Low-dose Capecitabine Research Articles

Combined Metronomic Chemo-immunotherapy (CMCI) in Head and Neck Cancers-An Experience from a Developing Country.

Head and neck squamous cell carcinomas (HNSCC) have proven to be inherently resistant to systemic treatments as a result of histological, molecular, and etiological heterogeneity, with limited responses seen after second-line therapy and beyond. With limited treatment options after progression on systemic chemotherapy in HNSCCs, immunotherapy has a role to play with improved results. In this prospective, observational, non-randomized, open-label study, a total of 12 patients with advanced, relapsed, or metastatic HNSCC received Inj. Nivolumab weight-based dose of 3mg per kg, intravenously every 2weeks along with low-dose capecitabine 500mg twice a day, was prospectively assessed. The patient's clinical, hematological, and staging characteristics were described and the clinical benefit rate (CBR) was calculated. A total of 12 patients received the combined metronomic chemo-immunotherapy (CMCI). The majority of patients were belonging to ECOG-PS 1(66%), with all patients being in stage IV disease. Six, four, and two patients received immunotherapy as the 5th, 3rd, and 4th line of therapy, respectively. Nivolumab and low-dose capecitabine were used in all 12 patients. CBR was seen in 66% (8/12) of patients, one patient died due to hepatitis and hepatic encephalopathy, another patient died due to pneumonia and respiratory complications, two patients had progressive disease, and two patients with stable disease discontinued treatment because of financial constraints and kept on capecitabine alone. The majority tolerated therapy well with no grade 3/4 immune-related adverse events (IRAEs). Two patients required supportive therapy with packed red cell transfusion and albumin infusions. Six-month overall survival (OS) and progression-free survival (PFS) in the study population were 83.3% and 66.6%, respectively. In conclusion, nivolumab along with metronomic chemotherapy with low-dose capecitabine was very well tolerated and exhibited anti-tumor activity with a CBR of 66%, 6-month OS of 83.3%, and 6-month PFS of 66.6%, in extensively pretreated patients with HNSCCs. Additional studies of nivolumab and metronomic chemotherapy and immuno-immuno combination therapy in these diseases are ongoing.

PP047 Concomitant 177Lu-DOTATATE and low dose capecitabine versus 177Lu-DOTATATE alone in patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumours – a randomized controlled trial

PP047 Concomitant 177Lu-DOTATATE and low dose capecitabine versus 177Lu-DOTATATE alone in patients with advanced well-differentiated gastroenteropancreatic neuroendocrine tumours – a randomized controlled trial

Combined Metronomic Chemo-Immunotherapy in Metastatic Carcinoma of Esophagus in Second Line and Beyond

Background and Aims: Approximately 570,000 new cases are diagnosed with esophageal cancer worldwide annually and approximately 510,000 deaths from this disease per year. There are currently no effective second-line treatments for patients who progress on cisplatin and 5-fluorouracil. Esophageal squamous cell carcinomas and adenocarcinomas have proven to be inherently resistant to systemic treatments as a result of histological, molecular and etiological heterogeneity, with limited responses seen after first line therapy. Methods: We are presenting 3 case reports of 57 year old man, 53 year old man & 47 year old woman who, presented with dysphasia for solid foods, weight loss and dyspepsia since 1 month, 3 months & 1.5 months respectively. Upper gastro oesophageal endoscopy shows ulcerated friable lesion with minimal luminal compromise with biopsy showing poorly differentiated adenocarcinoma (PDAC) and PECT-CT showed FDG avid lesions in gastroesophageal junction, gastric cardia, multiple retroperitoneal lymph nodes and bilateral liver lesions. All 3 were having stage IV disease, with PDAC, squamous cell carcinoma & PDAC respectively. We have started 1st patient on DOX regimen containing Docetaxel, Oxaliplatin and Capecitabine at an interval of 2 weeks and after 4 cycles he was having stable disease in GE junction, liver and slightly increased size of retroperitoneal lymph nodes. Second & 3rd patient was put on Pclitaxel-carboplatil protocol, after 6 cycles both were having partial response & was managed with 6 cycles CAPOX as second line che otherapy. After 5th & 6th months of second line chemotherapy both patients were having progressive disease. Results: In view of radiological progression we started him on Injection, Nivolumab 240mg intravenously every 2 weekly along with low dose capecitabine 500mg twice a day. After 4 cycles of treatment his PET-CT showing complete metabolic response in GE junction, liver and retroperitoneal lesions. Now we are continuing Nivolumab and low dose capecitabine planned to complete for 2 years. Conclusion: So to conclude nivolumab along with metronomic chemotherapy with low dose capecitabine was very well tolerated and exhibited antitumor activity in extensively pretreated patient with metastatic esophageal poorly differentiated adenocarcinoma. Additional studies of Nivolumab and metronomic chemotherapy and immuno-immuno combination therapy in these diseases are ongoin.

