Prognostic factors effective on survival of patients with glioblastoma: Anadolu Medical Center experience.

AIM: The aim of this study is to offer survival following radiation therapy using intensity-modulated radiotherapy or volumetric arc therapy with temozolomide in patients with glioblastoma. MATERIALS AND METHODS: Ninety-two previously treated patients with high-grade glioma (World Health Organization [WHO] grade IV) were studied in Anadolu Medical Center, Department of Radiation Oncology, between January 2006 and July 2015. The diagnosis was established by pathology in all cases. The median age was 59 years (range, 19-86 years). The median tumor diameter was 45 mm, and the rate of the multicentric tumors was 16.3%. The location of the tumor was temporal in 33.7%, parietal in 14.1%, frontal in 23.9%, occipital in 9.8%, and others in 18.5%. The gross total and subtotal resection were performed in 60.9% of the patients, partial resection in 26.1%, and only stereotactic biopsy in 13.0% of the patients. RESULTS: The median overall survival (OS) was 33.01 ± 4.76 months (95% confidence interval 25.64-40.38 months). 1, 2, and 5 years OS was 74.3%, 44.3%, and 31.8%, respectively. The median progression-free survival (PFS) was 27.36 ± 3.87 months (95% confidence interval 19.82-34.89 months). 1, 2, and 5 years PFS was 62.7%, 32.6%, and 27.2%, respectively. On univariate analysis, gender, extent of surgery, tumor size, Karnofsky performance status, and tumor suppressor gene (P53) were significant predictors of OS and PFS. On multivariate analysis, gender (PFS: P = 0.006, OS: P = 0.003), extent of surgery (PFS: P = 0.004, OS: P = 0.012), P53 (PFS: P = 0.003, OS: P = 0.021), and size of tumor (PFS: P = 0.005, OS: 0.012) remained significantly associated with PFS and OS. There is no statistically significant in OS and PFS between female and male (OS: log-rank: 0.79 P = 0.375, PFS: log-rank: 0.54 P = 0.465). PSF and OS were not significantly significant with total/near total resection compared with partial resection (PSF: P = 0.46 log-rank = 0.54, OS: P = 0.340 log-rank = 0.91). Patients with P53 <50% value and patients with P53 >50% value were compared and results were not found statistically significant (PSF: P = 0.917 log-rank = 0.01, OS: P = 0.892 log-rank = 0.02). For patients with tumor size <0 mm, small tumor size did not improve the PSF and OS (PSF: P = 0.291 log-rank = 1.11, OS: P = 0.288 log-rank = 1.13). CONCLUSION: Ninety-two previously treated patients with high-grade glioma (WHO Grade IV) were evaluated with multivariate analysis. Gender, extent of surgery, P53, and tumor size were found as prognostic factors affecting on survival.

Clinical evaluation of the neuroprotective effect of alpha-tocopherol against glaucomatous damage.

PURPOSE: To evaluate the vasoregulatory effect of antioxidant alpha-tocopherol on retina via protein kinase C pathway. METHODS: Thirty glaucomatous patients (60 eyes) were included in this study. The patients were divided into three groups. For patients in Group A, tocopherol was not supplemented in their therapy. Patients in Groups B and C received 300 and 600 mg/day of oral alpha-tocopherol acetate, respectively. The ultimate blood tocopherol levels were confirmed via high-performance liquid chromatography assay. Progression of the disease for each subject was monitored via visual field measurements and color Doppler imaging of ophthalmic and posterior ciliary arteries at the beginning and at the 6th and 12th months of this study. RESULTS: The average differences between the pulsatility indexes (PI) and resistivity indexes (RI) of both ophthalmic arteries (OA) and posterior ciliary arteries (PCA) of Groups B and C were significantly lower than those of Group A at months 6 and 12. In trial groups, RI decreases observed in PCAs at months 6 and 12 and PI decreases observed in OAs at the 6th month were statistically significant. Differences of mean deviations with visual fields in Groups B and C were highly significantly lower than that of Group A. CONCLUSIONS: Alpha-tocopherol deserves attention beyond its antioxidant properties for protecting retina from glaucomatous damage.

[Calcification of hydrophilic acrylic intraocular lenses: clinical and pathological aspects]. / Calcification postopératoire des lentilles intraoculaires acryliques hydrophiles: aspects cliniques et pathologiques.

