Screening and Stepped Care Targeting Psychological Distress in Patients With Metastatic Colorectal Cancer: The TES Cluster Randomized Trial.

BACKGROUND: This study evaluated the effectiveness of a screening and stepped care program (the TES program) in reducing psychological distress compared with care as usual (CAU) in patients with metastatic colorectal cancer starting with first-line systemic palliative treatment. PATIENTS AND METHODS: In this cluster randomized trial, 16 hospitals were assigned to the TES program or CAU. Patients in the TES arm were screened for psychological distress with the Hospital Anxiety and Depression Scale and the Distress Thermometer/Problem List (at baseline and 10 and 18 weeks). Stepped care was offered to patients with distress or expressed needs, and it consisted of watchful waiting, guided self-help, face-to-face problem-solving therapy, or referral to specialized mental healthcare. The primary outcome was change in psychological distress over time, and secondary outcomes were quality of life, satisfaction with care, and recognition and referral of distressed patients by clinicians. Linear mixed models and effect sizes were used to evaluate differences. RESULTS: A total of 349 patients were randomized; 184 received the TES program and 165 received CAU. In the TES arm, 60.3% of the patients screened positive for psychological distress, 26.1% of which entered the stepped care program (14.7% used only watchful waiting and 11.4% used at least one of the other treatment steps). The observed low use of the TES program led us to pursue a futility analysis, which showed a small conditional power and therefore resulted in halted recruitment for this study. No difference was seen in change in psychological distress over time between the 2 groups (effect size, -0.16; 95% CI, -0.35 to 0.03; P>.05). The TES group reported higher satisfaction with the received treatment and better cognitive quality of life (all P<.05). CONCLUSIONS: As a result of the low use of stepped care, a combined screening and treatment program targeting psychological distress in patients with metastatic colorectal cancer did not improve psychological distress. Our results suggest that enhanced evaluation of psychosocial concerns may improve aspects of patient well-being.

Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer.

BACKGROUND: Fluoropyrimidine-based chemotherapy plus the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab is standard first-line treatment for metastatic colorectal cancer. We studied the effect of adding the anti-epidermal growth factor receptor (EGFR) antibody cetuximab to a combination of capecitabine, oxaliplatin, and bevacizumab for metastatic colorectal cancer. METHODS: We randomly assigned 755 patients with previously untreated metastatic colorectal cancer to capecitabine, oxaliplatin, and bevacizumab (CB regimen, 378 patients) or the same regimen plus weekly cetuximab (CBC regimen, 377 patients). The primary end point was progression-free survival. The mutation status of the KRAS gene was evaluated as a predictor of outcome. RESULTS: The median progression-free survival was 10.7 months in the CB group and 9.4 in the CBC group (P=0.01). Quality-of-life scores were lower in the CBC group. The overall survival and response rates did not differ significantly in the two groups. Treated patients in the CBC group had more grade 3 or 4 adverse events, which were attributed to cetuximab-related adverse cutaneous effects. Patients treated with cetuximab who had tumors bearing a mutated KRAS gene had significantly decreased progression-free survival as compared with cetuximab-treated patients with wild-type-KRAS tumors or patients with mutated-KRAS tumors in the CB group. CONCLUSIONS: The addition of cetuximab to capecitabine, oxaliplatin, and bevacizumab resulted in significantly shorter progression-free survival and inferior quality of life. Mutation status of the KRAS gene was a predictor of outcome in the cetuximab group. (ClinicalTrials.gov number, NCT00208546.)

Phase I trial with BMS-275183, a novel oral taxane with promising antitumor activity.

PURPOSE: BMS-275183 is an orally administered C-4 methyl carbonate analogue of paclitaxel. We did a dose-escalating phase I study to investigate its safety, tolerability, pharmacokinetics, and possible antitumor activity. EXPERIMENTAL DESIGN: A cycle consisted of four weekly doses of BMS-275183. The starting dose was 5 mg, which was increased by 100% increments (i.e., 5, 10, 20 mg/m2, etc.) in each new cohort consisting of one patient. Cohorts were expanded when toxicity was encountered, and 20 patients were treated at the maximum tolerated dose (MTD). Plasma pharmacokinetics were done on days 1 and 15. RESULTS: A total of 48 patients were enrolled in this trial. Dose-limiting toxicities consisted of neuropathy, fatigue, diarrhea, and neutropenia. First cycle severe neuropathy was reported in four patients treated at 320 (n = 1), 240 (n = 2), and 160 mg/m2 (n = 1), whereas eight patients treated at dose levels ranging from 160 to 320 mg/m2 experienced grade 2 neuropathy in cycle one. The MTD was 200 mg/m2, as 3 of 20 patients experienced grade 3 or 4 toxicity in cycle one [fatigue (n = 2), and neutropenia/diarrhea (n = 1)]. BMS-275183 was rapidly absorbed with a mean plasma half-life of 22 hours. We observed a significant correlation between drug-exposure and toxicity. Tumor responses were observed in 9 of 38 evaluable patients with non-small cell lung cancer, prostate carcinoma, and other tumor types. CONCLUSIONS: BMS-275183 is generally well tolerated on a weekly schedule. The main toxicity is peripheral neuropathy, and the MTD is 200 mg/m2. Promising activity was observed in several tumor types, and a phase II trial in non-small cell lung cancer has been initiated.

