Safety and efficacy of transdermal fentanyl in patients with cancer pain: phase IV, Turkish oncology group trial.

We have performed a prospective evaluation of the efficacy, safety and convenience of the transdermal therapeutic system - fentanyl (TTS-F) in Turkish cancer patients when it was newly available in Turkey. Ninety-nine patients with historically confirmed malignancy and pain entered the study; the mean age was 55.1 (16-58) years. The study duration was 28 days. Transdermal therapeutic system - fentanyl was used in opioid-naïve or pre-treated patients. Most patients reported a decrease in pain severity. Use of rescue medication decreased from day 4 to day 28. The majority of patients rated patch convenience of use as excellent. A total of 22.2% of patients experienced adverse events that were either probably related or very likely to be related to the study drug. The majority of the adverse events mentioned were related to the digestive system. Eighteen serious adverse events were reported by 13 patients. Six events were doubtfully related, and 12 events were not related to the study drug. Four patients died during the trial. None of these deaths was attributed to the study drug. In conclusion, the trial showed that TTS-F is easily managed, effective and will help to enable the appropriate opioid administration to patients who are suffering from cancer pain in Turkey.

Effect of ticlopidine in the prevention of radiation enteropathy.

Impairment of vascular function is considered to play an important role in chronic radiation enteropathy. In this experimental study, the role of ticlopidine, an inhibitor of ADP-induced platelet aggregation, was investigated in radiation enteropathy. 80 male Wistar albino rats, each weighing 170-200 g, were divided into four groups: (a) radiation alone (n = 20); (b) radiotherapy plus ticlopidine (n = 20); (c) ticlopidine control (n = 20) and (d) control (n = 20). Both radiation groups received 19 Gy radiation to the exteriorized intestinal segments in a single fraction. Ticlopidine or vehicle was administered 12 h after radiotherapy and continued for 1 month. Rats from every group were euthanized randomly at intervals of 6 weeks from 2 weeks to 26 weeks. Histopathological radiation injury was assessed using radiation injury scoring (RIS). Radiation with ticlopidine or radiation alone groups showed significant RIS deterioration compared with controls in all time points studied. Comparison of median RIS of radiotherapy and radiotherapy+ticlopidine groups at the 2nd, 14th and 26th weeks yielded statistically significant RIS in favour of radiotherapy+ticlopidine group (p = 0.05). However, these differences were less pronounced at the 8th and 20th week (p = 0.07). Both radiation groups had poor weight gain when compared with control and ticlopidine groups. The weight gain in radiotherapy+ticlopidine group was significantly superior to only radiation group between 10th and 20th weeks (p = 0.05). This study showed that inhibition of platelet aggregation with ticlopidine might be useful in radiation enteropathy. However, the precise role of antiaggregant therapies on radiation enteropathy should be comprehensively studied before clinical consideration.

Benefit of high-dose methylprednisolone in comparison with conventional-dose prednisolone during remission induction therapy in childhood acute lymphoblastic leukemia for long-term follow-up.

Eight-year event-free survival (EFS) was evaluated in 205 patients with acute lymphoblastic leukemia (ALL), to consider the efficacy of high-dose methylprednisolone (HDMP) given during remission induction chemotherapy between 1 and 29 days. The St Jude Total XI Study protocol was used after some minor modifications in this trial. Patients were randomized into two groups. Group A (n = 108) received conventional dose (60 mg/m(2)/day orally) prednisolone and group B (n = 97) received HDMP (Prednol-L, 900-600 mg/m(2) orally) during remission induction chemotherapy. Complete remission was obtained in 95% of the 205 patients who were followed-up for 11 years; median follow-up was 72 months (range 60-129) and 8-year EFS rate was 60% overall (53% in group A, 66% in group B). The EFS rate of group B was significantly higher than of group A (P = 0.05). The 8-year EFS rate of groups A and B in the high-risk groups was 39% vs 63% (P = 0.002). When we compared 8-year EFS rate in groups A and B in the high-risk subgroup for both ages together /=10 years, it was 44% vs 74%, respectively. Among patients in the high-risk subgroup with a WBC count >/=50 x 10(9)/l, the 8-year EFS was 38% in group A vs58% in group B. During the 11-year follow-up period, a total of 64 relapses occurred in 205 patients. In group A relapses were higher (39%) than in group B (23%) (P = 0.05). These results suggest that HDMP during remission-induction chemotherapy improves the EFS rate significantly for high-risk patients in terms of the chances of cure.

