TPF plus cetuximab induction chemotherapy followed by biochemoradiation with weekly cetuximab plus weekly cisplatin or carboplatin: a randomized phase II EORTC trial.

BACKGROUND: Our aim was to test the safety of cetuximab added to chemoradiation with either cisplatin or carboplatin after prior induction chemotherapy. METHODS: Patients with stage III/IV unresectable, squamous cell carcinoma of the head and neck received up to four cycles of TPF-E (cisplatin and docetaxel 75 mg/m2 on day 1 followed by 5-FU 750 mg/m2/day as a continuous infusion on days 1-5 plus cetuximab at a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2), with prophylactic antibiotics but no growth factors. Patients not progressing after four cycles of TPF-E were randomly assigned to radiotherapy (70 Gy over 7 weeks in 2 Gy fractions) and weekly cetuximab with either weekly cisplatin 40 mg/m2 or carboplatin, AUC of 1.5 mg/ml/min. Primary endpoint was feasibility. RESULTS: Forty-seven patients were recruited. One patient did not start TPF (hypersensitivity reaction during the cetuximab loading dose). Induction TPF-E was discontinued in 12 patients due to toxicity (6 patients), medical decision (2), death (1), patient refusal (1), protocol violation (1), co-morbidity (1). Three further patients were not randomized [progressive disease (1), protocol violation (1), toxicity and co-morbidity (1)]. Of particular interest are three patients who suffered from bowel perforation, one patient who died as results of pneumonia and septic shock, and a second patient who was found dead at home 12 days after starting TPF-E (cause of death unknown). Weekly cisplatin and carboplatin was stopped early in seven and four patients, respectively. Radiotherapy was stopped in two patients with cisplatin and interrupted in one patient with cisplatin and four patients with carboplatin. CONCLUSIONS: The addition of cetuximab to full dose TPF induction chemotherapy led to unacceptable complications and premature closing of the study. Only 34 out of 46 patients completed four cycles of TPF-E and only 30 started biochemoradiation.

Prognostic value of the S100B protein in newly diagnosed and recurrent glioma patients: a serial analysis.

The S100B protein is associated with brain damage and a breached blood-brain barrier. A previous pilot study showed that high serum levels of S100B are associated with shorter survival in glioma patients. The aim of our study was to assess the prognostic value in terms of survival and longitudinal dynamics of serum S100B for patients with newly diagnosed and recurrent glioma. We obtained blood samples from patients with newly diagnosed and recurrent glioma before the start (baseline) and at fixed time-points during temozolomide chemotherapy. S100B-data were dichotomized according to the upper limit of the reference value of 0.1 µg/L. Overall survival (OS) was estimated with Kaplan-Meier curves and groups were compared with the log rank analysis. To correct for potential confounders a Cox regression analysis was used. We included 86 patients with newly-diagnosed and 27 patients with recurrent glioma. Most patients in both groups had baseline serum levels within normal limits. In the newly diagnosed patients we found no significant difference in OS between the group of patients with S100B levels >0.1 µg/L at baseline compared to those with <0.1 µg/L. In the patients with recurrent glioma we found a significantly shorter OS for patients with raised levels. In both groups, S100B values did not change significantly throughout the course of the disease. Serum S100B levels do not seem to have prognostic value in newly diagnosed glioma patients. In recurrent glioma patients S100B might be of value in terms of prognostication of survival.

Real-world cost-effectiveness of cetuximab in locally advanced squamous cell carcinoma of the head and neck.