PURPOSE: The aim of this study was to evaluate the clinical aspects of ten eyes with calcified hydrophilic acrylic intraocular lenses and pathological data obtained from seven explanted lenses. MATERIAL AND METHODS: Forty-seven eyes of 40 patients received the same implant in the first 6-month period of 2001. Ten eyes showed intraocular lens opacification detected 6-18 months after the operation: seven lenses were explanted and three were left in place because they were not causing a decrease in visual acuity or glare at light. Five of ten eyes were diabetic. The explanted lenses were examined under the light microscope and the electron microscope. The elemental analysis of the lens surfaces was made by energy dispersive spectrometry. RESULTS: The light microscopy showed an irregular surface covered by a gray-white opacity. The electron microscopy detected multiple granulations on the front and back surfaces of the lenses including some portions of the haptics. The size and density of these granulations were smaller on the back surface. The energy dispersive spectrometry showed the presence of calcium and phosphate on both surfaces. The spikes of calcium and phosphate were smaller for the back surface of the lenses. DISCUSSION: Calcification was predominantly seen on the surfaces that were in contact with aqueous not covered with anterior capsule. Half (5/10) of the cases were diabetic even though 18% of all patients receiving this lens were diabetic. The presence of diabetes is very common in other series. These data suggest the role of a metabolic factor influencing the milieu of the lens in this calcification process. CONCLUSION: Calcification of the hydrophilic acrylic lenses is a relatively serious complication, but the conditions leading to its appearance and the physiopathology have not yet been fully elucidated. The surgeon should be very careful in the choice of the intraocular lens to implant, and even more so if the patient is diabetic.

Randomized phase 2 study of radiotherapy alone versus radiotherapy with paclitaxel in non-small cell lung cancer.

This randomized phase 2 study aimed to assess and compare the toxicity and response rates in patients with unresectable non-small cell lung cancer treated with radiotherapy (1.8-2 Gray [Gy] daily, five fractions a week, total 63 Gy) or radiotherapy + paclitaxel administered weekly (1.8 Gy daily, five fractions a week, total 59.4 Gy). Twelve patients in the latter arm received 30 mg/m2 paclitaxel (median six cycles) over a 3-h infusion once weekly. After assessing toxicity, the remaining nine patients received 60 mg/m2 paclitaxel weekly (median six cycles). Response was evaluated radiologically 1 month after treatment. Grade 3 toxicity was 20% and 38% in the radiotherapy and chemoradiotherapy groups, respectively. Overall survival rates in complete and objective (complete plus partial) responders and progression-free survival rate of the objective responders were significantly better in the chemoradiotherapy arm. We believe that using paclitaxel in concurrent chemoradiotherapy regimens may be effective in patients with unresectable, locoregionally advanced non-small cell lung cancer.

Factors influencing cosmetic results after breast conserving management (Turkish experience).

We aimed to determine predictive factors affecting cosmetic results after breast conserving management in breast cancer. Data on 96 patients with 97 breast cancer cases, who had been admitted to Uludag University M.A. Radiotherapy Center between October 1995 and December 1998 and managed with breast-conserving treatment, were analysed to determine the factors affecting cosmetic outcome. Possible factors affecting cosmesis were grouped as patient-related, tumor-related and treatment-related. Mann-Whitney U test was used in univariate analyses whereas logistic regression was used in multivariate analyses. Median follow-up time was 29.5 months ranging between 11 and 53 months and median age at admission was 50 (range 22-84). Cosmetic results were grouped in five categories; excellent; good; fair; poor and, very poor, using criteria, such as presence of fibrosis, telangiectasia, shape of breast, asymmetry, status of areola, pigmentation. Treated breasts were scored by the patients, three radiation oncologists and a breast surgeon independently. In the analysis performed using scores given by the patients, cases with scores 3 and above (unsatisfactory) were compared with cases with scores below 3 (satisfactory). Eighty-two patients (84%) considered cosmetic result as satisfactory (excellent/good) whereas 15 patients (16%) considered unsatisfactory (fair/poor/very poor). In univariate analysis using Mann-Whitney U test, type of surgery (P=0.0655) was the statistically significant factors affecting cosmetic results. In multivariate analysis using logistic regression, tumor quadrant (P=0.0060) and elapsed radiation therapy days (P=0.0090) were the most significant factors. Median values were taken into consideration for the scores given by the physicians and cases with scores 3 and above (unsatisfactory) were compared with cases with scores below 3 (satisfactory). Eighty-two cases were evaluated as satisfactory (84%) whereas 15 cases were unsatisfactory (16%). In this set of data, patient age (P=0.0144), menopausal status (P=0.0111), institution which surgery was performed (P=0.0045), type of surgery (P=0.0044), placement of metallic clips (P=0.0083) and skin fibrosis (P=0.038) were found to be significant in univariate analysis using Mann-Whitney U test. In multivariate analysis using logistic regression, institution where surgery took place (P=0.0015), menopausal status (P=0.0087) and telangiectasia (P=0.0657) were the most significant factors.

Effects of Taxol plus radiation on the apoptotic and mitotic indices of mouse intestinal crypt cells.