Bilateral adrenal enlargement with an unexpected diagnosis.

A 78-year-old man, previously treated for prostate and colorectal cancer, was admitted to the hospital because of persistent fever. He was found to have bilateral large adrenal masses and adrenal insufficiency. Primary large B-cell lymphoma was proven by aspiration biopsy of the left adrenal gland. On presentation, no evidence of lymphoma outside the adrenal glands was found. The patient died before treatment could be initiated. The autopsy report is discussed briefly. Primary adrenal lymphoma is a rare entity and should be considered in a patient with bilateral adrenal masses without nodular involvement.

A phase I study of monohydroxyethylrutoside in healthy volunteers.

The flavonol monohydroxyethylrutoside (monoHER) has demonstrated protection against doxorubicin-induced cardiotoxicity in in vitro and in vivo studies without affecting the antitumor effect. In the present phase I study, the possible side effects and the pharmacokinetics of monoHER were evaluated in healthy volunteers with the aim to develop a safe and feasible dose to be evaluated in cancer patients treated with doxorubicin. The study was performed as a single blind, randomized trial in healthy volunteers (age between 19 and 56 years). At each dose level, six subjects received monoHER and three placebo. MonoHER was solubilized in 100 ml dextrose 5% and administered as an i.v. infusion in 10 min. The placebo consisted of 100 ml dextrose 5%. The starting dose of monoHER was 100 mg/m(2). Dose escalation by 100% of the preceding dose took place after finishing each dose level until the protecting pharmacokinetic values for C (max) and AUC(infinity) (as observed in mice after 500 mg/kg monoHER i.p.) were reached and/or serious side effects were observed. The dose was escalated up to 1,500 mg/m(2). The mean values of C (max) and AUC(infinity) were 360+/-69.3 microM and 6.8+/-2.1 micromol min/ml, respectively. These values were comparable to the C (max) and AUC(infinity) observed under the protecting conditions in mice. No serious side effects occurred during the entire study. Thus, 1,500 mg/m(2) is a feasible and safe dose to be evaluated in a phase II study to investigate the protective properties of monoHER against doxorubicin-induced cardiotoxicity in cancer patients.

Thallium-201 single-photon emission computed tomography as an early predictor of outcome in recurrent glioma.

PURPOSE: With limited response rates and potential toxicity of chemotherapeutic treatment in patients with recurrent glioma, reliable response assessment is essential. Currently, the assessment of treatment response in glioma patients is based on the combination of radiologic and clinical findings. However, response monitoring with computed tomography (CT) or magnetic resonance imaging (MRI) is hampered by several pitfalls and is prone to interobserver variability. The aim of this study was to establish the value of thallium-201 single-photon emission computed tomography (201Tl-SPECT) as a predictor of overall survival and response to chemotherapy in recurrent glioma, and to compare the value of 201Tl-SPECT with that of CT and MRI. PATIENTS AND METHODS: We studied patients who underwent CT or MRI and 201Tl-SPECT before chemotherapy (n = 57), and patients who also had undergone CT or MRI and 201Tl-SPECT after two courses of chemotherapy (n = 44). The value of the radiologic variables (CT-MRI tumor size, 201Tl-SPECT tumor size, and maximal tumor intensity) at baseline and at follow-up in predicting overall survival, and the percentage of patients alive and progression-free at 6 months (APF6) were examined using Cox regression and logistic regression analysis. RESULTS: Both at baseline and at follow-up, 201Tl-SPECT maximal tumor intensity was the strongest predictive variable and was inversely related to overall survival and APF6. In particular, progression of maximal tumor intensity after two courses of chemotherapy was a powerful predictor of poor outcome. CONCLUSION: 201Tl-SPECT is superior to conventional CT-MRI in the early prediction of overall survival and response to chemotherapy in patients with recurrent glioma.

