Giovanna Masci

Minidose Warfarin Prophylaxis for Catheter-Associated Thrombosis in Cancer Patients: Can It Be Safely Associated With Fluorouracil-Based Chemotherapy?

PURPOSE The use of prophylactic low-dose oral warfarin in cancer patients with a central venous catheter (CVC) in place has an established role in the prevention of thrombotic complications and is associated with a low hemorrhagic risk. Despite the literature indicating an adverse interaction between warfarin and fluorouracil (FU), the frequency of this interaction and whether it occurs when minidose warfarin is used is unknown. We analyzed the incidence of alterations in the International Normalized Ratio (INR) and bleeding in cancer patients given minidose warfarin during treatment with continuous-infusion FU-based regimens. PATIENTS AND METHODS Between July 1999 and August 2001, 95 cancer patients were evaluated. Forty-one patients (43%) had liver metastases. Seventy-nine patients (83%) had a Groshong CVC (Bard Access System, Salt Lake City, UT), and 16 (17%) had a Port-a-Cath device (Bard Access System). All patients received oral warfarin at a dose of 1 mg/daily as prophylaxis beginning the day after the catheter was positioned. An INR of more than 1.5 was considered significantly elevated. RESULTS INR elevation occurred in 31 patients (33%), with 18 patients (19%) having an INR more than 3.0. Twelve (39%) of the 31 patients had liver metastases. Bleeding was observed in eight patients (8%); seven of these patients had elevated INR levels. We observed INR elevations in 12 of 21 patients treated with a FU, folinic acid, and oxaliplatin (FOLFOX) regimen, 11 of 40 treated with a de Gramont regimen (FU and folinic acid), and five of 19 treated with a FU, folinic acid, and irinotecan (FOLFIRI) regimen. CONCLUSION A high incidence of INR abnormalities was observed in our cohort of patients, especially those treated with FOLFOX regimen. Clinicians should be aware of this interaction and should regularly monitor the prothrombin time in patients receiving warfarin and FU.

Phase I-II study of hypofractionated simultaneous integrated boost using volumetric modulated arc therapy for adjuvant radiation therapy in breast cancer patients: a report of feasibility and early toxicity results in the first 50 treatments

BackgroundTo report results in terms of feasibility and early toxicity of hypofractionated simultaneous integrated boost (SIB) approach with Volumetric Modulated Arc Therapy (VMAT) as adjuvant treatment after breast-conserving surgery.MethodsBetween September 2010 and May 2011, 50 consecutive patients presenting early-stage breast cancer were submitted to adjuvant radiotherapy with SIB-VMAT approach using RapidArc in our Institution (Istituto Clinico Humanitas ICH). Three out of 50 patients were irradiated bilaterally (53 tumours in 50 patients). All patients were enrolled in a phase I-II trial approved by the ICH ethical committee. All 50 patients enrolled in the study underwent VMAT-SIB technique to irradiate the whole breast with concomitant boost irradiation of the tumor bed. Doses to whole breast and surgical bed were 40.5 Gy and 48 Gy respectively, delivered in 15 fractions over 3 weeks. Skin toxicities were recorded during and after treatment according to RTOG acute radiation morbidity scoring criteria with a median follow-up of 12 months (range 8–16). Cosmetic outcomes were assessed as excellent/good or fair/poor.ResultsThe median age of the population was 68 years (range 36–88). According to AJCC staging system, 38 breast lesions were classified as pT1, and 15 as pT2; 49 cases were assessed as N0 and 4 as N1. The maximum acute skin toxicity by the end of treatment was Grade 0 in 20/50 patients, Grade 1 in 32/50, Grade 2 in 0 and Grade 3 in 1/50 (one of the 3 cases of bilateral breast irradiation). No Grade 4 toxicities were observed. All Grade 1 toxicities had resolved within 3 weeks. No significant differences in cosmetic scores on baseline assessment vs. 3 months and 6 months after the treatment were observed: all patients were scored as excellent/good (50/50) compared with baseline; no fair/poor judgment was recorded. No other toxicities or local failures were recorded during follow-up.ConclusionsThe 3-week course of postoperative radiation using VMAT with SIB showed to be feasible and was associated with acceptable acute skin toxicity profile. Long-term follow-up data are needed to assess late toxicity and clinical outcomes.