Clinical trial EMR 62202-006 demonstrates prolonged median locoregional control (24.4 vs. 14.9 months), progression-free survival (17.1 vs. 12.4 months) and overall survival (49.0 vs. 29.3 months) for patients who receive cetuximab added to the comparator radiotherapy for locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). In the Netherlands, hospitals receive reimbursement for cetuximab conditional on cost-effectiveness in daily practice. To estimate the real-world incremental cost per quality adjusted life-year (QALY) gained for radiotherapy + cetuximab over radiotherapy alone in first line treatment of LA SCCHN, a Markov model is constructed with health states "alive without progression", "alive following progression" and "death". Transition probabilities per month are estimated from clinical trial data and retrospectively collected real-world data from two Dutch head and neck cancer treatment centres (2007-2010, n = 141). 5-year, 10-year and lifetime horizons are used, without and with discounting (4 % costs, 1.5 % effects) to calculate incremental cost-effectiveness ratios. Two scenarios explore different assumptions on prognosis of real-world versus trial patients. Adding cetuximab to radiotherapy results in increased costs and health gains in both scenarios and across each of the time horizons. Incremental costs per QALY gained range between 14,624 and 38,543 in the base-case. For a willingness to pay of 80,000 per QALY, the acceptability curves for the different scenarios show probabilities between 0.76 and 0.87 of radiotherapy + cetuximab being cost-effective compared to radiotherapy alone. Current results show the combined treatment of radiotherapy + cetuximab to be a cost-effective treatment option for patients with LA SCCHN.

Central neurotoxicity of standard treatment in patients with newly-diagnosed high-grade glioma: a prospective longitudinal study.

Following tumor resection, the majority of high-grade glioma (HGG) patients are treated with a combined modality regimen of radiotherapy and temozolomide. As a result of the tumor itself or as treatment-related neurotoxic side-effects, these patients may experience cognitive deficits. Additionally, radiological abnormalities expressed as white matter hyperintensities (WMH) and cerebral atrophy (CA) can develop. In this study, these functional and morphological parameters are evaluated, and their relation is investigated. After surgery, HGG patients underwent chemo-irradiation for six weeks, followed by six cycles of temozolomide. Assessments were performed before chemo-irradiation, post-concomitantly, after the third and sixth adjuvant cycle, and 3 and 7 months after treatment. Degree of WMH and CA was scored on MRI. Patients' neuropsychological performance was compared to healthy matched controls, yielding six cognitive domain z-scores. Development or progression of pre-existing WMH and CA during follow-up was observed in 36 and 45 % of the patients (n = 39) respectively. Cognitive functioning remained stable or improved in 70 % of the patients and deteriorated in 30 % of the patients (n = 33). Of the cognitive decliners, 80 % had tumor progression within 4 months thereafter. No clear association between cognitive functioning and WMH or CA was found. Central neurotoxic effects of combined modality treatment in HGG patients expressed by radiological abnormalities are encountered in approximately 40 % of patients. However, functional impact as indexed by cognitive functioning was found to be limited. Furthermore, development or progression of pre-existing WMH and CA does not consistently result in functional impairment as measured by cognitive tests.

Cetuximab in locally advanced squamous cell carcinoma of the head and neck: generalizability of EMR 062202-006 trial results.

In a randomized controlled trial in patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), treatment with RT plus cetuximab resulted in improved survival compared to treatment with RT alone. Uncertainty exists about the generalizability of the trial results for the Dutch healthcare setting due to possible discrepancies in treatment allocation. Retrospective patient chart review was performed for 141 patients treated with first line RT plus cetuximab or RT alone, diagnosed in 2007-2010 in two head and neck treatment centers. Combined with aggregated population-based data from the Netherlands Cancer Registry and patient level clinical trial data, use of cetuximab in Dutch daily practice was assessed through comparison of patient characteristics, treatment characteristics and treatment outcomes between trial and daily practice. 61 daily practice patients fulfilled the selection criteria. In line with Dutch guidelines, RT plus cetuximab is prescribed in patients requiring combined therapy unfit to receive traditional platinum-based chemotherapeutics. These patients have unfavorable baseline characteristics, due to selection on--amongst others--high age of the patients. Beyond 1 year after treatment start, patients treated with RT plus cetuximab in daily practice died earlier than patients treated with RT plus cetuximab in the trial. Selective treatment allocation in daily practice limits generalizability of EMR 062202-006 trial results. Evidence is needed about the effectiveness of RT plus cetuximab compared to other treatments for patients with unfavorable clinical baseline characteristics.

Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy.

BACKGROUND: The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies. METHODS: Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m(-2) loading dose then 250 mg m(-2) weekly). Assessments included adverse events, PK, tumour response, 2[18F]fluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses. RESULTS: Toxicities observed were manageable; the most common treatment-related toxicities (>10% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months. CONCLUSIONS: The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.

