Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial.

PURPOSE: Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkin's lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied. PATIENTS AND METHODS: Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 × 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP(baseline)) + 30 Gy of IFRT; or four cycles of BEACOPP(baseline) + 20 Gy of IFRT. RESULTS: With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPP(baseline) was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPP(baseline) and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, -3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPP(baseline), 20 Gy was not inferior to 30 Gy (5-year FFTF difference, -0.8%; 95% CI, -5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, -4.7%; 95% CI, -10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy. CONCLUSION: Moderate dose escalation using BEACOPP(baseline) did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.

Chemoradiotherapy with weekly cisplatin 40 mg/m(2) in 103 head-and-neck cancer patients: a cumulative dose-effect analysis.

BACKGROUND AND PURPOSE: In patients with head-and-neck cancer treated with chemoradiotherapy (CRT), a cisplatin-based regimen is often used. Several treatment schedules are accepted with a cumulative cisplatin dose of 200 mg/m(2) (CisCD200) given during radiotherapy. The aim of this analysis was to investigate feasibility and efficacy of a weekly cisplatin 40 mg/m(2) regimen. PATIENTS AND METHODS: During 08/2001 and 12/2006, 103 patients with squamous head-and-neck cancer received concurrent CRT with intended weekly cisplatin 40 mg/m(2) and were analyzed retrospectively. CRT was definitive for a newly diagnosed primary in 62, postoperative in 16, and for recurrence in 25 patients. Most patients had carcinoma of the hypo- and oropharynx (81%). Patients received a median total dose of 70 Gy (range, 42-71.2 Gy). RESULTS: Only 42 patients (41%) received a CisCD200 predominantly due to hematotoxicity. Actuarial 12- and 18-month overall survival (OS) for patients with and without CisCD200 was 83.3% versus 72.1% (p = 0.19) and 66.7% versus 67.2% (p = 0.86), the 12- and 18-month locoregional control (LRC) 66.7% versus 78.7% (p = 0.325) and 59.5% versus 78.7% (p = 0.109), respectively. Multivariate analysis revealed only type of CRT (definitive vs. recurrent) and T-classification as significant variables predicting OS and LRC. CONCLUSION: Feasibility and efficacy of CRT with weekly cisplatin 40 mg/m2 were suboptimal in this analysis. However, the prospects of weekly cisplatin may be its more suitable integration into emerging trimodality concepts combining CRT with molecularly targeted agents.

Anal cancer treated with radio-chemotherapy: correlation between length of treatment interruption and outcome.

AIM: The purpose of this study was the evaluation of the feasibility and outcome of definitive radio-chemotherapy without split-course technique but with individualised short treatment interruption in anal cancer patients. METHOD: Between 1993 and 2008, 101 patients with anal cancer were treated in our institution with definitive radio-chemotherapy with individualised short treatment interruptions. Treatment was halted independent of dose in case of acute grade 3 toxicities and started again until improvement. Short interruption was defined as completing treatment without exceeding six cumulative treatment days beyond a scheduled plan; otherwise, it was defined as prolonged interruption. RESULTS: Median overall treatment time was 47 days corresponding to an interruption of six cumulative treatment days. Fifty-one patients (50%) had treatment interruption of

Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics.

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.

ATM missense variant P1054R predisposes to prostate cancer.

BACKGROUND: Prostate cancer is associated with defective DNA strand break repair after DNA damage leading to genetic instability and prostate cancer progression. The ATM (ataxia-telangiectasia mutated) gene product is known to play an important role in cell cycle regulation and maintenance of genomic integrity. We investigated whether the prevalence of the ATM missense substitution P1054R is increased in a hospital-based series of prostate cancer patients and whether carriers are at increased risk for treatment-related side effects. MATERIALS AND METHODS: A consecutive series of 261 patients treated for early-stage prostate cancer with I-125 brachytherapy (permanent seed implantation) between 10/2000 and 04/2006 at our institution and a comparison group of 460 male control individuals were screened for the presence of the P1054R variant. Outcome of therapy regarding morbidity was assessed prospectively and compared between carriers vs. non-carriers with the International Prostate Symptom Score (IPSS), a Quality-of-Life-index (QoL) and the International Index of Erectile Function (IIEF-15) with its subgroups (IIEF-5 and EF). RESULTS: The proportion of carriers of the P1054R variant was significantly higher among prostate cancer patients than in the general population (25 out of 261 vs. 22 out of 460; OR 2.1; 95% CI 1.2-3.8, p<0.01). A subgroup of the carriers additionally harboured the ATM missense variant F858L that was associated with a similar risk (OR=2.2; 95% CI 1.1-4.6; p=0.03). After a mean follow-up of 18 months there were no statistically significant differences regarding IPSS (p=0.48), QoL (p=0.61), IIEF-15 score (p=0.78), IIEF-5 score (p=0.83), and EF score (p=0.80), respectively. CONCLUSIONS: The ATM missense variant P1054R confers an about twofold increased risk for prostate cancer in our series. The subgroup of patients with the second-site variant F858L is not at significantly higher risk. After 18 months, there was no evidence for an increased adverse radiotherapy response in P1054R carriers.

