PET/CT-guided treatment planning for paediatric cancer patients: a simulation study of proton and conventional photon therapy.

OBJECTIVE: To investigate the impact of including fluorine-18 fludeoxyglucose ((18)F-FDG) positron emission tomography (PET) scanning in the planning of paediatric radiotherapy (RT). METHODS: Target volumes were first delineated without and subsequently re-delineated with access to (18)F-FDG PET scan information, on duplicate CT sets. RT plans were generated for three-dimensional conformal photon RT (3DCRT) and intensity-modulated proton therapy (IMPT). The results were evaluated by comparison of target volumes, target dose coverage parameters, normal tissue complication probability (NTCP) and estimated risk of secondary cancer (SC). RESULTS: Considerable deviations between CT- and PET/CT-guided target volumes were seen in 3 out of the 11 patients studied. However, averaging over the whole cohort, CT or PET/CT guidance introduced no significant difference in the shape or size of the target volumes, target dose coverage, irradiated volumes, estimated NTCP or SC risk, neither for IMPT nor 3DCRT. CONCLUSION: Our results imply that the inclusion of PET/CT scans in the RT planning process could have considerable impact for individual patients. There were no general trends of increasing or decreasing irradiated volumes, suggesting that the long-term morbidity of RT in childhood would on average remain largely unaffected. ADVANCES IN KNOWLEDGE: (18)F-FDG PET-based RT planning does not systematically change NTCP or SC risk for paediatric cancer patients compared with CT only. 3 out of 11 patients had a distinct change of target volumes when PET-guided planning was introduced. Dice and mismatch metrics are not sufficient to assess the consequences of target volume differences in the context of RT.

Predictive value of modelled tumour control probability based on individual measurements of in vitro radiosensitivity and potential doubling time.

OBJECTIVE: The aim of this study was to compare patient-specific radiobiological parameters with population averages in predicting the clinical outcome after radiotherapy (RT) using a tumour control probability (TCP) model based on the biological effective dose (BED). METHODS: A previously published study of 46 head and neck carcinomas with individually identified radiobiological parameters, radiosensitivity and potential doubling time (Tpot), and known tumour size was investigated. These patients had all been treated with external beam RT, and the majority had also received brachytherapy. The TCP for each individual based on the BED using patient-specific radiobiological parameters was compared with the TCP based on the BED using average radiobiological parameters (α=0.3 Gy(-1), Tpot=3 days). RESULTS: 43 patients remained in the final analysis. There was only a weak trend for increasing local tumour control with increasing BED in both groups. However, when the TCP was calculated, the use of patient-specific parameters was better for identifying local control correctly. The sensitivity and specificity for tumour-specific parameters were 63% and 80%, respectively. The corresponding values for population-based averages were 0% and 91%, respectively. The positive predictive value was 92% when tumour-specific parameters were used compared with 0% for population-based averages. A receiver operating characteristic curve confirmed the superiority of patient-specific parameters over population averages in predicting local control. CONCLUSION: Individual radiobiological parameters are better than population-derived averages when used in a mathematical model to predict TCP after curative RT in head and neck carcinomas. ADVANCES IN KNOWLEDGE: TCP based on individual radiobiological parameters is better than TCP based on population-based averages for identifying local control correctly.

Superiority of intensity-modulated radiotherapy over three-dimensional conformal radiotherapy combined with brachytherapy in nasopharyngeal carcinoma: a planning study.