Impact of radiotherapy on normal brain tissue: semi-automated quantification of decrease in perfusion.

PURPOSE: We attempted to ascertain the impact of Co-60 conventional external radiotherapy (cRT) on the perfusion of normal brain tissue in relation to the radiation doses delivered to the tumors in patients with primary brain tumors. MATERIALS AND METHODS: After surgery 18 patients (pts) were due to undergo cRT with a total dose of 5400- 6400 cGy. All the patients had a Tc-99m-HMPAO SPECT study prior to cRT (basal), 15th and 30th days of cRT as well as 1 (in 6 pts), 3 (in 9 pts), and 6 (in 3 pts) months after cRT. For quantitative evaluation, the entire set of transverse slices were divided into 4 regions as frontal, parietal, occipital and temporal regions by means of a computer software program. Semi-automated quantification was performed on a total of 1392 regions in 87 studies to determine left to right ratios. An interregional difference of at least 10% was considered abnormal. RESULTS: After elimination of tumor sites, 80 normal brain regions showed decreased perfusion after cRT. The percent decrease in perfusion was (mean 22.5+/-9.9) significantly higher in areas irradiated with doses > 3000 cGy (p < 0.05). CONCLUSION: cRT has adverse effects on the perfusion of normal brain tissue for doses > 500 cGy. Our findings justify treating patients with small and limited lesions with stereotactic radiotherapy in order to minimize the adverse effects of cRT on normal tissues.

Radiotherapy in the management of giant pituitary adenomas.

BACKGROUND AND PURPOSE: The description of giant pituitary adenoma is not clear yet. In this study we tried to identify which adenomas can be defined as giant pituitary adenomas when tumor control and progression free survival (PFS) are taken as end points and we also tried to evaluate prognostic factors other than tumor size. MATERIALS AND METHODS: Between January 1981 and December 1997, 74 patients with pituitary macroadenomas more than 2 cm in size were treated. Of these 30 had tumors of more than 4 cm, while 44 patients were with tumors of 2-4 cm. Two patients received primary radiotherapy, while 72 were treated postoperatively. In the postoperative group, 52 patients underwent immediate radiotherapy after surgery and 20 were treated with irradiation after regrowth or progression of the tumor after initial surgery. The mean and median tumor doses were 5518 and 5425 cGy, respectively. RESULTS: Overall primary tumor control rate was 84%. The local control rates among patients with tumors more than 4 cm and among patients with tumors 2-4 cm after radiotherapy were 73 and 91%, respectively. PFS was 65% for patients who had a tumor size of more than 4 cm and 87% for the patients with tumor size of 2-4 cm (P = 0.09). Young age (<20) and tumors of unclassified histology were the bad prognostic factors. Six months after radiotherapy normalisation or improvement in hormonal hypersecretion and visual field and acuity deficits were 82 and 63%, respectively. CONCLUSION: Tumors more than 4 cm in size may be more convenient for the definition of 'giant pituitary adenoma' when tumor control and PFS are taken as the end points.

Extrahepatic Hodgkin's disease with intrahepatic cholestasis: report of two cases.