[Inaccuracy in the acquisition of glowcurves with the TL-Reader Harshaw 5500]. / Ungenauigkeit bei der Glühkurvenakquisition mit dem TL-Reader Harshaw 5500.

Putting into operation a TL Reader Type Harshaw 5500 revealed some inaccuracies in the acquisition of glowcurves, i.e., a shift of the glowcurves upon exposure to different temperatures in sequential measurements. These inaccuracies hinder a precise analysis of parts of the glowcurves with easy methods. The present investigation focused on the analysis of possible causes for these observations. It was found out that one requirement for a reproducible data acquisition is the stability and precise positioning of the thermoluminescence dosimeter in the heating position. These conditions allow constant heating and therefore a stable glowcurve concerning the temperature. The accuracy of glowcurve acquisition could be clearly improved with mechanical changes of the TL Reader. Long-term observations are still required.

Role of radiotherapy in the treatment of motor dysfunction due to metastatic spinal cord compression: comparison of three different fractionation schedules.

PURPOSE: The optimum fractionation schedule for radiotherapy (RT) of metastatic spinal cord compression (MSCC) is still debated in the literature. Several reports have compared different fractionation schedules for pain relief. To our knowledge, this retrospective analysis is the first to compare three different schedules for functional outcome. METHODS AND MATERIALS: For posttreatment functional and ambulatory outcome, three schedules, 30 Gy in 10 fractions (n = 93), 37.5 Gy in 15 fractions (n = 80), and 40 Gy in 20 fractions (n = 74), were compared. Motor function was evaluated by a 6-point scale before and at the end of RT and 3, 6, and 12 months later. A multivariate analysis was performed for functional outcome, including fractionation schedule and the three relevant prognostic factors (primary tumor type, time of developing motor deficits before RT, and ambulatory status). RESULTS: No significant difference was observed for posttreatment motor function or ambulatory rates among the three schedules. According to the multivariate analysis, the radiation schedule had no significant impact on functional outcome (p = 0.223) in contrast to the three prognostic factors (p <0.001, p <0.001, and p = 0.012). CONCLUSION: The three fractionation schedules were comparable for functional outcome. The least time-consuming schedule (30 Gy in 10 fractions) should be considered for patients with a markedly reduced life expectancy.

A comparison of two different radiation schedules for metastatic spinal cord compression considering a new prognostic factor.

BACKGROUND: Patients with metastatic spinal cord compression are often presented for emergency radiotherapy. The optimum radiotherapeutic regimen is still debated, studies comparing different radiation schedules on therapeutic outcome are scarce. This analysis compares the effect of two schedules on motor function considering three relevant prognostic factors (type of primary tumor, pre-treatment ambulatory status, time of developing motor deficits before radiotherapy). PATIENTS AND METHODS: In this retrospective analysis, two radiation schedules, 30 Gy/10 fractions (n=78) and 37.5 Gy/15 fractions (n = 75), applied due to motor deficits caused by metastatic spinal cord compression, were compared for post-treatment functional outcome and ambulatory status. Response and ambulatory status were evaluated directly, 3, 6 and 12 months after radiotherapy. For functional outcome a multivariate analysis including radiation schedule and the relevant prognostic factors was performed. RESULTS: Between the two radiation schedules no significant difference was observed for post-treatment ambulatory rates (p values: 0.450-0.888) and for functional outcome (p values: 0.940-0.999). According to the multivariate analysis, the strongest predictors for functional outcome were the time of developing motor deficits before radiotherapy (p < 0.001) and the pre-treatment ambulatory status (p < 0.001), followed by the type of primary tumor (p = 0.058). For the radiation schedule a significant impact on functional outcome was not observed (p = 0.822). CONCLUSIONS: The two radiation schedules were comparable for functional outcome. The less time consuming schedule (30 Gy/10 fractions) can be recommended in metastatic spinal cord compression, as life expectancy is markedly reduced in the majority of these patients.