Continuous administration of irinotecan by hepatic arterial infusion: a phase I and pharmacokinetic study.

PURPOSE: The main advantage of administering chemotherapy by means of hepatic arterial infusion (HAI) is the achievement of a high concentration of the drug in the liver. Irinotecan (CPT-11) is an active agent for the treatment of advanced colorectal cancer and other tumor types, which frequently metastasize in the liver. We performed a Phase I and pharmacokinetic study to investigate CPT-11 by hepatic arterial administration in patients with liver metastases. PATIENTS AND METHODS: Patients with liver metastases received CPT-11 at doses ranging from 15 to 25 mg/m(2)/day for 5 days every 3 weeks by continuous HAI. All of the patients also received one cycle CPT-11 i.v. Primary end points of the study were to define the maximum tolerated dose (MTD) of hepatic arterial CPT-11 and to study its pharmacokinetics. RESULTS: Twenty patients were included. The MTD was 25 mg/m(2)/day and the dose-limiting toxicities were neutropenia and diarrhea. The metabolic ratio was significantly increased with HAI compared with i.v. administration (P = 0.015). The steady-state concentrations of total CPT-11 and CPT-11 carboxylate and lactone were all lower than those during i.v. infusion (P = 0.008, 0.013, and 0.004, respectively), whereas the levels of total SN-38, and SN-38 carboxylate, lactone, and glucuronide were similar. The total body clearance of CPT-11 was significantly higher with HAI (P = 0.008). CONCLUSIONS: The MTD of CPT-11 given by hepatic 5-day continuous infusion was 25 mg/m(2)/day. HAI of CPT-11 resulted in a higher metabolic ratio because of increased elimination of CPT-11. We recommend 20 mg/m(2)/day for additional Phase II studies.

Randomised study of tegafur-uracil plus leucovorin versus capecitabine as first-line therapy in elderly patients with advanced colorectal cancer--TLC study.

BACKGROUND: Prospective data on chemotherapy for (frail) elderly patients with advanced colorectal cancer (aCRC) are scant. UFT/leucovorin might be as effective as and less toxic than capecitabine. We firstly randomized both agents in patients >65 years with aCRC not amenable to receive combination chemotherapy. PATIENTS AND METHODS: Patients were randomised between first-line oral UFT/leucovorin and capecitabine in a Dutch multicentre trial. Primarily, efficacy and toxicity were determined. Secondary, quality of life (QoL) and abbreviated common geriatric assessment (aCGA) were analysed. RESULTS: Sixty-seven patients were randomised with a median age of 77 years and 96% being frail. After interim analysis it was decided to stop recruitment because of low accrual. At a median follow up of 34 months, the median progression-free survival (PFS) and overall survival (OS) were similar for both therapies, being 21 weeks (p=0.17) and 12 months (p=0.83), respectively. The overall response rates were 24% and 21%, respectively. Two patients died of possible treatment related complications in the UFT/leucovorin arm and 3 patients in the capecitabine arm. For UFT/leucovorin significantly less grade 3 or 4 hand/foot syndrome (0 vs 5) was observed. Overall, PFS was related to Charlson-comorbidity index (p=0.049), LDH (p=0.0011) and albumin (p=0.009). OS was related to LDH (p=0.0003), albumin (p=0.0001), QoLC30/CR38 (p=0.041), QoL visual analogue scale (VAS; p=0.016), and GFI (p=0.028). CONCLUSION: UFT/leucovorin and capecitabine had similar efficacy and different toxicity profiles in frail elderly patients with aCRC. Baseline serum levels of albumin and LDH, Charlson-comorbidity index, GFI and QoL were prognostic for clinical outcome.

[Brain metastases occurring more often in colorectal carcinoma]. / Vaker hersenmetastasen bij colorectaal carcinoom.

BACKGROUND: Colorectal carcinoma (CRC) has a high incidence. If metastatic disease develops, the liver and lungs are the most frequently involved sites. Brain metastases are rare. CASE DESCRIPTION: We present a male patient (70 years old) with lung and liver metastases of CRC. For many years the disease was in good remission with palliative chemotherapy. He developed very acute neck pain and later also vomiting. The latter turned out to be based on the presence of brain metastases, which was soon fatal. CONCLUSION: The incidence of CRC is rising and with it the incidence of symptomatic brain metastases in CRC. Due to the development of more effective systemic chemotherapy, survival of advanced CRC has improved, providing more time for symptomatic brain metastases to develop.

