Interleukin-2 chronotherapy for metastatic renal cell carcinoma: Results of a phase I-II study.

BACKGROUND: Interleukin-2 (IL-2) was the cornerstone treatment for metastatic renal cell carcinoma (RCC) until the advent of tyrosine kinase inhibitors, but it still has therapeutic value. As a single bolus of IL-2 causes toxicity, there is interest in administration regimens with better tolerability and efficacy. Chronotherapy is the administration of therapy according to the circadian rhythm's influence on the immune and hormonal systems. This phase I-II trial evaluated the safety of IL-2 chronotherapy in metastatic RCC patients and determined the maximum tolerated dose. The secondary objective was to identify prognostic factors for survival. METHODS: Three chronomodulation schedules (5:00-13:00, 13:00-21:00, and 21:00-5:00) were tested. Each schedule was an 8-h IL-2 infusion, with a Gaussian distribution of drug concentration peaking at 4 h. To identify the maximum tolerated dose, the dose for different patients was escalated from 2 MIU/m2 (level I) to 18.6 MIU/m2 (level VI). RESULTS: Thirty patients were enrolled and completed treatment. Two patients were treated at 5:00-13:00, 15 at 13:00-21:00, and 13 at 21:00-5:00. Nine cases of grade 3 toxicity occurred in 7 patients at the highest dose (18.6 MIU/m2); no grade 4 toxicity occurred. The maximum tolerated dose was 14.0 MUI/m2. Patients were followed for a median of 16 months (range, 2-107). One patient was lost to follow-up, 3 patients were alive at last contact, and 26 patients died. Six patients achieved long-term survival (≥48 months). There was one complete response, four partial responses, 11 cases of stable disease and 14 of progressive disease. The response rate was 16% (5/30) and disease-control rate was 53% (16/30). Median progression-free survival was 4.5 months, and median overall survival was 14.5 months. Kaplan-Meier analyses revealed significant associations between overall survival and ECOG performance score (0 vs. 1-2), MSKCC score (0-2 vs. ≥ 3), IMDC risk score (0-2 vs. ≥ 3), IL-2 dose level (IV-VI vs. I-III), and prolactin (increase vs. no increase), and but not for chronotherapy schedule. CONCLUSION: IL-2 chronotherapy appears to be safe, moderately toxic and active in metastatic RCC. It may represent a new modality of IL-2 administration for these patients.

Characterizing Metastatic HER2-Positive Gastric Cancer at the CDH1 Haplotype.

The CDH1 gene, coding for the E-cadherin protein, is linked to gastric cancer (GC) susceptibility and tumor invasion. The human epidermal growth factor receptor 2 (HER2) is amplified and overexpressed in a portion of GC. HER2 is an established therapeutic target in metastatic GC (mGC). Trastuzumab, in combination with various chemotherapeutic agents, is a standard treatment for these tumors leading to outcome improvement. Unfortunately, the survival benefit is limited to a fraction of patients. The aim of this study was to improve knowledge of the HER2 and the E-cadherin alterations in the context of GC to characterize subtypes of patients that could better benefit from targeted therapy. An association between the P7-CDH1 haplotype, including two polymorphisms (rs16260A-rs1801552T) and a subset of HER2-positive mGC with better prognosis was observed. Results indicated the potential evaluation of CDH1 haplotypes in mGC to stratify patients that will benefit from trastuzumab-based treatments. Moreover, data may have implications to understanding the HER2 and the E-cadherin interactions in vivo and in response to treatments.

Adjuvant Treatment of Early Breast Cancer in the Elderly.

