncological treatment of primary malignant brain tumors and metastases. Herein, for the first time, we present preliminary results of IORT in the setting of awake craniotomies. From 2021 to 2022, all patients undergoing awake craniotomies for tumor resection combined with IORT were analyzed retrospectively. Demographical and clinical data, operative procedure, and treatment-related complications were evaluated. Five patients were identified (age (mean ± standard deviation (SD): 65 ± 13.5 years (y)). A solid left frontal metastasis was detected in the first patient (female, 49 y). The second patient (male, 72 y) presented with a solid metastasis on the left parietal lobe. The third patient (male, 52 y) was diagnosed with a left temporoparietal metastasis. Patient four (male, 74 y) was diagnosed with a high-grade glioma on the left frontal lobe. A metastasis on the left temporooccipital lobe was detected in the fifth patient (male, 78 y). After awake craniotomy and macroscopic complete tumor resection, intraoperative tumor bed irradiation was carried out with 50 kV x-rays and a total of 20 Gy for 16.7 ± 2.5 min. During a mean follow-up of 6.3 ± 2.6 months, none of the patients developed any surgery- or IORT-related complications or disabling permanent neurological deficits. Intraoperative radiotherapy in combination with awake craniotomy seems to be feasible and safe.

Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations : An overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO).

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included.

Shortened irradiation scheme, continuous infusion of 5-fluorouracil and fractionation of mitomycin C in locally advanced anal carcinomas. Results of a phase II study of the European Organization for Research and Treatment of Cancer. Radiotherapy and Gastrointestinal Cooperative Groups.

The European Organization for Research and Treatment of Cancer (EORTC) 22861 randomised trial established that combined radiochemotherapy is the standard treatment for locally advanced anal cancer. This EORTC phase II study (#22953) tests the feasibility of reducing the gap between sequences to 2 weeks, to deliver Mitomycin C (MMC) in each radiotherapy sequence and 5-FU continuously during the treatment. The first sequence consisted of 36 Gy over 4 weeks. 5-FU 200 mg/m(2)/days 1-26, MMC 10 mg/m(2)/day 1 gap 16 days. Then a second sequence of 23.4 Gy over 17 days, 5-FU 200 mg/m(2)/days 1-17 and, MMC 10 mg/m(2)/day 1 was given. 43 patients with a World Health Organization (WHO) status of 0 (n=27) or 1 (n=16) and with T2-T4, N0-3 tumours were included. Compliance with the planned treatment, doses and duration was 93%. The complete response rate was 90.7%. Grade 3 toxicities of 28, 12 and 2% were observed for skin, diarrhoea and haematological toxicities, respectively. The 3-year estimated rates for trials 22861 and 22953 are: 68 and 88% for local control; 72 and 81% for colostomy-free interval, 62 and 84% for severe late toxicity-free interval, and 70 and 81% for survival, respectively. The 22953 scheme is feasible and the results are promising. This is now considered as the new standard scheme by the EORTC.

Radiation-induced apoptosis in human non-small-cell lung cancer cell lines is secondary to cell-cycle progression beyond the G2-phase checkpoint.

PURPOSE: To characterize the relationship between cell-cycle progression and radiation-induced apoptosis in NSCLC cell lines with different p53 status. MATERIALS AND METHODS: Cell lines with functional (H460, A549) and non-functional p53 (H661 and H520) were irradiated with 20 Gy. Multiparameter flow-cytometry was used to follow the progression of synchronized cells through the cell cycle after irradiation. RESULTS: Delayed apoptosis was observed after cell-cycle progression beyond the G2 block, either in the late G2/M-phase of the same cell cycle being irradiated (H661, H520) or in the G1-phase of the subsequent cell cycle (H460, A549). The apoptotic fraction in H661 and H520 was 60-80% at 144h after irradiation, higher than in A549 and H460 (5 and 35%, respectively). As an alternative to apoptosis in cells cycling beyond the G2 restriction point, hyperploid cells were generated by all cell lines. Inhibition of cell-cycle progression through the G2/M-phase efficiently reduced the induction of late apoptosis. After irradiation in S-phase, 50-60% of cells with functional p53 remained arrested at the G2 restriction point until 144 h post-irradiation, while only 20% of the H661 or H520 did so. CONCLUSIONS: These data characterize radiation-induced apoptosis in NSCLC cell lines as a removal pathway of clonogenically inactivated cells secondary to cell-cycle progression beyond G2/M, and is unlikely to be a critical factor for cellular radiation sensitivity.