Capecitabine Plus Aromatase Inhibitor as First Line Therapy for Hormone Receptor Positive, HER2 Negative Metastatic Breast Cancer.

(1) Background: recent evidence suggests that long low-dose capecitabine regimens have a synergistic effect with endocrine therapy as aromatase inhibitors (AIs), and might increase overall survival for hormone-receptor-positive, HER2-negative, metastatic breast cancer compared to both treatments. We performed a retrospective study to confirm the efficacy and expand the safety data for capecitabine plus AI (a combination henceforth named XELIA) for this indication. (2) We conducted a single-center retrospective cohort study of 163 hormone receptor-positive metastatic breast cancer patients who received either the XELIA regimen, capecitabine, or an aromatase inhibitor (AI) as single agents in first-line treatment. The primary endpoint was progression-free survival, and the secondary endpoints were overall survival, best objective response, and toxicity incidence. (3) Results: the median progression-free survival for patients receiving XELIA, AI, and capecitabine was 29.37 months (20.91 to 37.84; 95% CI), 20.04 months (7.29 to 32.80; 95% CI) and 10.48 (8.69 to 12.28; 95% CI), respectively. The overall response rate was higher in the XELIA group (29.5%) than in the AI (14.3%) and capecitabine (9.1%) groups. However, the differences in overall survival were not statistically significant. Apart from hand-foot syndrome, there were no statistically significant differences in adverse events between the groups. (4) Conclusions: this retrospective study suggests that progression-free survival and overall response rates improved with the XELIA regimen compared to use of aromatase inhibitors and capecitabine alone. Combined use demonstrated an adequate safety profile and might represent an advantageous treatment in places where CDK 4/6 is not available. Larger studies and randomized clinical trials are required to confirm the effects shown in our study.

Leukocytoclastic vasculitis associated with capecitabine.

Leukocytoclastic vasculitis (LCV) is a vasculitic inflammation against blood vessels. Various anticancer therapies can cause vasculitis, but capecitabine-induced LCV is an unusual entity. Here, we describe an LCV case associated with neoadjuvant capecitabine use for locally advanced rectal cancer (LARC). A 70-year-old man presented with rectal bleeding. A colonoscopic biopsy revealed rectal adenocarcinoma and he was diagnosed with LARC after imaging studies. Capecitabine plus radiation therapy was started as a neoadjuvant treatment. Seven days after the first capecitabine dose, the patient was admitted with a rash. The LCV diagnosis was histopathologically proven. Capecitabine was withheld. After the patient's rash began to regress under corticosteroid pressure, capecitabine was started at a lower dose. His treatment was completed successfully with oral corticosteroids plus low-dose capecitabine. We aimed to point out a rare and unusual adverse effect of a frequently used drug in oncologic practice.

Abstract P101: Combined metronomic chemo-immunotherapy in head and neck cancers: An experience from the developing and resource poor country

Abstract Background: Head and Neck squamous cell carcinomas (HNSCC) have proven to be inherently resistant to systemic treatments; with limited treatment option after progression on systemic chemotherapy in HNSCCs Immunotherapy has a role to play with improved results. Methods: All 7 patients with advanced, metastatic-HNSCCs, received Inj. Nivolumab 240mg flat dose or 3mg per kg, intravenously every 2 weekly along with low dose capecitabine 500mg twice a day, were prospectively assessed. Patient’s clinical, hematological and staging characteristics were described and Clinical Benefit Rate (CBR) was calculated. Results: Total 7 patients received the combined metronomic chemo-immunotherapy (CMCI). Majority of patients were belonging to ECOG-PS 1(66%), with all patients being in stage IV disease. Three, three &one patient received Immunotherapy as 5th, 3rd and 4th line of therapy respectively. Nivolumab and low dose Capecitabine was used in all 7 patients. CBR was seen in 71.42% (5/7) patients, one patient died due hepatitis and hepatic encephalopathy, and one patient was having progressive disease, and one patient with stable disease discontinued of treatment because of financial constraints and kept on capecitabine alone. Majority tolerated therapy well with no grade 3/4 Immune related adverse events (IRAEs). One patient required supportive therapy with packed red cell transfusion and Albumin infusions. Conclusions: To conclude nivolumab along with metronomic chemotherapy with low dose capecitabine was very well tolerated and exhibited antitumor activity with CBR of 71% in extensively pretreated patients with HNSCCs. Additional studies of Nivolumab and metronomic chemotherapy and immuno-immuno combination therapy in these diseases are ongoing. Citation Format: Irappa Madabhavi, Malay Sarkar, Pham Nguyen Quy, Apurva Patel. Combined metronomic chemo-immunotherapy in head and neck cancers: An experience from the developing and resource poor country [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P101.