Breast cancer is common in the elderly, as more than 50% of these tumors are diagnosed in patients aged 65 years or older. Elderly women may also delay reporting or underreport to their physician suspicious symptoms and lesions, so that breast cancer is more likely to be diagnosed at a more advanced stage, with putatively inferior outcomes. Adjuvant hormonal therapy has clear benefits for all women with hormone receptor-positive early breast cancer, despite the fact that it is still under-prescribed in elderly women, but the benefits of tamoxifen are more evident than that observed in younger patients. Aromatase inhibitors significantly prolong disease-free survival, reducing the risk of metastases and contralateral cancer compared with tamoxifen, and these benefits are greater in women aged ≥65 years. However, in case of a history of pathological fractures, arthritis or chronic musculoskeletal pain syndromes, tamoxifen still represents the preferred adjuvant option. In patients with a high risk of recurrence with hormonal therapy alone, the cardiac toxicity of nonanthracycline regimens should be taken into account. Trastuzumab-based therapy should be offered to most patients with HER2-overexpressing tumors. Older patients have an increased risk of disease recurrence and cancer-related mortality, because they are usually undertreated due to their age and longevity. Thus, a multidisciplinary geriatric approach is required, but the optimal management of these patients is still not well defined.

Advances in the Treatment of Triple-negative Early Breast Cancer.

Triple-negative breast cancer represents approximately 10-20% of all breast cancers and is associated with worse prognosis than other subtypes, with a higher risk of recurrence and death than other breast cancer types. This cancer is considered a heterogeneous disease comprising a spectrum of cancers with distinct activated biological pathways, various levels of chemosensitivity and different propensity for metastasis. Currently, chemotherapy represents the mainstay of medical treatment of these patients, because of the absence of well-defined molecular target agent, and we cannot use investigational classifications to determine appropriate systemic therapy outside of clinical trials. The specific adjuvant chemotherapy that may be most effective is still being determined but there is general consensus that regimens containing anthracyclines and taxanes are the standard approach for patient after surgery. Unfortunately, although some patients respond to treatment, other women have a high degree of intrinsic resistance to the same therapy. Moreover, in some studies, the pathological complete response was significantly higher in women treated with platinum-based regimen with respect to those treated with other chemotherapy regimen. The systematic evaluation of the predictive value of genomic alterations is critically important for a better comprehension of this entity and to develop new effective therapeutic strategies. In the future, a personalized therapeutic approach based on biology-oriented characteristics and molecular profiling may be effective for the patients.

Adjuvant Hormonal Therapy in Women with Early-stage Breast Cancer.

For decades, adjuvant hormonal therapy has become the standard treatment of patients with estrogen receptor-positive breast cancer. Currently, the drugs available are GnRH agonists, selective estrogen receptor modulators, and aromatase inhibitors. The use of GnRH agonists represents a potentially reversible treatment that can restore ovarian function after chemotherapy. In premenopausal women, systemic therapy based on selective estrogen receptor modulators administration (e.g., tamoxifen) usually represents the standard adjuvant treatment. There are not sufficient data to recommend the routine addition of GnRH agonists to other endocrine therapies. In postmenopausal women, the disease-free survival was significantly prolonged in patients treated with aromatase inhibitor compared with those treated with tamoxifen, but the survival benefit was modest. Better results were obtained when the two drugs were administered sequentially. According to the ASCO guidelines, after 5 years of tamoxifen treatment, either tamoxifen or aromatase inhibitors therapy should be suggested for an additional 5 years. Unfortunately, most adverse events are consistent with estrogen deprivation and are common to all therapies, and the cumulative toxicity causes discontinuation and nonadherence to therapy in up to 50% of patients. Switching tamoxifen to an aromatase inhibitor may reduce adverse event incidence. Molecular-targeted therapy is useful in patients with advanced, relapsed or hormonal therapy-resistant tumors, usually as second- or third-line treatment. These drugs are usually added to aromatase inhibitors; however, currently, they have not yet been used in patients with early breast cancer.

Current medical treatment of estrogen receptor-positive breast cancer.