[The value of radiotherapy in treatment of meningeal melanocytoma]. / Stellenwert der Strahlentherapie bei der Behandlung des meningealen Melanozytoms.

BACKGROUND: Meningeal melanocytoma is described as rare benign lesion with a high risk of recurrence. There are no well-substantiated treatment recommendations in the literature. Only case reports have been published by now. PATIENTS AND METHODS: In 1997 a patient was irradiated for a recurrent spinal meningeal melanocytoma and 2 years later for brain metastases indicating malignant transformation. This case gave rise to a literature review for therapeutic options. All sufficiently documented cases published since 1972, when the term meningeal melanocytoma was established, were evaluated. Based on published and on original data recurrence and overall survival rates up to 5 years were calculated for three different therapeutic approaches, namely complete tumor resection, incomplete resection with subsequent radiotherapy, and incomplete resection alone. Statistical evaluation was performed using the chi 2 test and Kaplan-Meier-analysis. RESULTS: 53 patients (including our patient) met selection criteria. Complete tumor resection was superior to incomplete resection alone with lower recurrence (4-38% versus 50-92%) and better overall survival rates (86-95% versus 30-58%). After incomplete resection radiotherapy seemed to improve prognosis (recurrence 15-45%; overall survival 91-92%). Between complete resection and incomplete resection plus radiotherapy no significant differences were observed. CONCLUSIONS: For meningeal melanocytoma complete resection must be regarded as the best of the modalities compared. After incomplete resection radiotherapy should be considered, although a specific radiotherapeutic regimen cannot be recommended at present. However, for multiple cranial or spinal lesions total cranial irradiation or craniospinal irradiation is indicated.

Falsely low serum prolactin in two cases of invasive macroprolactinoma.

The differential diagnosis of tumors at the base of the skull comprises meningiomas, neurinomas, gliomas, metastatic carcinomas, chordomas, epidermoids, and pituitary adenomas. About half of the pituitary adenomas are prolactinomas which are unique in a sense that medical therapy causes rapid tumor shrinkage and symptomatic improvement. We report on two patients in which the diagnosis of an invasive macroprolactinoma was masked by apparently low prolactin levels caused by a high-dose hook effect in the chemiluminometric assay. The first case a 49 year old male with impairment of hearing on the left side was presented in the Department of Otorhinolaryngology. A massive invasively growing tumor was demonstrated on a cranial MRI. Endocrine tests revealed normal pituitary function and normoprolactinemia. The patient underwent debulking surgery, occipitocervical fusion because of destruction of the first cervical vertebra and subsequent irradiation. The histopathological diagnosis was invasive prolactinoma. A repeat prolactin (PRL) sample, which was assayed using serial dilutions, revealed a real PRL level of 89,700 ng/ml. Dopamine agonist therapy was initiated under which PRL levels declined in parallel with tumor size. The second case a 40 year old male was presented with acute visual loss. Cranial MRI showed a large tumor at the base of the skull. Based on a transnasal biopsy, the preliminary diagnosis was a poorly differentiated carcinoma for which emergency irradiation was performed. Endocrine tests demonstrated partial hypopituitarism and moderate hyperprolactinemia. Hydrocortisone was substituted and dopamine agonist therapy was started because of moderate hyperprolactinemia. The final histopathological diagnosis was invasive prolactinoma. A repeat PRL sample assayed in serial dilution demonstrated an apparent rise in PRL with a maximum value of 6,460 ng/ml. Under dopamine agonist therapy, PRL declined to normal values, tumor size decreased and cranial nerve palsies disappeared. The apparently falsely low prolactin levels in the initial work-up of both patients were caused by a high-dose hook effect in the PRL assay. Serial dilutions of serum PRL samples is, therefore, mandatory in the diagnostic work-up of patients with large invasive tumors at the base of the skull. This avoids unnecessary aggressive and dangerous treatment like surgery or radiotherapy in cases where pharmacological treatment may be the choice.