Orhan Onder Eren

Comparison of Metabolic and Anatomic Response to Chemotherapy Based on PERCIST and RECIST in Patients with Advanced Stage Non-small Cell Lung Cancer

BACKGROUND The aim of this study was to explore the prognostic role of metabolic response to chemotherapy, determined by FDG-PET, in patients with metastatic non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS Thirty patients with metastatic NSCLC were analyzed for prognostic factors related to overall survival (OS) and progression free survival (PFS). Disease evaluation was conducted with FDG-PET/CT and contrast-enhanced CT prior to and at the end of first-line chemotherapy. Response evaluation of 19 of 30 patients was also performed after 2-3 cycles of chemotherapy. Morphological and metabolic responses were assessed according to RECIST and PERCIST, respectively. RESULTS The median OS and PFS were 11 months and 6.2 months, respectively. At the end of first-line chemotherapy, 10 patients achieved metabolic and anatomic responses. Of the 19 patients who had an interim response analysis after 2-3 cycles of chemotherapy, 3 achieved an anatomic response, while 9 achieved a metabolic response. In univariate analyses, favorable prognostic factors for OS were number of cycles of first-line chemotherapy, and achieving a response to chemotherapy at completion of therapy according to the PERCIST and RECIST. The OS of patients with a metabolic response after 2-3 cycles of chemotherapy was also significantly extended. Anatomic response at interim analysis did not predict OS, probably due to few patients with anatomic response. In multivariate analyses, metabolic response after completion of therapy was an independent prognostic factor for OS. CONCLUSIONS Metabolic response is at least as effective as anatomic response in predicting survival. Metabolic response may be an earlier predictive factor for treatment response and OS in NSCLC patients.

Voltage-gated sodium channel blockers can augment the efficacy of chemotherapeutics by their inhibitory effect on epithelial-mesenchymal transition

Epithelial-mesenchymal transition (EMT) is a process during which cancer cells become more invasive and chemo resistant. EMT may also be associated with tumor dormancy which prevents the cure of cancer with adjuvant treatment. Chemo resistance and dormancy may also decrease response to cytotoxic agents during treatment of metastatic disease. Voltage gated sodium channels (VGSCs) are overexpressed in many cancer types, particularly in those with more aggressive and metastatic potential. VGSCs are thought to be associated with increased invasive and migratory capacity of cancer cells. Inhibition of VGSCs may inhibit EMT and angiogenesis through interaction with intracellular calcium activity and endothelial cells respectively. Blockage of these channels combined with other anticancer therapies may be effective in both adjuvant and palliative setting. Colonization at secondary site may be decelerated by VGSCs inhibition through impeding angiogenesis. This may lead to a temporary palliation of symptoms related to tumor burden in patients with metastatic disease.

Pituitary Metastasis of Colon Adenocarcinoma: A Rare Occurrence

Metastasis to the pituitary gland from solid tumors is quite rare [1, 2]. It is usually detected in the presence of widespread metastatic disease [1–4]. The most common primaries of metastatic pituitary carcinomas are breast and lung cancers [2, 3]. Pituitary metastases are usually asymptomatic and constitute a small fraction of pituitary masses [3, 4]. Symptoms of pituitary metastasis may vary from visual disturbance to endocrine dysfunction such as diabetes insipidus [2, 5] and are caused by mass effect and compression of surrounding structures [5, 6]. Brain metastasis, particularly to the pituitary gland, from colorectal cancer is infrequent [7, 9]. Herein, we report a case of colon carcinoma with metastasis to the pituitary gland which developed diabetes insipidus and central hypothyroidism during follow-up.

Safety, Feasibility, and Efficacy of Capecitabine Maintenance in Patients With Advanced Gastric Cancer: A Retrospective Study

Gastric cancer is still one of the cancers with highest mortality. Most patients present with advanced-stage disease. Palliative chemotherapy is usually the only treatment option for patients with advanced gastric cancer (AGC). Maintenance chemotherapy is an evolving concept in medical oncology. Maintenance chemotherapy can be administered with the same drug(s) in the initial regimen or with an alternative agent. In this article, we report our experience with capecitabine as a maintenance agent for patients with AGC. No treatment-related death was observed due to use of capecitabine. Median progression-free survival was 10.4 months, and median overall survival was 19.7 months. Activity and toxicity profile of capecitabine seems favorable as a maintenance agent in AGC. We believe that capecitabine deserves further trials as a maintenance agent for patients with AGC.