Liver is involved in about 5-8% of newly diagnosed Hodgkin's disease (HD) cases. The incidence reaches up to 50-60% in postmortem studies. In the literature only a few cases of idiopathic cholestatic jaundice have been described without an apparent cause and a paraneoplastic etiology has been suggested. We report 2 cases with HD presenting with obstructive jaundice without obvious liver involvement. The first case died soon after diagnosis; the second case received chemotherapy and radiotherapy, and she is well at 26 months' follow-up. Extrahepatic HD with intrahepatic cholestasis is an extremely rare situation without an established approach. Such cases like the present ones may help to understand the pathogenesis of the liver involvement of HD and determine the best management of these cases.

Hodgkin's disease in Turkish children: clinical characteristics and treatment results of 210 patients.

Although Hodgkin's disease (HD) is one of the common malignancies in childhood, there is limited information from developing countries in English literature. The aim of this study is to give epidemiologic features and treatment results of 210 previously untreated children with HD from a developing country. Between 1 June 1984 and 31 December 1992, all children seen who were younger than 18 years old with newly diagnosed, untreated, biopsy-proven Hodgkin's disease were included in this study. A clinical staging system was used to determine the dissemination of the disease. While patients with stage I-II disease received canapé treatment protocol (three cycles COPP [cyclophosphamide, vincristine, procarbazine, prednisolone] or ABVD [doxorubicin, bleomycine, vinblastine, dacarbazine] plus low-dose involved-field radiotherapy), patients with stage III-IV disease were treated by sandwich protocol (six cycles COPP plus low-dose involved-field radiotherapy). A total of 210 patients with a median age of 8 years were eligible for this study. Male to female ratio was 3:1 and 37 (17.6%) were less than 5 years of age. The major histologic subtype was mixed cellularity (69.6%). Overall survival rates were 91.5 and 87.7%, and event-free survival rates were 71.5 and 70.5% at 5 and 10 years, respectively. No secondary malignancy has been observed so far. The prevalence of Hodgkin's disease in young children is higher and the distribution of histologic subtypes is also different from many Western countries. Canapé and sandwich treatment protocols could be used safely in clinically staged childhood HD with tolerable toxicity.

Reduced incidence of the somnolence syndrome after prophylactic cranial irradiation in children with acute lymphoblastic leukemia.

A prospective double blind randomized trial comparing two different dose schedules of continuous steroid coverage during prophylactic cranial radiotherapy (CRT) in leukemic children was conducted to find out the optimum dose to be prescribed to reduce the incidence of Somnolence Syndrome (SS). Between April 1994 and February 1996, 32 patients with acute lymphoblastic leukemia received CRT of 18 Gy in 10 fractions. Patients were randomized to receive oral dexamethasone of 2 or 4 mg/m2 during radiotherapy. The diagnosis of SS was made clinically based on symptoms of somnolence. All patients were followed for a minimum of 8 months. The overall incidence of SS was 40%. The development of SS was steroid dose dependent. In low dose steroid arm the incidence of SS was 64.3% (9/14), compared to 17.6% (3/17) in high dose arm with statistically significant difference (P = 0.008). The median time to development of SS was 4 weeks. The most common symptom of SS was drowsiness followed by anorexia, headache, nausea, vomiting, decreased activity, irritability, fever and ataxia, respectively. The duration of symptoms ranged from 2 to 14 days. The development of SS was not related to the presence of acute reactions, age at the time of CRT and sex. In all cases the symptoms subsided completely and spontaneously. Our results suggest that steroid coverage at a dose of 4 mg/m2 during CRT reduces the incidence of SS. However, a multicentric prospective randomized trial is needed to determine the role and the optimal dose of steroid.

A comparison of the effect of high-dose methylprednisolone with conventional-dose prednisolone in acute lymphoblastic leukemia patients with randomization.

