[Rich66]

Cancer Immunol Immunother. 2007 May;56(5):641-8. Epub 2006 Sep 8.
Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.

Ghiringhelli F, Menard C, Puig PE, Ladoire S, Roux S, Martin F, Solary E, Le Cesne A, Zitvogel L, Chauffert B.
Unité INSERM 517, Faculté de Médecine, Dijon, France. francois.ghiringhelli@wanadoo.fr
CD4+CD25+ regulatory T cells are involved in the prevention of autoimmune diseases and in tumor-induced tolerance. We previously demonstrated in tumor-bearing rodents that one injection of cyclophosphamide could significantly decrease both numbers and suppressive functions of regulatory T cells, facilitating vaccine-induced tumor rejection. In humans, iterative low dosing of cyclophosphamide, referred to as "metronomic" therapy, has recently been used in patients with advanced chemotherapy resistant cancers with the aim of reducing tumor angiogenesis. Here we show that oral administration of metronomic cyclophosphamide in advanced cancer patients induces a profound and selective reduction of circulating regulatory T cells, associated with a suppression of their inhibitory functions on conventional T cells and NK cells leading to a restoration of peripheral T cell proliferation and innate killing activities. Therefore, metronomic regimen of cyclophosphamide does not only affect tumor angiogenesis but also strongly curtails immunosuppressive regulatory T cells, favoring a better control of tumor progression. Altogether these data support cyclophosphamide regimen as a valuable treatment for reducing tumor-induced immune tolerance before setting to work anticancer immunotherapy.

PMID: 16960692 [PubMed - indexed for MEDLINE]




J Clin Oncol. 2008 Oct 20;26(30):4899-905. Epub 2008 Sep 15.
Metronomic cyclophosphamide and capecitabine combined with bevacizumab in advanced breast cancer.


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Dellapasqua S, Bertolini F, Bagnardi V, Campagnoli E, Scarano E, Torrisi R, Shaked Y, Mancuso P, Goldhirsch A, Rocca A, Pietri E, Colleoni M.
Medical Senology Research Unit and Division of Medical Oncology, Department of Medicine, European Institute of Oncology, Milan, Italy.
PURPOSE: Metronomic chemotherapy has shown efficacy in patients with metastatic breast cancer. When used in association with targeted antiangiogenic drugs, it was more active than metronomic therapy alone in preclinical and clinical studies.overall clinical benefit (CR + PR + SD > or = 24 weeks) of 68% PATIENTS AND METHODS: Patients with advanced breast cancer were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (10 mg/kg every 2 weeks). RESULTS: In 46 assessable patients, we observed one complete response (CR; 2%), 21 partial responses (PR; 46%), 19 patients (41%) with stable disease (SD), and five patients (11%) with progressive disease, for an overall response rate of 48% (95% CI, 33% to 63%). Additional long-term disease stabilization (SD > or = 24 weeks) occurred in eight patients, for an (95% CI, 51% to 81%). Median time to progression was 42 weeks (95% CI, 26 to 72 weeks). Toxicity was generally mild. Grade 3 or 4 nonhematologic adverse effects included hypertension (n = 8), transaminitis (n = 2), and nausea/vomiting (n = 2). Higher baseline circulating endothelial cells (CECs) were correlated with overall response (P = .02), clinical benefit (P = .01), and improved progression-free survival (P = .04). CONCLUSION: Treatment with metronomic capecitabine and cyclophosphamide in combination with bevacizumab was effective in advanced breast cancer and was minimally toxic. The number of baseline CECs significantly correlated with response and outcome, therefore supporting further studies on this surrogate marker for the selection of patients to be candidates for antiangiogenic treatments.

PMID: 18794539 [PubMed - indexed for MEDLINE]



Gan To Kagaku Ryoho. 2009 Sep;36(9):1525-8.
[A case of stage IV breast cancer with large cancer ulcer responding to combination therapy of capecitabine and medroxyprogesterone acetate and cyclophosphamide]

