Bulent Cetin

Is the Pretreatment Neutrophil to Lymphocyte Ratio an Important Prognostic Parameter in Patients with Metastatic Renal Cell Carcinoma

BACKGROUND Tyrosine kinase inhibitor is a standard treatment for mRCC. The NLR, an index of systemic inflammation, is associated with outcome in several cancer types. To study the association of pretreatment NLR with PFS and overall survival (OS) of patients treated with VEGF-targeted therapy. PATIENTS AND METHODS We retrospectively studied an unselected cohort of patients with mRCC, who were treated with TKIs. Kaplan-Meier and log-rank analyses were employed on PFS and OS and multivariate Cox proportional hazard model analyzed clinical parameters for their prognostic relevance. RESULTS A total of 100 patients with mRCC who had early progressed after first-line therapy with interferon-α were included in this retrospective multicenter study conducted at 4 centers between February 2008 and December 2011. The median of the NLR was 3.04 and patients were divided into 2 higher and lower NLR groups according to median of NLR. Median PFS was 9 versus 11 months in patients with baseline NLR > 3.04 versus ≤ 3.04 (P = .009). The median OS was 16 months versus 29 months, in patients with NLR > 3.04 versus ≤ 3.04, respectively (P = .004). In the whole group OS was independently associated with higher NLR (hazard ratio [HR], 2.406; P = .004), PFS more than 6 months (HR, 4.081; P = .0001), and sex (HR, 2.342; P = .040). On the other hand in the higher NLR group (HR, 1.107; P = .009) Memorial Sloan-Kettering Cancer Center score (HR, 3.398; P = .0001) was associated with PFS. CONCLUSION In patients with mRCC treated with VEGF-targeted therapy, pretreatment NLR, the duration of PFS might be associated with OS. This should be investigated prospectively.

Prognostic Factors for Overall Survival in Patients With Metastatic Colorectal Carcinoma Treated With Vascular Endothelial Growth Factor-Targeting Agents

OBJECTIVE Angiogenesis represents a key element in the pathogenesis of malignancy. There are no robust data on prognostic factors for overall survival (OS) in patients with metastatic colorectal cancer treated with vascular endothelial growth factor (VEGF)-targeted therapy. The present study was conducted to establish a prognostic model for patients using an oxaliplatin-based or irinotecan-based chemotherapy plus bevacizumab in metastatic colorectal cancer. METHODS Baseline characteristics and outcomes on 170 patients treated with FOLFIRI or XELOX plus anti-VEGF therapy-naive metastatic colorectal cancer were collected from three Turkey cancer centers. Cox proportional hazards regression was used to identify independent prognostic factors for OS. RESULTS The median OS for the whole cohort was 19 months (95% CI, 14.3 to 23.6 months). Three of the seven adverse prognostic factors according to the Anatolian Society of Medical Oncology (ASMO) were independent predictors of short survival: serum lactate dehydrogenase (LDH) greater than the upper limit of normal (ULN; p<0.001); neutrophils greater than the ULN (p<0.0014); and progression free survival (PFS) less than 6 months (p =0.001). CONCLUSION Serum LDH and neutrophil levels were the main prognostic factors in predicting survival, followed by PFS. This model validates incorporation of components of the ASMO model into patient care and clinical trials that use VEGF-targeting agents.

Lapatinib plus Capecitabine for HER2-Positive Advanced-Stage Breast Cancer in Elderly Women: Review of the Anatolian Society of Medical Oncology (ASMO) Experience.

Background: The efficacy and safety of the lapatinib and capecitabine combination remain elusive in elderly patients with metastatic breast cancer (MBC), who progress after trastuzumab-based therapy. Patients and Methods: A total of 26 patients with HER2-positive MBC were included in this retrospective multicenter study. Median age was 69 years (range 65-82 years). All patients were treated with the combination of lapatinib (1,250 mg/day, continuously) and capecitabine (2,000 mg/m2 on days 1-14 of a 21-day cycle). Data on demographics, clinical outcome, and toxicity were collected for descriptive analyses. Results: The median follow-up was 10 months (range 2-31 months). An overall response rate of 33.4% was achieved, including 1 complete response (3.8%), and 8 partial responses (30.8%). Median progression-free survival was 7 months (95% confidence interval (CI) 5-8), and the median overall survival was 15 months (95% CI 11-19). Most common side effects were fatigue (53.8%), diarrhea (46%), vomiting (36.3%), hand-foot syndrome (34.5%), and anorexia (34.6%). Grade 3-4 toxicities were identified as hand-foot syndrome (3.8%), diarrhea (7.6%), and fatigue (11.5%). There were no symptomatic cardiac events. Conclusion: Lapatinib and capecitabine combination therapy was effective and well tolerated in elderly patients with MBC, who had progressive disease after trastuzumab-based therapy.