Polymorphisms in the enhancer region of the thymidylate synthase gene are associated with thymidylate synthase levels in normal tissues but not in malignant tissues of patients with colorectal cancer.

BACKGROUND: The enhancer region of the thymidylate synthase (TS) gene (TSER) contains a polymorphic tandem repeat sequence (2 or 3 repeats, 2R or 3R) and a single-nucleotide polymorphism (G > C) within the second repeat of the 3R alleles which might influence TS expression/activity and response to fluoropyrimidines. However, clinical studies in patients with colorectal cancer (CRC) failed to find a consistent relationship between TSER polymorphisms and protein levels as well as with clinical outcome. The analysis of the relationship between TSER genotype and TS mRNA and activity in normal and malignant tissues might explain the previous controversial data and help in the selection of useful markers to predict drug response and/or toxicity. MATERIALS AND METHODS: To address this issue, we studied TSER genotype, TS expression, and activity with specific polymerase chain reaction and activity assays (TS catalytic activity and FdUMP binding) in normal (liver, mucosa) and malignant (primary tumor and liver metastasis) tissues from 83 patients with CRC. RESULTS: No correlation between TSER genotype and TS mRNA and protein levels was observed in malignant tissues. In contrast, normal tissues harboring one or two 3RG alleles were characterized by higher TS protein levels (2.4-fold; P = .008) and catalytic activity (P < .05) compared with the other TSER genotypes. CONCLUSION: These results suggest that TSER polymorphisms do not predict tumoral TS levels possibly depending on altered TS regulation in cancer tissues, and might explain the lack of clear correlation with clinical outcome after chemotherapy with fluoropyrimidines. However, the relationship between TS phenotype and TSER genotype in normal tissues warrants further investigations in large-scale prospective studies evaluating TS genotype and fluoropyrimidine tolerability.

Retroperitoneal mature teratoma after orchidectomy for a stage IB pure embryonal testicular carcinoma.

Nonseminomatous germ cell tumor of the testis stage I will relapse in approximately 30% of patients in the first year after orchidectomy. We report a 19-year-old patient on active surveillance who presented with a retroperitoneal lymph node enlargement suggestive of metastatic disease more than 1 year after the initial diagnosis of embryonal carcinoma stage IB. Complete resection of the lymph node was performed and showed the presence of mature teratoma. Our patient had an unusual case of metastasis formation of benign histology of a previously removed highly malignant primary tumor confined to the testis.

Thymidylate synthase and dihydropyrimidine dehydrogenase mRNA expression after administration of 5-fluorouracil to patients with colorectal cancer.

This study explores the effect of 5-fluorouracil (5FU) exposure on mRNA levels of its target enzyme thymidylate synthase (TS) and the rate-limiting catabolic enzyme dihydropyrimidine dehydrogenase (DPD) in tumors of colorectal cancer patients. TS and DPD mRNA levels were determined in primary tumor and liver metastasis samples from patients who were either not pretreated (n = 29) or given one presurgery bolus of 5FU (n = 67). In both groups a wide variation in TS mRNA levels was observed. Median TS mRNA expression in 17 primary tumors of exposed patients was 3.0-fold higher than in 19 primary tumors of unexposed patients (p = 0.015). TS mRNA expression in liver metastasis samples of exposed patients (n = 16) was also higher (5.2-fold) than that of unexposed patients (n = 48; p < 0.001). Also DPD mRNA expression displayed a large degree of interpatient variation. No difference in DPD expression in liver metastasis samples was observed between exposed and unexposed patients. However, median DPD mRNA expression in 15 primary tumors of exposed patients was 3.2-fold lower than in 18 primary tumors of unexposed patients (p = 0.027). In conclusion, administration of 5FU in vivo influences the gene expression of TS and DPD.

Early Intervention with epoetin alfa during platinum-based chemotherapy: an analysis of quality-of-life results of a multicenter, randomized, controlled trial compared with population normative data.