A planning study was performed in order to investigate the potential benefits of intensity-modulated radiotherapy using a simultaneous integrated multi-target treatment technique (SIMT-IMRT) over highly optimized three-dimensional conformal radiotherapy combined with intracavitary brachytherapy (3D-CRT + IBT) for the treatment of nasopharyngeal carcinoma (NPC). The subjects were eight patients with Stages I-IV NPC. For each case, two sets of plans were prepared after delineation of gross tumour volumes, three planning target volumes (PTVs) and 17 organs at risk (OARs). Dose prescriptions for PTVs were 72.6 Gy, 66 Gy and 52.8 Gy in 33 fractions for SIMT-IMRT vs 72 Gy (66 Gy in 33 fractions for 3D-CRT and 3 Gy twice for IBT), 66 Gy (in 33 fractions) and 46 Gy (in 23 fractions) for 3D-CRT + IBT plans. Compared with the combined plans, SIMT-IMRT provided superior results for the primary tumour (PT) in terms of mean equivalent uniform dose (67 Gy vs 63.7 Gy, p = 0.016). IMRT plans increased the mean tumour control probability (TCP) values (both uncorrected and corrected for accelerated tumour repopulation after 28 days) for PT when compared with 3D-CRT + IBT (98% and 94.3% vs 95.8% and 89.9%, respectively, p = 0.016). Mean doses to middle/external ears, parotid glands and temporomandibular joints were significantly lower in IMRT plans. Our conclusion is that, for all stages of NPC, SIMT-IMRT was superior to highly optimized 3D-CRT + IBT in terms of tumour coverage, increased local TCP, and dose reduction to some OARs. We recommend that SIMT-IMRT should be considered as a first-line radiotherapy technique for NPC.

Irradiation-induced progenitor cell death in the developing brain is resistant to erythropoietin treatment and caspase inhibition.

One hemisphere of postnatal day 8 (P8) rats or P10 mice was irradiated with a single dose of 4-12 Gy, and animals were killed from 2 h to 8 weeks after irradiation (IR). In the subventricular zone (SVZ) and the granular cell layer (GCL) of the dentate gyrus, harboring neural and other progenitor cells, nitrosylation and p53 peaked 2-12 h after IR, followed by markers for active caspase-3, apoptosis-inducing factor and TUNEL (6-24 h). Ki67-positive (proliferating) cells had disappeared by 12 h and partly reappeared by 7 days post-IR. The SVZ and GCL areas decreased approximately 50% 7 days after IR. The development of white matter was hampered, resulting in 50-70% less myelin basic protein staining. Pretreatment with erythropoietin did not confer protection against IR. Caspase inhibition by overexpression of XIAP prevented caspase-9 and caspase-3 activation but not cell death, presumably because of increased caspase-independent cell death.

Accuracy of tele-oncology compared with face-to-face consultation in head and neck cancer case conferences.

Telemedicine was introduced for weekly tumour case conferences between Sahlgrenska University Hospital and two district hospitals in Sweden. The accuracy of tele-oncology was determined using simulated telemedicine consultations, in which all the material relating to each case was presented but without the patient in person. The people attending the conference were asked to determine the tumour ('TNM') classification and treatment. The patient was then presented in person, to give the audience the opportunity to ask questions and perform a physical examination. Then a new discussion regarding the tumour classification and the treatment plan took place, and the consensus was recorded. Of the 98 consecutive patients studied in this way, 80 could be evaluated by both techniques. Of these 80, 73 (91%) had the same classification and treatment plan in the telemedicine simulation as in the subsequent face-to-face consultation. In four cases the TNM classification was changed and for three patients the treatment plan was altered. The specialists also had to state their degree of confidence in the tele-oncology decisions. When they recorded uncertainty about their decision, it was generally because they wanted to palpate the tumour. In five of the seven patients with a different outcome, the clinical evaluation was stated to be dubious or not possible. The results show that telemedicine can be used safely for the management of head and neck cancers.

MRI staging using gadodiamide for soft-tissue tumors of the head and neck region. Results from a phase II trial and a 5-year clinical follow-up.