Acute cholecystitis in a patient with metastatic renal cell carcinoma treated with everolimus

Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), a therapeutic target for metastatic renal cell carcinoma. A 58-year-old woman was treated with everolimus as a third-line therapy for metastatic clear-cell renal carcinoma. She was given oral everolimus 10 mg once daily. During the fourth week of her first cycle, the patient was admitted to our hospital because of an acute-onset, right upper quadrant pain associated with nausea and vomiting. She was diagnosed with acute cholecystitis, which was treated with broad-spectrum antibiotics, and everolimus therapy was discontinued. A follow-up computed tomography scan of the abdomen revealed a complete resolution of gallbladder changes. Our patient did not have major risk factors for developing a cholecystitis except for a relative immunosuppressed state secondary to her advanced renal cancer. The Naranjo adverse drug reaction probability scale score for this event was 5, indicating a probable association of the event with everolimus. Because the use of everolimus is expanding in clinical practice, we want to alert the oncology community about this uncommon and life-threatening complication in patients receiving everolimus or another agent with antiangiogenic activity. To our best knowledge, only one case of an acute cholangitis associated with everolimus in a metastatic renal cell carcinoma has been reported. We report herein the first case of a metastatic renal cell carcinoma developed everolimus-associated cholecystitis that was completely reversed after drug withdrawal.

Sunitinib- and Sorafenib-Induced Nephrotic Syndrome in a Patient with Gastrointestinal Stromal Tumor

Objective TO report a case of nephrotic syndrome (NS) induced by both sunitinib and sorafenib therapy. Case Summary A 61-year-old woman with metastatic gastrointestinal stromal tumor (GIST) presented with NS and hypertension following therapy with sunitinib 400 mg/day. Because of grade 3 toxicity, the drug was discontinued. After sunitinib discontinuation, NS and hypertension resolved. However, NS recurred on rechallenge. A similar picture developed following therapy with sorafenib 800 mg/day. A renal biopsy revealed a focal segmental glomerulosclerosis (FSGS). A few months after sorafenib cessation, resolution of NS and hypertension was again achieved. Discussion Several cases of NS have been reported among patients receiving sunitinib and sorafenib. However, renal histopathologic data were obtained in only a few patients. Although biopsy-proven cases of FSGS associated with sunitinib have been reported, this is, to our knowledge, the first reported case of biopsy-proven FSGS associated with sorafenib. The Naranjo probability scale indicated probable causality for NS developing with sorafenib, and definite causality with sunitinib. The clinical and histopathologic findings have led us to agree with the class effect proposal that all antiangiogenic drugs share a similar toxicity profile. Evidence supporting this hypothesis includes worsening of hypertension and proteinuria by both drugs, with full recovery occurring within a few months after cessation of the drugs, which favors the role of vascular endothelial growth factor receptor inhibition in FSGS development. Conclusions The clinical adverse spectrum of antiangiogenic drugs may be broader than initially observed because of a lack of renal biopsy data and routine screening for proteinuria. It can be speculated that proteinuria, as well as hypertension, is a class effect of all antiangiogenic drugs.