Cancer-related fatigue: can it be due to adrenal suppression secondary to high-dose steroids used as antiemetic?

To the editor: The use of dexamethasone for cancer-related fatigue (CRF) in patients with advanced cancer is a controversial issue. Beneficial effects of dexamethasone may be counterbalanced by its serious side effects. The exact mechanism of the action of steroids on cancer-related fatigue is unknown. Recently, Yennurajalingam et al. hypothesized that dexamethasone exerts its effects on CRF mainly by interfering with the peripheral effects of proinflammatory cytokines [1]. We believe that this may not be the case for some of patients with CRF. The exact pathogenesis of CRF is unknown. A role of systemic inflammation or imbalance between hypothalamicpituitary-adrenal (HPA) axis and systemic cytokines has been proposed [2, 3]. Advanced stage cancer represents a state of chronic stress. Low levels of endogenous cortisol, which may be associated with symptoms in advanced cancer, had been demonstrated by Lundstrom et al. [4]. Major symptoms of adrenal insufficiency (i.e., fatigue, nausea, loss of appetite) may be misinterpreted as CRF. Indeed, some patients treated for CRF may have unrecognized adrenal insufficiency. High dose of dexamethasone (8–16 mg/day) is commonly used as antiemetic therapy in highly and moderately emetic regimens. Updated ASCO guidelines on antiemetics recommend a 4-day course of dexamethasone (12 mg on day 1 and 8 mg on days 2–4) for highly emetogenic chemotherapy and 1–3-day 8 mg course for moderately emetogenic chemotherapy [5]. Highdose steroids may suppress the hypothalamic pituitary and adrenal axis, even with short-term use [6]. Han et al. published their article on adrenal suppression related to the use of dexamethasone as an antiemetic therapy in patients with cancer in July 2012 [7]. Patients receiving dexamethasone as an antiemetic for at least 3 days per cycle and for more than 3 months were included in this study. Adrenal suppression was demonstrated biochemically in 45 of the 103 patients (43.7 %). Adrenal suppression was more common in patients receiving megestrol acetate concomitantly. Daily replacement therapy with 7.5–10 mg of prednisolone for 1–2 weeks in patients with suppressed HPA axis resulted in the improvement of symptoms associated with adrenal insufficiency. This dose of prednisolone is approximately equivalent to 1 mg of dexamethasone [8]. This is about one eighth of the dose recommended in the study of Yennurajalingam et al. We believe that this lower dose may allow the use of steroid for longer periods and spare some of the patients with CRF from serious side effects of higher doses of steroids. Metabolic (i.e., hyperglycemia, hypokalemia) and muscular side effects (i.e., proximal muscle weakness) of long-term use of steroids may be confused with CRF or even increase the severity of CRF. Lower dexamethasone dose will probably cause less metabolic and muscular side effects. For those patients with continuing symptoms of CRF, steroid dose may be gradually increased. In the current study, no follow up for the quality of life was made after cessation of dexamethasone [1]. As CRF is a chronic problem, symptoms may become worse after cessation of high-dose dexamethasone. Lesser dose of dexamethasone may be used more safely for longer periods of time for some patients with this chronic problem. There are still unanswered questions about CRF: What should be done for patients without biochemical evidence of HPA axis suppression? Should we search for biochemical evidence of inflammation (i.e., C-reactive protein) in this group of patients? Should we start with higher doses of dexamethasone when we have laboratory evidence of both systemic inflammation and HPA axis suppression? Should adrenal insufficiency be in the routine checklist of evaluation O. O. Eren (*) :B. Oyan Medical Oncology Section, Department of Internal Medicine, Yeditepe University Hospital, Devlet yolu, Ankara Caddesi, 102-104 Istanbul, Turkey e-mail: droneren@hotmail.com

