Low-dose Metronomic Oral Cyclophosphamide Research Articles

Whether low-dose metronomic oral cyclophosphamide improves the response to docetaxel in first-line treatment of non-triple-negative metastatic breast cancer

Oral metronomic chemotherapy may target tumor cells indirectly via antiangiogenic activity, restoration of anticancer immune response, or induction of tumor dormancy. We initiated the single-center, randomized, open-label, phase II study to determine whether the addition of metronomic cyclophosphamide to docetaxel (T) (w/o trastuzumab) improves overall response rate (ORR) as first-line treatment among patients with non-triple-negative metastatic breast cancer (MBC). Eligible patients with previously untreated non-triple-negative MBC were randomly assigned (1:1) to receive 3-weekly cycles of Metro-TC (T 75mg/m2, d1 plus oral cyclophosphamide 50 mg daily) or T alone. All patients received treatment until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was ORR. Finally, 35 patients were randomized to Metro-TC group while 31 to T group. Median treatment cycles of T for both groups were 8. ORR was not improved by addition of metronomic cyclophosphamide to T (71.4% vs. 51.6%; P = 0.09). There was no statistically significant difference with regard to progression free survival (median 18.5 vs. 11.7 months; P = 0.07) or overall survival (median 33.7 vs. 33.6 months; P = 0.84) between the two group. Grade 3/4 adverse events (eg. neutropenia [100% vs. 100%], febrile neutropenia [29% vs. 29%], and neurotoxicity [6% vs. 3%]) were also comparable. There were no treatment-related deaths. We conclude that concomitant administration of metronomic cyclophosphamide and T does not appear to be a significantly active schedule for first-line treatment of non-triple-negative MBC.

Randomized phase II trial comparing docetaxel with or without low-dose metronomic oral cyclophosphamide in first-line treatment of non-triple-negative advanced breast cancer.

1041 Background: Oral metronomic chemotherapy may target tumor cells indirectly via antiangiogenic activity, restoration of anticancer immune response, or induction of tumor dormancy. This phase II...

Oncolytic Adenovirus With Temozolomide Induces Autophagy and Antitumor Immune Responses in Cancer Patients

Oncolytic adenoviruses and certain chemotherapeutics can induce autophagy and immunogenic cancer cell death. We hypothesized that the combination of oncolytic adenovirus with low-dose temozolomide (TMZ) is safe, effective, and capable of inducing antitumor immune responses. Metronomic low-dose cyclophosphamide (CP) was added to selectively reduce regulatory T-cells. Preclinically, combination therapy inhibited tumor growth, increased autophagy, and triggered immunogenic cell death as indicated by elevated calreticulin, adenosine triphosphate (ATP) release, and nuclear protein high-mobility group box-1 (HMGB1) secretion. A total of 41 combination treatments given to 17 chemotherapy-refractory cancer patients were well tolerated. We observed anti- and proinflammatory cytokine release, evidence of virus replication, and induction of neutralizing antibodies. Tumor cells showed increased autophagy post-treatment. Release of HMGB1 into serum--a possible indicator of immune response--increased in 60% of treatments, and seemed to correlate with tumor-specific T-cell responses, observed in 10/15 cases overall (P = 0.0833). Evidence of antitumor efficacy was seen in 67% of evaluable treatments with a trend for increased survival over matched controls treated with virus only. In summary, the combination of oncolytic adenovirus with low-dose TMZ and metronomic CP increased tumor cell autophagy, elicited antitumor immune responses, and showed promising safety and efficacy.

Low-dose metronomic oral cyclophosphamide plus prednisone for castration resistant prostate cancer (CRPC): A retrospective study.