The course of symptoms of anxiety and depression from time of diagnosis up to 2 years follow-up in head and neck cancer patients treated with primary (chemo)radiation.

OBJECTIVES: To identify sociodemographic and clinical factors, health-related quality of life (HRQOL) and head and neck cancer (HNC) symptoms associated with the course of symptoms of anxiety and depression from pretreatment to 24-month follow-up among HNC patients after (chemo)radiation. MATERIALS AND METHODS: Patients (n = 345) completed questionnaires on anxiety and depression (HADS), HRQOL and symptoms (EORTC QLQ-C30/QLQ-H&N35) before treatment, and 6-weeks,3-,6-12-,18-, and 24-months after treatment. Mixed model analyses were used to investigate the course of anxiety and depression from pretreatment to 24-months in relation to factors assessed at baseline, and the course of anxiety and depression from 6- to 24-months, in relation to factors assessed at 6-months. RESULTS: Increased risk for anxiety (HADS-anxiety > 7) was 28.7% among patients before treatment, which declined to 10.0% at 24-months. Increased risk for depression (HADS-depression > 7) was 15.1% before treatment, 18.2% at 3-months, 7.2% at 12-months and 16.0% at 24-months. Factors assessed at baseline which were significantly associated with the course of anxiety were age, pain, problems with social contact, and feeling ill, whereas chemotherapy, worse emotional functioning, speech problems and weight loss were significantly associated with the course of depression. Regarding factors assessed at 6-months, chemotherapy, worse cognitive and social functioning, insomnia, swallowing problems and trouble with social eating were associated with the course of anxiety. Nausea/vomiting, dyspnea, coughing, and feeling ill were associated with the course of depression (p-values < 0.05). DISCUSSION: Factors associated with a worse course of anxiety and depression are younger age, treatment with chemotherapy, worse HRQOL and higher symptom burden.

Phase II study of 3-AP Triapine in patients with recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Treatment options for recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) are limited with response rates to cytotoxic chemotherapy of approximately 30% and median survival of 6 months. PATIENTS AND METHODS: In a multicentre phase II study, 32 patients with recurrent or metastatic HNSCC received 3-AP Triapine (3-aminopyridine-2-carboxaldehyde thiosemicarbazone), an inhibitor of ribonucleotide reductase, 96 mg/m2, daily for 4 days every 14 days (one cycle). Eligibility criteria required Eastern Cooperative Oncology Group performance status (ECOG PS) of zero to two with a life expectancy of >3 months; one prior chemotherapy regimen was allowed. RESULTS: Thirty patients were assessable for response and toxicity. Median age was 57 years (range 36-79) and median ECOG PS was one (range 0-2). Thirteen patients had previously been treated with chemotherapy. A total of 130 cycles were administered with a median number of cycles of 3.5 (range 1-8). Mild anaemia (40%), nausea (22%) and fatigue (22%) were commonly reported with G3 and G4 neutropenia documented in 22% and 22%, respectively. Overall response rate was 5.9% (95% confidence interval 0.2% to 28.7%). One patient achieved a partial response, eight had stable disease and 21 progressive disease. Median time to disease progression was 3.9 months. CONCLUSIONS: 3-AP Triapine as a single agent, at this dose and schedule, is well tolerated but has only minor activity in the treatment of advanced HNSCC.

[Medical treatment of solid tumours]. / Medicamenteuze behandeling van maligne tumoren.

The medical treatment of solid tumours depends on many different factors. The choice of drug is stipulated by the tumour type, the stage of the disease and a number of patient characteristics, such as biological age, co-morbidity, and general performance status. The treatment can be curative, palliative or (neo-)adjuvant in nature. The groups of drugs which are used are hormones, cytostatics, immune-modulating drugs and (a new group) targeted-drugs consisting of small-molecules and monoclonal antibodies. Only a few tumour types are curable with chemotherapy in an advanced stage. In some tumour types an increase in life-expectancy can be achieved; other tumours are hardly or not at all sensitive to medical treatment. Treatment is limited by the side-effects of the drugs. With supporting medication some of the side-effects can be alleviated. With palliative therapy the aim is to improve the general condition by temporarily inhibiting the tumour with minimal side effects. Adjuvant chemotherapy raises the chance of cure after primary treatment with surgery or radiotherapy.

