Determining clinically important differences in health-related quality of life in older patients with cancer undergoing chemotherapy or surgery.

PURPOSE: Using the EORTC Global Health Status (GHS) scale, we aimed to determine minimal clinically important differences (MCID) in health-related quality of life (HRQOL) changes for older cancer patients with a geriatric risk profile, as defined by the geriatric 8 (G8) health screening tool, undergoing treatment. Simultaneously, we assessed baseline patient characteristics prognostic for HRQOL changes. METHODS: Our analysis included 1424 (G8 ≤ 14) older patients with cancer scheduled to receive chemotherapy (n = 683) or surgery (n = 741). Anchor-based methods, linking the GHS score to clinical indicators, were used to determine MCID between baseline and follow-up at 3 months. A threshold of 0.2 standard deviation (SD) was used to exclude MCID estimates too small for interpretation. Logistic regressions analysed baseline patient characteristics prognostic for HRQOL changes. RESULTS: The 15-item Geriatric Depression Scale (GDS15), Visual Analogue Scale (VAS) for Fatigue and ECOG Performance Status (PS) were selected as clinical anchors. In the surgery group, MCID estimates for improvement and deterioration were ECOG PS (5*, 11*), GDS15 (5*, 2) and VAS Fatigue (3, 9*). In the chemotherapy group, MCID estimates for improvement and deterioration were ECOG PS (8*, 7*), GDS15 (5, 4) and VAS Fatigue (5, 5*). Estimates with * were > 0.2 SD threshold. Patients experiencing pain or malnutrition (surgery group) or fatigue (chemotherapy group) at baseline showed a significantly stable or improved HRQOL (p < 0.05) after their treatment. CONCLUSION: The reported MCID for improvement and deterioration depended on the anchor used and treatment received. The estimates can be used to evaluate significant changes in HRQOL and to determine sample sizes in clinical trials.

Adherence to geriatric assessment-based recommendations in older patients with cancer: a multicenter prospective cohort study in Belgium.

Background: In the general older population, geriatric assessment (GA)-guided treatment plans can improve overall survival, quality of life and functional status (FS). In GA-related research in geriatric oncology, studies mainly focused on geriatric screening and GA but not on geriatric recommendations, interventions and follow-up. The aim of this study was to investigate the adherence to geriatric recommendations and subsequent actions undertaken in older patients with cancer. Patient and methods: A prospective Belgian multicenter (N = 22) cohort study included patients ≥70 years with a malignant tumor upon oncologic treatment decision. Patients with an abnormal result on the geriatric screening (G8 ≤14/17) underwent GA. Geriatric recommendations were formulated based on GA results. At follow-up the adherence to geriatric recommendations was documented including a description of actions undertaken. Results: From November 2012 till February 2015, G8 screening was carried out in 8451 patients, of which 5838 patients had an abnormal result. Geriatric recommendations data were available for 5631 patients. Geriatric recommendations were made for 4459 patients. Geriatric interventions data were available for 4167 patients. A total of 12 384 geriatric recommendations were made. At least one different geriatric recommendation was implemented in 2874 patients. A dietician, social worker and geriatrician intervened most frequently for problems detected on the nutritional, social and functional domain. A total of 7569 actions were undertaken for a total of 5725 geriatric interventions, most frequently nutritional support and supplements, extended home care and psychological support. Conclusions: This large-scale Belgian study focuses on the adherence to geriatric recommendations and subsequent actions undertaken and contributes to the optimal management of older patients with cancer. We identified the domains for which geriatric recommendations are most frequently made and adhered to, and which referrals to other health care workers and facilities are frequently applied in the multidisciplinary approach of older patients with cancer.

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.

Spotlight on Volasertib: Preclinical and Clinical Evaluation of a Promising Plk1 Inhibitor.