e16095 Background: CRPC remains a therapeutic challenge, although in recent years the introduction of new agents has allowed an improvement in overall survival of these patients. In the literature there are few data on the use of cyclophosphamide in this context. The current study was designed to evaluate the efficacy and toxicity of the metronomic oral administration of a combination of cyclophosphamide and prednisone in patients with CRPC, not candidates for docetaxel or after progression to it. Methods: We retrospectively evaluated the medical records of all patients with metastatic CRPC who were treated with prednisone and cyclophosphamide in our institution. Patients had been previously treated with a docetaxel-containing regimen or were not considered candidates for taxanes, because of important comomorbidities or poor Performance Status (PS). Results: Data from 40 patients treated with cyclophosphamide 50 mg/day vo and prednisone 5 mg bid from January 2010 to December 2012 has been analyzed. Baseline characteristics of the patients are listed in the Table. 36 patients were evaluable for efficacy and toxicity. The PSA response rate (RR) was 30%, with partial responses in 7/40 patients. The clinical benefit (stabilization disease + RR) was 52%. Median progression-free survival was 13 weeks (95% CI 13.2 – 14.5). Median overall survival was 46 weeks (95% CI 26.4 – 65.9). The overall 1-year and 2-year survival were 32% and 8 %, respectively. The treatment was safe and well tolerated. Anemia (grade 0-3) was observed in a third of all patients. Conclusions: In this study in patients with a poor prognosis, metronomic oral cyclophosphamide plus prednisone have demonstrated efficacy with excelent tolerance. Oral cyclophosphamide is an interesting alternative to consider in patients non candidates for intravenous chemotherapy. [Table: see text]

Increased mean corpuscular volume of red blood cells predicts response to metronomic capecitabine and cyclophosphamide in combination with bevacizumab

BackgroundThere is an urgent need for the identification of commonly assessable predictive factors in the treatment of patients with metastatic breast cancer. MethodsDuring the course of a treatment including low dose metronomic oral cyclophosphamide and capecitabine plus i.v. bevacizumab (plus erlotinib in one third of the patients) for metastatic breast cancer, we observed that a relevant number of patients developed repeatedly elevated levels of mean corpuscular volume (MCV) of red blood cells without a significant fall in hemoglobin levels. We conducted a retrospective analysis on these 69 patients to evaluate if the increase in MCV could be associated to tumor response. ResultsDuring the course of treatment 42 out of 69 patients (61%) developed macrocytosis. Using Cox proportional hazards modeling that incorporated macrocytosis (MCV≥100 fl) as a time-dependent covariate, macrocytosis resulted in a halved risk of disease progression (HR 0.45; 95% CI, 0.22–0.92, p-value 0.028). In a landmark analysis limited to patients with no sign of progression after 24 weeks of treatment, median time to progression was 72 weeks (48 weeks after landmark) in patients who had developed macrocytosis, and 43 weeks (19 weeks after landmark) in patients who had not (p = 0.023). ConclusionMacrocytosis inversely related to risk of disease progression in patients treated with metronomic capecitabine plus cyclophosphamide and bevacizumab for metastatic breast cancer. This finding may be explained through thymidylate synthase inhibition by capecitabine. Whether bevacizumab has a role in determining macrocytosis, similarly to what happens with sunitinib, has to be further investigated. If other studies will confirm our findings, macrocytosis might be used as an early marker of response during metronomic treatment with capecitabine and cyclophosphamide with or without bevacizumab.

Bevacizumab plus Low-Dose Metronomic Oral Cyclophosphamide in Heavily Pretreated Patients with Recurrent Ovarian Cancer

Aim: To retrospectively assess the efficacy and safety of bevacizumab plus low-dose metronomic oral cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer. Patients and Methods: Patients with recurrent ovarian cancer and prior treatment with platinum- and taxane-based chemotherapy were included. Treatment consisted of bevacizumab 10 mg/kg intravenously every 2 weeks plus oral cyclophosphamide 50 mg daily until disease progression or unacceptable toxicity. Response rates (RR) were determined according to RECIST criteria and by monitoring the CA 125 serum tumor marker according to Rustin’s criteria. The endpoints were progression-free survival (PFS), RR, overall survival (OS), and safety. Results: Thirty-eight patients were treated; 79% were platinum resistant and 21% were platinum sensitive. The median number of previous treatments was 4 (range 1–8). Seventy-nine percent of patients had received more than 2 previous lines of treatment. Eighty-one percent of patients had received gemcitabine, 76% liposomal doxorubicin, and 50% topotecan. A median of 8 (range 1–70) cycles of bevacizumab were administered. The overall RR was a complete response (CR) in 3 patients (8.1%), a partial response (PR) in 12 (32.4%), and stable disease (SD) ≧6 months in 3 (8.1%). The median PFS and OS were 4.5 and 10.7 months, respectively. Thirty-nine percent of patients were progression free for at least 6 months. In an exploratory analysis there was a significant relation of prior platinum response and performance status with the risk of progression. Grade 3–4 toxicities included anemia (1), hypertension (2), hematuria (1), arterial thrombosis in the leg (1), dyspnea (1), and intestinal fistulae (1). There were no cases of gastrointestinal perforation (GIP) or treatment-related deaths. Conclusion: The combination of bevacizumab and metronomic cyclophosphamide was active and well-tolerated in heavily pretreated patients with recurrent ovarian cancer.