The course of sexual interest and enjoyment in head and neck cancer patients treated with primary (chemo)radiotherapy.

INTRODUCTION: The aim of this prospective study was to investigate the course of sexual interest and enjoyment in relation to sociodemographic and clinical factors, health-related quality of life (HRQOL), and symptoms of psychological distress in head and neck cancer (HNC) patients treated with primary (chemo)radiotherapy. METHODS: HNC patients (n = 354) completed patient-reported outcome measures (PROMs) on HRQOL (EORTC QLQ-C30 and QLQ-H&N35, including the sexuality subscale covering less sexual interest and enjoyment), and psychological distress (HADS) pretreatment, at 6-week follow-up and at 3-, 6-, 12-, 18-, and 24-month follow-up (i.e., after treatment). Linear mixed models were used to analyze the course of sexuality from pretreatment to 24-month follow-up, and to investigate its relation to sociodemographic and clinical factors, HRQOL, and psychological distress as measured at baseline, and to investigate the course of sexuality from 6- to 24-month follow-up in relation to these factors measured at 6-month follow-up. RESULTS: Before start of treatment, 37% of patients reported having less sexuality, which increased to 60% at 6-week follow-up, and returned to baseline level from 12-month follow-up onwards. Older age (p = 0.037) and trouble with social contact (p < 0.001), weight loss (p = 0.013), and constipation (p = 0.041) before treatment were associated with less sexuality over time. Female gender (p = 0.021) and poor social functioning (p < 0.001) at 6-month follow-up were associated with less sexuality from 6- to 24-month follow-up. DISCUSSION: Less sexuality is often reported in HNC patients treated with (chemo)radiotherapy. Using PROMs in clinical practice may help identify patients who might benefit from supportive care targeting sexuality.

The additional value of chemotherapy to radiotherapy in locally advanced nasopharyngeal carcinoma: a meta-analysis of the published literature.

PURPOSE: The purpose of this meta-analysis was to determine the additional value of neoadjuvant, concurrent, and/or adjuvant chemotherapy to radiation in the treatment of locally advanced nasopharyngeal carcinoma (NPC) with regard to the overall survival (OS) and the incidence of local-regional recurrences (LRR) and distant metastases (DM). PATIENTS AND METHODS: To be eligible, full published studies had to deal with biopsy-proven NPC and have patients randomly assigned to receive conventional radiotherapy (66 to 70 Gy in 7 weeks) or radiotherapy combined with chemotherapy. RESULTS: Ten randomized clinical studies were identified, including 2,450 patients. The pooled hazard ratio (HR) of death for all studies was 0.82 (95% CI, 0.71 to 0.95; P = .01) corresponding to an absolute survival benefit of 4% after 5 years. Three categories of trials were defined according to the sequence of chemotherapy, including neoadjuvant chemotherapy, at least concomitant chemoradiotherapy, and adjuvant chemotherapy. A significant interaction term (P = .02) was found among these three categories. The largest effect was found for concomitant chemotherapy, with a pooled HR of 0.48 (95% CI, 0.32 to 0.72), which corresponds to a survival benefit of 20% after 5 years. Comparable results were found for the incidence of LRR and DM. CONCLUSION: The results of this study indicate that concomitant chemotherapy in addition to radiation is probably the most effective way to improve OS in NPC.

Phase II study of subcutaneous interleukin-2 in unselected patients with advanced renal cell cancer on an outpatient basis.