Induction chemotherapy followed by concurrent chemotherapy and definitive high-dose radiotherapy for patients with locally advanced non-small-cell lung cancer (stages IIIa/IIIb): a pilot phase I/II trial.

BACKGROUND: Overall prognosis of patients with locally advanced non-small-cell lung cancer (LAD-NSCLC) is still unfavourable. Different attempts to improve treatment results have been made using combinations of chemotherapy and radiotherapy. The aim of this pilot phase I/II investigation was to test the feasibility and toxicity of a definitive multimodality protocol in patients with irresectable NSCLC stages IIIA (N2) and IIIB. PATIENTS AND METHODS: Thirty LAD-NSCLC patients (stages IIIA/IIIB: 3/27; median age: 54 years, range 34-70; male/female: 17/13) who were consecutively enrolled onto our ongoing neoadjuvant multimodality protocol from October 1996 to February 1999 remained inoperable after induction treatment. Three cycles of cisplatin/etoposide (PE) were followed by hyperfractionated accelerated radiotherapy (HF-RTx: 1.5 Gy bid up to a total dose of 45 Gy in 3 weeks) concurrent with one cycle of PE. Definitive local treatment was completed with a small volume boost of 20 Gy (qd), adding up to a total dose of 65 Gy to the primary. Patients were routinely offered prophylactic cranial irradiation (PCI; 30 Gy; 2 Gy qd). RESULTS: Overall toxicity of the definitive CTx/RTx protocol-the main endpoint of this investigation-turned out to be acceptable (oesophagitis grade 3/4: 6/4 patients; pneumonitis grade 3/4: 0/1 patients; no treatment-related deaths). Actuarial survival at 2 years was 31% with a loco-regional control rate of 21%. CONCLUSIONS: This regimen turned out to be feasible with acceptable toxicity and will serve as a reference arm in a planned randomised trial in stage IIIB NSCLC, testing the value of surgery in this setting: preoperative induction CTx/RTx followed by surgery versus definitive CTx/RTx.

[Brachytherapy with (192)Iridium in the treatment of recurrent nasopharyngeal carcinoma]. / Brachytherapie mit (192)Iridium bei lokalen Rezidiven von Nasopharynxkarzinomen.

BACKGROUND: Local recurrence of nasopharyngeal carcinomas can be treated in different ways. One option is re-irradiation e. g. as stereotactically guided convergent beam. An operative approach is possible in small recurrent tumours. Brachytherapy is a good alternative because of the steep dose gradient in the pre-irradiated area. METHODS: First step is the creation of a wide approach to the nasopharynx. This leads to a tumour mass reduction and gives space for the applicator. The radioactive substance will be brought into contact with the tumour by an afterloading procedure. The advantage of this therapy is the possibility to protect the surrounding tissue whereas the tumour receives a relatively high dosage. Between 2/90 and 12/96 10 men and 3 women were treated according to this protocol. RESULTS: The median age was 56 years (37- 66 years), the average follow-up period was 49,7 months (8 -123 months). 2 non keratinising and 11 undifferentiated carcinomas were treated. 5 of 13 patients were still alive at the end of the follow-up period. The 5 year over all survival rate was 46 %. 3 patients are free of disease for 5 years or longer. The patients were treated 2 to 6 times with 7 Gy in 5 mm depth. CONCLUSIONS: The results show that good palliation can be achieved by the applied method but larger studies are required to give a definite statement.