In this preliminary study the efficacy of high-dose methylprednisolone (HDMP) during remission-induction chemotherapy was evaluated on 166 children with acute lymphoblastic leukemia (ALL). The St. Jude Total Therapy Study XI protocol with minor modifications was used in this trial. Patients were randomized into two groups. Group A received conventional-dose (2 mg/kg/day orally) prednisolone, and group B received high-dose methylprednisolone (HDMP, Prednol-L, 900-600 mg/m2 orally) during remission-induction chemotherapy. Complete remission was achieved in 97% of the children. For the 80 patients who were followed up for 3 years, median follow-up was 44 (range 5-60) months and the 3-year event-free survival (EFS) rate was 68.5%) overall, 58.6% in group A and 78.4% in group B. The EFS among patients in group B was significantly higher than in group A (p=0.05). When we compared the 3-year EFS of groups A and B in the high-risk groups and high-risk subgroups with white blood cell (WBC) counts > or = 50 x 10(9)/l and age > or = 10 years, the survival rates were 45% versus 77.2%, 33% versus 78% and 45% versus 89%, respectively. During the follow-up of 162 patients, relapses were significantly higher in group A. Bone marrow relapses in 162 patients, and also in a subgroup of patients > or = 10 years of age were significantly higher in group A. These results suggest that HDMP during remission-induction chemotherapy improves long-term EFS, particularly for high-risk patients.

Turkish experience with rhabdomyosarcoma: an analysis of 255 patients for 20 years.

Two hundred and fifty-five previously untreated patients (pts) with rhabdomyosarcoma (RMS) (age range 15 days to 17 years, median 5 years) were evaluated and treated in our institution. Head and neck primaries were seen in 125 patients (49%), abdominopelvic in 73 (29%), trunk and lung in 20 (5%) and extremity lesions in 37 (15%). The histology was: embryonal 137; alveolar 42; botryoid 18; pleomorphic 14. Forty-four patients could not be subclassified. The stage of the patients were as follows: 15 in state I, 74 in stage II, 139 in stage III and 27 in stage IV, according to the IRS grouping system. Patients were treated with a combination of surgery and radiation to doses of 35-55 Gy according to the patient's age and stage. All the patients received chemotherapy according to VAC or pulse-VAC (before 1988) and modified AVAC (after 1988) protocol. Survival curves were calculated by the Kaplan-Meier method. The statistical significance of each variable was tested by the log-rank test. Overall survival was 42 percent at 10 years. Three important predictors for survival time were clinical group (p < 0.001), age (p < 0.001) and primary site (p = 0.005). The best results involved clinical group I-II, age one to five years and orbital and genitourinary primary sites. An important predictor of survival time was also detected between those treated during the first ten years (1972-82) and last 10 years (1982-92), p < 0.005. Of the 96 deaths, 37 were from progressive disease, 24 from infection, 4 during postoperative period (first 7 days), 18 from unknown causes and 13 from other causes.

Monitoring response to therapy with thallium-201 and technetium-99m-sestamibi SPECT in nasopharyngeal carcinoma.

UNLABELLED: This study prospectively assessed the value of 201Tl and 99mTc-sestamibi (MIBI) SPECT in monitoring disease regression/progression as compared with MRI findings in patients with nasopharyngeal carcinoma (NPC) having radiotherapy with or without chemotherapy. METHODS: Eighteen patients (age range 15-78 yr, mean 45 yr) had consecutive SPECT imaging using a dual-head gamma camera after the injection of 111 MBq 201Tl and 555 MBq MIBI before therapy and at 3 mo and 6 mo after completion of therapy. A total of 106 SPECT studies was correlated with contemporaneous MRI studies. Tumor-to-background ratios were obtained on coronal slices. Visually detectable lesions in the region of the nasopharynx and cervical lymph nodes were considered positive for residual disease. The gold standard for the presence of disease was the combination of repeat MRI scans, endoscopic examination and clinical evaluation performed 12-15 mo after completion of therapy. RESULTS: MIBI-SPECT proved superior to both 201Tl SPECT and MRI after 3 or 6 mo follow-up in predicting complete response. Accuracy rates in the detection of residual disease in the nasopharynx are 39%, 72% and 89% for MRI, 201Tl and MIBI, respectively, for the 3-mo evaluation; 71%, 71% and 94% for MRI, 201Tl and MIBI, respectively, for the 6-mo evaluation. CONCLUSION: MIBI SPECT could be used as a screening test in predicting response to therapy in patients with NPC.