Is It Time for Maintenance Chemotherapy for Advanced Gastric Adenocarcinoma

TO THE EDITOR: The recent article by Shah et al described a randomized, multicenter, phase II study of modified docetaxel, cisplatin, and fluorouracil (mDCF) versus docetaxel, cisplatin, and fluorouracil plus growth factor support in patients with metastatic gastric adenocarcinoma. Docetaxel, although effective in treatment of advanced gastric cancer (AGC), also has a serious adverse effect profile. The incidence and severity of adverse events may also increase with concomitant use of platinum analogs and/or fluoropyrimidines. Hematologic and GI toxicities are particularly considerable. We believe that the results of the trial by Shah et al not only render triplet regimens more feasible for oncology practice, but also raise the concept of maintenance on the agenda of AGC. The authors state that patients could have continued with less intensive or maintenance chemotherapy after 6 months of therapy. We would like to know how many patients received some sort of maintenance treatment in each group. If the percentage of patients receiving maintenance in the mDCF group was greater (which can be expected as a result of better efficacy and tolerability), this might have contributed to longer median overall survival in this group of patients. Maintenance chemotherapy is an evolving concept in medical oncology. The role of maintenance therapy has been demonstrated in non–small-cell lung cancer. We and others have shown that capecitabine maintenance may be feasible in treatment of AGC, although data are still limited. Considering the toxicity and cost associated with docetaxelcontaining regimens, capecitabine may be a viable option as maintenance treatment of AGC if no progression occurs after a predefined number of cycles of chemotherapy. In addition, we would like to know whether the human epidermal growth factor receptor 2 status of the patients is known? If human epidermal growth factor receptor 2 status is known, is there any overall survival difference in this subset of patients? The impressive median overall survival time of greater than 18 months in this trial is longer than the median survival reported in the phase III Trastuzumab for Gastric Cancer trial. Therefore, the mDCF regimen may be a better backbone for combination with trastuzumab in future trials and may further improve overall survival.