OBJECTIVE: To evaluate the effect of epoetin alfa on quality of life (QOL) in patients with solid tumors and mild-to-moderate anemia receiving platinum-based chemotherapy relative to population norms. METHODS: In the original study, patients (n = 316) with hemoglobin (Hb) levels < or =12.1 g/dl were randomized 2:1 to receive either epoetin alfa at a dose of 10,000 U thrice weekly s.c. or best supportive care (BSC) to compare the effects on transfusion use, hematologic response, and QOL (measured by the Functional Assessment of Cancer Therapy-Anemia [FACT-An]and Cancer Linear Analogue Scale [CLAS]). The QOL data from this previously reported trial were reanalyzed here relative to population norms. RESULTS: Mean baseline QOL scores were similar between groups. At study completion, mean CLAS, FACT-An, FACT-An Anemia subscale, and FACT-An Fatigue subscale scores were significantly higher for patients given epoetin alfa than for those treated with BSC. Compared with population norms, both groups had impaired QOL at baseline. Differences in mean QOL change scores from baseline to study end for epoetin alfa versus BSC were 3.17 points for the FACT-General Total, 9.90 for the FACT-An Fatigue subscale, and 7.30 for the FACT-An Anemia subscale. This was equivalent to corrections in QOL deficits attributable to epoetin alfa of 97.3%, 40.7%, and 38.0% for the FACT-General Total, FACT-An Fatigue, and FACT-An Anemia subscale scores, respectively, versus BSC. A somewhat greater QOL benefit was observed for the FACT-An Fatigue and FACT-An Anemia subscales in the subset of patients with baseline Hb levels >10.5 g/dl. CONCLUSION: Patients in this study had impaired QOL compared with population norms. Early treatment with epoetin alfa to correct anemia improved QOL in a statistically significant and clinically meaningful way, and improvements were greater in patients with baseline Hb levels >10.5 g/dl.

Early intervention with epoetin alfa during platinum-based chemotherapy: an analysis of the results of a multicenter, randomized, controlled trial based on initial hemoglobin level.

OBJECTIVE: This analysis of the results of a randomized, controlled trial evaluating the effects of epoetin alfa (EPO) therapy on transfusion requirements, hemoglobin (Hb), and quality of life (QOL) in patients with cancer receiving platinum-based chemotherapy was conducted to evaluate the effect of initial Hb level on study outcomes. METHODS: Patients with Hb levels < or =12.1 g/dl were randomized 2:1 to receive EPO, 10,000 U three times weekly s.c. or best supportive care (BSC) until 4 weeks after their last chemotherapy cycle. For this analysis, patients were stratified by baseline Hb level (< or =9.7 g/dl, >9.7 g/dl to < or =10.5 g/dl, >10.5 g/dl to < or =11.3 g/dl, and >11.3 g/dl to < or =12.1 g/dl), and study results were reanalyzed. RESULTS: Significantly fewer EPO patients than BSC patients with initial Hb levels >9.7 g/dl to < or =12.1 g/dl required transfusions. EPO maintained Hb levels throughout the study for patients with Hb levels >11.3 g/dl to < or =12.1 g/dl, compared with a decrease with BSC. For patients with baseline Hb levels >10.5 g/dl, for whom the mean changes from baseline to last assessment were measured by the Cancer Linear Analogue Scale assessments of energy and overall QOL as well as by the Functional Assessment of Cancer Therapy (FACT)-Fatigue and FACT-An Anemia subscale, QOL scores were significantly greater with EPO than with BSC. QOL declined in patients receiving BSC, and the mean decreases in QOL scores were greater for BSC patients with baseline Hb levels >10.5 g/dl, compared with the overall BSC group. CONCLUSION: In patients with cancer receiving platinum-based chemotherapy and with baseline Hb levels >10.5 g/dl, early intervention with EPO reduces transfusions, maintains Hb level, and maintains or improves QOL. This study supports the positive effects of early intervention when analyzed according to initial Hb value.

Electroporation therapy in soft tissue sarcoma: a potentially effective novel treatment.

Purpose. Examination of the potential of electroporation therapy (EPT) in a patient with metastatic soft tissue sarcoma. Patient. A 24-year-old male who underwent extensive resection and postoperative radiotherapy for a malignant peripheral nerve sheath tumor in the right infratemporal fossa with intracranial extension and invasion of the maxillary sinus and mandible had a recurrence in the scar of his craniotomy for which he was initially treated with doxorubicin. After discontinuation of doxorubicin he developed a metastatic mass at the same site for which he was treated with electroporation therapy. Method. The subcutaneous metastasis was infiltrated with bleomycin and electroporated. Results. Gradually the tumor became increasingly necrotic and demarcated from surrounding tissue. After 10 weeks no tumor was seen anymore. The wound healed secondarily. Discussion. Intralesional bleomycin followed by EPT is potentially effective, well tolerated, and easy to perform in well accessible soft tissue sarcoma sites.