[Article in Japanese]
Konishi K, Hasegawa N, Kaneko H, Iimura Y, Shoji Y, Kawabata M.
Dept. of Surgery, Kushiro City General Hospital.
A 53-year-old woman suffering from nausea and vomiting was admitted to our hospital. There was a large ulcer from her left anterior chest to her right side chest. After pathological examination from the ulcer, she was diagnosed as breast cancer, scirrhous carcinoma. The estrogen and progesterone receptors were positive in the tumor. HER2 score was 1+ in the tumor. The stage was T4bNxM1(OTH). Uterine metastases of the breast cancer caused obstructive nephropathy. Ureteral obstruction was treated by urinary tract catheter. After improvement of renal failure, chemotherapy with 5-FU+epirubicin+cyclophosphamide (FEC) and docetaxel was performed. The efficacy was judged as stable disease (SD). For third-line chemotherapy, she was then treated with oral combination chemoendocrine therapy with capecitabine and medroxyprogesterone acetate. After the combination chemoendocrine therapy, the local tumor was remarkably reduced. With added cyclophosphamide, the partial response (PR) continued for 19 months. She died of peritonitis carcinomatosa and pleuritis carcinomatosa. No adverse reactions occurred with the combination chemoendocrine therapy. It is suggested that this oral combination chemoendocrine therapy may be useful with consideration for treatment effectiveness and the quality of life of the patient.

PMID: 19755825 [PubMed - indexed for MEDLINE]



LETTER TO THE EDITOR
Successful treatment with low-dose capecitabine for disseminated esophageal adenocarcinoma
H. CARSTENS & M. ALBERTSSON
Department of Oncology, Karolinska University Hospital, So¨dersjukhuset, Huddinge, Stockholm, Sweden
To the Editor
A 75-year-old man was diagnosed in 2004 with adenocarcinoma of the esophagus. At the time of diagnosis the disease was considered resectable and surgery was done in April 2004. Histological examination of the resected esophagus showed poorly
differentiated adenocarcinoma with growth extending through all wall layers and metastases in all 20 resected lymph nodes however radically resected.
Postoperative complications prolonged care in the intensive care unit and his clinical status was still poor (Karnofsky 60), when he came to see the oncologist 2 months after surgery. He was therefore considered too weak for adjuvant chemotherapy and
was actively monitored with regular CT scanning and clinical examinations. During the first year of follow-up his clinical condition was improved and CT scan showed no signs of cancer. About one year after surgery, in March 2005, CT scan showed liver metastases. Since his clinical status and quality of life were good, active monitoring was continued. Over the next 6 months liver metastases were slowly progressing and new changes appeared in the lungs and there were enlarged para-aortic lymph nodes. By September 2005, he became symptomatic from his metastatic tumor, with difficulties eating, back and stomach pain, coughing, and breathing problems.
Palliative treatment with Oxaliplatin- 5-Fluorouracil/Leucovorin was initiated. This was administered for 2 months during which time symptoms diminished and partial regression (PR) of the tumor was seen on CT scan. However, treatment had to be interrupted due to severe nephrotoxicity arising from the combination of NSAIDs and x-ray contrast. During the following 6 months, while recovering from renal failure, no antitumor treatment was given. By June 2006 CT scan showed progressive disease in all locations and the patient suffered from pain and weight loss. At that time treatment was reinitiated with low-dose capecitabine at a continuous dose of 500 mg/day. There was a clinical response already after one month and by 2 months therapy, CT scan
showed good tumor regression and the patient’s clinical status had further improved, with weight gain, absence of pain, and good quality of life. Onassessment after 4 months, CT scan showed further regression of changes in the lungs, liver, and lymph nodes. Some metastases were no longer measurable (Figure 1).
At the time his disease had progressed in June 2006, therapeutic options were highly limited because of the patient’s age and compromised renal function, which included mild residual elevation of serum creatinine (S-creatinine 125 micro mol/l). One option would have been no treatment at all, but he wanted treatment if possible. Consequently, a relatively non-toxic treatment regimen was chosen in order to provide the best possible quality of life. To date in December 2006 his improvement has been
sustained and his quality of life remains excellent.

Continuously administered low-dose chemotherapy with metronomic scheduling seems to be clinically effective for various types of tumors and is well tolerated, as supported by a range of clinical data. Two breast cancer studies have explored this approach.

In one, low-dose oral cyclophosphamide added to Letrozole (n/57) was compared to
Letrozole alone (n/57) as primary treatment ofestrogen receptor-positive breast cancer in elderly women. Overall response was improved by 15.8% (87.7% vs. 71.9%) in the combination therapy group. There was also a significant difference in VEGF reduction [1].

CONCLUSION: Both letrozole and letrozole plus cyclophosphamide treatments appeared active as PST in elderly breast cancer patients. Metronomic scheduling of cyclophosphamide may have an antiangiogenetic effect and the combination of letrozole plus cyclophosphamide warrants testing in a randomized phase III trial.