Lapatinib plus Capecitabine for Brain Metastases in Patients with Human Epidermal Growth Factor Receptor 2-Positive Advanced Breast Cancer: A Review of the Anatolian Society of Medical Oncology (ASMO) Experience

Background: We investigated the clinical outcome of patients with brain metastases (BMs) from human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) treated with lapatinib and capecitabine (LC). Patients and Methods: A total of 203 patients with HER2+ MBC, who had progressed after trastuzumab-containing chemotherapy, were retrospectively evaluated in 11 centers between September 2009 and May 2011. 85 patients who had developed BMs before the initiation of treatment with LC were included. All patients had received prior cranial radiotherapy. All patients were treated with the combination of lapatinib (1,250 mg/day continuously) and capecitabine (2,000 mg/m2 on days 1–14 of a 21-day cycle). Results: The median follow-up was 10.5 months (range 1–38 months). An overall response rate of 27.1% was achieved, including complete response in 2 (2.4%) and partial response in 21 (24.7%) patients. Median progression-free survival was 7 months (95% confidence interval (CI) 5–9), with a median overall survival of 13 months (95% Cl 9–17). The most common side effects were hand-foot syndrome (58.8%), nausea (55.3%), fatigue (48.9%), anorexia (45.9%), rash (36.5%), and diarrhea (35.4%). Grade 3–4 toxicities were hand-foot syndrome (9.4%), diarrhea (8.3%), fatigue (5.9%), and rash (4.7%). There were no symptomatic cardiac events. Conclusion: LC combination therapy was effective and well-tolerated in patients with HER2+ MBC with BMs, who had progressive disease after trastuzumab-containing therapy.

Bevacizumab-containing Chemotherapy is Safe in Patients with Unresectable Metastatic Colorectal Cancer and a Synchronous Asymptomatic Primary Tumor

OBJECTIVE Surgical resection of asymptomatic primary colorectal cancer in patients presenting with synchronous unresectable metastatic disease is controversial. Concerns and controversies remain over combining cytotoxic chemotherapy with bevacizumab in this patient population. METHODS We identified medical records of 99 patients with synchronous metastatic primary colorectal cancer who received chemotherapy with bevacizumab as their initial treatment. The incidence of subsequent use of surgery and surgical outcomes were recorded. Patients were also assessed for overall survival. RESULTS Patients who received bevacizumab-containing chemotherapy for synchronous metastatic primary colorectal cancer were divided into the non-surgery and surgery groups according to the resection status of their asymptomatic primary tumor. In the non-surgery group, two patients (4.4%) underwent additional surgery, while three patients (5.7%) required surgery for rectovesical fistula in the surgery group. The median overall survival was 17 months for the non-surgery group (95% CI: 10.6-23.3 months) and 23 months for the surgery group (95% CI: 21.3-24.6 months; P = 0.322). CONCLUSIONS This study utilizing chemotherapy with bevacizumab did not result in an increased rate of morbidity related to the unresected primary tumor. Survival is not compromised by leaving the primary colon tumor intact.

Lymphoproliferative disorders in multiple primary cancers.

BACKGROUND Cancer survivors are at increased risk of second cancers. Lymphoproliferative disorders (LPD) are common neoplasms that are primary or subsequent cancers in cases of multiple primary cancer. We here analyzed metachronous or synchronous LPD in multiple primary cancers. METHODS Between 2001 and 2010, LPD were assessed retrospectively in 242 multiple primary cancers patients. RESULTS Forty nine (20.2%) patients with LPD were detected. Six patients had two LPD where one patient had three LPD. The median age of patients was 60.5 years (range: 28-81). LPD were diagnosed in 29 patients as primary cancer, in 23 patients as second cancer, and in three patients as third cancer in multiple primary cancers. Primary tumor median age was 56 (range: 20-79). Diffuse large B cell lymphoma (n=16), breast cancer (n=9), and lung cancer (n=6) were detected as subsequent cancers. Alklylating agents were used in 19 patients (43.2%) and 20 patients (45.5%) had received radiotherapy for primary cancer treatment. The median follow-up was 70 months (range: 7-284). Second malignancies were detected after a median of 51 months (range: 7-278), and third malignancies with a median of 18 months (range: 6-72). CONCLUSIONS In this study, although breast and lung cancer were the most frequent detected solid cancers in LPD survivors, diffuse large B cell lymphoma was the most frequent detected LPD in multiple primary cancers.