Considering the important side effects of conventional microtubule targeting agents, more and more research focuses on regulatory proteins for the development of mitosis-specific agents. Polo-like kinase 1 (Plk1), a master regulator of several cell cycle events, has arisen as an intriguing target in this research field. The observed overexpression of Plk1 in a broad range of human malignancies has given rise to the development of several potent and specific small molecule inhibitors targeting the kinase. In this review, we focus on volasertib (BI6727), the lead agent in category of Plk1 inhibitors at the moment. Numerous preclinical experiments have demonstrated that BI6727 is highly active across a variety of carcinoma cell lines, and the inhibitor has been reported to induce tumor regression in several xenograft models. Moreover, volasertib has shown clinical efficacy in multiple tumor types. As a result, Food and Drug Administration (FDA) has recently awarded volasertib the Breakthrough Therapy status after significant benefit was observed in acute myeloid leukemia (AML) patients treated with the Plk1 inhibitor. Here, we discuss both preclinical and clinical data available for volasertib administered as monotherapy or in combination with other anticancer therapies in a broad range of tumor types.

A Belgian Survey on Geriatric Assessment in Oncology Focusing on Large-Scale Implementation and Related Barriers and Facilitators.

OBJECTIVES: The aim of this study is to describe a large-scale, Belgian implementation project about geriatric assessment (=GA) in daily oncology practice and to identify barriers and facilitators for implementing GA in this setting. Design / setting / participants: The principal investigator of every participating hospital (n=22) was invited to complete a newly developed questionnaire with closed- and open-ended questions. The closed-ended questions surveyed how GA was implemented. The open-ended questions identified barriers and facilitators for the implementation of GA in daily oncology practice. Descriptive statistics and conventional content analysis were performed as appropriate. RESULTS: Qualifying criteria (e.g. disease status and cancer type) for GA varied substantially between hospitals. Thirteen hospitals (59.1%) succeeded to screen more than half of eligible patients. Most hospitals reported that GA data and follow-up data had been collected in almost all screened patients. Implementing geriatric recommendations and formulating new geriatric recommendations at the time of follow-up are important opportunities for improvement. The majority of identified barriers were organizational, with high workload, lack of time or financial/staffing problems as most cited. The most cited facilitators were all related to collaboration. CONCLUSION: Interventions to improve the implementation of GA in older patients with cancer need to address a wide range of factors, with organization and collaboration as key elements. All stakeholders, seeking to improve the implementation of GA in older patients with cancer, should consider and address the identified barriers and facilitators.

A proof of concept trial of the anti-EGFR antibody mixture Sym004 in patients with squamous cell carcinoma of the head and neck.

PURPOSE: The purpose of the trial was to assess the efficacy and tolerability of Sym004, a novel 1:1 mixture of two chimeric monoclonal antibodies (992 and 1024) targeting non-overlapping epitopes of the anti-epidermal growth factor receptor (EGFR), in patients with squamous cell carcinoma of the head and neck (SCCHN). METHODS: Incurable, recurrent and/or metastatic SCCHN patients with acquired resistance to anti-EGFR monoclonal antibody-containing treatment received weekly infusions of 12 mg/kg Sym004 until disease progression or unacceptable toxicity. RESULTS: Among the 26 patients treated with Sym004, the proportion of patients alive without disease progression at 6 months was 12 % (95 % CI 1-39 %). The median duration of progression-free survival was 82 days (95 % CI 41-140 days). Of 19 patients evaluable for response, eight showed a decrease in the sum of the largest diameter in their target lesions (median 11 %; range 7-27 %). The best overall response was stable disease in 13 patients (50 %). Paired biopsies showed a significant down-regulation of EGFR in both skin and tumors following exposure to Sym004. All patients had EGFR-related adverse events, including grade 3 skin toxicities and grade ≥3 hypomagnesemia reported in 13 (50 %) and 10 (38 %) of 26 patients, respectively. One event fulfilling the protocol-defined criteria for infusion-related reactions (grade 2) was reported. No anti-drug antibodies were detected. CONCLUSIONS: The marked EGFR down-regulation shown in target tissues supports the proposed mechanism of action of Sym004. This trial revealed modest anti-tumor activity of Sym004 in extensively pretreated advanced SCCHN patients.