Metastasis of hepatocellular carcinoma to the heart: a case report and review of the literature.

Hepatocellular carcinoma (HCC) with extension or metastasis to the right atrium is an uncommon form of cardiac malignancy. This report describes a rare case of right intraventricular metastasis from HCC in a patient who had undergone a partial hepatectomy for HCC more than two years earlier. Open heart surgery was performed and the mass was partially excised. Symptoms (dyspnea, edema of the lower extremities, palpitations) improved after surgery. Two months later a recurrence of the ventricular mass was observed. Systemic chemotherapy with cisplatin and doxorubicin resulted in significant tumor reduction. The patient died of progressive hepatic failure six months later. In addition to this case report, a review of the literature on heart involvement from HCC is presented.

High Incidence of Hypocalcemia and Serum Creatinine Increase in Patients with Bone Metastases Treated with Zoledronic Acid

BACKGROUND Zoledronic acid belongs to the new generation of bisphosphonates with demonstrated clinical benefit for the treatment of bone metastases from different kinds of neoplasms. Hypocalcemia and serum creatinine elevation are expected adverse events during this therapy. The monitoring of serum calcium and creatinine is therefore recommended. The primary aim of this study was to establish the actual incidence of hypocalcemia and serum creatinine elevation during treatment with zoledronic acid. Skeletal-related events and side effects were also assessed. METHODS Serum creatinine and calcium levels were evaluated in 240 consecutive patients (83 males, 157 females; mean age, 62 years) with metastatic bone lesions from different solid tumors treated with zoledronic acid. RESULTS Overall, 93 of 240 patients (38.8%) developed hypocalcemia, which was grade (G)1 in 45 patients (48.4%), G2 in 37 patients (39.8%), G3 in 10 patients (10.8%), and G4 in one patient (1.1%). The median time to occurrence of hypocalcemia (any grade) was 2.3 months after the beginning of the treatment (range, 0-34.9 months). Increased serum creatinine was observed in 33 of 240 patients (13.7%), of whom 19 had G1 (57.6%), 11 had G2 (33.3%), and three had G3 (9.1%). The median time to serum creatinine increase (for any grade) was 4.7 months (range, 0-29.2 months). CONCLUSIONS Our analysis shows a high incidence of hypocalcemia and increased serum creatinine level during treatment with zoledronic acid. These results strongly support the need for accurate monitoring of plasma calcium and creatinine levels.

Clinicopathological and Immunohistochemical Characteristics in Male Breast Cancer: A Retrospective Case Series

BACKGROUND Due to its rarity, male breast cancer (mBC) remains an inadequately characterized disease, and current evidence for treatment derives from female breast cancer (FBC). METHODS We retrospectively analyzed the clinicopathological characteristics, treatment patterns, and outcomes of mBCs treated from 2000 to 2013. RESULTS From a total of 97 patients with mBC, 6 (6.2%) with ductal in situ carcinoma were excluded, and 91 patients with invasive carcinoma were analyzed. Median age was 65 years (range: 25-87 years). Estrogen receptors were positive in 88 patients (96.7%), and progesterone receptors were positive in 84 patients (92.3%). HER-2 was overexpressed in 13 of 85 patients (16%). Median follow-up was 51.5 months (range: 0.5-219.3 months). Five-year progression-free survival (PFS) was 50%, whereas overall survival (OS) was 68.1%. Patients with grades 1 and 2 presented 5-year PFS of 71% versus 22.5% for patients with grade 3 disease; 5-year OS was 85.7% for patients with grades 1 and 2 versus 53.3% of patients with grade 3. Ki-67 score >20% and adjuvant chemotherapy were also statistically significant for OS on univariate analyses. Twenty-six of 87 patients (29.8%) experienced recurrent disease and 16 of 91 patients (17.6%) developed a second neoplasia. CONCLUSION Male breast cancer shows different biological patterns compared with FBC, with higher positive hormone-receptor status and lower HER-2 overexpression. Grade 3 and Ki-67 >20% were associated with shorter OS. IMPLICATIONS FOR PRACTICE There is little evidence that prognostic features established in female breast cancer, such as grading and Ki-67 labeling index, could be applied to male breast cancer as well. This study found that grade 3 was associated with shorter overall survival and a trend for Ki-67 >20%; this could help in choosing the best treatment option in the adjuvant setting. Many questions remain regarding the impact of HER-2 positivity on survival and treatment with adjuvant anti-HER-2 therapy. Regarding metastatic male breast cancer, the results suggest that common regimens of chemo-, endocrine and immunotherapy used in female breast cancer are safe and effective for men. Male breast cancer patients show a higher incidence of second primary tumors, especially prostate and colon cancers and should therefore be carefully monitored.