PURPOSE: In this study we investigated the effect of Taxol, radiation, or Taxol plus radiation on highly proliferative normal tissue--the intestinal crypt cells of Swiss albino mice. MATERIALS AND METHODS: Swiss-albino mice, 3-4 months old, were used in this study. Taxol was administered by bolus intravenously through the tail vein. Radiation was given using a linear accelerator. There were four treatment categories, which comprised a total of 34 groups. Each group consisted of five animals. The first category was a control category which comprised one group (n = 5). The second treatment category was Taxol alone which comprised three groups (n = 15). The third treatment category was radiation alone which comprised three groups (n = 15). The fourth treatment category was Taxol plus radiation which comprised 27 groups (n = 135). Mice were killed 24 h after Taxol or radiation or combined administration using ether anesthesia. Using a light microscope, apoptotic and mitotic indices were counted on jejunal crypt cells of mice that were stained with hematoxylin-eosin. Differences between groups were statistically evaluated with Student's t-test. RESULTS: Taxol caused a dose-dependent increase in apoptosis (P = 0.045) and decreased the mitotic index (P = 0.006) at high doses. Similarly, radiation caused a dose-dependent increase in apoptosis (P = 0.046) and decreased the mitotic index (P = 0.299) at higher radiation doses. Compared to radiation alone, Taxol caused a significant induction of apoptosis (P = 0.010). In combination, no significant radiosensitizing effect of Taxol was observed (enhancement ratio < 1), when compared to radiation alone. However, an increase in apoptosis was observed after 24 h of Taxol exposure when compared to 12 or 48 h of Taxol exposure (P = 0.0001 and P = 0.0001). CONCLUSION: These findings suggest that Taxol did not cause a radiosensitizing effect in intestinal crypt cells. However, a 24-hour pretreatment of Taxol exposure followed by radiation caused significant induction of apoptosis and reduction of the mitotic index when compared to other Taxol timing sequences. Thus, the lack of a radiosensitizing effect of Taxol in these proliferative cells may be due to enhanced mitotic death rather than apoptotic death.

The relationship between genetic susceptibility to head and neck cancer with the expression of common fragile sites.

BACKGROUND: Numerous studies have recently been conducted to investigate genetic mechanisms in cancer causes and pathogenesis. Some of these studies have shown that there were certain specific chromosomal defects in normal cells of cancer patients and in their first-degree relatives. It was suggested that these individuals were susceptible to cancer development when compared with people without these defects. Materials and Methods Chromosomal anomalies, such as gaps, breaks, and acentric fragments, and fragile site expression rates were determined in peripheral blood lymphocyte cultures in 14 head and neck cancer patients, 17 first-degree relatives of these patients, and 20 healthy individuals as a control group in this study. RPMI 1640 medium, composed of aphidicolin, 5-bromodeoxyuridine, and caffeine were used for the induction of fragile sites. RESULTS: In cytogenetic and statistical evaluation, it was observed that both chromosomal aberration rates and fragile site expression frequencies in head and neck cancer patients and in their first-degree relatives were significantly greater than the control group (p <.05). It was found that fragile site expression was site specific in head and neck cancer patients and in their first-degree relatives. These specific sites were determined to be 1p21-22, 1q21, 1q25, 2q21, 2q31-33, 3p14, 16q22-23, 18q21, and 22q12 sites. CONCLUSIONS: These findings support studies showing that the fragile sites might be unstable factors in human genomes and their expression could be affected by some genetic factors, such as tumor suppressor genes and mismatch repair genes, and by some environmental factors, such as benzo (a) pyrene, dimethylnitrosamine, and dimethylsulfate. In conclusion, fragile sites may be playing an important role in the genetic tendency to head and neck cancer. Overexpression of these sites in normal lymphocytes may be used as a reliable marker to determine the genetic susceptibility in head and neck cancer patients and in their first-degree relatives.

Effect of i.v. glucose versus combined i.v. plus oral glucose on human tumour extracellular pH for potential sensitization to thermoradiotherapy.