Approximately 80% of breast cancers (BC) are estrogen receptor (ER)-positive and thus endocrine therapy (ET) should be considered complementary to surgery in the majority of patients. The advantages of oophorectomy, adrenalectomy and hypophysectomy in women with advanced BC have been demonstrated many years ago, and currently ET consist of (1) ovarian function suppression (OFS), usually obtained using gonadotropin-releasing hormone agonists (GnRHa); (2) selective estrogen receptor modulators or down-regulators (SERMs or SERDs); and (3) aromatase inhibitors (AIs), or a combination of two or more drugs. For patients aged less than 50 years and ER+ BC, there is no conclusive evidence that the combination of OFS and SERMs (i.e., tamoxifen) or chemotherapy is superior to OFS alone. Tamoxifen users exhibit a reduced risk of BC, both invasive and in situ, especially during the first 5 years of therapy, and extending the treatment to 10 years further reduced the risk of recurrences. SERDs (i.e., fulvestrant) are especially useful in the neoadjuvant treatment of advanced BC, alone or in combination with either cytotoxic agents or AIs. There are two types of AIs: type I are permanent steroidal inhibitors of aromatase, while type II are reversible nonsteroidal inhibitors. Several studies demonstrated the superiority of the third-generation AIs (i.e., anastrozole and letrozole) compared with tamoxifen, and adjuvant therapy with AIs reduces the recurrence risk especially in patients with advanced BC. Unfortunately, some cancers are or became ET-resistant, and thus other drugs have been suggested in combination with SERMs or AIs, including cyclin-dependent kinase 4/6 inhibitors (palbociclib) and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus. Further studies are required to confirm their real usefulness.

Prognostic factors of survival in patients treated with nab-paclitaxel plus gemcitabine regimen for advanced or metastatic pancreatic cancer: a single institutional experience.

PURPOSE: The objectives of this study were to evaluate the effectiveness of nab-paclitaxel plus gemcitabine (NAB-P/GEM) regimen in an unselected population of patients with advanced inoperable or metastatic pancreatic cancer (PC), and to identify the prognostic factors influencing overall survival (OS). EXPERIMENTAL DESIGN: Patients with age < 85 years, ECOG-performance status (PS) < 3, and adequate renal, hepatic and hematologic function were eligible. NAB-P (125 mg/m2) and GEM (1000 mg/m2) day 1,8,15 every 4 weeks were employed for 3-6 cycles or until highest response. RESULTS: Overall, 147 cycles (median 4, range 1-11 cycles) were administered on thirty-seven consecutive patients (median 66 years old, range 40-82) treated. The median overall progression-free survival and OS were 6.2 and 9.2 months, respectively. The G 3-4 dose-limiting toxicity were neutropenia (20.7%), severe anemia (17.2%), and cardiovascular toxicity (10.3%). PS, number of cycles, baseline CA 19-9 and LDH serum levels, were found to be significantly related to OS. The multivariate analysis showed that both number of cycles (HR = 9.14, 95% CI 1.84-45.50, p = 0.001) and PS (HR = 13.18, 95% CI 2.73-63.71, p = 0.001) were independently associated with OS. CONCLUSION: NAB-P/GEM regimen should be used in all patients with advanced or metastatic PC, with the exception of those with serious contraindications to chemotherapy, such as severe renal or hepatic impairment or major cardiovascular diseases.

Preoperative serum C-reactive protein and its prognostic significance in patients with stage III-IV colorectal cancer.