Another study of metastatic breast cancer, using low-dose methotrexate and cyclophosphamide, demonstrated clinical benefit in 31.7% of patients and a significant drop in S-VEGF [2].

Conclusions
Continuously low-dose CTX and MTX is minimally toxic and effective in heavily pretreated breast cancer patients. A drop in VEGF was associated with the treatment and so alternative hypotheses, other than that of direct toxicity on tumor cells, must be favored when trying to explain the anticancer effect.

Patients with a variety of solid tumors were given low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib with the intention of inhibiting angiogenesis. Thirty percent of the patients achieved clinical benefit (CR, PR, SD) [3].

Conclusions: This low-dose regimen consisting of daily oral cyclophosphamide and weekly vinblastine injections given concurrently with rofecoxib is associated with minimal toxicity and provides significant clinical benefit to patients with advanced solid tumors. These results are particularly encouraging given the nature of the study population, and indicate that this regimen merits further investigation in specific disease site studies.

Since the 1970s data have supported the importance of vascularization and angiogenesis for tumor growth. Several studies show that VEGF is involved in angiogenesis and is secreted in response to a variety of stress factors, thereby stimulating angiogenesis. High-dose chemotherapy has been in use for a long time. This approach requires scheduling of treatment-free intervals to allow for recovery of normal cells, e.g. hematopoietic cells. This strategy entails both a risk of drug resistance and tumour cell proliferation during treatment-free intervals. However,
this problem does not seem to be relevant in slowly proliferating vascular endothelial cells. Since angiogenesis appears to be important for tumor growth, the theory that chemotherapeutic dosing might influence tumor growth was tested. Preclinical studies support the theory that continuously administered low-dose chemotherapy may
improve the therapeutic index and be better tolerated because of less toxicity. The antitumor effect of low-dose chemotherapy seems not to result from cytotoxicity only, but rather from a mechanism involving antiangiogenesis. This has been shown by
Albertsson et al. for several cytotoxic agents [4]. Browder et al. studied the importance of chemotherapy scheduling on drug-resistant Lewis lung carcinoma
and breast cancer cell lines. With a schedule for cyclophosphamide continuously at short intervals a significant improvement in long-term suppression of tumor growth, increased apoptosis of endothelial cells, and eradication tumours were seen [5].

Each dose of the antiangiogenic schedule of cyclophosphamide induced the apoptosis of endothelial cells within tumors, and endothelial cell apoptosis preceded the apoptosis of drug-resistant tumor cells. This antiangiogenic effect was more pronounced in p53-null mice in which the apoptosis of p53-null endothelial cells induced by cyclophosphamide was so vigorous that drug-resistant tumors comprising 4.5% of body weight were eradicated. Thus, by using a dosing schedule of cyclophosphamide that provided more sustained apoptosis of endothelial cells within the vascular bed of a tumor, we show that a chemotherapeutic agent can more effectively control tumor growth in mice, regardless of whether the tumor cells are drug resistant.

Lowdose vinblastine affects functions involved in angiogenesis, such as proliferation, chemotaxis, spreading on fibronectin, and morphogenesis. Vascular proliferation
was also affected [6].



Klement et al. studied protocols for low-dose vinblastine alone and a VEGF-receptor inhibitor, alone and in combination. This treatment was tested in immunodeficient mice inoculated with human neuroblastoma cell lines. Both treatments alone produced tumor regression and inhibition of angiogenesis. However the combination therapy yielded complete and sustained tumor regression without toxicity or development of drug resistance and this effect persisted throughout the course of treatment [7]. Tomoda et al. inoculated a cell line of highly metastasing osteosarcoma, into Figure 1. (a) Liver metastases before treatment. (b) Liver metastases after 2 months therapy. (c) Liver metastases after 4 months therapy.
Successful treatment with low-dose capecitabine 867 Acta Oncol Downloaded from informahealthcare.com by 173.53.243.92 For personal use only.
rats and confirmed this finding. Low-dose methotrexate inhibited development of lung metastases and an inhibitory effect on endothelial cells was produced at lower concentrations than those required for affecting osteosarcoma cells directly [8].
According to Hanahan, low-dose metronomic schedules exert a non-cytotoxic effect on the tumor environment that might be related to angiogenesis and vasculogenesis [9]. Patients with metastatic esophageal carcinoma have few therapeutic options. Fluorouracil is one of the most widely used drugs, why capecitabine was chosen. Capecitabine is easy to administer and does not require hospital admission. In this situation, where the aim of treatment is to sustain good quality of life, it is important that the treatment is well tolerated and has minimal impact on daily life. We believe that this case presentation is an interesting example of successful palliative treatment in a setting where treatment options are highly limited and that this approach deserves further exploration.
References
[1] Bottini A, Generali D, Brizzi MP, Fox S, Bersiaga A, Berruti A, et al. Randomized Phase II trial of Letrozole and Letrozole plus low-dose metronomic oral Cyclophosphamide as primary systemic treatment in elderly breast cancer patients. J Clin Oncol 2006;/24:/36238.