Voltage-gated sodium channel blockade for inhibition of EMT

We read the excellent review article by Davis et al. entitled ‘Targeting EMT in cancer: opportunities for pharmacological intervention’ [1xTargeting EMT in cancer: opportunities for pharmacological intervention. Davis, F.M. et al. Trends Pharmacol. Sci. 2014; 35: 479–488Abstract | Full Text | Full Text PDF | PubMed | Scopus (34)See all References[1] with great interest. The authors listed possible targets for inhibiting epithelial–mesenchymal transition (EMT)-associated metastasis. We think that the concept of blockade of voltage-gated sodium channels (VGSCs) for inhibiting the metastatic process deserves further consideration.It is known that VGSCs, which are normally expressed in excitable cells, are expressed aberrantly in many types of cancer cells [2xVoltage-gated sodium channels and metastatic disease. Brackenbury, W.J. Channels. 2012; 6: 352–361Crossref | PubMed | Scopus (41)See all References[2]. Their expression is associated with the aggressive clinical behavior of cancer cells. VGSCs (as other ion channels) are thought to be associated with many characteristics of cancer [3xIon channels and the hallmarks of cancer. Prevarskaya, N. et al. Trends Mol. Med. 2010; 16: 107–121Abstract | Full Text | Full Text PDF | PubMed | Scopus (123)See all References[3]. VGSCs are known to strengthen the migratory and invasive properties of cancer cells via regulation of pH, gene expression, and intracellular calcium (Ca2+) levels [4xVoltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Fraser, S.P. et al. Clin. Cancer Res. 2005; 11: 5381–5389Crossref | PubMed | Scopus (145)See all References, 5xNav1.5 enhances breast cancer cell invasiveness by increasing NHE1-dependent H+ efflux in caveolae. Brisson, L. et al. Oncogene. 2011; 30: 2070–2076Crossref | PubMed | Scopus (51)See all References, 6xVoltage-gated Na+ channel SCN5A is a key regulator of a gene transcriptional network that controls colon cancer invasion. House, C.D. et al. Cancer Res. 2010; 70: 6957–6967Crossref | PubMed | Scopus (74)See all References, 7xTherapeutic potential for phenytoin: targeting Nav1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Yang, M. et al. Breast Cancer Res. Treat. 2012; 134: 603–615Crossref | PubMed | Scopus (42)See all References]. Recently, Davis and colleagues [8xInduction of epithelial–mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent. Davis, F.M. et al. Oncogene. 2013; 33: 2307–2316Crossref | PubMed | Scopus (42)See all References[8] reported that attenuation of Ca2+ signaling via intracellular Ca2+ chelation inhibits epidermal growth factor (EGF)- and hypoxia-induced EMT in breast cancer cell lines. In addition, Ca2+ chelation causes downregulation of EGF-induced activation of STAT3 phosphorylation and expression of the EMT marker vimentin [8xInduction of epithelial–mesenchymal transition (EMT) in breast cancer cells is calcium signal dependent. Davis, F.M. et al. Oncogene. 2013; 33: 2307–2316Crossref | PubMed | Scopus (42)See all References[8]. Blockade of VGSCs inhibits metastatic capacity, but not proliferation, of cancer cells, and this has been shown in breast and prostate cancer models [9xVoltage-gated sodium channel expression and potentiation of human breast cancer metastasis. Fraser, S.P. et al. Clin. Cancer Res. 2005; 11: 5381–5389Crossref | PubMed | Scopus (178)See all References, 10xContribution of functional voltage-gated Na+ channel expression to cell behaviors involved in the metastatic cascade in rat prostate cancer. I. Lateral motility. Fraser, S.P. et al. J. Cell. Physiol. 2003; 195: 479–487Crossref | PubMed | Scopus (94)See all References]. The researchers reported that the mechanisms governing primary and secondary tumor growth (i.e., colonization at secondary sites) differ, which might be why proliferation at secondary sites is not affected by VGSCs. Blockade of VGSCs via tetrodotoxin – a potent highly-selective sodium channel blocker – significantly decreased the number, but not the size, of metastatic lesions in an xenograft model of prostate carcinoma [11xVoltage-gated sodium channel activity promotes prostate cancer metastasis in vivo. Yildirim, S. et al. Cancer Lett. 2012; 323: 58–61Abstract | Full Text | Full Text PDF | PubMed | Scopus (30)See all References[11]. The researchers concluded that VGSC blockers were unable to inhibit proliferation at secondary sites. We think this effect of VGSG blockade is due to inhibition of EMT and a consequent reduction in the metastatic capacity of cancer cells. Because inhibition of VGSCs does not appear to have a significant effect on proliferation at secondary sites, the size of the metastatic lesions was not affected. This also indicates that VGSCs do not have strong inhibitory activity on the mesenchymal–epithelial transition (MET). We agree that inhibition of EMT (i.e., strategies to promote MET) might hasten the colonization of cancer cells that have already left the primary site and/or reinforce the viability of metastatic deposits; however, we also know that proliferating cells are more sensitive to the effects of cytotoxic chemotherapy and targeted therapies. In the presence of effective systemic treatment, inhibition of EMT might be of less potential hazard. Inexpensive drugs without serious side effects that have significant sodium channel-blocking activity, such as local anesthetics, anticonvulsants, anti-arrhythmics, and anti-hypertensives, could be tested in future trials on blockade of VGSCs and inhibition of EMT [12xPersistent current blockers of voltage-gated sodium channels: a clinical opportunity for controlling metastatic disease. Djamgoz, M.B. et al. Recent Pat. Anticancer Drug Discov. 2013; 8: 66–84Crossref | PubMedSee all References[12].In conclusion, blockade of VGSCs could be a potential strategy for inhibiting EMT, and might reduce the invasion, migratory capacity, and chemoresistance of cancer cells. Because blockade of VGSCs does not appear to negatively affect MET, we think this treatment strategy could even be combined with cytotoxic chemotherapy or targeted therapies.