Difluorodeoxyuridine plasma concentrations after low-dose gemcitabine during chemoradiation in head and neck cancer patients.

PURPOSE: The aim of this study was to investigate whether relevant plasma levels of dFdU could be detected during concurrent chemoradiation (CRT) with low doses of dFdC administered in patients with head and neck cancer and to assess the toxicity related to dose. METHODS: dFdC was administered at doses of 5 mg/m² twice weekly or 10, 50, or 100 mg/m² weekly. Plasma concentrations of dFdU were determined daily for 7 days after the first administration and before each administration, thereafter. A high-performance liquid chromatographic method was used. During CRT, skin and mucosal toxicity were scored weekly according to the RTOG toxicity scoring system. RESULTS: Eight patients were sampled at the 10-50 mg/m² dose and nine at the 5-100 mg/m² dose. dFdU levels were in the micromolar range, inducing RS in vitro. There was a strong correlation between the area under the curve of dFdU and the dose of dFdC (r = 0.803, P < 0.001) and a weak correlation between trough concentrations and total dose of dFdC (r = 0.408, P = 0.017). Duration of severe mucositis correlated with dFdC dose. CONCLUSIONS: During CRT with 10-100 mg/m(2) of dFdC weekly or 5 mg/m(2) twice weekly, dFdU remains detectable at potentially radiosensitizing concentrations.

Optimal treatment for recurrent/metastatic head and neck cancer.

While a large proportion of patients presenting with stage I and II squamous cell carcinoma of the head and neck (SCCHN) will remain disease free after single modality treatment, the majority of patients presenting in a more advanced disease stage and very often treated with a form of combined modality treatment, will eventually relapse, either locoregionally only, at distant sites only or both. A few patients with a locoregional recurrence can be salvaged by surgery or reirradiation. However, most patients with recurrent or metastatic (R/M) disease only qualify for palliative treatment. Treatment options in these patients include supportive care only, or in addition single agent chemotherapy, combination chemotherapy or targeted therapies either alone or in combination with cytotoxic agents. Prognostic factors analysis in such patients treated with (platinum-based) chemotherapy has identified five adverse prognostic factors, which seems worthwhile to take into consideration when performing trials; one pathologic feature (tumor cell differentiation) and four clinical baseline characteristics (ECOG performance status, weight loss, location of the primary tumor and prior radiotherapy). Moreover, it has been shown that response to systemic therapy has a major impact on survival. None of the trials performed in the past, even those with a reasonable sample size, have shown that aggressive platinum-based combination chemotherapy leads to survival benefit when compared to single agent methotrexate, cisplatin or 5-fluorouracil. After decades without real progress, a recent European randomized trial showed that adding cetuximab, the first clinically available EGFR-directed monoclonal antibody, to a standard chemotherapy regimen (platinum/5-fluorouracil) leads to an important survival benefit and this, with support of an additional smaller study in the US, has changed practice.

Acute hemiplegia caused by a retrograde cerebral venous air embolism after central venous catheter removal: an illustrative case.

Central venous catheters are widely used in clinical practice. Air embolism is a rare, but potentially life threatening complication of central venous catheterisation. We describe a case of collapse and transient hemiplegia after removal of central venous catheter. This was accidentally performed with the patient in upright position. A CT scan of the brain demonstrated air in the sinus cavernosus bilaterally and at the posterior wall of the foramen magnum.

Phase II feasibility study of concurrent radiotherapy and gemcitabine in chemonaive patients with squamous cell carcinoma of the head and neck: long-term follow up data.

