H.W.M. van Laarhoven

Beyond RECIST: molecular and functional imaging techniques for evaluation of response to targeted therapy.

The development of targeted therapies is a major breakthrough in the treatment of cancer. By evoking necrosis and cavitation, evaluation based on tumour size alone, as is done in the RECIST criteria, is no longer an adequate method. New molecular and functional imaging techniques are developed. This review focuses on the use of new imaging modalities for the evaluation of treatment response of pathway based targeted therapies. First, the basic principles of functional and molecular imaging modalities are briefly discussed. Thereafter, their clinical application in targeted therapies is correlated to the underlying biological mechanism. In this way, the best method for response evaluation for a new agent can be identified.

The Cancer Worry Scale: detecting fear of recurrence in breast cancer survivors.

Background: In 9% to 34% of cancer patients, the fear of cancer recurrence becomes so overwhelming that it affects quality of life. Clinicians need a brief questionnaire with a cutoff point that is able to differentiate between high- and low-fearful survivors. Objective: This study investigated if the Cancer Worry Scale (CWS) could serve as an instrument to detect high levels of fear of recurrence in female breast cancer survivors. Methods: One hundred ninety-four female breast cancer patients were assessed up to 11 years after their primary treatment for cancer. The women returned the questionnaires including the 8-item CWS, 2 items of the Cancer Acceptance Scale, the Checklist Individual Strength-Fatigue subscale, and the Cancer Empowerment Questionnaire. Results: A cutoff score of 13 versus 14 (low: ⩽13, high: ≥14) on the CWS was optimal for detecting severe levels of fear of recurrence. A cutoff score of 11 versus 12 (low: ⩽11, high: ≥12) was optimal for screening. The Cronbach &agr; coefficient of the CWS was .87; evidence to support the convergent and divergent validity of the CWS was also obtained. The CWS is able to detect high levels of fear of recurrence. Conclusion: The CWS is a reliable and valid questionnaire to assess fear of recurrence in breast cancer survivors. Implications for Practice: With the CWS, it is possible for nurses to screen breast cancer survivors for severe levels of fear of cancer recurrence. Thereby, nurses can screen and assist survivors in accessing appropriate and available support.

Lymph node retrieval during esophagectomy with and without neoadjuvant chemoradiotherapy: prognostic and therapeutic impact on survival.

Objectives:We aimed to examine the association between total number of resected nodes and survival in patients after esophagectomy with and without nCRT. Background:Most studies concerning the potentially positive effect of extended lymphadenectomy on survival have been performed in patients who underwent surgery alone. As nCRT is known to frequently “sterilize” regional nodes, it is unclear whether extended lymphadenectomy after nCRT is still useful. Methods:Patients from the randomized CROSS-trial who completed the entire protocol (ie, surgery alone or chemoradiotherapy + surgery) were included. With Cox regression models, we compared the impact of number of resected nodes as well as resected positive nodes on survival in both groups. Results:One hundred sixty-one patients underwent surgery alone, and 159 patients received multimodality treatment. The median (interquartile range) number of resected nodes was 18 (12–27) and 14 (9–21), with 2 (1–6) and 0 (0–1) resected positive nodes, respectively. Persistent lymph node positivity after nCRT had a greater negative prognostic impact on survival as compared with lymph node positivity after surgery alone. The total number of resected nodes was significantly associated with survival for patients in the surgery-alone arm (hazard ratio per 10 additionally resected nodes, 0.76; P = 0.007), but not in the multimodality arm (hazard ratio 1.00; P = 0.98). Conclusions:The number of resected nodes had a prognostic impact on survival in patients after surgery alone, but its therapeutic value is still controversial. After nCRT, the number of resected nodes was not associated with survival. These data question the indication for maximization of lymphadenectomy after nCRT.