779P Metronomic low-dose capecitabine in metastatic, recurrent or persistent carcinoma of cervix as 3rd line and beyond

Systemic administration of cytotoxic drugs is the primary treatment strategy for patients with advanced carcinoma of cervix, but poor tolerance and side effects of the drugs led us to conduct this trial in patients who are ineligible for any type of intravenous chemotherapy.

Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment

Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. ClinicalTrials.gov Identifier: NCT01112826.

Efficacy and safety of concomitant 177Lu-DOTATATE and low-dose capecitabine in advanced medullary thyroid carcinoma: a single-centre experience

Peptide receptor radionuclide therapy (PRRT) has been shown to be useful in inoperable/metastatic medullary thyroid carcinoma (MTC). However, the role of concomitant PRRT and low-dose capecitabine therapy has not yet been studied in these patients. This study was conducted to evaluate the efficacy and safety of this combination approach in advanced MTC. This was a retrospective, single-centre study. Data of consecutive patients of advanced inoperable/metastatic MTC treated with concomitant Lu-DOTATATE+capecitabine, from January 2014 to August 2018, were collected and analysed for radiological, molecular and biochemical responses and treatment-related toxicity. Eight patients with advanced MTC received a median cumulative dose of 20.9 GBq (interquartile range 8.9-27.7 GBq) Lu-DOTATATE over 1-4 cycles and 1250 mg/m capecitabine from days 0 to 14 of each PRRT cycle. Radiological response according to Response Evaluation Criteria in Solid Tumours 1.1 criteria could be assessed in seven patients. Six out of seven patients (86%) had stable disease, while disease progression was observed in 1/7 (14%) patients. However, molecular response, as per the European Organization for Research and Treatment of Cancer criteria, was observed in all the seven patients. Biochemical response with reduction in serum calcitonin levels was observed in 3/5 (60%) patients. With the exception of grade 2 anaemia in one patient, no other significant toxicity was observed in this cohort. Our results indicate the efficacy and safety of concomitant Lu-DOTATATE and capecitabine in advanced MTC. Larger randomized controlled trials are, however, required to establish the role of capecitabine as a radiosensitizer along with PRRT in these patients.

358P - Evaluation of continuous low dose versus standard dose capecitabine monotherapy as second/third-line chemotherapy for metastatic malignancies

BackgroundCapecitabine (CapX) monotherapy is often employed as a second/third line regimen for various malignancies in the metastatic setting. The use of radical doses of CapX in the palliative setting entails severe toxicities which makes it incompatible with the principles of palliative care. It was a local policy to offer each patient eligible for palliative CapX monotherapy the choice of a standard dose (StD) approach (1-1.25g/m2 bid on Days 1-14 of a 21 day cycle) or a continuous low dose (CLD) approach (0.5g bid daily without a break). Patients were provided information about each regimen's toxicity and efficacy. We recognized a unique retrospective opportunity to compare StD versus CLD. MethodsAfter alteast one prior line of chemotherapy, 52 & 44 patients had received CapX monotherapy with StD & CLD, respectively between march 2013 & August 2016 for metastatic malignancies of the gall bladder, pancreas and stomach. Differences in toxicities/discontinuations were assessed by the Fisher Exact Test. For each patient, the date of initiation of CapX, the date of progression and the date of death were noted. The differences in survival outcomes between the two groups was assessed by the Mann Whitney U test. ResultsThe incidence of Grade>2 toxicity was significantly higher in the StD compared to the CLD group (68% vs. 3.8%; p < 0.0001). Discontinuations were significantly higher in the StD compared to the CLD group (41% vs. 3.8%; p < 0.0001). The median PFS after initiation of CapX was higher in the CLD than the StD group (123 vs 106 days; z score 2.24, p 0.0251). The median OS after initiation of CapX was higher in the CLD than the StD group (199 vs 166 days; z score 1.98, p 0.047). ConclusionsWhile lower toxicities and discontinuation rates were expected in the CLD arm, it was very surprising that survival outcomes too were better in the CLD group. In addition to possible pharmacodynamic advantages of the CLD approach, the better outcomes could also be attributed to better tolerability when compared to the StD approach. Further research would be worthwhile as it could potentially help spare future patients from toxicity while improving efficacy. Legal entity responsible for the studySwami Rama Cancer Hospital & Research Institute. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Pulsed Reduced Dose Rate for Reirradiation of Recurrent Breast Cancer