BACKGROUND: Radiotherapy (RT) with concurrent chemotherapy is the current standard of care for patients with unresectable locally advanced squamous cell carcinoma of the head and neck (SCCHN). Gemcitabine (GEM) is a potent radiosensitizer and in addition has activity as an anticancer agent in SCCHN. PATIENTS AND METHODS: Twenty-six patients with locally far advanced SCCHN were enrolled in a chemoradiation feasibility study between November 1998 and September 2003. Use was made of conventionally fractionated RT and GEM 100 mg/m(2), which was given within 2 h prior to radiotherapy on a weekly basis starting on day 1 of RT. Response was assessed according to WHO criteria, toxicity according to NCI-CTC version 2. RESULTS: The patients received a median of 7 (2-8) weekly cycles of gemcitabine and a median cumulative RT dose of 70 Gy (66-84.75). Hematologic toxicity was mild, but non-hematologic toxicity was severe: grade 3-4 stomatitis occurred in 85% of patients, dermatitis in 69%, pharyngitis/esophagitis in 81% and 80% of the patients needed a feeding tube during treatment. All 22 evaluable patients responded (50% complete, 50% partial). Median follow up of the surviving patients is 46 months. Median disease-free and overall survival is 13 months and 19 months, respectively; 27% of the patients are alive without evidence of recurrence beyond 3 years. CONCLUSIONS: Conventionally fractionated RT in combination with GEM 100 mg/m(2) weekly is feasible and highly active in the treatment of locally advanced SCCHN. In particular, long-term local control rate is promising. Acute mucosal toxicities are significant but manageable. Long-term toxicity interferes with normal food intake.

Sequential treatment with vindesine-ifosfamide-platinum (VIP) chemotherapy followed by platinum sensitized radiotherapy in stage IIIB non-small cell lung cancer: a phase II trial.

PURPOSE: Daily administration of cisplatin concomitant with radiotherapy improved the overall survival in inoperable non-small cell lung cancer (NSCLC) in one EORTC study. In this study, we prospectively investigated the efficacy and toxicity of a sequential treatment with three cycles of vindesine-ifosfamide-platinum (VIP) induction chemotherapy, followed by daily cisplatin-sensitized radiotherapy. METHODS: Between June 1993 and June 1995, 23 previously untreated patients with stage IIIB NSCLC with World Health Organization performance status 0 or 1 were included. Chemotherapy consisted of platinum 30 mg/m2 and ifosfamide 1200 mg/m2 i.v. on days 1, 2 and 3, and vindesine 3 mg/m2 i.v. on days 1 and 8, every 4 weeks. After three cycles and at least stable disease, radiotherapy was started (30 Gy in 10 fractions, followed by a boost of 22 Gy in 10 fractions). Each fraction was preceded by Platinum 6 mg/m2 i.v. RESULTS: Nineteen patients completed the sequential therapy. One patient died from neutropenic sepsis during the first cycle of chemotherapy, and three patients had progressive disease after chemotherapy. The overall response rate after sequential therapy was 47% (95% confidence interval 24-80), median survival was 10.6 months, 1- and 2-year survival rates were 47 and 16%, respectively. Major toxicity consisted of neurotoxicity grade III-IV in 18% and of leukopenia grade III-IV in 22% of the patients. Acute radiation pneumonitis grade III occurred in 11% of the patients. CONCLUSION: Three-drug VIP induction chemotherapy followed by cisplatin-sensitized radiotherapy is feasible, with acceptable, albeit substantial, toxicity. In spite of the theoretically promising sequence of therapies, survival results remain disappointingly low.

The treatment of osseous metastases of hormone-refractory prostate cancer with external beam radiotherapy and Strontium-89.

Metastatic bone disease from hormone-refractory prostate cancer can lead to significant morbidity such as pain, nerve compression and fractures which diminishes the quality of life of these patients substantially. Pain from osteoblastic metastases can significantly be improved by both external radiotherapy and Strontium-89 (89Sr), whereas lytic metastases are only responsive to external irradiation. Pain relief is obtained in approximately 80% of patients. Toxicity is mild and retreatment is usually possible. External beam radiotherapy is indicated when spinal cord or nerve root compression is demonstrated, or when osteolytic metastases with danger of fracture are visualized. External radiotherapy and Strontium-89 are important treatments to palliate patients suffering from metastatic prostate cancer. Because of their mild toxicity and highly effective analgesic effect, implementation of irradiation and 89Sr should be start of early in the disease process of these patients in order to keep them ambulatory and pain-free as long as possible.