Abstract Metronomic chemotherapy (MC) refers to the close administration of a chemotherapeutic drug for a long time with no extended drug-free breaks. It was developed to overcome drug resistance, ...partly by shifting the therapeutic target from tumor cells to the tumor vasculature, with less toxicity. Because of this peculiar way of administration, MC can be viewed as a form of long-term ‘maintenance’ treatment, and can be integrated with standard and conventional chemotherapy in a “chemo-switching” strategy. Additional mechanisms are involved in its antitumor activity, such as activation of immunity, induction of tumor dormancy, chemotherapy-driven dependency of cancer cells, and the ‘4D effect’. In this paper we report the most important studies that have analyzed these processes. In fact, a number of preclinical and clinical studies in solid tumors as well as in multiple myeloma, have been reported regarding several chemotherapy drugs which have been proposed with a metronomic schedule: vinorelbine, cyclophosphamide, capecitabine, methotrexate, bevacizumab, etoposide, gemcitabine, sorafenib, everolimus and temozolomide. The results of these studies have been sometimes conflicting, highlighting the need to develop reliable tools for patient selection and stratification. However, a more precise evaluation of MC strategies with the ongoing randomized phase II/III clinical is fundamental, because of the strict correlation of this approach with translational research and target therapy. Moreover, because of the low toxicity of MC, these studies will also help to better evaluate the clinical benefit of this treatment, with a special focus on elderly and low performance status patients.
In the last decades, the prognosis of metastatic renal cell carcinoma (mRCC) has remarkably improved following the advent of the "targeted therapy" era. The expanding knowledge on the prominent role ...played by angiogenesis in RCC pathogenesis has led to approval of multiple anti-angiogenic agents such as sunitinib, pazopanib, axitinib, cabozantinib, sorafenib, and bevacizumab. These agents can induce radiological responses and delay cancer progression for months or years before onset of resistance, with a clinically meaningful activity. The need for markers of prognosis and efficacy of anti-angiogenic agents has become more compelling as novel systemic immunotherapy agents have also been approved in RCC and can be administered as an alternative to angiogenesis inhibitors. Anti PD-1 monoclonal antibody nivolumab has been approved in the second-line setting after tyrosine kinase inhibitors failure, while combination of nivolumab plus anti CTLA-4 monoclonal antibody ipilimumab has been approved as first-line therapy of RCC patients at intermediate or poor prognosis. In this review article, biomarkers of prognosis and efficacy of antiangiogenic therapies are summarized with a focus on those that have the potential to affect treatment decision-making in RCC. Biomarkers predictive of toxicity of anti-angiogenic agents have also been discussed.
Head and neck cancer is one of the most commonly diagnosed malignancies worldwide. Patients with advanced disease stages frequently develop recurrences or distant metastasis, which results a ...five-year survival rates of less than 60% despite considerable advances in multimodality therapy. A better understanding of molecular basis of tumorigenesis is required to improve clinical outcomes and to develop new anti-cancer drugs. microRNAs (miRNAs) are a class of small, non-coding, RNA molecules that modulate gene expression post-transcriptionally. They are important regulator in normal biological process; however miRNAs deregulation has been observed in many different tumors and is involved in tumorigenesis. miRNAs may act as tumor suppressors or as oncogenes. Several studies on head and neck cancer demonstrated how aberrant expression of miRNAs is involved in proliferation, metastasis, chemoresistence, and radioresistance. In addition, miRNAs are excellent biomarker targets because they circulate stable in human body fluids and can be obtained with non-invasive methods. Moreover, miRNAs up and down regulation has been correlated with specific cancer phenotype (poor prognosis, aggressiveness and resistance to treatment), playing a role as prognostic biomarkers. This review summarizes current finding on miRNAs in head and neck cancer and their potential role as target for next drug therapy.
Background The non-inferiority of dexamethasone (DEX) on day 1, with or without low-dose DEX on days 2 and 3, combined with oral NEPA (netupitant/palonosetron), compared with the guideline-consistent ...use of DEX was demonstrated in cisplatin. Here, we complete the analysis by assessing the impact of emesis on daily lives of patients receiving DEX-sparing regimens using the Functional Living Index-Emesis (FLIE). Methods Chemotherapy-naïve patients undergoing cisplatin (greater than or equal to70 mg/m.sup.2), were given NEPA and DEX (12 mg) on day 1 and randomized to receive either 1) no further DEX (DEX1), 2) oral DEX (4 mg daily) on days 2-3 (DEX3), or 3) DEX (4 mg twice daily) on days 2-4 (DEX4; control). Patients completed the FLIE questionnaire on day 6 of cycle 1. Endpoints included the FLIE nausea domain, vomiting domain, and overall combined domain scores, as well as the proportion of patients with no impact on daily life (NIDL; overall score > 108). This was a protocol-planned analysis. Results In the DEX1 group, no significant differences were observed in the FLIE nausea score (48.9 + or -1.8; SE vs. 53.7 + or -1.5), vomiting score (56.6 + or -1.4 vs. 58.7 + or -0.8) and overall score (105.6 + or -2.8 vs.112.4 + or -1.9) versus DEX4 control; similar results were observed in the DEX3 group for nausea score (49.6 + or -1.7), vomiting score (58.2 + or -1) and overall score (107.8 + or -2.4) versus control. There were no significant between-group differences in the proportion of patients reporting NIDL. Conclusion Reducing DEX, when administered with NEPA, does not seem to adversely impact the daily functioning in patients undergoing cisplatin. Trial registration ClinicalTrials.govNCT04201769. Registration date: 17/12/2019 - Retrospectively registered. Keywords: Cisplatin, Dexamethasone, NEPA, Quality of life, Functional living index-Emesis, Chemotherapy-induced nausea and vomiting (CINV)
Optimizing chemotherapy to achieve disease and symptoms control is a noteworthy purpose in advanced breast cancer (ABC). We reported the activity and quality of life of a phase II study, comparing ...metronomic regimen with standard schedule as first line chemotherapy for ABC.