[2] Colleoni M, Rocca A, Sandri M, Zorzino L, Masci G, Goldhirsch A, et al. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: Antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol 2002;/13:/7380.

[3] Yuong S, Whissell M, Noble J, Cano P, Lopez P, Germond C. Phase II clinical trial results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine and rofecoxib in patients with advanced solid tumors. Clin Cancer Res
2006;/12:/30928.



[4] Albertsson P, Lennerna¨s B, Norrby K. On metronomic chemotherapy: Modulation of angiogenesis mediated by VEGF-A. Acta Oncol 2006;/45:/14455.

[5] Browder T, Butterfield C, Kra¨ling B, Shi B, Marshall B, Folkman J, et al. Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res 2000;/60:/187886.

[6] Vacca A, Iurlaro M, Ribatti D, Minischetti M, Nico B, Dammacco F, et al. Antiangiogenesis is produced by nontoxic doses of vinblastine. Blood 1999;/94:/414355.

[7] Klement G, Baruchel S, Rak J, Man S, Clark K, Kerbal R, et al. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest 2000;/105:/R1524.

[8] Tomoda R, Seto M, Hioki Y, Sonoda J, Matsumine A, Uchida A, et al. Low-dose methotrexate inhibits lung metastasis and lengthens survival in rat osteosarcoma. Clin Exp Metastasis 2005;/22:/55964.

[9] Hanahan D, Bergers G, Bergsland E. Less is more, regularly: Metronomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000;/105:/10457.868 H. Carstens and M. Albertsson Acta Oncol Downloaded from informahealthcare.com by 173.53.243.92
For personal use only.


Cancer Chemother Pharmacol. 2009 Jun;64(1):189-93. Epub 2009 Jan 17.
To widen the setting of cancer patients who could benefit from metronomic capecitabine.

Nannini M, Nobili E, Di Cicilia R, Brandi G, Maleddu A, Pantaleo MA, Biasco G.
Department of Hematology and Oncology Sciences LA Seragnoli, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. maggie.nannini@gmail.com
PURPOSE: We investigated the efficacy and toxicity of metronomic capecitabine administered at a fixed dose of 1,000 mg daily in three elderly or poor performance status patients with advanced colorectal cancer (CRC) and gastric cancer. METHODS: In this study a pretreated advanced CRC patient (patient 1), a not previously treated advanced gastric cancer patient (patient 2), and a not previously treated advanced rectal cancer patient (patient 3) were given metronomic capecitabine administered at a fixed dose of 1,000 mg daily (day 1-28 continuously). The efficacy was evaluated every 3 months by instrumental evaluation and the treatment was continued until progression of disease or toxicity. RESULTS: A stable disease was observed in all three patients. The duration of treatment was above 3 months and no major toxicities occurred. CONCLUSIONS: Our results indicate that metronomic capecitabine may be considered a safe and valid treatment option for advanced CRC and gastric cancer patients, both after failure of previous lines of chemotherapy or in front-line when standard chemotherapy is contraindicated, especially when the aim of medical treatment is to achieve disease control and to arrest tumour growth without affecting the patient's quality of life. Nevertheless, further clinical studies, as well as a greater clinical experience are required in order to better define the role of this strategy in medical oncology.


PMID: 19151974 [PubMed - indexed for MEDLINE]

Lapatinib and metronomic capecitabine combination in an HER2-positive inflammatory breast cancer patient: a case report.
Montagna E, Cancello G, Torrisi R, Rizzo S, Scarano E, Colleoni M.
Ann Oncol. 2009 Dec 23. [Epub ahead of print] No abstract available. PMID: 20032127 [PubMed - as supplied by publisher]Related articles