Functional MRI techniques demonstrate early vascular changes in renal cell cancer patients treated with sunitinib: a pilot study

Abstract Objective: To assess the early vascular effects of sunitinib in patients with renal cell carcinoma (RCC) with diffusion-weighted magnetic resonance imaging (DWI), dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and T2* perfusion MRI. Patients and methods: In 10 patients with abdominal RCC lesions, DWI, DCE-MRI and T2* perfusion MRI measurements at 3 Tesla were performed at baseline, 3 and 10 days after start of sunitinib. VEGF-A plasma levels were measured on days 0, 3 and 10. Results: DWI showed a significant increase in the apparent diffusion coefficient (×10−6 s/mm2) from baseline (mean 1158, range 814–2003) to day 3 (mean 1306, range 1008–2097, P = 0.015) followed by a decrease to baseline levels at day 10 (mean 1132, range 719–2005, P = 0.001). No significant changes were found in mean DCE-MRI parameters. T2* perfusion MRI showed a significant decrease in relative tumor blood volume (rBV) and relative tumor blood flow (rBF) at day 3 (rBV P = 0.037, rBF P = 0.018) and day 10 (rBV P = 0.006, rBF P = 0.009). VEGF-A plasma levels significantly increased after 10 days, but did not correlate with MRI parameters. Conclusions: Sunitinib induces antiangiogenic effects as measured by DWI and T2*-perfusion MRI, 3 and 10 days after the start of the initial treatment. DCE-MRI did not show significant changes. In the near future, early functional MRI-based evaluation can play an important role in tailoring treatment to the individual patient with RCC. Further investigation is warranted.

Effects of the tumor vasculature targeting agent NGR-TNF on the tumor microenvironment in murine lymphomas.

SummaryTNF-α may improve drug delivery to tumors by alteration of vascular permeability. However, toxicity precludes its systemic administration in patients. NGR-TNF comprises TNF coupled to the peptide CNGRC, which is a ligand for CD13. CD13 is expressed on tumor vasculature. Therefore, to assess the efficacy of NGR-TNF its biological effect on tumor vasculature should be measured rather than its effect on tumor growth. The aim of this study was to assess the effects of a low dose of NGR-TNF (5 ng/kg) on vascular permeability, tumor hypoxia, perfusion and proliferation in lymphoma bearing mice. MRI measurements with blood pool contrast agent showed an increased leakage of the contrast agent from the vasculature in NGR-TNF treated tumors compared with controls (p < 0.05), suggesting NGR-TNF-induced vascular permeability. Immunohistochemical analysis two hours after NGR-TNF treatment showed a decrease in tumor hypoxia (p < 0.1) and an increase in labeling index of the S-phase marker bromodeoxyuridine (p < 0.1), possibly due to an increase in tumor blood flow after NGR-TNF treatment. Although a decrease in tumor hypoxia and an increase in labeling index could have lead to increased tumor growth, in this experiment after one day a decrease in tumor volume was measured. Possibly, the effects on tumor hypoxia and proliferation two hours after treatment are transient and overruled by other, more longlasting effects. For example, the observed increase in vascular permeability may lead to haemoconcentration and increased interstitial pressure, ultimately resulting in an reduction of tumor blood flow and thus a decrease in tumor growth. A beneficial effect of NGR-TNF in combination with other therapeutical agents may therefore critically depend on the sequence and timing of the regimens. Currently, NGR-TNF is being tested in clinical studies.

Definitive chemoradiation for patients with inoperable and/or unresectable esophageal cancer: locoregional recurrence pattern

A locoregional recurrence after definitive chemoradiation (dCRT) for patients with inoperable or unresectable esophageal cancer occurs in about 50% of the patients and is a major cause of failure with a poor prognosis. The aim of this study was to determine the pattern of locoregional recurrence and its prognostic factors after dCRT in order to search for improvements in radiation treatment. We retrospectively reviewed 184 patients treated with external beam radiotherapy (50.4 Gray/28 fractions), combined with weekly concurrent paclitaxel and carboplatin. Locoregional recurrences were defined by clinical signs of recurrent or progressive disease, combined with progression on computed tomography/positron emission tomography-computed tomography scan, or suspicious endoscopic findings and/or histological proof of recurrence. The site of locoregional recurrence was analyzed with respect to the borders of the radiation fields. After a mean follow up of 22.8 months, 76 patients (41%) had evidence of locoregional recurrence. The 3-years locoregional recurrence-free rate was 45%. The majority of locoregional recurrences occurred within 12 months, nearly all within 24 months. The majority of these patients failed at the site of the primary tumor (86%). Infield locoregional recurrences at the site of the lymph nodes only occurred in 1% compared with 57% at the site of the primary tumor only. Outfield locoregional lymph node recurrences occurred in 22%, without infield recurrence occurred in only 4% of all patients. The 1-, 3-, and 5-year overall survival was 65%, 28%, and 21%, respectively. The current analysis demonstrates that a locoregional recurrence after dCRT occurs in 41% of the patients, the majority at the site of the primary tumor. These data suggest a benefit of dose intensification of the primary tumor, but not at the site of the lymph nodes. Higher radiation doses should be assessed with prospective trials.

