Rafal Tarnawski

Randomized clinical trial on 7-day-continuous accelerated irradiation (CAIR) of head and neck cancer – report on 3-year tumour control and normal tissue toxicity

Purpose: To evaluate tumour and normal tissues 3-year response to 7-day-a-week continuous accelerated irradiation (CAIR) compared to a conventional treatment (5 days per week) in a randomized trial. Materials and methods: One hundred patients with squamous cell carcinoma of the head and neck in stage T2‐4N0‐1M0 were entered into the trial between December 1, 1993 and June 30, 1996. Dose per fraction of 2.0 Gy (to the end of 1994), and 1.8 Gy (since January 1, 1995) was the same in both arms and delivered once a day at regular 24-h intervals to total dose in the range of 66‐72 Gy (depending on tumour stage). The only difference was overall treatment time being 5 weeks in the CAIR and 7 weeks in control arm. Results: Actuarial 3-year local tumour control was 82% in the CAIR and 37% in the control group (P , 0:0001) with reduction in local recurrence rate of 83%. Actuarial 3-year overall survival was 78 and 32% (P , 0:0001), respectively. Confluent mucositis was significantly more severe and lasted longer in the CAIR than in control arm. After 2.0 Gy fractions five of 23 patients (22%) in the CAIR developed early necroses over a period of 2‐4 months of follow-up which can be considered as a consequential to severe protracted acute mucosal reactions (CLE). For this reason dose per fraction was lowered to 1.8 Gy and the CLE was not observed again until now. Thus the overall rate of CLE decreased to 10%. Conclusions: The gain in tumour control is likely the effect of shortening of overall treatment time by 14 days and regular continuous dose delivery during the whole course of radiation therapy including weekends. A 7-day schedule produces more severe acute mucosal reactions lasting longer than in conventional fractionation, however tolerable by patients. Relatively high rate (22%) of CLE in the 7-day arm observed during the first year of the study was eliminated by decreasing dose per fraction from 2.0 Gy to 1.8 Gy. q 2000 Elsevier Science Ireland Ltd. All rights reserved.

How fast is repopulation of tumor cells during the treatment gap

PURPOSE/OBJECTIVE Our goal was to analyze the repopulation of surviving tumor cells during a treatment gap in radiotherapy for head-and-neck cancer. METHODS AND MATERIALS Clinical material is based on the records of 1502 patients treated by radiotherapy alone in Maria Sklodowska-Curie Memorial Institute in Gliwice during the period between1980 and 1989. All patients had histologically confirmed squamous cell carcinoma of the larynx or pharynx. The mean gap duration was 9 days. Only 10% of patients were treated without gaps. The dose per fraction was in the range of 1.5 to 2.5 Gy. Patient data were fitted directly to the mixed linear-quadratic model using maximum-likelihood estimation. Tumor stage or tumor localization was introduced into the equation as a categorical variable. Tumor proliferation was estimated by dividing the treatment gaps into three groups: the first 2 weeks, second 2 weeks, and the period after 4 weeks of irradiation. RESULTS Tumor control probability was significantly correlated with radiation dose, tumor progression (according to TNM), overall treatment time, and gap duration. Laryngeal cancers had a better prognosis than cancers of the oro- and nasopharynx. Significant tumor repopulation was found after the first 2 weeks of radiotherapy. During the treatment gap, the proliferation rate was equal to 0.75 Gy/day. During the days with irradiation, repopulation was slower and equal to 0.2 Gy/day. CONCLUSION The repopulation of tumor cells is faster during a gap than during the normal days of irradiation. Accelerated repopulation probably starts soon after 2 weeks of irradiation.