The purpose of this study was to determine whether intravenous or combined intravenous plus oral glucose administration was more effective inducing acute tumour acidification. Seventeen nondiabetic patients at the Henan Tumour Hospital with superficial tumour deposits of various histologies and size were administered, after fasting, either 50 g glucose intravenously (i.v., in 100 ml over 10 min) or 50 g i.v. glucose (in 100 ml over 10 min) combined with 100 g oral glucose (in 200 ml; i.v. + oral). Extracellular tumour pH (pHe) was determined with one or two indwelling needle combination pH microelectrodes. Blood glucose concentration was determined every 15-20 min by finger stick with Chem-Strips and a Glucometer. Ten patients received i.v. glucose, and seven patients received i.v. + oral glucose. Blood glucose rose to 430 +/- 15 mg/dL in both groups. However, the rate of clearance of blood glucose was greater for the i.v. glucose than for the i.v. + oral glucose group (p < 0.00002), and thus the blood glucose levels remained elevated longer after i.v. + oral than after i.v. glucose administration. Relative to the initial fasting blood glucose concentration, blood glucose was -2 +/- 7 mg/dL at 110 min after glucose administration by the i.v. route, whereas, blood glucose relative to initial values was 143 + 23 mg/dL by 110 min after glucose administration by the i.v. + oral route, p = 0.000004. The initial pHe values in the two groups of tumours were similar, 7.34 +/- 0.09 (6.78-7.71) and 7.35 +/- 0.08 (6.99-7.61), respectively. After i.v. glucose, tumour acidification occurred in nine of ten patients (-0.16 + 0.02 pH unit, range -0.24 to -0.05), and after i.v. + oral glucose tumour acidification occurred in six of seven patients (-0.19 +/- 0.07 pH unit, range -0.43 to -0.06). When the initial fasting blood glucose concentration was in excess of 82 mg/dL, all patients (12/12) exhibited tumour acidification during hyperglycaemia, whereas, only 3/5 patients exhibited tumour acidification when the initial blood glucose concentration was less than 82 mg/dL (p = 0.07). The time to maximum decrease in tumour pHe was significantly shorter after i.v. + oral glucose than after i.v. glucose (e.g., 67 +/- 11 versus 102 +/- 8 min, p = 0.02) and correlated with the rate of clearance of blood glucose (p = 0.02, r = 0.55). Larger tumours tended to exhibit a greater decrease in pHe (p = 0.08, r = 0.04). The only side effects of hyperglycaemia were transient nausea and increased urinary output. The effect of hyperglycaemia induced by administration of 200 g oral glucose was similar to i.v. administration in that 83% of tumours exhibited acidification of 0.14 +/- 0.02 pH unit by 91 +/- 7 min. We conclude that i.v. and i.v. + oral glucose administration are equally effective inducing tumour acute acidification, but no more effective than 200 g oral glucose, for investigation of hyperglycemic sensitization to thermoradiotherapy.

Biological rationale and clinical experience with hyperthermia.

Hyperthermia (HT) as an adjunct to radiation therapy (RT) has been a focus of interest in cancer management in recent years there have been numerous randomized and nonrandomized studies conducted to assess the efficacy of HT combined with either RT or chemotherapy especially in the treatment of superficially seated malignant tumors. The major impact of HT is currently on locoregional control of tumor. Heat may be directly cytotoxic to tumor cells or inhibit repair of both sublethal and potentially lethal damage after radiation. These effects are augmented by the physiological conditions in tumor that lead to states of acidosis and hypoxia. Blood flow is often impaired in tumor relative to normal tissues, and HT may lead to a further decrease in blood flow and augment heat sensitivity. Three major areas of clinical investigation have borne the greatest fruit for HT as adjunctive therapy to RT. These include recurrent and primary breast lesions, melanoma, and head and neck neoplasms. Thermal enhancement ratio was increased in all cases and is approximately 1.4 for neck nodes, 1.5 for breast, and 2 for malignant melanoma. In general, the most important prognostic factors for complete response (CR) are RT dose, tumor size and minimal thermal parameters minimal thermal dose (t43min), mean minimal temperature (Tmin) or T90, i.e., temperature exceeded by 90% of thermal sensors]. The number of HT fractions administered per week appears to have no bearing on the overall response, which may be indicative of the effects of thermotolerance. The total number of HT fractions delivered also appears irrelevant provided adequate HT is delivered in one or two sessions. The major prognostic factors for the duration of local control were tumor histology, concurrent RT dose, tumor depth and Tmin. Although numerous single institution studies showed increased CR rates and improved local control, the efficacy of HT as an adjunct to RT should be assessed with well-designed multi-institutional randomized clinical trials. Such clinical trials are underway.

Predictive factors for skin reactions in patients treated with thermoradiotherapy.

In this study we performed univariate analyses to analyse the predictive factors for skin reactions, i.e. erythema, thermal blisters and ulceration, that occur during thermoradiotherapy. One hundred and twenty-six fields in 126 patients were treated with thermoradiotherapy using 915 MHz external microwave hyperthermia. Mean age of patients was 62 years. All but 11 lesions received previous therapy. Prior treatment included surgery (75%), chemotherapy (60%) and/or radiation therapy (51%). The mean previous radiation dose was 54 +/- 2 Gy. The concurrent tumour radiation dose was 45 +/- 1 Gy, in 16 fractions, over 35 elapsed days (dose per fraction of 1.6-4.8 Gy). The mean number of heat sessions administered was 5.5 +/- 0.2 (range 1-14). In 83% of cases hyperthermia was administered biweekly. Forty-two patients were treated without any skin reaction (33%), erythema occurred in 59 fields (47%), transient thermal blisters occurred in 25 fields (20%) and ulceration occurred in 23 fields (18%). In 25 cases, two or more skin reactions (20%) were observed concurrently. Concurrent radiation dose correlated with skin reactions (p = 0.02). The incidence of skin reactions was inversely correlated with previous radiation therapy (p = 0.04) and previous radiation therapy dose (p = 0.04) possibly due to fibrosis. None of the tumour or skin thermal parameters correlated with the reaction rate.

Extracellular pH distribution in human tumours.