Accelerated hyperfractionated radiotherapy with concurrent chemotherapy in locally advanced nasopharyngeal carcinoma: a phase II study.

PURPOSE: The incidence of nasopharyngeal carcinoma in Germany is relatively low in comparison with certain regions in south-east Asia. However, standardised therapeutical regimes are required in the treatment of these tumours. METHODS: Between August 1990 and December 1997, 25 patients with stage III and IV nasopharyngeal carcinoma received an accelerated and hyperfractionated radiotherapy with concurrent chemotherapy (5-FU and mitomycin C). The primary tumour and positive lymph nodes received a total dose of 72 Gy over a period of 6 weeks. In the first 3 weeks, irradiation fields were treated five times per week with 2 Gy per fraction. Thereafter, treatment was accelerated, giving two daily fractions of 1.4 Gy. Salvage surgery was offered for residual lymph node disease after radiotherapy. RESULTS: The overall response rate defined as complete and partial response of the primary was 100%. Sixteen of the 25 patients were still alive and were free of any evidence of tumour recurrence or distant metastases at a mean follow-up period of 34 months (range 7-95 months). Six patients received salvage surgery. Only one of these six patients had histologically proven evidence of vital tumour. No severe late complications such as blindness or temporal lobe necrosis were observed. CONCLUSIONS: The presented data are promising and show that the combination of hyperfractionated accelerated radiotherapy and chemotherapy is feasible and effective.

Recombinant human erythropoietin increases the radiosensitivity of xenografted human tumours in anaemic nude mice.

PURPOSE: The effect of recombinant human erythropoietin (Epo) on the radiosensitivity of human tumour xenografts growing in anaemic nude mice was studied. METHODS AND MATERIALS: Anaemia was induced by total body irradiation (TBI) of mice prior to tumour transplantation. The development of anaemia was prevented by Epo (1000 U/kg s.c.) given 3 times weekly starting 2 weeks prior to TBI (5 Gy). Epo treatment did not influence the growth rate of the tumours, which were transplanted into the subcutis of the hind leg of mice. Thirteen days after TBI (tumour volume of approx. 40 mm3), a single-dose irradiation (12 Gy) of the tumour was performed resulting in a growth delay with subsequent regrowth of the tumours. RESULTS: In Epo-treated animals the tumour growth delay was significantly longer compared to anaemic mice. However, the radiosensitivity of tumours in non-anaemic animals' (non-Epo-treated) tumours could not fully be restored. CONCLUSION: These data give evidence for restored radiosensitivity after correction of anaemia with Epo.

Radiation sensitivity of lymphocytes from healthy individuals and cancer patients as measured by the comet assay.

Lymphocytes of healthy volunteers (n = 24) and of tumour patients (n = 30, 18 of whom had experienced severe side-effects) were irradiated with x-rays in vitro. DNA damage was analysed after 0.25-2 Gy and DNA repair after 2 Gy, and quantification of both endpoints was done by the comet assay. The individual differences in radiation-induced DNA damage as well as in the repair kinetics were observed to be striking for both healthy donors and tumour patients. After a repair time of 3 h, following 2 Gy x-irradiation, some of the healthy volunteers showed no residual DNA damage at all in their lymphocytes, whereas others revealed about 30%. There was no indication that our results were affected by either age, gender or smoking habits. Slow repair kinetics and high amounts of residual damage were characteristic for many but not all tumour patients who had experienced severe side-effects in their normal tissues during or after radiotherapy (n = 18). Our conclusion is that those individuals showing poor DNA repair characteristics in the lymphocytes following in vitro irradiation, have a high probability of being radiosensitive. The opposite conclusion is not necessarily true: if repair is effective, this does not mean that the individual is radioresistant, because factors other than impaired repair may cause radiosensitivity.

[Neoadjuvant chemotherapy and chemoradiotherapy in surgically treated non-small-cell stage III bronchial carcinoma]. / Neoadjuvante Chemotherapie und Chemoradiotherapie beim operiertem nicht-kleinzelligen Bronchialkarzinom Stadium III.