PURPOSE: A single-institution phase II study was undertaken to evaluate the efficacy and toxicity of interleukin-2 (IL-2) administered by subcutaneous injection. PATIENTS AND METHODS: Twenty-seven unselected patients (15 male) with a mean age of 60 years (range, 42 to 76 years) who had advanced renal cell cancer were treated as outpatients. IL-2 was given once a day, 5 days per week for 6 weeks. During the first 5-day cycle, 18 x 10(6) IU was given once daily; in the following cycles, the doses in the first 2 days were reduced to 9 x 10(6) IU. After a 3-week rest period, treatment was repeated in patients who had a response or stable disease (SD). To prevent pyretic reactions, patients also received acetaminophen (250 to 500 mg given orally every 4 to 6 hours). RESULTS: After 6 weeks, 26 patients were assessable for response. Two patients (8%) had a complete remission (CR), four (15%) had a partial remission (PR), and 13 (50%) had SD. A second cycle of 6 weeks was given to 19 patients; one patient with a PR and six with SD showed progression. Duration of the CR was 17+ and 19+ months, and length of the PR was 2, 8, 11, and 11+ months. The median survival of the patients who were nonresponders and responders was 10 and 20+ months, respectively, and for all patients was 13 months. One patient died as a result of myocardial infarction and brain stem ischemia. Systemic side effects in the other patients were tolerated and accepted, and included transient inflammation and local induration at the injection sites, fever and chills, and nausea. CONCLUSION: Subcutaneous IL-2 is clinically active, has an acceptable toxicity, and can be given to patients with concomitant disease.

Salvage surgery in post-chemoradiation laryngeal and hypopharyngeal carcinoma: outcome and review.

Our objective was to evaluate recurrence patterns of hypopharyngeal and laryngeal carcinoma after chemoradiation and options for salvage surgery, with special emphasis on elderly patients. In a retrospective study all patients who underwent chemoradiation for hypopharyngeal and laryngeal carcinoma in a tertiary care academic center from 1990 through 2010 were evaluated. Primary outcome measures were the survival and complication rates of patients undergoing salvage surgery, especially in elderly patients. Secondary outcome measures were the predictors for salvage surgery for patients with locoregional recurrence after failed chemoradiotherapy. A review of the literature was performed. Of the 136 included patients, 60 patients had recurrent locoregional disease, of whom 22 underwent salvage surgery. Fifteen patients underwent a total laryngectomy with neck dissection(s) and 7 neck dissection without primary tumour surgery. Independent predictors for salvage surgery within the group of 60 patients with recurrent disease, were age under the median of 59 years (p = 0.036) and larynx vs. hypopharynx (p = 0.002) in multivariate analyses. The complication rate was 68% (14% major and 54% minor), with fistulas in 23% of the patients. Significantly more wound related complications occurred in patients with current excessive alcohol use (p = 0.04). Five-year disease free control rate of 35%, overall survival rate of 27% and disease specific survival rate of 35% were found. For the 38 patients who were not suitable for salvage surgery, median survival was 12 months. Patients in whom the tumour was controlled had a 5-year overall survival of 70%. In patients selected for salvage surgery age was not predictive for complications and survival. In conclusion, at two years follow-up after chemoradiation 40% of the patients were diagnosed with recurrent locoregional disease. One third underwent salvage surgery with 35% 5-year disease specific survival and 14% major complications. Older patients selected for salvage surgery had a similar complication rate and survival as younger patients.

Phase I/II study of low-dose intravenous OKT3 and subcutaneous interleukin-2 in metastatic cancer.

In a phase I/II study the safety, immunostimulatory and antitumor effects of a combined OKT3/interleukin 2 (IL-2) treatment was studied in 15 cancer patients who failed IL-2 treatment. OKT3 was given as a 2-h intravenous infusion. Doses of 50, 100, 200 and 400 micrograms OKT3 were studied. Within 24 h, subcutaneous IL-2 was started 5 days/week for 4 weeks, at a dose of 9-18 x 10(6) U daily. Maximum tolerated dose was 400 micrograms OKT3 with neurotoxicity as dose-limiting toxicity. Toxicity of subcutaneous IL-2 was acceptable. At the maximum tolerated dose, 9 patients with renal cell carcinoma with measurable disease were treated in a phase II setting. 8 patients were evaluable for response. 4 patients had stable disease and 4 had progressive disease. An increase of activated lymphocyte subpopulations could not be found, although OKT3 was detectable on lymphocytes in vivo. Only if laboratory studies shed light on methods of improving immunostimulating effects of OKT3 will further clinical studies be warranted.

Phase I-II study of the addition of alpha-2a interferon to 5-fluorouracil/leucovorin. Pharmacokinetic interaction of alpha-2a interferon and leucovorin.