Extracellular pH (pHc) was determined by needle microelectrodes in 67 tumour nodules in 58 patients. The objective was to evaluate the relationship between pHe, tumour histology and tumour volume. The mean age of the patients was 62 years, mean depth of the lesions was 2.7 +/- 0.2 cm, and mean tumour volume was 187 +/- 60 cm3. Lesions were located in readily accessible areas such as on the limbs, neck or chest wall. Tumour histologies included: 48% adenocarcinoma; 34% squamous cell carcinoma; 8% soft tissue sarcoma; and 10% malignant melanoma. The mean tumour pHe for the entire group of tumours was 7.06 +/- 0.05 (range 5.66-7.78). Variation in pHe measurements between tumours was greater than the variation in measurements within tumour (F = 7.11, p < 0.01). In adenocarcinomas pHe was 6.93 +/- 0.08 (range 5.66-7.78), in soft tissue sarcomas 7.01 +/- 0.21 (6.25-7.45), in squamous cell carcinomas 7.16 +/- 0.08 (6.2-7.6), and in malignant melanomas 7.36 +/- 0.1 (6.98-7.77). Tumour pHe was significantly different between the four histological groups (p < 0.001). When adenocarcinoma and soft tissue sarcoma lesions were grouped together, pHe was 6.94 +/- 0.08 compared with 7.20 +/- 0.07 in squamous cell carcinomas and malignant melanomas lesions (p < 0.01). Tumour pHe increased as a function of the logarithm of tumour volume at 0.07 +/- 0.02 pH unit/ln cm3 (p = 0.006, r = 0.34). In conclusion, tumour histology and tumour volume were the most important factors determining the range of pHe's.(ABSTRACT TRUNCATED AT 250 WORDS)

Thermoradiotherapy in the management of superficial malignant tumors.

In recent years there have been numerous randomized and nonrandomized studies conducted to assess the efficacy of hyperthermia combined with either radiation therapy or chemotherapy, especially in the treatment of superficially seated malignant tumors. The major impact of hyperthermia is currently on locoregional control of tumor. Heat may be directly cytotoxic to tumor cells or inhibit repair of both sublethal and potentially lethal damage after radiation. These effects are augmented by the physiological conditions in tumors which lead to states of acidosis and hypoxia. Blood flow is often impaired in tumor relative to normal tissue, and hyperthermia may lead to a further decrease in blood flow and augment heat sensitivity. Three major areas of clinical investigation have borne the greatest fruit for hyperthermia as adjunctive therapy to radiation therapy. These include recurrent and primary breast lesions, melanoma, and head and neck neoplasms. The thermal enhancement ratio was increased in all cases and is estimated to be 1.4 for neck nodes, 1.5 for breast, and 2 for malignant melanoma. In general, the most important prognostic factors for complete response are radiation dose, tumor size, and minimal thermal parameters (minimum thermal dose, mean minimum temperature or temperature exceeded by 90% of thermal sensors). The number of heat fractions administered per week appears to have no bearing on the overall response, which may be indicative of the effects of thermotolerance. The total number of heat fractions delivered also appears to be irrelevant provided adequate heat is delivered in one or two sessions. The major prognostic factors for the duration of local control are tumor histology, concurrent radiation therapy dose, tumor depth, and mean minimum temperature.

Multiple field hyperthermia combined with radiotherapy in advanced carcinoma of the breast.

Extensive recurrences on the chest wall of advanced carcinoma of the breast in 20 patients were treated with multiple field patchwork hyperthermia combined with radiation therapy between 1987-1991. The objective of the study was to evaluate the feasibility, tumour response and complications of treating extensive lesions with multiple, overlapping fields of hyperthermia. All lesions were diffuse encompassing up to 2900 cm2 in area with or without multiple nodules < or = 3 cm deep. All lesions had failed previous therapy with all but three failing previous radiotherapy. Hyperthermia consisted of 282 hyperthermia applicator fields and 357 hyperthermia treatments with external 915 MHz microwaves using commercially available applicators. Hyperthermia applicator fields were defined by the surface 50% SAR distribution of a particular applicator, and hyperthermia fields were abutted to cover the entire tumour bearing area. Radiation therapy consisted of 81 fields to a mean dose of 40 +/- 1 Gy (SE), 88% of fields received between 30 and 50 Gy. The equivalent dose was 42 +/- 1 Gy, based on the linear-quadratic model and alpha/beta = 25 (Fowler 1989). Overlapping hyperthermia fields were separated by an interval of at least three days. Up to four heat sessions per week were required to cover the entire tumour in a rotating fashion. The hyperthermia treatment time was 60 min. Hyperthermia treatments were continued for the duration of radiation therapy. Each hyperthermia applicator field was heated at least once. Patients were exposed to a mean of 14 +/- 3 hyperthermia applicator fields (range of 3-46 fields) and a mean of 18 +/- 3 hyperthermia treatments (range of 6-61) delivered over a mean of 7.5 +/- 0.9 weeks (range of 3-17 weeks). Each field was heated an average of 1.3 times. The tumour complete response rate was 95% with a recurrence rate of 5%. Nevertheless, the mean survival of patients with a complete response was only 10.8 +/- 1.7 months (range of 2-28 months) because of the systemic tumour burden existing outside of the treated fields in these patients. Neither complete response, local control nor survival after thermoradiotherapy correlated with the disease free interval between initial mastectomy and recurrence. There was no evidence of increased thermal damage to skin nor evidence of tumour recurrence at junctions of hyperthermia field overlap. It is concluded that recurrent advanced carcinoma of the breast presenting as extensive, diffuse lesions on the chest wall can be treated as effectively with multiple field patchwork thermoradiotherapy as can nodular lesions treated with single hyperthermia fields.