Patients with unfavorable stages of lung cancer are rarely cured with local treatment modalities alone. Aim of our phase II trial was to investigate the effectivity of a multimodality treatment. Ninety-four patients with NSCLC (stage IIIA/IIIB) were treated preoperatively with chemoradiotherapy (cisplatin and etoposide, 45 Gy hyperfractionated accelerated radiotherapy). After repeat mediastinoscopy patients underwent surgery. Complete resection (R0) was achieved in 53% of all patients with NSCLC. Two patients died of sepsis preoperatively and four postoperatively (90-days lethality: 6.4%). The median survival time was 20 months for IIIA and 18 months for IIIB. Calculated survival rates at 6 years were 34% for IIIA and 17% for IIIB. This multimodality treatment demonstrates high efficacy in prognostically unfavorable NSCLC compared with historical controls.

Induction chemotherapy followed by concurrent chemotherapy and high-dose radiotherapy for locally advanced squamous cell carcinoma of the upper-thoracic and midthoracic esophagus.

The purpose of this study was to evaluate the efficacy and toxicity of an induction chemotherapy schedule followed by high-dose radiotherapy and concurrent chemotherapy for locally advanced squamous cell carcinomas of the upper and midthoracic esophagus. Patients were treated with three courses of fluorouracil, leucovorin, etoposide, and cisplatin-containing induction chemotherapy followed by high-dose external beam radiotherapy to 65 Gy in 6 weeks for T4 and obstructing T3 tumors. Transversable T3 tumors received 60 Gy in 6 weeks by external radiotherapy, followed by two high-dose-rate esophageal brachytherapy fractions of 4 Gy in 5-mm tissue depth. Concurrent to radiotherapy, cisplatin and etoposide were given. Long-term survival of 22 patients was 41% and 31% at 2 and 3 years, respectively, with a median follow-up of 39 months. The probability of locoregional tumor recurrence was 60% at 3 years for all patients and 30% for those with a partial or complete response to induction chemotherapy. Acute toxicity of this schedule was moderate. Long-term survivors had a good swallowing function. This schedule offers a considerable chance of long-term survival for patients with locally advanced squamous cell carcinomas of the upper and midthoracic esophagus. Local in-field recurrences are the main risk after definitive radiochemotherapy. Dose escalation of radiotherapy is possible because of the observed low late toxicity.

Prognostically orientated multimodality treatment including surgery for selected patients of small-cell lung cancer patients stages IB to IIIB: long-term results of a phase II trial.

Following mediastinoscopy, a prognostically orientated multimodality approach was chosen in selected small-cell lung cancer (SCLC) patients with hyperfractionated accelerated chemoradiotherapy (Hf-RTx) and definitive surgery (S). Stage IB/IIA patients had four cycles of cisplatin/etoposide (PE) and surgery. Stage IIB/IIIA patients had three cycles PE followed by one cycle concurrent chemoradiation including Hf-RTx and surgery. Most stage IIIB patients were not planned for surgery and had CTx followed by sequential RTx or one cycle concurrent CTx/RTx. Of 46 consecutive patients (stage IB six, IIA two, IIB/IIIA 22, IIIB 16) 43 (94%) showed an objective response. Twenty-three of patients (72%) planned for inclusion of S were completely resected (R0) (IB 6/6, IIA 2/2, IIB/IIIA 13/22, IIIB 2/2). Overall toxicity was acceptable--one patient died of septicaemia, no perioperative deaths occurred. Median follow-up of patients alive (n = 21) is 52 months (30+ - 75+). Median survival and 5-year survival rate of all patients are 36 months and 46%, in R0 patients 68 months and 63% (R0-IIB/IIIA/IIIB: not yet reached and 67%). This multimodality treatment including surgery proved highly effective with 100% local control and remarkable long-term survival after complete resection, even in locally advanced SCLC stages IIB/IIIA patients.

Prophylactic cranial irradiation in locally advanced non-small-cell lung cancer after multimodality treatment: long-term follow-up and investigations of late neuropsychologic effects.