Oral ulcer as an exclusive sign of gastric cancer: report of a rare case

BackgroundThe oral cavity is a rare but occasional target for metastases, which may masquerade as various benign and inflammatory lesions, and sometimes also be asymptomatic. Oral metastatic lesions have been described in various cancers, particularly lung, breast and kidney carcinoma.Case presentationWe here describe an uncommon case of a hard palate mucosa and gingival metastasis from gastric carcinoma that was originally diagnosed as a periodontal disease.Histopathological examination of a biopsy of the lesion revealed a signet-ring cell carcinoma, and a subsequent biopsy of an ulcerated stomach lesion showed a poorly differentiated gastric carcinoma. The patient underwent gastric resection but died of heart failure on the tenth postoperative day; a post-mortem examination revealed a residual bilateral ovarian infiltration by gastric carcinoma (Krukenbergs tumor).ConclusionAn occult carcinoma of the stomach may rarely metastasise to the oral cavity even as a first and exclusive manifestation; it is important to bear this possibility in mind because such conditions may mimic a benign disease.

Multimodal Approach to the Management of Metastatic Epidural Spinal Cord Compression (MESCC) Due to Solid Tumors

PURPOSE To assess the impact of a multidisciplinary approach for treatment of patients with metastatic epidural spinal cord compression in terms of feasibility, local control, and survival. METHODS AND MATERIALS Eighty-nine consecutive patients treated between January 2004 and December 2007 were included. The most common primary cancers were lung, breast, and kidney cancers. Ninety-eight surgical procedures were performed. Radiotherapy was performed within the first month postoperatively. Clinical outcome was evaluated by modified visual analog scale for pain, Frankel scale for neurologic deficit, and magnetic resonance imaging or computed tomography scan. Nearly all patients (93%) had back pain before treatment, whereas major or minor preoperative neurologic deficit was present in 62 cases (63%). RESULTS Clinical remission of pain was obtained in the vast majority of patients (91%). Improvement of neurologic deficit was observed in 45 cases (72.5%). Local relapse occurred in 10%. Median survival was 11 months (range, 0-46 months). Overall survival at 1 year was 43.6%. Type of primary tumor significantly affected survival. CONCLUSIONS In patients with metastatic epidural spinal cord compression, the combination of surgery plus radiotherapy is feasible and provides clinical benefit in most patients. The discussion of each single case within a multidisciplinary team has been of pivotal importance in implementing the most appropriate therapeutic approach.

Level of HER2/neu gene amplification as a predictive factor of response to trastuzumab-based therapy in patients with HER2-positive metastatic breast cancer

SummaryTo explore the clinical significance of the level of HER2/neu gene amplification in a homogenous cohort of 33 patients with HER2-positive metastatic breast cancer (MBC) and available tumor samples treated with a trastuzumab-based regimen, we retrospectively performed dual-color fluorescence in-situ hybridization test and correlated them for each patient with time-to-progression (TTP) and overall survival (OS). We obtained values of HER2/chromosome 17 centromere (CEP17) ratio ranging from 2.5 to 21 (median 7.2). At the Cox model there is indication that patients whose tumors have high-level HER2/CEP17 ratio have shorter TTP and OS than those with lower ratio, when treated with a trastuzumab-based regimen. Correlations do not reach the limits of statistical significance but no formal sample size calculation was performed due to the explorative nature of the study. If confirmed in larger cohorts of patients, HER2/CEP17 ratio could represent a reliable and economical predictor of response to trastuzumab-based therapy in MBC.