A comparative study of technetium-99m sestamibi and technetium-99m tetrofosmin single-photon tomography in the detection of nasopharyngeal carcinoma.

The intention of this prospective study was to compare the diagnostic potential of technetium-99m sestamibi (MIBI) and a novel radiotracer, 99mTc-Tetrofosmin (Tetro), for the assessment of primary nasopharyngeal carcinoma (NPC) and the differentiation of residual disease from post-therapy changes. A total of 38 patients underwent MIBI and Tetro single-photon emission tomography (SPET) imaging at initial presentation (n=22) or following therapy (n=16). The findings were correlated with computed tomography or magnetic resonance imaging (MRI) on a site-by-site basis. Tumour/background (Tm/Bkg) ratios were obtained on coronal sections. Biopsy (nine patients) and/or 12- to 24-month clinical follow-up data were available in the post-therapy group. All primary disease sites were accurately detected by both imaging studies. Although there was no statistical difference between the two imaging techniques in the detection of primary disease, MIBI was superior to Tetro in the detection of regional lymph node metastases (sensitivity: 95% vs 79%). Tetro and MIBI SPET were true-positive in all patients (n=7) with proven residual/recurrent disease. In nine patients who had no evidence of residual/recurrent tumour, MRI was false-positive in five while Tetro and MIBI SPET were false-positive in two and three patients, respectively. Tm/Bkg ratios were

High-dose methylprednisolone for children with acute lymphoblastic leukemia and unfavorable presenting features.

In an attempt to improve treatment outcome high-dose methylprednisolone (HDMP, 20-30 mg/kg, once a day orally) was used instead of a conventional dose of steroid (2 mg/kg/d, in 3 divided doses) in children with acute lymphoblastic leukemia (ALL) with increased risk factors. HDMP combined with cytotoxic agents (vincristine and L-asparaginase) resulted in an improved complete remission rate (94%) in 48 newly diagnosed children with ALL compared to 81% in 86 historical controls receiving standard dose steroid combined with the same treatment regimen. The bone marrow relapse rate was lower in patients who received HDMP (31%) than in controls (56%). Treatment was discontinued in 56% of 48 patients receiving HDMP and in 35% of 86 controls. The difference was significant (p < 0.05). The 5-yr continuous complete remission rate was significantly greater in patients received HDMP compared with the control patients (60% vs. 43%, p < 0.05). HDMP treatment was well tolerated without significant adverse effects. Moreover, during induction therapy the duration of leukopenia (< 2 x 10(9)/L) was shorter in patients receiving HDMP. We conclude that HDMP combined with other antileukemic agents increased the CR rate and prolonged the duration of remission in children with ALL who had increased risk factors. However, the optimal dosage of HDMP and its role in maintenance therapy should be determined in future, randomized studies.

Double-phase Tc-99m-SestaMIBI SPECT imaging in a case of glomus jugulare tumor.

We performed a double-phase Tc-99m-SestaMIBI SPECT study on a patient who presented with a mass located at the skull base. The results were compared with double-phase T1-201 SPECT study. Early phase (30 min) SPECT images of both radiopharmaceuticals demonstrated increased radiotracer uptake in the region of the tumor. However, late images (180 min) revealed rapid wash-out of Tc-99m-SestaMIBI from the tumor, suggestive of a benign vascular tumor, while T1-201 images showed slower wash-out. Tc-99m-SestaMIBI SPECT findings were also confirmed by carotid angiography and biopsy, while a contemporaneous MRI scan was inconclusive in differentiating benign from malignant tumor. Initial and one-year follow-up whole body CT scans were negative for any metastatic sites, supporting the diagnosis of benign glomus jugulare tumor.