Bilateral synchronous adrenal metastasis of invasive ductal carcinoma treated with multimodality therapy including adrenalectomy and oophorectomy.

A 38-year-old woman presented with a mass in the left breast. Biopsy of the lesion revealed invasive ductal carcinoma. Bilateral adrenal metastasis was detected in whole body positron emission tomography scanning. Needle biopsy of the left adrenal lesion proved infiltration of malignant cells from breast carcinoma. After eight cycles of neoadjuvant (preoperative) chemotherapy, mastectomy, bilateral adrenalectomy, and bilateral oopherectomy were performed. No further hormonal treatment was recommended due to the resection of both adrenal glands and ovaries. The patient is still followed without any sign of progression. To our knowledge, this is the first case representing multimodality approach to breast cancer with bilateral synchronous adrenal metastasis. Patients with oligometastatic disease may benefit from aggressive treatment including local therapies.

Should we be more cautious about replacement of vitamin B12 in patients with cancer receiving cytotoxic chemotherapy

Vitamin B12 (Cbl) deficiency may cause hematologic and neurologic dysfunction. Replacement therapy is effective in correcting hematologic abnormalities and improving neurologic symptoms. Cbl is known to have antioxidant activity. This antioxidant activity may antagonize the effects of chemotherapeutics (i.e. genotoxic effects of paclitaxel) on tumor DNA. We claim that Cbl replacement should be done more cautiously in patients receiving cytotoxic chemotherapy.

Gastric metastasis in a patient with lobular breast carcinoma 6 years after diagnosis.

To the editor: The stomach is a rare site of metastasis for solid tumors. Breast cancer is among the most common tumors that metastasize to the stomach [1]. Herein we present a case of breast cancer with gastric metastasis 6 years after diagnosis. A 37-year-old woman presented with chief complaint of abdominal pain in 2008. Ascites and left adnexal mass were detected on radiologic imaging. Diagnostic laparotomy was performed. Pathologic examination of adnexial mass revealed metastasis of invasive lobular carcinoma of the breast. The tumor stained immunohistochemically positive for estrogen and progesteron receptors. Magnetic resonance imaging showed diffuse bilateral infiltration in the breasts. Biopsy of the breast revealed invasive lobular carcinoma staining positively for estrogen and progesteron receptors. The patient was treated with palliative intent with various cytotoxic and hormonal agents. In December 2013, she presented with dyspepsia refractory to proton pump inhibitors and antiacid medications. Many millimetric eroded areas were detected at gastric corpus at upper gastrointestinal endoscopy. Mucosa was pale and edematous at peripyloric region where raised and eroded lesions from mucosa were seen. Multiple biopsies from these lesions were performed (Fig. 1). Pathologic examination revealed submucosal infiltration with atypical epithelial cells. These cells were immunostaining positively for estrogen receptor and gross cystic disease fluid protein (GCDFP-15) (Fig. 1). These findings were compatible with metastasis of invasive lobular carcinoma. Treatment with eribulin started due to disease progression. Ascites accumulation was detected at the same time, and paracentesis was performed for palliation. Ascitic fluid was containing malignant cells. The patient died 3 months after stomach metastasis due to septic shock. Invasive lobular carcinoma of the breast have higher risk of metastasis to atypical sites (e.g., peritoneum, adnexa, stomach) than invasive ductal carcinoma [2]. Most of the breast tumors that metastasize to the stomach are histologically lobular carcinomas [3, 4]. Pain and epigastric symptoms are commonly seen in gastric metastasis. We performed upper gastrointestinal system endoscopy for persistent and refractory epigastric pain. Endoscopic view was compatible with erosive gastritis albeit final pathologic examination of the endoscopic biopsy revealed metastasis of lobular carcinoma. Breast cancer may metastasize to the stomach many years after diagnosis, usually in the presence of widespread metastatic disease. In our case, positive immunostaining for O. O. Eren :O. Sonmez : B. Oyan Department of Medical Oncology, Yeditepe University Hospital, Istanbul, Turkey