PurposeLocoregionally recurrent breast cancer within a previously irradiated field requires weighing the benefits of reirradiation against the increased rates of toxicity. Here we evaluate the outcomes of patients treated with pulsed reduced dose rate (PRDR) radiation therapy with concurrent low-dose capecitabine as a method to increase the therapeutic ratio of re-treatment. Methods and MaterialsPatients treated from November 2000 to June 1, 2018 with PRDR radiation therapy at University of Wisconsin were identified. Patients were re-treated to a median dose of 54 Gy (range, 37.5-66 Gy) using PRDR radiation therapy, delivering radiation at an apparent dose rate of 6.67 cGy/min to allow for increased sublethal damage repair of normal tissues. The median cumulative dose was 109.8 Gy. Twenty-two patients were treated with concurrent capecitabine, most frequently at 500 mg twice per day. The Kaplan–Meier method was used for survival analysis, and Cox regression analysis was used for univariate and multivariate analysis. ResultsForty-three patients were identified who underwent reirradiation for locoregionally recurrent invasive breast cancer, with a median follow-up of 20.5 months. Twenty-four patients had gross disease. Nineteen patients had simultaneous metastatic disease. The complete response rate was 83.3% in treated patients with gross disease. Locoregional recurrence–free survival was 81.3% and 73.8% for all patients at 1 and 2 years, respectively. Overall survival for patients with localized disease was 95.7% at 1 year and 91.1% at 2 years. The rate of acute grade 3 radiation dermatitis was 25.6% with no other acute grade 3 toxicities. Grade 3 late toxicity occurred in 18.6% of patients. ConclusionsPRDR radiation therapy with capecitabine was a well-tolerated and effective method for treating patients with recurrent breast cancer. Prospective studies are necessary to compare side effects and efficacy with conventional dose rate reirradiation and to evaluate the potential role for capecitabine in the recurrent setting.

Maintenance of antiangiogenic and antitumor effects by orally active low-dose capecitabine for long-term cancer therapy

Long-term uninterrupted therapy is essential for maximizing clinical benefits of antiangiogenic drugs (AADs) in cancer patients. Unfortunately, nearly all clinically available AADs are delivered to cancer patients using disrupted regimens. We aim to develop lifetime, nontoxic, effective, orally active, and low-cost antiangiogenic and antitumor drugs for treatment of cancer patients. Here we report our findings of long-term maintenance therapy with orally active, nontoxic, low cost antiangiogenic chemotherapeutics for effective cancer treatment. In a sequential treatment regimen, robust antiangiogenic effects in tumors were achieved with an anti-VEGF drug, followed by a low-dose chemotherapy. The nontoxic, low dose of the orally active prodrug capecitabine was able to sustain the anti-VEGF-induced vessel regression for long periods. In another experimental setting, maintenance of low-dose capecitabine produced greater antiangiogenic and antitumor effects after AAD plus chemotherapy. No obvious adverse effects were developed after more than 2-mo of consecutive treatment with a low dose of capecitabine. Together, our findings provide a rationalized concept of effective cancer therapy by long-term maintenance of AAD-triggered antiangiogenic effects with orally active, nontoxic, low-cost, clinically available chemotherapeutics.