Bevacizumab plus low-dose metronomic oral cyclophosphamide in heavily pretreated recurrent ovarian cancer.

e15507 Background: To assess the efficacy and safety of bevacizumab plus low-dose metronomic oral cyclophosphamide in heavily pretreated patients with recurrent ovarian cancer. Methods: Patients wi...

Spontaneous rectovaginal fistula during bevacizumab therapy for ovarian cancer: a case report

Recent studies have demonstrated efficacy of bevacizumab for recurrent ovarian cancer, but few data on its use and gastrointestinal potential complications when administered as adjuvant chemotherapy after cytoreductive surgery are available. In this study, we report the first case of a rectovaginal fistula in this indication.

Phase II Clinical Trial of Bevacizumab and Low-Dose Metronomic Oral Cyclophosphamide in Recurrent Ovarian Cancer: A Trial of the California, Chicago, and Princess Margaret Hospital Phase II Consortia

Vascular endothelial growth factor (VEGF) plays an important role in the biology of ovarian cancer (OC). Inhibitors of VEGF suppress tumor growth in OC models. Metronomic chemotherapy, defined as frequent administration of low doses of cytotoxic chemotherapy, suppresses tumor growth, possibly by inhibiting angiogenesis. A phase II trial was conducted to evaluate the antitumor activity and adverse effects of bevacizumab and metronomic oral cyclophosphamide in women with recurrent OC. Patients with measurable disease and prior treatment with a platinum-containing regimen were eligible. Up to two different regimens for recurrent disease were allowed. Treatment consisted of bevacizumab 10 mg/kg intravenously every 2 weeks and oral cyclophosphamide 50 mg/d. The primary end point was progression-free survival at 6 months. Plasma levels of VEGF, E-selectin, and thrombospondin-1 were obtained serially. Seventy patients were enrolled. The probability of being alive and progression free at 6 months was 56% (+/- 6% SE). A partial response was achieved in 17 patients (24%). Median time to progression and survival were 7.2 and 16.9 months, respectively. The most common serious toxicities were hypertension, fatigue, and pain. Bevacizumab-related toxicities included four episodes of gastrointestinal perforation or fistula, two episodes each of CNS ischemia and pulmonary hypertension, and one episode each of gastrointestinal bleeding and wound healing complication. There were three treatment-related deaths. Levels of VEGF, E-selectin, and thrombospondin-1 were not associated with clinical outcome. The combination of bevacizumab and metronomic cyclophosphamide is active in recurrent OC. Further study of this combination is warranted.

Low Dose Metronomic Oral Cyclophosphamide for Hormone Resistant Prostate Cancer: A Phase II Study

Cyclophosphamide is a bifunctional alkylating agent long associated with immune activation. Continuous, uninterrupted, low (so-called metronomic) doses of cyclophosphamide can lead to enhanced immunity against a variety of antigens possibly by targeting regulatory T cells and/or tumor angiogenesis. In this study we tested the observations from animal models and evaluated the safety and efficacy of continuous low dose oral cyclophosphamide in patients with hormone resistant prostate cancer. A total of 80 patients were recruited during a 2-year period and 58 received at least 2 cycles (8 weeks) of 50 mg/m(2) oral cyclophosphamide to be included in the safety and intent to treat analysis. Metronomic cyclophosphamide was safe and well tolerated, and although lymphopenia (up to grade 3) was observed in a third of all patients, there were no clinical complications. The response rate was 34.5% inclusive of objective and prostate specific antigen (absolute reduction and reduction in prostate specific antigen velocity). The median duration of response was 7.5 months (range 3 to 18). Oral cyclophosphamide can be used on a metronomic basis safely in men with hormone resistant prostate cancer. The efficacy, low toxicity, low cost and ease of administration of cyclophosphamide justifies further studies in prostate cancer in combination with other agents.