5-Fluorouracil (5-FU) activity has been improved by the use of leucovorin (LV) or alpha-2a interferon (alpha-IF). We investigated the feasibility and activity of addition of alpha-IF to a 5-FU/LV regimen. A phase I study with 26 patients (14 previously untreated, 12 previously treated) with disseminated cancer was conducted. 15 patients were treated with 5-FU/LV and 11 with 5-FU/LV/alpha-IF. The 5-FU/LV regimen consisted of escalating doses of 5-FU bolus intravenously on days 2 and 3, combined with repeated oral LV on days 1, 2 and 3. Treatment was every 2 weeks. In the 5-FU/LV/alpha-IF schedule, 18 x 10(6) U alpha-IF subcutaneously daily was added on days 1, 2 and 3. The phase I study was followed by a phase II study of 5-FU/LV/alpha-IF at the established 5-FU dose in 29 previously untreated patients with disseminated colorectal cancer. The optimal 5-FU dose in both parts of the phase I study was 750 mg/m2/day. Mucositis, diarrhea and leucopenia were dose limiting. Although alpha-IF added its own toxicity (fever, flu-like symptoms, fatigue), it did not decrease the optimal dose of 5-FU. In the phase II study 28 patients were evaluable for response: three complete responses and 12 partial responses were observed (response rate 54%, 95% confidence interval, 34 to 72%). Pharmacokinetics of oral LV was performed in patients treated with and without alpha-IF: significantly higher serum levels of LV and 5-methyltetrahydrofolate were found after alpha-IF addition. Influence of alpha-IF on gastrointestinal absorption or renal clearance could be excluded. In conclusion, this 5-FU/LV/alpha-IF combination seems active in metastatic colorectal cancer. The pharmacokinetic interaction between alpha-IF and LV may play a role in the activity of this regimen. Controlled studies are necessary to establish the value of addition of alpha-IF to 5-FU/LV regimens.

Extended neoadjuvant chemotherapy in locally advanced breast cancer combined with GM-CSF: effect on tumour-draining lymph node dendritic cells.

The effect of long-term administration of granulocyte-macrophage colony-stimulating factor (GM-CSF) on dendritic cell (DC) activation and survival in patients with locally advanced breast cancer (LABC) was studied. To this end, the number of activated DC (i.e. positive for the marker S100) in tumour-draining lymph nodes (TDLN) was determined and compared between LABC patients receiving neoadjuvant chemotherapy with GM-CSF (n=52) or without GM-CSF (n=11), and a control group of chemonaïve breast cancer patients (n=10). A significantly higher mean percentage of S100+ DC in the TDLN of the GM-CSF-treated patients (9.9%) was found compared with each of the respective control groups (5.3 and 5.1%, P=0.002). Moreover, intrapatient comparison before and after treatment showed that the percentage of S100+ DC significantly increased over the course of the GM-CSF treatment (P=0.018). In a univariate survival analysis with a median follow-up of 64 months, relatively high percentages of S100+ DC (> or =8%) were associated with a longer disease-free survival (DFS) (P=0.078). In patients with a high tumour load, where immunosuppressed conditions generally prevail, long-term administration of GM-CSF may thus contribute to survival through enhanced DC activation and consequently improved chances of effective antitumour immunity.

Malignant peripheral nerve sheath tumors in patients with and without neurofibromatosis.

Malignant peripheral nerve sheath tumors (MPNST) are rare. They account for 10% of all soft tissue sarcomas. The incidence of MPNST in patients with neurofibromatosis type 1 (NF-1) is 4%. A retrospective study was undertaken to evaluate the prognosis of patients with MPNST and NF-1 vs patients with MPNST alone. Twenty-two patients with MPNST were diagnosed. The MPNST was diagnosed with NF-1 in 11 patients (50%). Treatment was defined as curative in 20 patients (90%), non-curative in one patient (5%), and one patient received no treatment. The median disease-free survival (DFS) was 14 months (range 0-153 months). The median overall survival 24 months (range 1-153 months). There were three patients with isolated local failures (14%), four patients with local and distant failures (18%), and seven patients with isolated distant failures (32%). There was no statistical difference between patients with and without NF-1. Five patients with NF-1 developed a second MPNST (45%), none of the patients without NF-1 did (P = 0.018). A statistically worse survival was found when the duration of the first symptoms had been longer than six months. Patients with MPNST have a poor prognosis with a high risk for local and distant failures (> 50%). There is no statistical difference in the final outcome for MPNST with or without NF-1, but patients with NF-1 have a high risk for developing a second MPNST.