In order to document the safety, tolerability and efficacy of gadodiamide outside CNS, an open, non-drug comparative study was performed in patients with tumors of the head and neck region. Fifty adult patients were included and 48 patients received the contrast medium. The examinations were performed on a 1.5 T imager using transverse, non-enhanced T1- and PD-/T2-weighted conventional spin-echo sequences, followed by a contrast-enhanced transverse T1-weighted sequence. Post-contrast images provided more diagnostic information compared to unenhanced images in 33 of 48 patients (69%). This information was of significant help in four and of moderate help in 14 cases. Post-contrast images compared to non-enhanced T1-weighted showed improvement in lesion delineation for 29 of the 43 patients where a lesion was observed. Only in two patients was the diagnostic information lower post-contrast. A comparison between all pre-contrast images versus contrast medium enhanced showed post-contrast images to give more diagnostic information in 14 and less in nine patients. No patient experienced discomfort in relation to gadodiamide injection. Only one adverse event occurred which was described as thirst, being of moderate intensity. The 5-year clinical outcome was analyzed and compared with the pre-operative staging. The case-books of all patients were reviewed and in 44 patients all information could be found. Of those, 18 were still alive, one with active disease (AAD) and 17 with no evidence of disease (NED). Two of those four patients, where information was incomplete, showed NED and two had died. This trial showed that contrast-enhancement using gadodiamide for evaluation of soft tissue tumors in the head and neck region was safe and provided statistically significant more diagnostic information compared with unenhanced images. MRI, when compared with palpation/inspection, changed tumor staging in approximately 30% of all cases.

Tumor radiosensitivity (SF2) is a prognostic factor for local control in head and neck cancers.

PURPOSE: To evaluate prospectively the prognostic value of SF2 for local control and survival in patients undergoing radiation therapy for head and neck cancers. METHODS AND MATERIALS: Following informed consent tumor specimens were obtained from 156 patients with primary carcinomas of the head and neck region. The specimens were assessed for the ability to grow in vitro (colony forming efficiency, CFE) and inherent radiosensitivity measured as the surviving fraction at 2 Gy (SF2) using a soft-agar clonogenic assay. Patients were treated mainly with neoadjuvant chemotherapy plus radiation therapy usually as a combination of accelerated external beam and interstitial radiotherapy. The probabilities of local control and survival were analyzed by univariate, bivariate and Cox multivariate analyses. RESULTS: Successful growth was achieved in 110/156 specimens and SF2 values were obtained from 99/156. Eighty four out of these patients underwent radical treatment. The median SF2 value for the 84 tumors was 0.40. At a mean follow-up time of 25 months (range 7-65) the median SF2 value of tumors from 14 patients who developed local recurrence was 0.53, which was significantly higher than the median of 0.38 for tumors from 70 patients without local recurrence (p = 0.015). Tumor SF2 was a significant prognostic factor for local control (p = 0.036), but not for overall survival (p = 0.20). Tumor SF2 was an independent prognostic factor for local control within bivariate and Cox multivariate analyses. CONCLUSIONS: This study has shown that tumor radiosensitivity measured as SF2 is a significant prognostic factor for local control in head and neck cancers.

Fewer problems with dry nasal mucous membranes following local use of sesame oil.

Many people experience problems with a dry nasal mucous membrane, often without wondering why. Their noses itch and burn and dried mucus collects there. These problems are exacerbated during the winter, in air-conditioned environments and after nasal irradiation. Twenty patients experiencing problems with dryness of the nose were selected from outpatient clinics, together with twenty patients who had previously undergone nasal irradiation. During the first five days no treatment was administered. For the following twenty days the patients sprayed sesame oil into each nostril three times a day. For the last five days no treatment was given. When both groups received treatment and sprayed sesame oil (Nozoil) in their noses, the nasal problems decreased significantly. The greatest effect is exerted on dryness. The side effects from using this oil are few in number and mild.

The immunohistochemical expression of DNA-PKCS and Ku (p70/p80) in head and neck cancers: relationships with radiosensitivity.