Targeting myeloid derived suppressor cells: Phase 0/1 trial of low dose capecitabine + bevacizumab in patients with recurrent glioblastoma.

e13507 Background: Glioblastoma (GBM) creates an immunosuppressive environment that allows tumor growth. Myeloid derived suppressor cells (MDSCs), a heterogeneous class of immunosuppressive cells, mediate immune suppression in GBMs. MDSCs are up-regulated in the blood of patients with GBM and multiple other tumor types. We have developed a novel strategy to target GBM immunosuppression using low dose 5-fluorouracil (5-FU) that, targets immune cells and does not depend on blood brain or blood tumor barrier penetration. Marked MDSC depletion occurs at 5-FU doses in mice equivalent to &lt; 10% of the normal human dosing. Goal: proof of concept that MDSC suppression in feasible in GBM pts with low-dose capecitabine [cap], an oral 5-FU analogue). Methods: Eligibility: Recurrent GBM in need of surgical resection; no prior cap or bevacizumab (bev). Cohorts of 3-6 patients receive low-dose cap 150 mg/m2/d (dose level [DL] 1) for 7 days before surgery. After surgery, patients resume cap for one cycle after which bev is added. Blood MDSC, immune cell levels, and relevant secreted factors are measured at baseline; pre- and post-op; and after the addition of bev. Tumors are assayed for MDSCs and glioma stem-like cells (GSCs). Primary endpoint: MDSC and T-Regulatory cell reduction after cap. Secondary endpoints: Tumor concentrations of MDSCs, GSCs, and T-reg cells; safety; and PFS6. Results: Three of the 4 patients enrolled have data available. All patients received 5 days of pre-op cap at DL 1 with MDSC reductions of 20, 26, and 79% from baseline. The first patient reached a reduction of 93% (measured 2 days after pre-op course) whereas the other 2 experienced return to baseline. The regulatory T cells (T-reg) also fell approximately 15, 20, and 50%, respectively. CD8 concentrations appeared to rise at the time of MDSC and T-reg reduction. No patient experienced grade 3 or higher toxicity. Conclusions: Low dose capecitabine appears to reduce MDSC concentrations with minimal toxicity. During this course T-regs also fell and CD8 concentrations rose. Dose escalation continues. (NCT02669173) (Supported by Musella Foundation, Blast GBM, Sontag Foundation, Velosano, Mylan Pharmaceuticals) Clinical trial information: NCT02669173.

Efficacy of low dose capecitabine and sorafenib in patients with advanced alfa-fetoprotein secreting hepatocellular carcinoma: a 1year experience.

BackgroundThere is no global consensus for the optimal management of HCC. Most of patients at the time of diagnosis are not candidate for potentially curative therapy. The study aimed to evaluate the efficacy of low dose capecitabine combined with sorafenib in subset of Egyptian HCV patients presented with advanced HCC unfit for surgical or locoregional therapies.Methods15 patients with advanced HCC, unfit for surgical or locoregional intervention, with PS <2 recieved Capecitabine 500 mg/day with sorafeneb 200 mg twice daily till normalization of AFP then the treatment was modified to capecitabine 250 mg every other day and sorafenib 400 mg once daily. They were followed every 3 months for size, number of focal masses and AFP. 30 patients were selected as a control group, they received supportive therapy (n = 15) or sorafenib only (n = 15).ResultsAfter 10 months of therapy, 6 patients showed complete response (40 %) with complete recanalization of portal vein (n = 2) and treatment was stopped and the others (n = 4) showed partial portal vein recanalization so, treatment is continued till now. 1 patient (6.7 %) showed recurrence of the disease and died after 1 month, 8 patients showed partial response (53.3 %) and still on treatment. The control groups showed a highly significant reduction in survival when compared to patients who received capecitabine and sorafenib (12.9 ± 2.1, 7.9 ± 0.9, 4.5 ± 1.3 months, p = 0.000).ConclusionsCombined low dose capecitabine and sorafenib proved to be safe with low toxicity profile and deserves further attention as a convenient, outpatient-based chemotherapy in patients with advanced HCC.

The TYMS-TSER polymorphism is associated with toxicity of low-dose capecitabine in patients with advanced gastrointestinal cancer.