The molecular mechanism underlying the development of colorectal cancer (CRC) is not yet fully-understood, but there is evidence that inflammation plays a key role. Several circulating tumor and inflammatory markers can be useful for studying patients with CRC. It has been suggested that high serum levels of C-reactive protein (CRP) are associated with elevated risk of various malignancies and that CRP may affect survival of patients with CRC. We analyzed the relationship existing between the stage of the disease and baseline CRP serum levels in a group of 91 patients undergoing surgery for stage III (N=72, 79.1%) and IVa (N=19, 20.9%) CRC. There were 51 (56%) men and 40 (44%) women, with a median age of 66 years. Prior to surgery, all patients underwent quantitative serum CRP measurement. The overall 5-year survival was 37.1 ± 13.0 months. Patients with stage III disease and the sub-group with CRP<3 mg/l (N=43, 47.3%) had a longer survival (p<0.01) than patients with stage IVa and the sub-group with CRP ≥ 3 mg/l (N=48, 52.7%). No relationship between the age of the patients and CRP levels was found (R=-0.005, p=0.96), whilst there was a significant inverse relationship between survival and CRP level (R=-0.37, y=37.5343-0.5868x, p=0.0003). Using multivariate Cox model analysis (forward stepwise method), adjusted for age, CRP and CRC stage were independent parameters related to survival, with a relative risk of 3.5 (95% confidence interval=1.5-8.2) and 8.1 (95% confidence interval=3.0-21.3), respectively. In conclusion, CRP is a sensitive and easily detectable serum marker that can be useful in patients with CRC, allowing their better clinical stratification.

Preoperative assessment of peritoneal carcinomatosis in patients undergoing hyperthermic intraperitoneal chemotherapy following cytoreductive surgery.

The present study evaluates the accuracy of computed tomographic (CT) scan and positron emission tomography with (18)F-fluorodeoxyglucose (FDG-PET)/CT for the quantification of peritoneal carcinomatosis (PC) in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Data were retrospectively collected for 58 patients, who were considered for CRS and HIPEC. The predictability, sensitivity, specificity and accuracy values of FDG-PET/CT and CT were tested. Preoperative CT and FDG-PET/CT failed to detect PC in 9% and 17% of cases, respectively, with a sensitivity of 91% and 82%, a specificity of 33% and 67%, an area under the curve (AUC) of 62% and 74% and a negative likelihood ratio of 0.27 (CI.95 0.07-1.09) and 0.27 (CI.95 0.11-0.62), respectively (p=0.469). Both techniques showed a high prevalence of PC extent underestimation (CT 47% and FDG-PET/CT 43% of cases). Small bowel involvement and optimal CRS had a prevalence of 60% and 76%, respectively, and both the CT and FDG-PET/CT imaging techniques were inaccurate at predicting them (AUC 53% and 52% for small bowel involvement, and 63% and 58% for optimal CRS, respectively). In conclusion both CT and FDG-PET/CT had low preoperative staging reliability for PC, and this can strongly influence the ability to implement the correct treatment strategy for patients with PC.

Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy as salvage treatment for a late wound recurrence of endometrial cancer.

Endometrial cancer (EC) is usually diagnosed at an early stage, when surgery-alone may be curative, but 20-25% of patients with EC have higher-risk early-stage disease requiring radiation therapy alone or in combination with chemotherapy, in addition to surgery. Most EC relapses are either pelvic or distant metastases and occur within the first three years after hysterectomy. Laparotomy wound recurrences of EC are extremely rare, and only a few cases have been previously reported. We describe the unusual case of a late wound recurrence from an EC surgically removed 10 years previously which was successfully treated by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) after response to a hormonal therapy. Ten years after abdominal hysterectomy and bilateral salpingo-oophorectomy, on computed tomographic (CT) scan, a 70-year-old woman exhibited an abdominal mass of 3.5 cm, strictly adherent to the abdominal rectal muscle. CT-guided biopsy revealed estrogen- and progesterone receptor-positive metastasis from EC and the patient was treated with megestrole acetate. The whole body (18)F-fluoro-2-deoxyglucose (FDG)-positron emission tomography (PET)/CT showed a marked metabolic response at the single metastatic site, with no further metastases, and the patient underwent surgical resection of the mass followed by immediate HIPEC perfusion with cisplatin. No residual macroscopic disease was present at the end of surgery and no complications occurred during the hospital stay. At 12-month follow-up, the patient is alive without evidence of disease. Although this approach is still being investigational for peritoneal recurrence of EC, our report confirms its feasibility and its promising results in highly selected patients.