Patients with HER2 negative ABC were randomized to non-pegylated liposomal doxorubicin (NPLD, 60 mg/m2 every 3 weeks) and cyclophosphamide (CTX, 600 mg/m2 every 3 weeks) (Arm A) or NPLD (20 mg/m2 day, on day 1, 8 and 15 every 4 weeks) and metronomic daily oral CTX 50 mg (ARM B). Primary end-points were overall response rate (ORR) and quality of life, secondary progression-free survival (PFS), overall survival (OS) and toxicity.
From August 2012 to December 2017, 121 patients were enrolled, 105 evaluable. Median follow-up was 21.3 months. Most patients had hormone receptor positive. ORR was 43 % in arm A and 50 % in arm B. Median PFS was 8.9 months in arm A and 6,4 months in arm B. There was no difference in OS. Total score was not clinically different between the two arms. Grade 4 neutropenia was observed in 12 patients and 16 patients respectively; alopecia G2 in 41 % (77 %) vs 14 (27 %) in arm A and in arm B respectively. One cardiac toxicity was observed (arm A).
First line metronomic chemotherapy for HER2 negative ABC had similar clinical activity and quite better tolerability than standard schedule and could be considered a further treatment option when chemotherapy is indicated.
•Despite the role of biological and targeted drugs, chemotherapy remains a fundamental component of the therapeutic algorithm of ABC.•The purpose of treatment for ABC is relief of symptoms related tas well the maintenance of a good quality of life.•Treatment with low doses of anticancer drugs given on a continuous or frequent regular schedule over a long time is called metronomic chemotherapy. Metronomic chemotherapy causes less severe side effects than standard chemotherapy.•In our study, a metronomic schedule with liposomal anthracyclines is able to achieve similar ORR when compared to standard anthracycline schedule, while maintaining quality of life.•Toxicity was quite similar in the two arms, however dose delay was less frequent in metronomic arm.
Background. The combination of chemotherapy plus anti HER-2 agents is the mainstay of HER-2 positive advanced breast cancer (ABC) therapy. We conducted a phase II trial testing activity and safety of ...trastuzumab and metronomic capecitabine/cyclophosphamide (HEX) as first-line therapy in HER-2 positive ABC. Methods. Patients at first relapse or with synchronous metastasis were treated with trastuzumab (4 mg/kg, biweekly) plus oral capecitabine (1500 mg/daily) and cyclophosphamide (50 mg/daily). Primary endpoint was objective response rate (ORR), secondary endpoints progression-free survival (PFS), clinical benefit rate (CBR; PR + CR + SD for ≥ 24 weeks) and tolerability. Optimal two-stage design was applied. Results. Sixty patients with measurable ABC, tumors scored as +3 for HER-2 or FISH +, untreated for advanced disease were enrolled. Median age was 62.5 years, visceral metastases were present in most patients (57.9%). Median number of cycles was 16 (range 1–98). ORR was 56.7% (95% CI, 44.1–68.4%), with 5 CR (8.3%) and 29 PR (48.3%). Fifteen patients had SD (25%). The CBR was 78.2%. Nine progressions were observed (15%). Median PFS was 11 months. One year PFS was 47.7%. Median OS was 45.9 months. Worst toxicities were grade 3 hand-foot syndrome in 2 pts (3.3%), grade 3 anaemia in 2 pts (3.3%), grade 2 nausea in 2 pts (3.3%) and grade 3–4 diarrhea in 2 pts (3.3%). Cardiac toxicity grade 1 was reported in 1 pt. Conclusions. Combination of trastuzumab and metronomic oral chemotherapy has clinical activity. The tolerability was excellent and allowed the prolonged delivery of treatment.
•Combination of chemotherapy plus anti HER-2 agents is the standard treatment of HER-2 positive breast cancer.•Combination of trastuzumab and metronomic chemotherapy is an alternative therapeutic approach.•Metronomic therapy allows long-term administration of drugs.•Mild toxicity in advanced breast cancer is desirable.