Low doses of drugs delivered at close, regular intervals are increasingly being used to manage patients with different neoplasms. Despite the good tolerability, treatment-related adverse events still occur following metronomic protocols. The aim of this study was to retrospectively investigate whether polymorphisms of different genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with the outcome of a low-dose capecitabine schedule. Genotyping of DPYD IVS14+1 G>A, MTHFR C677T, and A1298C single-nucleotide polymorphisms was performed by pyrosequencing technology. A PCR technique was used for genotyping TYMS-TSER. Using peripheral blood mononuclear cells, we also evaluated the 5-FU degradation rate, which determines the net result of all the enzymatic transformation of 5-FU, in terms of the amount of drug consumed by the cells in a time unit. The association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. Eighty-four patients with metastatic gastrointestinal cancer, who had been treated with a low-dose fluoropyrimidine schedule, as a rescue therapy were included in the study. The TSER 2R/2R genotype was significantly associated with both hematologic (odds ratio=7.90, P=0.002) and gastrointestinal toxicity (odds ratio=3.24, P=0.009). Because DPYD IVS14 G>A single-nucleotide polymorphism was not observed in the cohort, it was excluded from the statistical analysis. No significant association was detected between clinical outcome and both MTHFR polymorphisms and the 5-FU degradation rate. In the advanced setting of cancer care, high attention should be paid toward avoiding toxicity and worsening of quality of life. Although metronomic chemotherapy is generally well tolerated, treatment toxicity nonetheless does occur. Our data suggest a possible role of the TSER 2R/2R polymorphism as a predictive marker of toxicity in patients treated with low-dose capecitabine.

Safety and Efficacy of Low-Dose Metronomic Capecitabine in the Treatment of Elderly Patients with Breast Cancer: Report of Two Cases and Literature Review

Summary Capecitabine, a 5-fluorouracil prodrug, is increasingly used in breast cancer due to its more convenient oral route of administration compared to 5-fluorouracil. Despite its widespread use, there are only a few reports on low-dose efficacy, while the clinical significance of such agents remains to be illustrated. Here, we report two cases of breast cancer in women older than 85 years. Both were treated with capecitabine 500 mg t.i.d. every day for 9 and 12 courses, respectively; each course was 21 days. After treatment with low-dose capecitabine, both patients achieved partial tumor response. The side-effects were analyzed during chemotherapy; the primary adverse effects included mild fatigue, loss of appetite, and diarrhea. In conclusion, we observed that the administration of low-dose metronomic capecitabine improved two elderly patients with advanced breast cancers. It might be a well-tolerated treatment option, but its clinical significance still remains to be explored in large scale cohorts.

Pseudomyxoma peritonei, a rare tumors of the abdomen: Palliative treatment and response to low-dose capecitabine and/or bevacizumab

Pseudomyxomaperitonei is a rare abdominal tumor originating from epithelial appendiceal cancer. Its incidence is estimated at 1 per million per year. In this chapter, we present case reports of two separate patients treated with palliative intent with low-dose capecitabine daily ± bevacizumab and therapy beginning after clear radiological and clinical signs of disease progression. During the period of palliative low-dose capecitabine treatment, both patients had at least a two-year period of stabilized disease and progression-free interval with an outstanding quality of life. Low-dose capecitabine and/or bevacizumab may be beneficial in the palliative treatment of pseudomyxoma peritonei.

Combining Fulvestrant with Low-Dose Capecitabine is Effective and Tolerable in Woman with Metastatic Breast Cancer

Although the use of endocrine therapy in combination with intravenous chemotherapy has not been standardized, the combination of fulvestrant and chemotherapy may be promising. A 62-year-old woman came to our hospital's outpatient clinic with extensive ascites. Approximately 10 years earlier, she had undergone mastectomy and sentinel lymph node biopsy. Pathologically invasive lobular carcinoma, with a maximum diameter of 28 mm, had been diagnosed in the left breast. The cancer had a histological grade of 2, was positive for estrogen receptor (95% or more positive cells), and was negative for both progesterone receptor (less than 1% positive cells) and human epidermal growth factor receptor 2. For 5 years the patient underwent adjuvant endocrine therapy with tamoxifen and then with anastrozole. Four years 2 months after adjuvant endocrine therapy had been completed, she felt abdominal distention, and her symptoms gradually worsened. A series of intensive examinations indicated that the invasive lobular carcinoma had metastasized to the peritoneum, pleura, uterus, and bone. Aromatase inhibitor was administered as a first-line therapy for the metastatic disease and was accompanied by denosumab injected every 28 days. For 2 months after the start of treatment with anastrozole, the ascites did not decrease and tumor markers increased. Because anastrozole had not been effective, fulvestrant (500 mg) and low-dose capecitabine (500 mg) were administered for the first 21 days of a 28-day cycle; this regimen had been shown by a phase 2 trial to be effective and tolerable in patients with metastatic breast cancer. The patient felt an improvement in abdominal distention, and the tumor markers decreased 2 weeks after the start of this combination therapy. By 10 months after the start of the combined therapy the ascites had decreased and pleural effusion had completely disappeared. The uterine wall became thinner, and the endometrial cavity became smaller. Tumor markers continued decreasing. No adverse events were observed. The combination of fulvestrant and low-dose capecitabine is promising because of its efficacy and tolerability for the treatment of patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer.