Carboxy-terminal telopeptide (CTX) and amino-terminal propeptide (PINP) of type I collagen as markers of bone metastases in patients with non-small cell lung cancer.

The early diagnosis of non-small cell lung carcinoma (NSCLC) is difficult, and 30-40% of patients with NSCLC develop bone metastases (BMs) during the course of their disease. Because the delayed demonstration of skeletal involvement may seriously affect survival, there is a need for early diagnosis of BMs. Unfortunately, the sensitivity of common serum tumor markers is low and they are used mainly for monitoring the efficacy of therapy and detection of recurrence. The aim of this study was to evaluate the utility of a panel of serum biomarkers in patients with NSCLC and BMs. Sixteen patients (11 males, 5 females; median age=64 years, range 54-68 years) with NSCLC and BMs (cases), and 18 age- and stage-matched patients without BMs (controls) underwent measurement of serum carboxy-terminal telopeptide of type I collagen (CTX), tartrate-resistant acid phosphatase isoform type 5b (TRAP5b) and amino-terminal propeptide of type I collagen (PINP), carcinoembryonic antigen (CEA) and fragments of cytokeratin 19 (CYFRA 21-1. CTX (443.7 ± 945.1 vs. 402.7 ± 28.4 pg/ml, p=0.003) and PINP (75.9 ± 11.4 vs. 64.1 ± 7.5 µg/l, p=0.001) were significantly higher in patients with BMs, while the mean value of the other markers did not differ (p=NS) between cases and controls. The sensitivity, specificity and accuracy were 73.3%, 86.7% and 79.4% for CTX; 55.5%, 62.5% and 58.8% for CEA; 65.0%, 78.6% and 70.6% for CYFRA; 30.4%, 76.2% and 67.6% for TRAP5b; and 72.2%, 81.2% and 76.5% for PINP, respectively. The area under the receiver operating characteristic curve (AUC) for CTX was 0.68. In conclusion, CTX and PINP measurement can be useful in monitoring patients with NSCLC during follow-up, with the aim of detecting BMs early.

Improved quality of life in patients with malignant pleural effusion following videoassisted thoracoscopic talc pleurodesis. Preliminary results.

Malignant pleural effusion (MPE) is a common, debilitating complication of several types of advanced malignancy, which may significantly reduce the quality of life of patients. There are several options to treat MPE, including thoracentesis, placement of a long-term indwelling pleural catheter and chemical pleurodesis. The best treatment is still debated, but talc remains the agent of choice to achieve pleurodesis. Forty-six patients (28 men and 18 women; median age 67 years, range 47-82 years) with MPE related to different malignancies underwent video-assisted thoracoscopy talc pleurodesis. There were 26 (56.5%) patients with non-small cell lung cancer, 8 (17.4%) with breast cancer, 7 (15.2%) with pleural mesothelioma and 5 (10.9%) with other malignancies. The average operative time was 28±8 minutes, and the duration of chest tube drainage was 9.4±4.1 days. Side-effects were mild (temporary pain, fever for 2-3 days), affecting only three (12%) patients. Two patients (8%) died during hospitalization, due to progression of disease. Overall, pre- and postoperative Karnofsky performance index (KI) and Medical Research Council (MRC) dyspnea score were 62.1±12.2 vs. 71.3±13.2 (p=0.014), and 4.2±0.8 vs. 2.7±1.0 (p<0.001), respectively. A significant relationship between total amount of preoperative pleural effusion and both KI (R=-0.54, p=0.002) and MRC (R=0.64, p=0.0001) was found. No correlation (p=NS, log-rank test) was found between preoperative KI or MRC and underlying malignancy related to MPE. In conclusion, thoracoscopic large-particle talc pleurodesis is a feasible and effective treatment for MPE, significantly improving quality of life of patients.