We demonstrated the non-inferiority of a dexamethasone (DEX)-sparing (single-dose) regimen with NEPA, a netupitant/palonosetron fixed combination, for preventing chemotherapy-induced nausea and ...vomiting (CINV) caused by cisplatin. This pre-planned exploratory analysis assessed the effect of the DEX-sparing regimen on a patient's food intake. Chemotherapy-naïve patients undergoing cisplatin (≥ 70 mg/m
) were given NEPA and DEX (12 mg) on day 1 and randomized to receive either no further DEX (DEX1), or oral DEX (4 mg BID) on days 2-4 (DEX4). Patient-reported endpoint maintenance of usual daily food intake was assessed during the 5-days post-chemotherapy. The relationship between usual daily food intake and CINV control, pre-chemotherapy self-rated food intake and BMI-adjusted weight loss (WL) were evaluated. One-hundred fifty-two patients (76/group) were assessable. The proportion of patients reporting maintenance of usual daily food intake was similar in both groups: 69.7% (95% CI, 58.6-78.9) for DEX1 vs. 72.4% (95% CI, 61.4-81.2) for DEX4. Only CINV control was significantly associated with maintenance of usual daily food intake (P ≤ 0.001) during the overall phase. The DEX-sparing regimen does not adversely affect patient-reported daily food intake post-chemotherapy. The current analysis adds further insights into antiemetic efficacy of DEX sparing beyond day 1 in the challenging setting of cisplatin.Trial registration: The parent study was registered on ClinicalTrials.gov (NCT04201769).
We report a case report regarding the eradication of isolated lymph-nodal para-aortic recurrence in the aortic region down the left renal vein (LRV) in a patient treated two years earlier in another ...hospital for a FIGO stage IC2 high-grade serous ovarian carcinoma with a video showing the para-aortic space after eradication of the metastatic tissue. A 66 year-old woman was admitted 24 months after the initial surgical procedure for an increased Ca 125 level and CT scan that revealed a 3 cm para-aortic infrarenal lymph-nodal recurrence that was confirmed by PET/CT scan. A secondary cytoreductive surgery (SCS) with a para-aortic lymph-nodal dissection of the tissue down the LRV and radical omentectomy were performed: during the cytoreduction, the right hemicolon was mobilized. The anterior surface of the inferior vena cava (IVC), aorta and LRV were exposed. The metastatic lymph nodes were detected in the para-ortic space down the proximal part of the LRV and eradicated; an en bloc infrarenal lymph-node dissection from the aortocaval region was performed. The operative time during the surgical procedure was 212 min with a blood loss of 120 mL. No intra- and postoperative complications, including ureteral or vascular injury or renal dysfunction, occurred. At histological examination, three dissected lymph nodes were positive for metastasis, and the patient was discharged five days after laparotomy without side effects and underwent chemotherapy 3 weeks later; after a follow-up of 42 months, no recurrence was detected. In conclusion, secondary debulking surgery can be considered a safe and effective therapeutic option for the management of recurrences, although long-term follow-ups are necessary to evaluate the overall oncologic outcomes of this procedure.
It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and ...antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6-11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients.
A total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21-81) and M1c stage, observed in 74% of the patients, with brain metastases in 15% and high LDH levels in 42% of the patients. The following schedule was used: oral TMZ 100 mg/m
on days 1 and 2 and FM iv 100 mg/m
on day 2, 4 h after TMZ; A translational study aiming to analyse MGMT methylation status and base-excision repair (BER) gene expression was performed in a subset of 14 patients.
We reported an overall response rate of 30.3% with 3 complete responses and a disease control rate of 50.5%. The related toxicity rate was low and mainly of haematological types. Although our population had a very poor prognosis, we observed a PFS of 6 months and an OS of 10 months. A non-significant correlation with response was found with the mean expression level of the three genes involved in the BER pathway (APE1, XRCC1 and PARP1), whereas no association was found with MGMT methylation status.
This schedule could represent a good alternative for patients who are not eligible for immune or targeted therapy or whose previous therapies have failed.
EUDRACT 2009-016487-36l ; date of registration 23 June 2010.
Thymic tumors are the most common primary neoplasms of the anterior mediastinum, although, when compared with the entire thoracic malignancies, they are still rare. Few studies addressed the ...questions about lymph node involvement pattern in thymic neoplasms, about which subgroup of patients would be appropriate candidates for lymph node dissection or about the extent of lymphadenectomy or which lymph nodes should be harvested. The aim of this review is to collect evidence from the literature to help physicians in designing the best surgical procedure when dealing with thymic malignancies. A literature review was performed through PubMed and Scopus in May 2021 to identify any study published in the last 20 years evaluating the frequency and the extent of lymph node dissection for thymic tumors, its impact on prognosis and on postoperative management. Fifteen studies met the inclusion criteria and were included in this review, with a total of 9452 patients with thymic cancers; lymph node metastases were found in 976 (10.3%) patients in total. The current literature is heterogeneous in the classification and reporting of lymph node metastases in thymic carcinoma, and data are hardly comparable. Surgical treatment should be guided by the few literature-based pieces of evidence and by the experience of the physicians.
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