PROGNOSTIC VALUE OF HEMOGLOBIN CONCENTRATION IN RADIOTHERAPY FOR CANCER OF SUPRAGLOTTIC LARYNX

PURPOSE The aim of this work is the estimation of correlations between hemoglobin concentration either before or after radiotherapy and local tumor control probability for laryngeal cancer. METHODS AND MATERIALS Retrospective analysis of 847 cases of laryngeal supraglottic squamous cell carcinoma treated with radiation alone was performed using maximum likelihood estimations, and step-wise logistic regression. All patients were in good initial performance status (Karnofsky index >70). The minimum follow-up time was 3 years. RESULTS Logistic regression showed that the hemoglobin concentration after radiotherapy is an important prognostic factor. There was a very strong correlation between hemoglobin concentration and tumor local control probability. Hemoglobin concentration at the beginning of radiotherapy does not correlate with treatment outcome, but any decrease of hemoglobin during therapy is a strong prognostic factor for treatment failure. CONCLUSIONS Although regression models with many variables may be instable, the present results suggest that hemoglobin concentration after treatment is at least as important as overall treatment time. It was not possible to find out whether the low concentration of hemoglobin is an independent cause of low TCP or whether it reflects other mechanisms that may influence both hemoglobin level and the TCP.

Clinical radiobiology of glottic T1 squamous cell carcinoma

PURPOSE Radiation therapy is the treatment of choice for early glottic squamous cell cancer in many institutions over the world. Despite a relatively homogenous clinical model of T1 glottic tumors for the fractionation studies, the relationships between dose-time parameters remain unclear. To analyze the influence of fractionation parameters and hemoglobin level on tumor cure, this study has been performed. MATERIALS AND METHODS This is a retrospective review of 235 patients with T1N0M0 glottic cancer treated by radiation therapy alone given in a conventional schedule with 5 fractions each week. The individual total dose, dose per fraction, and overall treatment time (OTT) ranged from 51-70 Gy, 1.5-3.0 Gy, and 24-79 days, respectively. The median follow-up was 48 months. Patient data--total dose, dose per fraction, OTT, and hemoglobin level (Hb) measured before the radiation treatment--were fitted by the mixed LQ/log-logistic model. RESULTS The 5-year local relapse-free survival rate was 84%. All parameters included in the mixed LQ/log-logistic model improved the fit significantly. The dose-response curve for 235 patients with T1 glottic cancer was well defined and steep, and showed significant decrease in tumor control probability (TCP) when total doses were below 61 Gy. The 10-day prolongation of OTT, from 45 to 55 days, decreased the TCP by 13%. The dose of 0.35 Gy/day, compensated repopulation during the 1 day of prolongation, which indicates a potential doubling time (Tpot) for glottic T1 tumor clonogens of 5.5 days. The drop of Hb level of 1 g/dl (from 13.8 g/dl to 12.8 g/dl) gave a 6% decrease of TCP, provided that OTT was 45 days. CONCLUSION The significant correlation between the total dose, overall treatment time, hemoglobin concentration, and tumor control probability has been found for T1 glottic cancer.

Mass spectrometry-based serum proteome pattern analysis in molecular diagnostics of early stage breast cancer

BackgroundMass spectrometric analysis of the blood proteome is an emerging method of clinical proteomics. The approach exploiting multi-protein/peptide sets (fingerprints) detected by mass spectrometry that reflect overall features of a specimens proteome, termed proteome pattern analysis, have been already shown in several studies to have applicability in cancer diagnostics. We aimed to identify serum proteome patterns specific for early stage breast cancer patients using MALDI-ToF mass spectrometry.MethodsBlood samples were collected before the start of therapy in a group of 92 patients diagnosed at stages I and II of the disease, and in a group of age-matched healthy controls (104 women). Serum specimens were purified and the low-molecular-weight proteome fraction was examined using MALDI-ToF mass spectrometry after removal of albumin and other high-molecular-weight serum proteins. Protein ions registered in a mass range between 2,000 and 10,000 Da were analyzed using a new bioinformatic tool created in our group, which included modeling spectra as a sum of Gaussian bell-shaped curves.ResultsWe have identified features of serum proteome patterns that were significantly different between blood samples of healthy individuals and early stage breast cancer patients. The classifier built of three spectral components that differentiated controls and cancer patients had 83% sensitivity and 85% specificity. Spectral components (i.e., protein ions) that were the most frequent in such classifiers had approximate m/z values of 2303, 2866 and 3579 Da (a biomarker built from these three components showed 88% sensitivity and 78% specificity). Of note, we did not find a significant correlation between features of serum proteome patterns and established prognostic or predictive factors like tumor size, nodal involvement, histopathological grade, estrogen and progesterone receptor expression. In addition, we observed a significantly (p = 0.0003) increased level of osteopontin in blood of the group of cancer patients studied (however, the plasma level of osteopontin classified cancer samples with 88% sensitivity but only 28% specificity).ConclusionMALDI-ToF spectrometry of serum has an obvious potential to differentiate samples between early breast cancer patients and healthy controls. Importantly, a classifier built on MS-based serum proteome patterns outperforms available protein biomarkers analyzed in blood by immunoassays.