Randomized Phase II Trial of Letrozole and Letrozole Plus Low-Dose Metronomic Oral Cyclophosphamide as Primary Systemic Treatment in Elderly Breast Cancer Patients

Randomized Phase II Trial of Letrozole and Letrozole Plus Low-Dose Metronomic Oral Cyclophosphamide as Primary Systemic Treatment in Elderly Breast Cancer Patients

Randomized Phase II Trial of Letrozole and Letrozole Plus Low-Dose Metronomic Oral Cyclophosphamide As Primary Systemic Treatment in Elderly Breast Cancer Patients

To investigate the activity of letrozole plus/minus oral metronomic cyclophosphamide as primary systemic treatment (PST) in elderly breast cancer patients. One hundred fourteen consecutive elderly women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to primary letrozole therapy (2.5 mg daily for 6 months) or a combination of letrozole plus oral cyclophosphamide (50 mg/daily for 6 months) in an open-labeled, randomized phase II trial. Tumor response was assessed clinically, and tumor Ki67 index and vascular endothelial growth factor (VEGF) -A levels were measured before and after treatment. Overall response rate was 71.9% (95% CI, 60.0 to 83.8) in the 57 patients randomly assigned to receive primary letrozole and 87.7% (95% CI, 78.6 to 96.2) in the 57 patients randomly assigned to receive letrozole plus cyclophosphamide. The difference in activity between treatment arms was predominantly confined to patients with ductal histology. There was a significantly greater suppression of Ki67 and VEGF-A expression in the letrozole/cyclophosphamide-treated group than in the letrozole-treated group, leading to lower Ki67 and VEGF expression at post-treatment residual histology (P = .03 and P = .002, respectively). Both letrozole and letrozole plus cyclophosphamide treatments appeared active as PST in elderly breast cancer patients. Metronomic scheduling of cyclophosphamide may have an antiangiogenic effect and the combination of letrozole plus cyclophosphamide warrants testing in a randomized phase III trial.

Interim report of a phase II clinical trial of bevacizumab (Bev) and low dose metronomic oral cyclophosphamide (mCTX) in recurrent ovarian (OC) and primary peritoneal carcinoma: A California Cancer Consortium Trial

5000 Background: Bev is a recombinant humanized anti-VEGF monoclonal antibody that inhibits the growth of a number of human cancers, including ovarian cancer. Low dose chronic chemotherapy (metronomic chemotherapy) inhibits angiogenesis. In preclinical models enhanced antitumor activity has been observed with the combination of anti-VEGF antibodies and metronomic chemotherapy. Methods: We developed a 2-stage phase II study to evaluate the activity and toxicity profile of the combination of Bev and mCTX in recurrent OC and to explore serologic markers of angiogenesis and genetic polymorphisms as potential surrogate markers of response and/or toxicity. Bev 10 mg/m2 i.v. was administered on days 1, 8 and 15 and then every 2 weeks with CTX 50 mg po qd. Patients were required to have uni-dimensionally measurable disease, recurrence after platinum and paclitaxel chemotherapy, 0–2 chemotherapy regimens for recurrent disease and performance status 0–2. Results: 29 patients have been enrolled and are evaluable for response. Median age 57 (39–83). Prior chemotherapy included: platinum and paclitaxel (100%), liposomal doxorubicin (31%), topotecan (31%). Grade 3–4 toxicities include: pain (6), hypertension (3), hyponatremia (3), urinary (2), fatigue (2), lymphopenia (2), gastrointestinal obstruction (2), and increased transaminases, thrombosis, prolonged PTT, CNS ischemia, hyperglycemia, hypomagnesemia, edema, hot flashes, pulmonary and arthritis (1 each). No treatment related deaths. Median number of courses 4 (range 2–9). Best response: 6 PR (21%), 17 SD (59%) and 6 PD (21%). Median PFS 5.8 months (95% CI 3.8–8.1), PFS at 6 months 47% (± 11%). Conclusions: Based on the encouraging response rate and 6 month PFS the second stage of accrual was opened. Correlation with serologic markers and genetic polymorphisms is ongoing. The combination of Bev and mCTX shows encouraging activity in recurrent ovarian cancer. Supported in part by NCI N01 CM17101 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech