NMR-based metabolomics in real-time monitoring of treatment induced toxicity and cachexia in head and neck cancer: a method for early detection of high risk patients.

INTRODUCTION: Nutritional treatment in head and neck squamous cell carcinoma cancer (HNSCC) patients undergoing radio-/chemo-radiotherapy (RT/CHRT) is complex and requires a multidisciplinary approach. In this study the real-time dynamic changes in serum metabolome during RT/CHRT in HNSCC patients were monitored using NMR-based metabolomics. OBJECTIVES: The main goal was to find the metabolic markers that could help prevent of acute radiation sequelae (ARS) escalation. METHODS: 170 HNSCC patients were treated radically with RT/CHRT. Blood samples were collected weekly, starting from the day before the treatment and stopping within the week after the RT/CHRT completion, resulting in a total number of 1328 samples. 1H NMR spectra were acquired on Bruker 400 MHz spectrometer at 310 K and analyzed using principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA). Additional statistical analyses were performed on the quantified metabolites. RESULTS: PCA has detected a group of distinct outliers corresponding to ketone bodies (3HB, Ace, AceAce). These outliers were found to identify the individuals at high risk of weight loss, mainly by the 3HB changes, which was confirmed by the patients' medical data. In the OPLS-DA models a transition from the lowest to the highest weight loss is seen, defining the metabolic time trajectories for the patients from the studied groups during RT/CHRT. 3HB is a relatively sensitive marker that allows earlier identification of the patients at higher risk of > 10% weight loss. CONCLUSION: Our findings indicate that metabolic alterations, characteristic for malnutrition or cachexia, can be detected already at the beginning of the treatment, making it possible to monitor the patients with a higher risk of weight loss.

Acute mucosal reactions in patients with head and neck cancer. Three patterns of mucositis observed during radiotherapy.

PURPOSE: To investigate the individual pattern of acute mucosal radiation reactions (AMRR) in patients with head and neck cancer who were treated with radiotherapy alone. Reactions were evaluated daily on an individual basis according to the Dische scoring system. MATERIALS AND METHODS: Treatment of 87 head and neck cancer patients comprised either conventional fractionation- (CF; n = 33), accelerated fractionation (AF; n = 33), hyperfractionated- (HPEFX; n = 12) or hypofractionated (HPOFX; n = 9) radiotherapy with radical intent. Daily evaluation of AMRR progression was performed prospectively using a modified, morphologically functional Dische scoring system. The daily sums of the score parameters were subsequently used to construct an individual AMRR course curve for each patient. RESULTS: A latency period ranging from 3 to 14 days between the start of radiotherapy and the occurrence of the first AMRR symptom was observed in all patients. Based on the three different shapes of AMRR course curve observed during radiotherapy, three types of AMRR course can be described: (1) a continual increase in AMRR intensity until the completion of radiotherapy; (2) the incidence of a plateau phase following the increase in AMRR (increase-plateau course) and (3) decreasing AMRR intensity with a healing phase. A continual increase in AMRR intensity was observed in about 25 % of CF and AF patients and in more than 50 % of HPOFX treatments. This type of reaction was not observed in the HPEFX group. The increase-plateau course was noted in the majority of AF and CF patients; in almost half of those treated with HPOFX and in all HPEFX patients. A decreasing AMRR intensity course was observed in 23 % of all patients, although not observed at all in the HPEFX and HPOFX fractionation groups. CONCLUSION: The course of AMRR during radiotherapy can differ between individual patients. After the initial increase in AMRR intensity, a stabilization of the reaction--visible as a plateau phase on the course curve--is observed in the majority of patients. A proportion of the irradiated patients experience a continual increase in AMRR intensity up until the end of radiotherapy. A further group of patients exists in whom signs of AMRR healing are observed during the final stages of radiotherapy.

Ewing's sarcoma of the larynx. Effective treatment with organ preservation.

Extraskeletal Ewing's sarcoma arising in the head and neck region is an extremely rare malignant neoplasm. We describe the unusual case of a tumor originating in the larynx of a 68-year-old male with hoarseness and occasional aphonia. We report successful treatment with sequential chemo- and radiotherapy. Complete regression and larynx preservation with voice function recovery was achieved. To our knowledge, this is the first report of this type of tumor in the larynx with cartilage invasion that documents the effectiveness of radiotherapy as an alternative to surgical management. At present, after 30 months of follow-up, the patient is free of tumor relapse and in very good condition.

Prognostic role of tumor volume for radiotherapy outcome in patient with T2 laryngeal cancer.

BACKGROUND AND PURPOSE: Tumor volume (TV) is recognized as a prognostic factor of treatment outcome for head and neck tumors but is not routinely included in the treatment decision-making process. The purpose of the study was to define its prognostic role for patients with T2 laryngeal cancer. MATERIAL AND METHODS: TV of 160 patients who underwent RT between 2002 and 2006 for T2 laryngeal squamous cell carcinoma were reviewed. The tumor was located in the glottis and epiglottis in 82 (51%) and 78 (49%) patients, respectively. TV was manually contoured on pretreatment, planning, contrast-enhanced CT scans and the volumetric measurement (cm3) was calculated by the volume algorithm. RESULTS: The median TV value was 2.01 cm3 (range 0.15-21.68 cm3). The median TV was significantly lower in patients with glottic tumors (p<0.0001), N0 (p<0.001), or well histopatologically differentiated tumors (p=0.01). A significant correlation between TV, hemoglobin concentration (p<0.01), and total dose (TD; p<0.001) was observed. On univariate analyses, TV influenced local control (LC; p=0.02) and overall survival (OS, p<0.001). On multivariate analysis, both age (HR 1.038, p=0.03) and TV (HR=1.075, p=0.01) remained significantly related to LC and OS (age: HR 1.038, p=0.005; TV: HR 1.097, p=0.0001). CONCLUSION: Large TV worsen prognosis of patients with T2 laryngeal cancer. A large TV is more common for supraglottic, poorly differentiated tumors and may suggest higher risk of nodal spread. The routine estimation of TV prior to therapy may be essential in order to select the best treatment option for patients with T2 laryngeal cancer.

Acute mucosal radiation reactions in patients with head and neck cancer. Patterns of mucosal healing on the basis of daily examinations.

PURPOSE: The goal of this research was to evaluate the healing processes of acute mucosal radiation reactions (AMRR) in patients with head and neck cancer. MATERIALS AND METHODS: In 46 patients with oral and oropharyngeal cancer patients irradiated with conventional (n = 25) and accelerated (n = 21) dose fractionation AMRR was evaluated daily during and after radiotherapy. Complex of morphological and functional symptoms according to the Dische score were collected daily until complete healing. RESULTS: Duration of healing after the end of radiotherapy ranged widely (12-70 days). It was on the average 8 days longer for accelerated than for conventional radiotherapy (p = 0.016). Duration of dysphagia was also longer for accelerated irradiation (11 days, p = 0.027). Three types of morphological symptoms were observed as the last symptom at the end of AMRR healing: spotted and confluent mucositis, erythema, and edema. Only a slight correlation between healing duration and area of irradiation fields (r = 0.23) was noted. In patients with confluent mucositis, two morphological forms of mucosal healing were observed, i.e., marginal and spotted. The spotted form was noted in 71% of patients undergoing conventional radiotherapy and in 38% of patients undergoing accelerated radiotherapy. The symptoms of mucosal healing were observed in 40% patients during radiotherapy. CONCLUSION: The wide range of AMRR healing reflects individual potential of mucosa recovery with longer duration for accelerated radiotherapy. Two morphological forms of confluent mucositis healing were present: marginal and spotted. Healing of AMRR during radiotherapy can be observed in a significant proportion of patients.

Predictors of radiotherapy outcome in patients with T2 supraglottic carcinoma.

The decision regarding treatment of early supraglottic carcinoma remains controversial. Single institution clinical data of patients with T2 supraglottic carcinoma treated exclusively with radiotherapy in terms of prognostic factors and treatment results were analyzed. Patient-related factors that would potentially by useful for optimal therapeutic decision to be undertaken were especially investigated. Between 1994 and 2004, 78 patients with T2 supraglottic carcinoma underwent radiotherapy (RT) in Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice Branch, Poland. There were 54 (69%) males and 24 (31%) females in the median age of 61 years. There were 17 (22%) patients with N+. Median body mass of patients before (BM0) and after RT (BM1) was 74 kg (range 45.2-130 kg) and 72.9 kg (range 49.9-122.5 kg), respectively. Median hemoglobin concentrations before (Hb0) and after (Hb1) RT were 14.3 and 13.4 g/dl, respectively. Median change of Hb concentration during RT (dHb) was -0.8 g/dl. All were treated up to total doses (TD) ranged from 62.5 to 72 Gy. The overall treatment time (OTT) ranged from 30 to 70 days. Estimates of local control (LC), ultimate local control (uLC), and overall survival (OS) were calculated using the Kaplan-Meier method. Log rank statistics, Cox proportional hazard model and step-wise Cox regression hazard model were employed to identify prognostic factors for LC, uLC, and OS in univariate and multivariate analyses. The 5-year LC, RC, uLC and OS rates were 85, 92, 88, and 56%, respectively. In multivariate analysis N+ (p = 0.01) and prolonged OTT (p = 0.03) significantly decreased LC. Females (p = 0.02), higher BM0 (p = 0.03), and HB0 (p = 0.006) significantly prolonged OS. Patient-related factors like gender, hemoglobin concentration, and body mass may predict treatment outcome. Radiotherapy is effective for T2 supraglottic carcinoma of the larynx unless higher dose intensity is provided. Involved regional lymph nodes significantly deteriorate locoregional cure.

Relationships between acute reactions to radiotherapy in head and neck cancer patients and parameters of radiation-induced DNA damage and repair in their lymphocytes.

PURPOSE: To study the relationship between lymphocyte radiosensitivity measured in vitro and acute reactions to radiotherapy in patients with head and neck cancer. MATERIALS AND METHODS: Acute reactions were measured in 34 patients using the Dische scale. Lymphocyte radiosensitivity was measured using the alkaline comet assay, the micronucleus assay, the nuclear division index and morphological assessment of apoptosis. RESULTS: There was a weak, statistically significant correlation between in vitro radiosensitivity measured as the rate of DNA damage repair and the cumulative radiation dose exerting the maximum acute reaction scored (r = -0.366, p = 0.039, n = 34). Subgroup analyses showed that for patients with a low level of radiation-induced DNA damage there was a statistically significant relationship between lymphocyte radiosensitivity measured as inhibition of proliferation and acute toxicity (r = -0.621, p = 0.007, n = 18). For patients with a high level of residual DNA damage, there was a relationship between lymphocyte radiosensitivity measured using the micronucleus assay and acute toxicity (r = -0.597, p = 0.023, n = 14). CONCLUSIONS: Combining two measures of radiosensitivity improves the ability to correlate in vitro lymphocyte radiosensitivity and acute radiotherapy toxicity data.

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.

The effect of patient position and treatment technique in conformal treatment of prostate cancer.

PURPOSE: The relative value of prone versus supine positioning and axial versus nonaxial beam arrangements in the treatment of prostate cancer remains controversial. Two critical issues in comparing techniques are: 1) dose to critical normal tissues, and 2) prostate stabilization. METHODS AND MATERIALS: Ten patients underwent pretreatment CT scans in one supine and two prone positions (flat and angled). To evaluate normal tissue exposure, prostate/seminal vesicle volumes or prostate volumes were expanded 8 mm and covered by the 95% isodose surface by both 6-field axial and 4-field nonaxial techniques. A total of 280 dose-volume histograms (DVHs) were analyzed to evaluate dose to rectal wall and bladder relative to patient position and beam arrangement. A CT scan was repeated in each patient after 5 weeks of treatment. Prostate motion was assessed by comparing early to late scans by three methods: 1) center of mass shift, 2) superior pubic symphysis to anterior prostate distance, and 3) deviation of the posterior surface of the prostate. RESULTS: For prostate (P) or prostate/seminal vesicle (P/SV) treatments, prone flat was advantageous or equivalent to other positions with regard to rectal sparing. The mechanism of rectal sparing in the prone position may be related to a paradoxical retraction of the rectum against the sacrum, away from the P/SV. Although there was no clear overall preference for beam arrangement, substantial improvements in rectal sparing could be realized for individual patients. In this limited number of patients, there was no convincing evidence prostate position was stabilized by prone relative to supine position. CONCLUSIONS: Prone flat positioning was advantageous over other positions and beam arrangements in rectal sparing. This study suggests that patient position is a more critical a factor in conformal therapy than beam arrangement, and may improve the safety of dose escalation.

[Comparison of natural history of squamous cell carcinoma and nondifferentiated carcinoma localized in oro- and nasopharynx]. / Ocena porównawcza przebiegu klinicznego raka plaskonablonkowego i niezróznicowanego czesci ustnej i nosowej gardla.

Aim of this study is comparison of natural history between two subtypes of cancer: squamous and undifferentiated, which were localised in oro- and nasopharynx. Analysis has contained 175 patients with undifferentiatied and 510 patients with squamous cell cancers of oro- and nasopharynx, who were treated in Centre of Oncology--Institute branch Gliwice in 1980-1998. Presence of undiferentiated subtypes were bounded with shortening time of presence the symptoms of disease, most frequent exophytic type of infiltration than in squamous cancer with ulcerative--necrotic type of infiltration. Higher aggressiveness of undifferentiated cancer is based on higher frequency of distant and nodal metastases, metastases to contralateral nodes and higher percentage of conglomerates.

[Prognostic factors in radiotherapy for hypopharyngeal cancer]. / Czynniki prognostyczne w radioterapii samodzielnej raka gardla dolnego.

This paper presents influence of selected prognostic factors on results of hypopharyngeal cancer radiotherapy used as only treatment in 97 patients irradiated in Centre of Oncology-Institute in Gliwice between 1980-1987. One-variant analysis showed statistically significant influence of gender, decrease of haemoglobin level during radiotherapy and higher T and N stages. Multivariant analysis demonstrated, that only locoregional status and treatment time has decisive importance on radiotherapy results. Thus, better results of treatment depend on lower T and N stages and correct radiotherapy time.

[[Radical radiotherapy in patients with laryngeal cancer in clinical material of Institute Oncology in Gliwice treated in year 1990-1996]. / Samodzielna radioterapia chorych na raka krtani w materiale klinicznym Instytutu Onkologii w Gliwicach w latach 1990-1996.

This paper presents influence of selected prognostic factors on results of laryngeal cancer radiotherapy used as the only treatment in 541 patients irradiated in Centre of Oncology-Institute in Gliwice between 1990-1996. The 3-year actuarial disease-free survival was 47.5% for supraglottic cancer and 67% for glottic cancer. Primary tumour localisation in glottis correlates with more favourable prognosis than that in supraglottic. For extralaryngeal involvement the most favourable prognosis was infiltration of cartilages and the worst one for the hypopharyngeal and oropharyngeal involvement. Pretreatment tracheostomy significantly correlates with the worst results.

[Head and neck lymph node metastases from unknown primary site]. / Przerzuty do wezlów chlonnych regionu glowy i szyi z nieznanego ogniska pierwotnego.

The aim of this paper was to evaluate the group of 50 patients with cervical nodes metastases from unknown primary site treated between 1980-1995 in Maria Sk_odowska-Curie Memorial Institute of Oncology in Gliwice. There were 42 males and 8 females ranging in age from 26 to 85 years (median 60). 24 patients underwent combined therapy (surgery with postoperative radiotherapy), 22 underwent radiotherapy. Only 4 patients were treated with surgery alone. 3-years DFS rates were 59% in group treated with combined method, and 10% in group treated only with radiation therapy (p = 0.003). After a median follow up of 39 months 10 primary tumors were discovered--8 in head and neck region, 2 in lower respiratory tracts. DFS rate in group with discovered primary tumors was 40%.