A randomized study of KRAS-guided maintenance therapy with bevacizumab, erlotinib or metronomic capecitabine after first-line induction treatment of metastatic colorectal cancer: the Nordic ACT2 trial

Maintenance treatment (mt) with bevacizumab (bev) ± erlotinib (erlo) has modest effect after induction chemotherapy in metastatic colorectal cancer (mCRC). We hypothesized the efficacy of erlo to be dependent on KRAS mutational status and investigated this by exploring mt strategies with bev ± erlo and low-dose capecitabine (cap). Included patients had mCRC scheduled for first-line therapy, Eastern Cooperative Oncology Group (ECOG) 0-1 and no major comorbidities. Treatment with XELOX/FOLFOX or XELIRI/FOLFIRI + bev was given for 18 weeks. After induction, patients without progression were eligible for randomization to mt; KRAS wild-type (wt) patients were randomized to bev ± erlo (arms wt-BE, N = 36 versus wt-B, N = 35), KRAS mutated (mut) patients were randomized to bev or metronomic cap (arms mut-B, N = 34 versus mut-C, N = 33). Primary end point was progression-free survival (PFS) rate (PFSr) at 3 months after start of mt. A pooled analysis of KRAS wt patients from the previous ACT study was performed. We included 233 patients. Median age was 64 years, 62% male, 68% ECOG 0, 52% with primary tumor in situ. A total of 138 patients started mt after randomization. PFSr was 64.7% versus 63.6% in wt-B versus wt-BE, P = 1.000; and 75% versus 66.7% in mut-B versus mut-C, P = 0.579, with no significant difference in median PFS and overall survival (OS). In the pooled cohort, median PFS was 3.7 months in wt-B (N = 64) and 5.7 months in wt-BE (N = 62) (hazard ratios 1.03, 95% confidence interval 0.70-1.50, P = 0.867). The frequency of any grade 3/4 toxicities during mt was: 28%/58%/18%/15% (wt-B/wt-BE/mut-B/mut-C). Addition of erlo to bev as mt in KRAS wt mCRC did not significantly improve PFS or OS, but it did increase toxicity. KRAS status does not seem to influence the outcome of treatment with erlotinib. Metronomic cap warrants further investigation in mt strategies, given our explorative results. NCT01229813.

Low-dose capecitabine plus trastuzumab as first-line treatment in patients 75 years of age or older with HER2-positive advanced gastric cancer: a pilot study

Single-agent chemotherapy is considered a good and safe treatment option for elderly patients with advanced gastric cancer (AGC). We investigated the efficacy and safety of trastuzumab plus low-dose capecitabine in elderly patients with previously untreated human epidermal growth factor receptor 2 (HER2)-positive AGC. Patients aged 75 years or older with tumors having HER2 overexpression defined as either immunohistochemistry (IHC) 3+ or IHC 2+ and in situ hybridization-positive were eligible for inclusion. Patients received capecitabine (1000 mg/m(2)) orally twice daily on days 1-14 and trastuzumab (8 mg/kg for cycle 1, followed by 6 mg/kg) intravenously on day 1 of a 21-day cycle. The primary endpoint was progression-free survival (PFS). Twenty patients were enrolled. The median age was 79 years (range 75-91). Nine patients (45 %) had ECOG performance status 2. Median PFS was 5.2 months (95 % CI 1.9-8.4 months), and median overall survival was 9.3 months (95 % CI 4.0-14.6 months). The confirmed response rate was 40 % (95 % CI 19-64 %) with disease control rate of 80 %. Grade 3-4 toxicities were anorexia (10 %), fatigue (5 %), stomatitis (5 %), and anemia (5 %). No treatment-related deaths or symptomatic congestive heart failure were observed. Low-dose capecitabine plus trastuzumab is effective and well tolerated in elderly patients with HER2-positive AGC.