Incidence of venous thromboembolism in breast cancer patients during chemotherapy with vinorelbine, cisplatin, 5-fluorouracil as continuous infusion (ViFuP regimen): is prophylaxis required?

Cancer patients have an increased risk of venous thromboembolism (VTE). Previous published reports indicated an incidence of cancer-related VTE between 1%-11% [1]. Pathogenesis of VTE is multifactorial depending upon procoagulant activity of tumor cells, procoagulant host-response and upon co-morbidity factors, which involve vascular damage. Moreover, chemotherapy and endocrine therapy, as well as implanted central venous catheters further increase the incidence of VTE [2, 3]. We retrospectively analyzed the incidence of VTE in 182 consecutive breast cancer patients treated in one institution (European Institute of Oncology) between January 1997 and April 1999 with the ViFuP regimen (Navelbine 20 mg tot i.v. on days 1 and 3, cisplatin 60 mg/m i.v. on day 1 and 5-fluorouracil (5-FU) 200 mg/m i.v. daily as continuous infusion) through a permanent central venous device (CVC; Dome Port®, Bard). Seventy-eight patients had early or locally advanced (T2-T4) and 104 patients had metastatic breast cancer. Sixty-one patients (58.6%) in the metastatic group and twenty patients (25%) in the neoadjuvant setting were postmenopausal. Median age was 48 years (range 23-72). All patients had performance status 0-1. In a previous series of 333 patients with a permanent central venous device treated at the same institution we observed a low incidence of symptomatic VTE (1.5%) and therefore we did not consider the use of prophylactic anticoagulation [4]. The median follow-up was 15 months (range 1-27+) for the metastatic group and 8 months (range 1-15+) for the patients treated in the neoadjuvant setting. We observed 14 episodes of VTE (7.7%; 95% confidence interval (95% CI): 4.3%-12.6%), similarly distributed among patients with overt metastases (8 out of 104 patients, 7.7%; 95% CI: 3.4%-14.6%) and those with early or locally advanced disease (6 out of 78 patients, 7.7%; 95% CI: 2.9%-16%). All patients experienced VTE during chemotherapy. Median time from surgery for implant of central venous device to thrombosis was 2 months (range 1-4 months). Only one woman had a history of previous thromboembolic disease. Two women had VTE of the lower limb and one of them developed pulmonary embolism while all other VTE involved veins next to implantation site. Three patients had no symptoms (21%) and diagnosis was occasionally made during evaluation of response to treatment. After diagnosis of VTE, all patients received five days of low molecular weight heparin at the dose of 100 mg/kg twice a day plus oral warfarin to maintain an INR between 2.0-3.0. Despite maintenance anticoagulation, two patients experienced a new episode of VTE. All patients who had VTE treated in the neoadjuvant setting stopped the chemotherapy and were candidates to surgery. The incidence of VTE observed in patients receiving the ViFuP regimen is not negligible. Similar incidence of VTE have been reported in breast cancer patients treated with combination chemotherapies in the adjuvant setting and with advanced disease [5]. Weiss reported an incidence of 5%-7% in 433 patients treated with adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) [2]. An increased thromboembolism (17%) in stage IV breast cancer treated with CMF and vincristine was also reported [3]. Patients with metastatic disease seemed to be at a higher risk of thrombosis than patients treated in the adjuvant setting, although in our series the incidence of thrombotic events in the two groups was similar. Limited data are available on the incidence of thrombosis in patients treated with 5-FU as continuous infusion for whom an incidence of VTE ranging from 4%—16% has been described [2]. The issue of antithrombotic prophylaxis in cancer patients was addressed in some randomized studies. Levine et al. demonstrated that very low-dose warfarin decreases the incidence of VTE in metastatic breast cancer patients treated with chemotherapy [5]. The daily use of low dose warfarin (lmg) or low molecular weight heparin (2500 UI) was protective in terms of catheter-related thrombosis in several studies [6, 7], while some reported lack of reduced risk of VTE with these treatments. There is limited information on the preoperative setting, and specifically for regimens delivered as continuos infusion. Smith observed a 10% catheter-related thrombosis in 50 breast cancer patients treated with a neoadjuvant infusional chemotherapy, despite the use of 1 mg of warfarin [8]. The routine use of anticoagulant prophylaxis during continuous infusion of 5-FU is theoretically hampered by a potential interaction between warfarin and this drug. Prolonged 5-FU half-life and increased INR were reported, thought to be due to interference with the synthesis of hepatic cytochrome 450 and impaired metabolism of warfarin and 5-FU [9, 10]. More information is needed on the proper anticoagulant regimen during infusional treatment containing 5-FU.