Pre- and post-therapy thallium-201 and technetium-99m-sestamibi SPECT in nasopharyngeal carcinoma.

UNLABELLED: We prospectively studied the diagnostic potential of 201Tl and 99mTc-sestamibi (MIBI) SPECT for evaluating the extent of primary disease and differentiating residual/recurrent disease from post-therapy changes in patients with nasopharyngeal carcinoma (NPC). METHODS: Fifty patients (20 initial presentation, 30 post-therapy evaluation) underwent 201Tl and MIBI imaging. The findings were correlated with CT/MRI results. Tumor-to-background ratios were obtained. Biopsy confirmation (14 patients) and/or 6-12 mo clinical follow-up data (16 patients) were available in the post-therapy group. RESULTS: All primary disease sites were accurately detected by both imaging studies in the pretherapy group. However, MIBI-SPECT was superior to 201Tl SPECT (p = 0.0057) in detecting regional metastases (sensitivities of 95% versus 68%). In the post-therapy group, MIBI and 201Tl imaging were true-positive in 14 of 16 patients with proven residual/recurrent. In 17 patients who had no evidence of residual/recurrent tumor. CT/MRI was false-positive in 13 when MIBI and 201Tl imaging were true-negative in 10 and false positive in 3. MIBI, 201Tl and CT/MRI had sensitivities of 87.5%, 87.5%, 100%, specificities of 82.4%, 76.5%, 23.5% and accuracies of 85%, 82%, 61%, respectively. Tumor-to-background ratios were < or = 1.5 in all false-positive cases except one. CONCLUSION: MIBI-SPECT proves more accurate than 201Tl SPECT in detecting regional metastases at initial presentation. MIBI and 201Tl imaging have higher specificity and accuracy than CT/MRI and MIBI-SPECT is slightly more specific than 201Tl SPECT in differentiating residual/ recurrent disease from post-therapy changes in patients with NPC.

Influence of immediate post-therapy bone scintigraphy in the assessment of response to therapy in a case of nasopharyngeal carcinoma.

A patient with undifferentiated stage IV (T3N3M0) nasopharyngeal carcinoma (WHO type III) underwent pre- and one-month post-therapy bone scintigraphy as part of an ongoing trial combining scintigraphic and radiographic modalities. The patient had advanced disease in the nasopharynx and bulky cervical lymph nodes at presentation. Initial bone scintigraphy performed 10 days prior to therapy was negative for bone metastases. Immediately after concomitant chemoradiotherapy, bone scintigraphy revealed distant metastases, whereas clinical assessment of disease disclosed complete response to therapy in the nasopharynx and cervical lymph nodes. The scintigraphic findings were also confirmed by a subsequent MRI scan of the corresponding regions.

Solitary phalanx plasmacytoma relapse with disseminated extramedullary plasmacytomas and myeloma after short duration of remission.

Solitary bone plasmacytomas account for 5-7% of multiple myeloma cases and are assumed to have a fairly good prognosis, with a long duration of relapse-free survival after primary local treatment. Isolated phalanx plasmacytoma is a very rare entity, because involvement of extremities is seen in less than 1% of all solitary bone plasmacytomas, where they are usually localized centripedally, often in the axial skeleton. A 68 year old patient with a lytic lesion involving 5th phalanx was diagnosed as having a biopsy-proven solitary plasmacytoma, with a negative work-up for coexisting plasma cell dyscrasia. Three and a half months after completion of radiotherapy of the involved phalanx, the patient was readmitted with hypercalcemia, renal insufficiency and subsequently diagnosed as having atypical plasma cell infiltration of marrow, and plasmacytomas involving the right vocal cord and the premaxillary region, as well as pathological ulna fracture. Plasmacytoma of the phalanx, with extreme short duration of remission and an aggressive type of clinical relapse, is in sharp contrast with the natural stable course of a solitary plasmacytoma where the use of systemic treatment is subject to intense debate.