Tumor extracellular pH as a prognostic factor in thermoradiotherapy.

PURPOSE: Tumor extracellular pH measurements in 26 human tumors were evaluated for the purpose of prognostic indication of response to thermoradiotherapy. METHODS AND MATERIALS: Twenty-six patients (10 male, 16 female; mean age 62 years, range 18-89) were treated with external microwave hyperthermia (915 MHz) combined with radiation therapy. Tumor histologies included: 46% adenocarcinoma, 38% squamous cell carcinoma, 12% soft tissue sarcoma, and 4% malignant melanoma. The mean tumor depth was 1.6 +/- 0.2 cm (range 0.4-3 cm) and the mean tumor volume was 73 +/- 11 cm3 (range 1-192 cm3). The mean radiation dose administered concurrently with hyperthermia was 39 +/- 1 Gy (range 24-60 Gy, median of 40 Gy), in 15 fractions (range 8-25), over 32 elapsed days (range 15-43). The mean number of hyperthermia sessions administered was 5.4 +/- 0.5 (range 2-10). A battery operated pH meter and combination 21 ga recessed glass, beveled needle microelectrodes were used for tumor pH measurements. Calibration in pH buffers was performed before and after each pH measurement. The needle microelectrodes were 2.5 cm in length. RESULTS: A complete response (CR) was obtained in 20 of 26 patients (77%) and a partial response in six (23%). The mean extracellular tumor pH was 6.88 +/- 0.09 in CR patients while it was 7.24 +/- 0.09 in noncompletely responding (NCR) patients (p = 0.08). Logistic regression analysis indicated that the probability of obtaining a complete response was influenced by the tumor volume (p = 0.02), tumor depth (p = 0.05), and extracellular tumor pH (p = 0.08). Lesions in the pH range of 6.00-6.40 and lesions in the pH range of 6.41-6.80 exhibited a CR rate of 100%, while those lesions in the pH range of 6.81-7.20 exhibited a CR of 90% and those in the pH range of 7.21-7.52 exhibited a CR of 50% (p = 0.002). In lesions with depth < or = 1.5 cm, the CR rate was 100% when the tumor pH was < 7.15 and 75% when the tumor pH was > or = 7.15. In lesions with depth between 1.5 and 3 cm, the CR rate was 66% when the tumor pH was < 7.15 and 43% when the tumor pH was > or = 7.15 (p = 0.02). In small tumors, that is, < or = 20 cm3, tumor pH increased with volume, whereas in larger tumors, that is, > 20 cm3, tumor pH decreased as a function of tumor volume. CONCLUSION: Tumor extracellular pH may be useful as a prognostic indicator of tumor response to thermoradiotherapy.

Human tumor extracellular pH as a function of blood glucose concentration.

PURPOSE: Mammalian cells are sensitized to hyperthermia when the extracellular pH (pHe) is acutely reduced to < pH 7.0-7.2. However, cells chronically adapted to low pHe may not demonstrate such sensitivity. Although much of the extracellular environment of human tumors is at lower than normal physiological pH, it may be necessary to acutely acidify tumors to cause a change in the therapeutic response to hyperthermia. The purpose of this study was to reduce extracellular pH in human tumors by elevation of blood glucose. METHODS AND MATERIALS: The change in tumor pHe was measured as a function of the change in blood glucose concentration after oral administration of 100 g glucose in 25 fasting, nondiabetic patients. pHe was determined by needle microelectrodes, and blood glucose determined by "Chemstrips" and a glucometer. In some patients blood glucose concentration rose with time after ingestion to a peak change of 50-100 mg/dL between 30-70 min and then began to decrease. In another group of patients glucose concentration increased by 100-200 mg/dL over 30-90 min and remained elevated as if the patients in this group were Type II diabetics. RESULTS: In 14 transient hyperglycemic patients (56%), as blood glucose increased tumor pHe decreased by a mean of -0.17 +/- 0.04 pH units (p < or = 0.0001, range of -0.41-(+)0.07). By contrast in eight persistent hyperglycemic patients, tumor pHe remained unchanged or actually increased an average of 0.03 +/- 0.04 pH units (range of -0.15-(-)0.14). Normal tissue pHe in five patients was unchanged by hyperglycemia, pHe = 7.33 +/- 0.03. Among all patients, 52% exhibited a pHe decrease > or = 0.1 pH unit, and 24% exhibited a pHe decrease > or = 0.2 pH unit. In five transient hyperglycemic patients whose preglucose tumor pHe was between 6.90 and 7.22, the average decrease in pHe induced by hyperglycemia was 0.25 +/- 0.05 pH unit. A linear relationship was observed between the change of pHe and the maximum change in blood glucose such that the greatest decrease in tumor pHe occurred when the glucose change was minimal. The slope was 0.0017 +/- 0.0005 pH units/mg/dL glucose (p < or = 0.005). The linear relationship included both tumors in transient hyperglycemic patients and in persistent hyperglycemia patients. CONCLUSION: Since patients who exhibited the lowest change in blood glucose exhibited the greatest decrease in tumor pHe, it may be that cells in these patients were better able to transport glucose intracellularly which in tumor cells would permit a more rapid production of lactic acid from aerobic and/or anaerobic glycolysis. These data may be helpful in predicting the response of individual patients to oral hyperglycemia as a clinical thermosensitizer.