Role of short TE 1H-MR spectroscopy in monitoring of post-operation irradiated patients

Post-surgical radiation therapy is a routine procedure in the treatment of primary malignant brain tumors. Along with modest therapeutic effects conventional fractionated radiotherapy, in spite of any modifications, produces damage to non-malignant brain tissues lying within the treatment volume, the extent of which depends on radiation dose. Serial 1H-MRS allows non-invasive investigation of tissue metabolic profiles. In the present study the ratios of resonance signals assigned to the major 1H-MRS-visible metabolites (N-acetylaspartate, choline, creatine, inositol, lactate and lipid methylene group) were evaluated before, during and after post-surgical fractionated radiotherapy in brain regions close to and more distant from the tumor bed, receiving different radiation exposures (60 and < 40 Gy, respectively). The study group consisted of ten patients (aged 28-51). A MRI/MRS system (Elscint 2T Prestige) operating at the field strength of 2 T and the proton resonance frequency of 81.3 MHz has been used and the 1H-MR spectra were acquired using single voxel double-spin-echo PRESS sequence with a short TE. The spectra were post-processed with automatic fitting in the frequency domain. It was found that although the metabolite profiles depend on the dose obtained, but other stress factors (like surgery) seem to contribute to the overall picture of the metabolic status of the brain as well. In studies of early irradiation injuries, an increase of choline related ratios may serve rather as cell proliferation indictors than as cell injury ones, whereas the mI/Cr ratio appears as one of the first indicators of local irradiation injury. In order to establish the prognostic marker for early radiation damage, however, it seems necessary to analyze all visible metabolites as well. None of the metabolites separately may serve as such an indicator due to the complexity of tissue metabolism. Interestingly, MRI reveals no changes during the therapy process, whereas the metabolite ratios are being affected in the course of time, thus supporting the presumption that the 1H-MRS is a valuable method of radiation therapy monitoring.

DALSA: Domain Adaptation for Supervised Learning From Sparsely Annotated MR Images

We propose a new method that employs transfer learning techniques to effectively correct sampling selection errors introduced by sparse annotations during supervised learning for automated tumor segmentation. The practicality of current learning-based automated tissue classification approaches is severely impeded by their dependency on manually segmented training databases that need to be recreated for each scenario of application, site, or acquisition setup. The comprehensive annotation of reference datasets can be highly labor-intensive, complex, and error-prone. The proposed method derives high-quality classifiers for the different tissue classes from sparse and unambiguous annotations and employs domain adaptation techniques for effectively correcting sampling selection errors introduced by the sparse sampling. The new approach is validated on labeled, multi-modal MR images of 19 patients with malignant gliomas and by comparative analysis on the BraTS 2013 challenge data sets. Compared to training on fully labeled data, we reduced the time for labeling and training by a factor greater than 70 and 180 respectively without sacrificing accuracy. This dramatically eases the establishment and constant extension of large annotated databases in various scenarios and imaging setups and thus represents an important step towards practical applicability of learning-based approaches in tissue classification.