PURPOSE: Relapse pattern and late toxicities in long-term survivors were analyzed after the introduction of prophylactic cranial irradiation (PCI) into a phase II trial on trimodality treatment of locally advanced (LAD) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Seventy-five patients with stage IIIA(N2)/IIIB NSCLC were treated with induction chemotherapy, preoperative radiochemotherapy, and surgery. PCI was routinely offered during the second period of study accrual. Patients were given a total radiation dose of 30 Gy (2 Gy per daily fraction) over a 3-week period starting 1 day after the last chemotherapy cycle. RESULTS: Introduction of PCI reduced the rate of brain metastases as first site of relapse from 30% to 8% at 4 years (P =.005) and that of overall brain relapse from 54% to 13% (P <.0001). The effect of PCI was also observed in the good-prognosis subgroup of 47 patients who had a partial response or complete response to induction chemotherapy, with a reduction of brain relapse as first failure from 23% to 0% at 4 years (P =.01). Neuropsychologic testing revealed impairments in attention and visual memory in long-term survivors who received PCI as well as in those who did not receive PCI. T2-weighted magnetic resonance imaging revealed white matter abnormalities of higher grades in patients who received PCI than in those who did not. CONCLUSION: PCI at a moderate dose reduced brain metastases in LAD-NSCLC to a clinically significant extent, comparable to that in limited-disease small-cell lung cancer. Late toxicity to normal brain was acceptable. This study supports the use of PCI within intense protocols for LAD-NSCLC, particularly in patients with favorable prognostic factors.

Quiescent S-phase cells as indicators of extreme physiological conditions in human tumor xenografts.

PURPOSE: During the last 20 years, evidence has been accumulating for the existence in animal and human tumors of quiescent S-phase cells, i.e. cells with an S-phase DNA content that do not actively synthesize DNA. In cell culture studies, quiescent S-phase cells have been observed under physiological conditions typical for poorly vascularized regions of tumors such as reduced pH, hypoxia, and glucose deprivation. Therefore, we studied the possible correlation between the frequency of quiescent S-phase cells and the oxygenation status as determined polarographically in a number of human tumor xenografts. METHODS AND MATERIALS: Five human tumor xenografts on nude mice were used. Oxygenation was measured polarographically with an Eppendorf pO2-Histograph in 24 to 30 individual tumors for each entity. Mice were injected intraperitoneally with 1 mg/30 g bodyweight bromodeoxyuridine (BrdU), tumors were excised 30 min later and prepared into a single-cell suspension. After immunofluorescence staining with an antibody against BrdU and staining of the DNA with propidium iodide, cells were measured in a FACScan flow cytometer and the frequency of cells in the S-phase compartment that did not incorporate BrdU was determined. RESULTS: In most cases, the frequency of measurements of an oxygen partial pressure <5 mm Hg in the tumor tissue increased with tumor volume. Likewise, the frequency of quiescent S-phase cells was generally higher in larger tumors. Taking all five tumor entities together, there was a highly significant correlation between tumor oxygenation and the occurrence of quiescent S-phase cells. CONCLUSIONS: Our data confirm earlier findings that inactive S-phase cells do exist in vivo. Because their frequency seems to be dependent (directly or indirectly) on the degree of oxygenation and has been shown to increase not only with hypoxia, but also with reduced pH and glucose deprivation in vitro, the frequency of inactive S-phase cells may be considered a summary indicator for extreme physiological conditions in tumors.

Preoperative chemoradiotherapy and surgery for selected non-small cell lung cancer IIIB subgroups: long-term results.