Dose escalation of dacarbazine combined with interferon alpha-2a, G-CSF and ondansetron in patients with metastatic melanoma.

To define the activity of an individually escalated dacarbazine (DTIC) dose combined with interferon-alpha-2a (IFN), granulocyte-colony stimulating-factor (G-CSF) and ondansetron, 20 patients (pts) with metastatic melanoma were treated with DTIC, ondansetron 8 mg iv, G-CSF 300 micrograms sc and IFN 9 MU sc. Treatment was performed every 21 days to a maximum of 6 courses. DTIC dose was escalated with 250 mg/m2 in case of acceptable toxicity to 1250, 1500 and 1750 mg/m2 in (projected/realized), 14/19, 8/11 and 0/5 pts, respectively. Dose escalation prohibiting toxicities were thrombocytopenia (10 pts), leukopenia (9 pts), and nausea/vomiting (2 pts). Four partial remissions were observed, for a response rate of 20% (95% confidence interval, 6 to 44%). Duration of responses was 1, 2, 3 and 3 months. Median overall survival was 8 months.

Outpatient-based subcutaneous interleukin-2 monotherapy in advanced renal cell carcinoma: an update.

To minimize interleukin-2-related toxicity while retaining its efficacy, a treatment schedule utilizing subcutaneous IL-2 was evaluated in a phase II setting. Eighty unselected, consecutive patients with metastatic or recurrent renal cell carcinoma (RCC), mean age 58 years (range, 21 to 76), received IL-2 on an outpatient basis, 5 days per week for 4 or 6 consecutive weeks. During the first 5-day cycle, a dose of 18 million IU IL-2 was administered once a day; during subsequent cycles the dose in the first two days was reduced to 9 million IU. Two 6-week or three 4-week courses were given maximally. Patients who had completed at least one full course were considered evaluable. To circumvent flu-like symptoms, all patients received a maximum oral dose of 3 g acetaminophen daily. Seventy-seven patients were assessable for response. Three (4%) complete responses (CR) and 6 (8%) partial responses (PR) were observed, and 44 (57%) patients had stable disease (SD). Response durations were 64, 29, 29+ months for the CR and 2, 6, 8, 11, 32, 47 months for the PR. The median length of survival of all patients was 12 months, whereas the median survival of responders and non-responders was 35+ and 10+ months, respectively (P < 0.001). Side effects included fever, chills, nausea, vomiting, and transient inflammation and induration at the injection sites. These complications were acceptable, even in the patients with concomitant disease, and completely disappeared after cessation of IL-2. Subcutaneous IL-2 mediates antitumor responses, has limited side effects and is also suitable for elderly RCC patients with concomitant disease.

Cytologic diagnosis of acinic-cell carcinoma of salivary glands.

The cytologic findings in fine-needle aspiration (FNA) biopsies obtained from 40 primary and 18 recurrent acinic-cell carcinomas (ACC) were retrospectively analyzed. Cytomorphologically, ACC is characterized by acinar differentiated tumor cells. In addition to these diagnostic clue cells, other types of neoplastic cells including vacuolated cells, cells resembling oncocytes, and nonspecific glandular cells are encountered. A pronounced lymphocytic reaction is a hallmark in 10% of ACC aspirates. Both the variety of tumor cell differentiation and the pronounced lymphocytic reaction observed in ACC aspirates may result in confusion with other salivary gland lesions. The differential diagnosis of ACC encompasses adenocarcinoma, mucoepidermoid carcinoma, pleomorphic adenoma, Warthin tumor, sebaceous lymphadenoma, benign lymphoepithelial lesion, sialoadenosis, sialadenitis caused by radiotherapy, and lymphadenitis. Primary ACCs were correctly diagnosed in 68%; additionally, ACC was suspected or included in the differential diagnosis in 15%. Increased familiarity with the spectrum of cytomorphologic findings and the potential diagnostic pitfalls in ACC will improve the cytodiagnosis of this neoplasm.