Fulvestrant for advanced male breast cancer patients: a case series

Male breast cancer is rare and treatment recommendations are mainly extrapolated from the results of trials on women. Most breast cancers in men are estrogen receptor (ER)/ progesterone receptor (PgR) positive; as a consequence, tamoxifen remains the standard adjuvant treatment and is also the mainstay first-line treatment of advanced disease, with reported response rates varying from 25% to 80% [1]. However, few data are available on treatments (e.g. aromatase inhibitors) for tamoxifen-resistant disease, and the novel ER antagonist fulvestrant has been very little studied. In postmenopausal women, fulvestrant has been shown to be effective in patients in whom tamoxifen or aromatase inhibitors failed and has also demonstrated activity in patients with visceral and human epidermal growth factor receptor (HER-2)-overexpressing disease [2]. Since men almost always develop ER-/PgR-positive breast cancer, fulvestrant is likely to be useful in male metastatic disease. By analogy with data in women, it may also show activity in HER2-overexpressing disease. We evaluated fulvestrant in five men with progressive visceral metastatic breast cancer (the largest series reported so far). The drug was injected i.m. at a loading dose of 500 mg on day 1 followed by 250 mg injected i.m. monthly thereafter, until disease progression. Response was assessed according to RECIST criteria. Partial response (PR) lasting 12 months was obtained in one heavily pretreated patient; while another patient, with HER2-positive cancer metastatic to lung, had stable disease (SD) (response <25%) lasting 22 months. Another patient with HER2-positive disease had SD lasting 6 months, after early PD on firstand second-line treatments with aromatase inhibitors; the patient died of causes unrelated to breast cancer a month after reevaluation. Of our two cases progressing on fulvestrant, one had low hormone receptor positivity (ER 20% and PgR 30%), which might explain the lack of response. No side-effects to fulvestrant were reported by all patients. A case of successful use of fulvestrant after tamoxifen was reported in a 64-year-old man with HER-2-negative receptor-positive metastatic breast cancer [3]. We were only able to find one other report on fulvestrant in men with metastatic breast cancer [4]. Two men were treated: one had PR and the other SD; both were given fulvestrant as primary first-line endocrine therapy, and both had HER-2-negative disease. A reason for trying fulvestrant is that aromatase inhibitors do not have a clear role in metastatic male breast cancer; in our limited experience, anastrozole and exemestane were not effective. These drugs inhibit aromatase, the enzyme that produces estrogens by peripheral aromatization of circulating androgens. In men, however, testicular production of estrogens is independent of aromatase and accounts for 20% of circulating estrogens. It has also been found that testosterone levels increase markedly after anastrozole treatment in men [5]. It is possible that the hypothalamic– pituitary feedback loop is responsible for this increased testosterone (substrate for peripheral aromatization), thereby rendering complete estrogen suppression impossible and explaining why treatment with aromatase inhibitors is less effective in males than females. To conclude, our data indicate that fulvestrant may be an effective and safe treatment of hormone receptor-positive pretreated metastatic male breast cancer, including cases that overexpress HER2.