BACKGROUND: Preoperative chemoradiotherapy is feasible for selected patients with non-small cell lung cancer stage IIIb. The aim of this investigation was to analyze long-term results after this multimodality approach and to identify subgroups with improved long-term prognosis. METHODS: From March 1991 to June 1996, 56 patients were entered. Three cycles of cisplatin (P) (60 mg/m2, days 1 + 7) and etoposide (E) (150 mg/m2, days 3 to 5 qd 22) were followed by one cycle of radiotherapy/chemotherapy (RTx/CTx) (45 Gy, 1.5 Gy bid/3 weeks with P 50 mg/m2 days 2 + 9/E 100 mg/m2 days 4 to 6) followed by repeat mediastinoscopy and surgery. RESULTS: There were 46 men and 10 women (age 34 to 69 years, median 55 years; World Health Organization status 0 to 2, median 1). Twenty-eight had T4, and 32 had proven N3, in detail: T4N0/1, 10; T4N2, 14; T3N3, 9; T4N3, 4; and T1/2N3, 19. Thirty-four (61%) were operated on; 27 (48%) were completely (R0) resected. Survival at 5 years is 26% for all, and 43% for R0 patients. Toxicity included two deaths (one septicemia, one anastomosis insufficiency). CONCLUSIONS: This intensive program proved to be highly effective in unfavorable IIIB subgroups with promising long-term survival for T4 tumors as well as N3 disease.

Induction chemotherapy followed by concurrent chemotherapy and high-dose radiotherapy for locally advanced squamous cell carcinoma of the cervical oesophagus.

The efficacy and toxicity of combined radiochemotherapy for locally advanced squamous cell carcinomas of the cervical oesophagus was evaluated retrospectively. Induction chemotherapy consisted of three courses of 5-fluorouracil (5-FU), leucovorin, etoposide and cisplatin (FLEP) or two courses weekly six times of 5-FU and leucovorin combined with biweekly cisplatin. This induction regimen was followed by high-dose external beam radiotherapy up to 60-66 Gy and concurrent chemotherapy with cisplatin and etoposide. Median follow-up of the recruited 17 patients was 37 months (13-73 months). Long-term survival was 24% at 2 and 3 years. The probabilities of locoregional tumour recurrences and distant metastases as sites of first relapse were 67 and 39% at 2 years. Acute and late toxicity of this schedule was moderate. The protocol offers a definitive chance of long-term survival for patients with locally advanced carcinomas of the cervical oesophagus, but local in-field recurrences remain the predominant risk after treatment. Intensification of the regimen seems possible because no dose-limiting late toxicities were observed.

Tumour oxygenation during fractionated radiotherapy--comparison with size-matched controls.

The effect of fractionated irradiation on the oxygenation status of experimental tumours was investigated using polarographic assessment of the pO2 distribution. Since an improvement in tumour oxygenation could simply be the result of tumour shrinkage, a comparison of pO2 readings of untreated size-matched control tumours was performed. Irradiation was carried out using 6 fractions of 6 Gy applied within 11 days. A comparison of polarographic pO2 data with size-matched untreated tumours revealed a significant improvement in oxygenation after the irradiation. The median pO2 was 0.9+/-0.1 mm Hg for unirradiated tumours at a volume of 180 mm3, while the corresponding data for irradiated tumours of comparable size were 2.3+/-0.5 mm Hg on day 21 and 4.8+/-0.9 mm Hg on day 28 after start of irradiation. From these results it can be concluded that the improvement of oxygenation after fractionated irradiation is not solely the result of a reduced tumour volume.

Characterization and validation of noninvasive oxygen tension measurements in human glioma xenografts by 19F-MR relaxometry.