Thermoradiotherapy for superficial tumour deposits in the head and neck.

Tumour deposits in the head and neck region were treated with hyperthermia using 915 MHz external microwave applicators and radiation therapy between 1986 and 1990. The mean (+/- SE) radiation dose was 47 +/- 2 Gy (range 21-77 Gy). All but four patients had failed previous therapy. Mean tumour volume was 40 +/- 10 cm3 (range 0.3-276 cm3). Hyperthermia was administered biweekly in 80% of the patients in 6.0 +/- 0.4 sessions (range 1-10); thermometry involved 3.6 +/- 0.4 catheters (range 1-9) and 5.7 +/- 0.4 sensors (range 1-12) per tumour. Of the 50 lesions evaluable for response, 29 had a complete response (58%), and 20 had a partial response (40%). Lesions were stratified by depth. In tumours considered potentially heatable (i.e. depth < or = 3 cm and lateral dimensions at least 2 cm less than boundary of applicator), the complete response rate was 81% (26/32, 47 +/- 2 Gy, 15 +/- 3 cm3); whereas for patients with tumours deeper than 3 cm, the complete response rate was 17% (3/18, 48 +/- 3 Gy, 110 +/- 21 cm3), p = 0.0001. Among lesions < or = 3 cm depth that exhibited a complete response, six recurred (24%, 5.8 +/- 1.8 months) while 20 lesions were recurrence free at last follow-up of 11.9 +/- 1.2 months). The overall survival of patients with lesions < or = 3 cm depth was 11.5 +/- 1.3 months (range 2.4-32.3 months) while for patients with lesions > 3 cm depth survival was 6.7 +/- 0.9 months (range 2.1-18.6 months), p = 0.01. In superficial lesions with depth < or = 3 cm, multivariate logistic regression analysis indicated that the model best correlating with complete response included radiation dose (p = 0.08) and tumour volume (p = 0.08, model p = 0.004). Multivariate proportional hazard analysis indicated that the model best correlating with duration of local control included tumour depth (p = 0.03) and previous radiation therapy (p = 0.08, model p = 0.006). Twenty-two fields were treated without any skin reactions (39%), 23 evidenced erythema (40%) and eight thermal blistering (14%). Ulceration occurred in 11 treatment fields but in all but one of these cases the ulceration may have been due to tumour breakdown as there was direct invasion of the skin by tumour prior to the initiation of treatment. The maximal skin temperature was the best predictor of morbidity although the correlation was not statistically significant (p = 0.19).

Cancers in multiple primary sites.

Seventy-six patients with multiple primary cancers have been found among 9180 cancer patients admitted to the Center of Oncology & Nuclear Medicine, Okmeydani Hospital, Istanbul, Turkey between 1980 and 1984. Overall incidence of multiple primary cancers (MPC) among all cancer patients was 0.83%. The majority of the patients were male in both MPC and all patients, i.e. 64.5% and 63.1%, respectively. In MPC patients, the great majority of the patients was in the 51-70 years age group (57.9%) at the time of initial cancer diagnosis. Combination of larynx cancer and lung cancer was the most commonly seen combination. It was followed by lip cancer-larynx cancer (6.6%), skin cancer-larynx cancer and skin cancer-lung cancer (5.3%), breast cancer-ovary cancer and breast cancer-endometrium cancer (4%) combinations. Larynx cancer was the most commonly seen multiple primary cancer component in all patients (46%) and in male patients (61.2%). It was followed by lung cancer, i.e. 39.5% in all patients and 55.1% in male patients. In female patients, breast cancer was a component in 63% of the cases. In eleven patients, two cancers were diagnosed concurrently. In other cases, the interval between two cancers varied between 1 month and 30 years. The mean interval was 4.1 +/- 0.6 years (median 3.0 years). In 62% of the cases, the interval between two cancers was shorter than 3 years. Smoking rate was 75.5% in male patients whereas it was only 18.5% in females. In larynx cancer-lung cancer patients, smoking rate was 81.2% and reached 83.3% when lip cancers were included.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological rationale for hyperthermia in cancer treatment (II).