PURPOSE: The DNA-PK complex is one of the major pathways by which mammalian cells respond to DNA double-strand breaks induced by ionizing radiation. This study evaluated the relationship between the immunohistochemical expression of the individual components of DNA-PK and cellular radiosensitivity in head and neck cancers. METHODS AND MATERIALS: Biopsies from patients with previously untreated squamous cell carcinomas of the head and neck were assessed for inherent tumor radiosensitivity measured as the surviving fraction at 2 Gy (SF2) using a soft agar clonogenic assay. Paraffin-embedded tumor material from 64 successfully grown specimens was immunohistochemically stained for expression of DNA-PKcs and Ku (p70/p80). The same tumor material was previously analyzed for the immunohistochemical expression of p53. RESULTS: A significant correlation was found between the degree of expression of DNA-PKcs and Ku (p70/p80) (r = 0.55, p<0.001). There were no overall significant differences in the levels of expression of DNA-PKcs and Ku (p70/p80) in tumors from patients of either sex, different sites, histologies, and stages. No relationship was found between SF2 and the expression of either DNA-PKcs (r = 0.22, p = 0.081) or Ku (p70/p80) (r = 0.064, p = 0.62). Comparison with previous immunohistochemical characterization showed no significant correlations between the expression levels of p53 and either DNA-PKcs (r = 0.093, p = 0.46) or Ku (p70/p80) (r = -0.17, p = 0.17). CONCLUSIONS: This study suggests that determining the immunohistochemical expression of DNA-PK in head and neck cancers from multiple sites does not have a role as a predictive assay of tumor in vitro radiosensitivity.

The lack of correlation between proliferation (Ki-67, PCNA, LI, Tpot), p53 expression and radiosensitivity for head and neck cancers.

A study was made of the relationship between measurements of radiosensitivity versus proliferation and p53 status in head and neck cancers. Inherent tumour radiosensitivity was assessed as surviving fraction at 2 Gy (SF2) using a clonogenic soft agar assay (n = 77). The results were compared to data on proliferation obtained by both flow cytometry (labelling index (LI), the potential doubling time (Tpot) n = 55) and immunohistochemistry (Ki-67 and PCNA; n = 68), together with immunohistochemical p53 expression (n = 68). There were no overall significant differences in the median values of the various parameters analysed for the different sites within the head and neck region, disease stages, grades of tumour differentiation or nodal states. A subgroup analysis showed that oropharyngeal (n = 22) versus oral cavity (n = 35) tumours were more radiosensitive (P = 0.056) and had a higher Ki-67 index (P = 0.001). Node-positive tumours had higher LI (P = 0.021) and a trend towards lower Tpot (P = 0.067) values than node-negative ones. No correlations were seen between SF2 and any of the parameters studied. The long-standing dogma of an increased radiosensitivity of rapidly proliferating cells in contrast to slowly proliferating cells was not confirmed. The study shows that parallel measurements of different biological markers can be obtained for a large number of patients with head and neck cancers. The independence of the various parameters studied suggests that there may be potential for their combined use as prognostic factors for the outcome of radiotherapy.

Discrimination of human tumor radioresponsiveness using low-dose rate irradiation.

PURPOSE: Evaluation of the theoretical and practical value of using low-dose rate (LDR) irradiation to increase the resolution of radiosensitivity testing of primary human tumors using clonogenic assays. METHODS AND MATERIALS: Fourteen human tumor cell lines were assessed for surviving fraction at 2-8 Gy (SF2-SF8) using low-dose rate irradiation and a clonogenic assay. Further data were collected from the literature for 64 low-dose rate irradiation survival curves from human tumor cell lines. The data were grouped into five different radioresponsiveness categories (A-E). An analysis was made of the ability of the graded survival levels to discriminate between the different radioresponse groups and compared with previous analyses for high-dose rate SF2. Fifteen human cervical carcinoma specimens were analysed for SF2 and SF3.5 following high- and low-dose rate irradiation. RESULTS: Low-dose rate irradiation increased the spread of tumor cell line radiosensitivity data and the ability to discriminate between radioresponse groups was greater at low than at high-dose rates. Using low-dose rate irradiation on primary tumor specimens and a soft agar clonogenic assay decreased the success rate in obtaining data. The latter dropped from 70% for high-dose rate SF2 to 51% for low-dose rate SF3.5. CONCLUSIONS: The work on cell lines illustrates that low-dose rate irradiation does improve the ability of clonogenic radiosensitivity measurements to discriminate between tumors of different radioresponsiveness groups. However, using low-dose rate irradiation on primary human tumors with a soft agar clonogenic assay was not practical because of reducing the success rate for obtaining data for radiosensitivity measurements.