PURPOSE: The aim of this study was to characterize and to validate noninvasive 19F-magnetic resonance relaxometry for the measurement of oxygen tensions in human glioma xenografts in nude mice. The following three questions were addressed: 1. When perfluorocarbon compounds (PFCs) are administrated intravenously, which tumor regions are assessed by 19F-MR relaxometry? 2. Are oxygen tension as detected by 19F-MR relaxometry (pO2/relaxo) comparable to Eppendorf O2-electrode measurements (pO2/electrode)? 3. Can 19F-MR relaxometry be used to detect oxygen tension changes in tumor tissue during carbogen breathing? METHODS AND MATERIALS: Slice-selective 19F-MR relaxometry was carried out with perfluoro-15-crown-5-ether as oxygen sensor. The PFC was injected i.v. 3 days before the 19F-MR experiments. Two datasets were acquired before and two after the start of carbogen breathing. The distribution of PFCs and necrotic areas were analyzed in 19F-Spin Echo (SE) density MR images and T2-weighted 1H-SE MR images, respectively. One day after the MR investigations, oxygen tensions were measured by oxygen electrodes in the same slice along two perpendicular tracks. These measurements were followed by (immuno)histochemical analysis of the 2D distribution of perfused microvessels, hypoxic cells, necrotic areas, and macrophages. RESULTS: The PFCs mainly became sequestered in perfused regions at the tumor periphery; thus, 19F-MR relaxometry probed mean oxygen tensions in these regions throughout the selected MR slice. In perfused regions of the tumor, mean PO2/relaxo values were comparable to mean PO2/electrode values, and varied from 0.03 to 9 mmHg. Median pO2/electrode values of both tracks were lower than mean pO2/relaxo values, because low pO2 electrode values that originate from hypoxic and necrotic areas were also included in calculations of median pO2/electrode values. After 8-min carbogen breathing, the average PO2/relaxo increase was 3.3 +/- 0.8 (SEM) mmHg and 2.1 +/- 0.6 (SEM) after 14 min breathing. CONCLUSIONS: We have demonstrated that PFCs mainly became sequestered in perfused regions of the tumor. Here, mean PO2/relaxo values were comparable to mean PO2electrode values. In these areas, carbogen breathing was found to increase the PO2/relaxo values significantly.

The effect of combined nicotinamide and carbogen treatments in human tumour xenografts: oxygenation and tumour control studies.

BACKGROUND AND PURPOSE: This was an investigation to study the effect of giving carbogen and nicotinamide (CON) on pO2 and the radiation response of human xenografted tumours. MATERIALS AND METHODS: The human xenografts were two sarcomas (ENE2 and ES3) and a glioblastoma (HTZ17). Nicotinamide (500 mg/ kg, i.p.) was administered 60 min before PO2 measurements and irradiation, while carbogen was given for 5 min before and during these treatments. Tumour pO2 was measured with an Eppendorf electrode and radiation response was assessed by local tumour control following irradiation with 10 daily fractions. RESULTS: All three xenografts were found to be poorly oxygenated (about 80% of all pO2 values were < or =2.5 mmHg). CON treatment improved the oxygenation status in all three tumours such that 65, 52 and 71% of the pO2 values were < or =2.5 mmHg in ENE2, ES3 and HTZ17, respectively. However, only in ES3 was this decrease significant. The TCD50 doses for all tumours were around 52-54 Gy. No significant improvement was seen with CON in ENE2 (TCD50 = 48 Gy) and HTZ17 (TCD50 = 56 Gy), but for the ES3 xenograft a significant decrease to 42 Gy was found. CONCLUSIONS: The three tumours used in this study appeared to show the same level of hypoxia as measured both by pO2 and radiation response. However, only one tumour showed a significant improvement after CON treatment, suggesting that not all hypoxic human tumours might benefit from this type of therapy.

Experimental studies on the possible influence of invasive oxygen measurements on tumour radiosensitivity.

The effects of tissue damage associated with invasive pO2 measurements on radiation sensitivity were investigated using a xenografted squamous cell carcinoma model. For the tumour cure experiments, single dose irradiations were given following different regimens of polarographic pO2 measurements associated with different degrees of mechanical tissue damage. With a dose of 32 Gy, 57% of animals were cured. Following 3 tracks of needle measurements, 73% of tumours were locally controlled, and 75% were cured after 8 needle tracks. The polarographic measurements gave virtually identical oxygenation data for recurrent or cured tumours (both median pO2 1.0 mmHg), respectively. There was thus no evidence of decreased radiosensitivity associated with tissue damage after invasive pO2 measurements. The pre-therapeutic oxygenation status gave no evidence for a prediction of radiation response on an individual basis.