Lapatinib plus capecitabine for HER2-positive advanced breast cancer: a multicentre study of Anatolian Society of Medical Oncology (ASMO)

Abstract Lapatinib is the first dual tyrosine kinase inhibitor of human epidermal growth factor receptor type 2 (HER2/neu) and epidermal growth factor receptor (EGFR). The present study evaluated the efficacy and tolerability of the combination of lapatinib and capecitabine in patients with metastatic breast cancer (MBC) who progressed after therapy with trastuzumab, a taxane and/or anthracycline. A total of 203 patients with a median age of 48 years (range: 25–82 years) were evaluated retrospectively in 11 centres between September 2007 and May 2011. All the patients had HER2-positive MBC progressing after trastuzumab and chemotherapy including an anthracycline and/or taxane. All patients were treated with the combination of lapatinib (1250 mg/day, continuously) and capecitabine (2000 mg/m2 on days 1 through 14 of a 21-day cycle). Data on demographics, clinical outcome, and toxicity were collected for descriptive analyses. The median follow-up was 10·7 months (range: 1–40 months). An overall response rate (ORR) of 33·4% was achieved including 7 complete responses (CR, 3·4%), 61 partial responses (PR, 30·0%), and 44 stable disease (37·9%). Clinical benefit rate of 71·3% was achieved. Median progression-free survival (PFS) was 7 months (95% CI: 6–10 months), with a median overall survival (OS) of 15 months (95% CI: 12–18 months). The most common side effects were hand–foot syndrome (46·8%), nausea (42·3%), fatigue (42·2%), anorexia (38·5%), diarrhea (31·5%), and rash (29·6%). Grade 3–4 toxicities were identified as hand foot syndrome (7·9%), diarrhea (6·9%), fatigue (5·9%), and rash (5·4%). There were no symptomatic cardiac events. Lapatinib and capecitabine combination therapy is effective and well tolerated in patients with MBC who had progressive disease after trastuzumab, taxane, and/or anthracycline therapy, as evidenced by this retrospective evaluation. Toxicity was mild to moderate with low grade 3–4 toxicity.

Lack of Prognostic Value of Mean Corpuscular Volume with Capecitabine Therapy in Metastatic Breast Cancer

BACKGROUND Capecitabine is an oral fluoropyrimidine derivative which is frequently used alone or in combination regimens for the treatment of metastatic breast cancer. Although overall and progression free survivals have increased in recent years with the use of new generation drugs, predictive factors that would further improve the outcomes are needed. Previous studies have demonstrated the relation between post-treatment increase in mean corpuscular volume (MCV) and predicting therapy response as well as survival. The present study investigated the clinical impact of MCV elevation in metastatic breast cancer patients treated with capecitabine. MATERIALS AND METHODS The data of a total of 82 patients from three centers followed between June 2005 and June 2013 were retrospectively analyzed. The demographic data and hormone receptor status of the patients, as well as initial examination before and after treatment and data concerning progression were recorded. MCV ≥ 100 fl was considered as macrocytosis. Capecitabine was given at a dose of 2500 mg/m2 daily for 14 days every three weeks. Pre-treatment and post-treatment MCV and other parameters of complete blood count were recorded. Post-treatment initial evaluation was performed after 2 cycles of therapy. RESULTS The median age of the patients was 46.5 years (range 26-72 years) and 54% were premenopausal. Performance status was ECOG 0 and 1 in 81 (99%) patients. The median number of cycles for capecitabine therapy was 5 (min-max: 2-18). The median ΔMCV level (post-treatment values at sixth week - baseline) was 6.4. Whilst ΔMCV was ≥ 6.4 in 42 patients, it was <6.4 in 40 patients. Clinical benefit (complete response+partial response+stable disease) was observed in 37 (88%) of 42 patients with a median ΔMCV ≥ 6.4 and in 30 (75%) of 40 patients with ΔMCV <6.4 with no statistically significant difference (p=0.158). No significant difference was determined between the group with ΔMCV ≥ 6.4 and the group with ΔMCV <6.4 in terms of progression-free survival (11 vs 12 months) (p=0.55) and overall survival (20 months vs. 24 months) (p=0.11). CONCLUSIONS The identification of new predictive markers in metastatic breast cancer is very important. In some recent studies, increase in MCV has been suggested as a marker in tumor response. In the present study, however, no significant difference was determined between tumor response and increase in MCV. Further studies including higher numbers of patients are needed to determine whether increase in MCV is a predictive marker or not.