Neurogenesis in the adult human hippocampus.

The genesis of new cells, including neurons, in the adult human brain has not yet been demonstrated. This study was undertaken to investigate whether neurogenesis occurs in the adult human brain, in regions previously identified as neurogenic in adult rodents and monkeys. Human brain tissue was obtained postmortem from patients who had been treated with the thymidine analog, bromodeoxyuridine (BrdU), that labels DNA during the S phase. Using immunofluorescent labeling for BrdU and for one of the neuronal markers, NeuN, calbindin or neuron specific enolase (NSE), we demonstrate that new neurons, as defined by these markers, are generated from dividing progenitor cells in the dentate gyrus of adult humans. Our results further indicate that the human hippocampus retains its ability to generate neurons throughout life.

The in vitro radiosensitivity of human head and neck cancers.

A study was made of the intrinsic radiosensitivity of 140 biopsy and surgical specimens of malignant head and neck tumours of different histologies. Using a soft-agar clonogenic assay, the material was assessed for the ability to grow in culture (colony-forming efficiency; CFE) and inherent tumour radiosensitivity (surviving fraction at 2 Gy, SF2). The success rate for obtaining growth was 74% (104/140) with a mean CFE of 0.093% (median 0.031) and a range of 0.002-1.3%. SF2 was obtained for 88 of 140 specimens, representing a success rate of 63% with a mean SF2 of 0.48 (median 0.43) and a range of 0.10-1.00. There were no significant differences in radiosensitivity between different sites of the head and neck region. There were no significant relationships between SF2 and disease stage, nodal status, tumour grade, patient age, primary tumour growth pattern and CFE. The results were compared with those for other tumour types previously analysed with the same assay. The distribution of the SF2 values for the head and neck tumours was similar to that for 145 cervix carcinomas and there was no significant difference in mean radiosensitivity between the two tumour types. Also, there was no significant difference in radiosensitivity between head and neck tumours and either breast or colorectal cancers. However, a group of eight lymphomas was significantly more radiosensitive. These results confirm the feasibility of carrying out radiosensitivity measurements using a soft-agar clonogenic assay on head and neck tumours. In addition, the work has shown that radiosensitivity is independent of many clinical parameters and that the mean value is similar to that reported for cervix carcinomas.

Potential impact on tumor control and organ preservation with cisplatin and 5-fluorouracil for patients with advanced tumors of the paranasal sinuses and nasal fossa. A prospective pilot study.

METHODS: Twelve patients with advanced epithelial nonadenocarcinoma of the paranasal sinuses and nasal fossa were treated with three cycles of cisplatin (100 mg/m2, day 1) and 5-fluorouracil (1000 mg/m2/24 hours on days 1-5 by continuous infusion), followed by preoperative external radiation therapy of 48 Gy and limited surgery, clearing the paranasal sinuses and nasal fossa. RESULTS: After chemotherapy, 11 of 12 patients were free of the previous symptoms of disease. Clinical response rates were different, however, with an overall response rate of approximately 70% with no complete responses. Histopathologic analysis of resected specimens showed no vital tumor in eight patients, minimal microscopic disease in three patients, and infiltrating tumor in one patient. Local control was achieved in 11 of 12 patients. Ten patients are alive with no evidence of disease (mean follow-up, 27 months). Surgical mutilation was avoided, with no functional or cosmetic loss. CONCLUSIONS: The results of this small pilot study seem to indicate a high chemosensitivity of carcinomas of the paranasal sinuses and nasal fossa, which, in this study, has meant significant relief of symptoms and an unusually high rate of local control (90%) without mutilation.