Inflammatory breast cancer: An overview

Inflammatory breast cancer (IBC) is the most aggressive entity of breast cancer. Management involves coordination of multidisciplinary management and usually includes neoadjuvant chemotherapy, ablative surgery if a tumor-free resection margin is expected and locoregional radiotherapy. This multimodal therapeutic approach has significantly improved patient survival. However, the median overall survival among women with IBC is still poor. By elucidating the biologic characteristics of IBC, new treatment options may become available. We performed a comprehensive review of the English-language literature on IBC through computerized literature searches. The objective of the current review is to present an overview of the literature related to the biology, imaging and multidisciplinary treatment of inflammatory breast cancer.

New biomarkers for early detection of cardiotoxicity after treatment with docetaxel, doxorubicin and cyclophosphamide

Abstract Objective: Assessing a diverse biomarker panel (NT-proBNP, TNF-α, galectin-3, IL-6, Troponin I, ST2 and sFlt-1) to detect subclinical cardiotoxicity after treatment with anthracyclines. Methods: Of 55 breast cancer patients biomarkers were assessed and echocardiography was performed one year after treatment with anthracyclines. Results: 29.1% of patients showed abnormal biomarker levels: NT-proBNP in 18.2%, TNF-α and Galectin-3 in 7.3%. IL-6, troponin I, ST2 and sFlt-1 were normal in all patients. A correlation between left ventricular ejection fraction (LVEF) and NT-proBNP was observed (r = −0.564, p ≤ 0.01). Conclusion: The evaluated biomarkers do not contribute to early detection. Future research should focus on NT-proBNP. Trial registration: ClinicalTrials.gov identifier: NCT01246856.

Arthralgia during aromatase inhibitor treatment in early breast cancer patients: prevalence, impact, and recognition by healthcare providers

Background: Many breast cancer patients experience arthralgia symptoms during aromatase inhibitor (AI) treatment, which leads to poor compliance and a lower quality of life. Objective: The research questions of this study were as follows: (1) What is the incidence of arthralgia during AI treatment in early breast cancer patients, (2) what is the impact of AI-associated arthralgia on hand function, daily activities, and AI adherence, and (3) does the healthcare provider recognize AI-associated arthralgia as relevant in clinical practice? Methods: A total of 57 breast cancer patients of a University Breast Cancer Clinic participated in this study. Each patient completed a questionnaire, performed 2 function tests (goniometry of the wrist and a handgrip strength measurement), and consented to a review of the medical chart. Results: Forty-two breast cancer patients (74%) reported symptoms of arthralgia. All patients with arthralgia symptoms experienced an impact on their daily activities, and 65% had a decrease in hand and finger function. Sixty-nine percent of all patients were fully adherent in their medicine treatment. In 26% of cases with arthralgia, the symptoms were not reported in the medical chart. Conclusion: Given the large number of patients with AI-associated arthralgia and its impact on daily life and functioning, it is of great importance to improve the recognition and care of arthralgia symptoms during AI treatment. Implications for Practice: Oncology nurses could play an important role in assessment of modifiable risk factors, providing lifestyle advice and support in coping.

Targeted therapy for advanced esophagogastric adenocarcinoma

BACKGROUND Esophagogastric adenocarcinoma (EGC) is a molecular heterogeneous disease, and therefore, strategies with targeted therapy may be effective. AIM This review will discuss phase III studies in advanced EGC concerning biologic agents targeting molecular pathways, such as EGFR, HER2, VEGFR, mTOR and c-MET. RESULTS HER2 inhibition with trastuzumab in combination with first line chemotherapy results in a significant survival benefit for HER2 positive carcinoma patients. Chemotherapy in combination with bevacizumab does not prolong survival in an unselected EGC patient cohort. Preliminary results of trials with EGFR, VEGFR and mTOR inhibitors are, thus far, disappointing in unselected patient cohorts. Promising studies in biomarker selected cohorts with HER2, EGFR and c-MET inhibitors are ongoing. CONCLUSION Targeted therapy in EGC is emerging. Improved insight in the biologic background of EGC is needed to improve patient selection, combine agents and discover new targets and agents. This may improve outcome for metastasized EGC patients.