Hyperthermia (HT) has gained a great interest in the past two decades. The nature of hyperthermia-induced cell lethality is quite different from that of radiation-induced killing. The G1-phase of the cell cycle is the most resistant to HT while S-phase cells are quite sensitive. In addition to heat-induced cytotoxicity, HT sensitizes cells to low LET ionizing radiation. The mechanism of heat cytotoxicity is distinct from that of ionizing radiation. Unlike the response to ionizing radiation, heat cytotoxicity is influenced by thermotolerance, low pH and nutritional deprivation, but is independent of acute hypoxia. Also, blood flow influences the heating characteristics of a tumor relative to normal tissue, and vascular collapse may occur after heating. Thermotolerance is a nonheritable resistance to HT induced by exposure to heat and other cytotoxic agents. Thermotolerance develops within 2-3 h during exposure to temperatures less than 43 degrees C. Cells exposed for a brief period to temperatures higher than 43 degrees C are sensitized to exposure to temperatures below 43 degrees C. This is called "stepdown heating, SDH". SDH results from the inhibition of thermotolerance development by exposure to the high temperature. Cells are sensitized to HT damage by acutely lowering pH, and thermotolerance development is reduced at low pH. Reduced pH also enhances thermoradiosensitization. Since much of a tumor population is at low pH, and these tumor cells are very likely to be hypoxic and radioresistant, this offers one of the strongest reasons for combining HT with radiation therapy in the treatment of human tumors. The neovasculature in tumors does not respond to increased temperatures as do blood vessels in normal tissues, and these differences in blood flow may lead to selective tumor heating. HT dramatically enhances the cytotoxicity of the electron affinic radiosensitizers in hypoxic cells. HT sensitizes the cell to many cytotoxic agents and even converts some drugs that are innocuous to highly toxic. HT chemosensitization may occur by an increased reaction rate, increased permeability, or decreased repair. The most promising chemosensitization by HT would seem to be with alkylating agents and cis-platinum since they are enhanced at all elevated temperatures.

Hyperthermia in cancer treatment (I).

In recent years there have been numerous randomized and nonrandomized studies conducted to assess the efficacy of hyperthermia combined with either radiation therapy or chemotherapy especially in the treatment of superficially seated malignant tumors. The major impact of hyperthermia is currently on loco-regional control of tumor. Heat may be directly cytotoxic to tumor cells or inhibit repair of both sublethal and potentially lethal damage after radiation. These effects are augmented by the physiological conditions in tumor which lead to states of acidosis and hypoxia. Blood flow is often impaired in tumor relative to normal tissue, and hyperthermia may lead to a further decrease in blood flow and augment heat-sensitivity. Three major areas of clinical investigation have borne the greatest fruit for hyperthermia as adjunctive therapy to radiation therapy. These include recurrent and primary breast lesions, melanoma, and head and neck neoplasms. Thermal enhancement ratio was increased in all cases and is estimated to be 1.4 for neck nodes, 1.5 for breast and 2 for malignant melanoma. In general, the most important prognostic factors for complete response are radiation dose, tumor size and minimal thermal parameters (minimal thermal dose (t43min), mean minimal temperature (Tmin) or T90, i.e., temperature exceeded by 90% of thermal sensors). The number of heat fractions administered per week appears to have no bearing on the overall response, which may be indicative of the effects of thermotolerance. The total number of heat fractions delivered also appears irrelevant provided adequate heat is delivered in one or two sessions. The major prognostic factors for the duration of local control are tumor histology, concurrent radiation therapy, dose, tumor depth and Tmin.

Prognostic factors in bilateral breast cancer.

Twenty-nine bilateral breast carcinoma patients were analyzed retrospectively. The incidence of bilateral carcinoma of the breast among unilateral breast cancer patients was approximately 2.4%. Median age was 46 years at the time of first cancer diagnosis (range 26-69 years). The majority of the lesions were invasive ductal carcinoma (86%). Of 58 tumors, 10 were staged as Stage I (17%), 30 as Stage II (52%), 8 as Stage III (14%) and 10 as Stage IV (17%). Patients were treated with various combinations of surgery, radiation treatment and chemotherapy. Of 29 patients with bilateral breast cancer, 5 presented with simultaneous bilateral disease (17%), 7 (24%) with synchronous tumors whereas 17 (59%) developed asynchronous tumors. The mean interval between two cancers was 2.6 +/- 0.6 years. Overall survival was 4.8 +/- 0.7 years and overall 5-year actuarial survival was calculated to be 51%. Age, menopausal status and tumor size at the time of initial cancer correlated with the time interval between two cancers. Age, tumor size and nodal status at the time of initial cancer and the time interval between two cancers correlated with the overall survival.