Mass spectrometry-based analysis of therapy-related changes in serum proteome patterns of patients with early-stage breast cancer

BackgroundThe proteomics approach termed proteome pattern analysis has been shown previously to have potential in the detection and classification of breast cancer. Here we aimed to identify changes in serum proteome patterns related to therapy of breast cancer patients.MethodsBlood samples were collected before the start of therapy, after the surgical resection of tumors and one year after the end of therapy in a group of 70 patients diagnosed at early stages of the disease. Patients were treated with surgery either independently (26) or in combination with neoadjuvant chemotherapy (5) or adjuvant radio/chemotherapy (39). The low-molecular-weight fraction of serum proteome was examined using MALDI-ToF mass spectrometry, and then changes in intensities of peptide ions registered in a mass range between 2,000 and 14,000 Da were identified and correlated with clinical data.ResultsWe found that surgical resection of tumors did not have an immediate effect on the mass profiles of the serum proteome. On the other hand, significant long-term effects were observed in serum proteome patterns one year after the end of basic treatment (we found that about 20 peptides exhibited significant changes in their abundances). Moreover, the significant differences were found primarily in the subgroup of patients treated with adjuvant therapy, but not in the subgroup subjected only to surgery. This suggests that the observed changes reflect overall responses of the patients to the toxic effects of adjuvant radio/chemotherapy. In line with this hypothesis we detected two serum peptides (registered m/z values 2,184 and 5,403 Da) whose changes correlated significantly with the type of treatment employed (their abundances decreased after adjuvant therapy, but increased in patients treated only with surgery). On the other hand, no significant correlation was found between changes in the abundance of any spectral component or clinical features of patients, including staging and grading of tumors.ConclusionsThe study establishes a high potential of MALDI-ToF-based analyses for the detection of dynamic changes in the serum proteome related to therapy of breast cancer patients, which revealed the potential applicability of serum proteome patterns analyses in monitoring the toxicity of therapy.

Hypofractionated stereotactic radiotherapy for large or involving critical organs cerebral arteriovenous malformations

Abstract Background. The treatment of large arteriovenous malformations (AVMs) or AVMs involving eloquent regions of the brain remains a challenge. For inoperable lesions, observation, volume-staged radiosurgery or hypofractionated stereotactic radiotherapy (HFSRT) are proposed. The aim of our study was to assess the safety and efficiency of HFSRT for large AVMs located in eloquent areas of the brain. Materials and methods. An analysis of records of 49 patients irradiated for cerebral AVMs with a mean dose of 19.9 Gy (12-28 Gy) delivered in 2-4 fractions with planned gap (at least one week) between fractions. Actuarial obliteration rates and annual bleeding hazard were calculated using Kaplan-Meier survival analysis and life tables. Results. Annual bleeding hazard rates were 4.5% and 1.6% after one and two years of the follow-up, respectively. Actuarial total obliteration rates were 7%, 11%, and 21% and total response rate (total and partial obliterations) 22%, 41%, and 55% after one, two and three years of the follow-up, respectively. There was a trend towards larger total obliteration rate in patients irradiated with fraction dose ≥ 8 Gy and total dose > 21 Gy for lesions of volume ≤ 8.18 cm3 which was not observed in case of partial obliterations. Conclusions. HFSRT results with relatively low obliteration rate but is not associated with a significant risk of permanent neurological deficits if both total and fraction doses are adjusted to size and location of the lesion. Predictive factors for total and partial obliterations can be different; this observation, however, is not firmly supported and requires further studies.

Repopulation of Tumour Cells During Radiotherapy is Doubled During Treatment Gaps

The aim of this work is to analyse the proliferation of tumour cells in the treatment gap during the radiotherapy for head neck cancer. Material and Methods The clinical material is based on records of head and neck patients treated by radiotherapy alone in our institution. The effect of radiotherapy was assumed to be described by a linearquadratic model. The patient data were fitted directly to the radiobiological model and the parameters were estimated using maximum-likelihood procedures. Results According to our model results of treatment were significantly correlated with Normalised Total Dose of radiation, the tumour progression (according to TNM), the overall treatment time and the gap duration. The laryngeal cancers had better prognosis then cancers of oroand nasopharynx. When the treatment time is prolonged without treatment interruptions 0.36 Gylday is lost due to the repopulation of tumour cells. During the treatment gap proliferation is faster and 0.67 Gylday is lost. Conclusion Proliferation of tumour cells is faster during the treatment gap then during the days with irradiation.