Metronomics Global Health Initiative

A phase Ib/IIa trial of 9 repurposed drugs combined with temozolomide for the treatment of recurrent glioblastoma: CUSP9v3

2021-08-12T07:43:42Z

Marc-Eric Halatsch, Richard Kast, Georg Karpel-Massler, Benjamin Mayer, Oliver Zolk, Bernd Schmitz, Angelika Scheuerle, Ludwig Maier, Lars Bullinger, Regine Mayer-Steinacker, Carl Schmidt, Katharina Zeiler, Ziad Elshaer, Patricia Panther, Birgit Schmelzle, Anke Hallmen, Annika Dwucet, Markus D Siegelin, Mike-Andrew Westhoff, Kristine Beckers, Gauthier Bouche, Tim Heiland from the Ulm University Hospital, Ulm, Germany; the Department of Neurosurgery, Cantonal Hospital of Winterthur, CH-8401 Winterthur, Switzerland, the IIAIGC Study Center, Burlington, Vermont, USA, the IIAIGC Study Center, Burlington, Vermont, USA and the AntiCancerFund, Brussels, Belgium have just published in Neuro-Oncoly Advances a phase I trial entitled : A phase Ib/IIa trial of 9 repurposed drugs combined with temozolomide for the treatment of recurrent glioblastoma: CUSP9v3

Background
In 2013, a new concept to treat patients with recurrent GBM called Coordinated Undermining of Survival Paths (CUSP) was introduced.
The CUSP concept attempts to block growth-driving signaling pathways active in GBM. It takes advantage of repurposing already-marketed non-oncological drugs and and relies on their ability to inhibit one or more of the identified GBM growth and cell survival pathways. Including pharmacology, drug interaction, and safety considerations.
The dismal prognosis of glioblastoma (GBM) may be related to the ability of GBM cells to develop mechanisms of treatment resistance. designed a protocol called Coordinated Undermining of Survival Paths combining 9 repurposed non-oncological drugs with metronomic temozolomide—version 3—(CUSP9v3) was designed to address this issue. The aim of this phase Ib/IIa trial was to assess the safety of CUSP9v3.

Methods
Ten adults with histologically confirmed GBM and recurrent or progressive disease were included. Treatment consisted of aprepitant, auranofin, celecoxib, captopril, disulfiram, itraconazole, minocycline, ritonavir, and sertraline added to metronomic low-dose temozolomide. Treatment was continued until toxicity or progression. Primary endpoint was dose-limiting toxicity defined as either any unmanageable grade 3–4 toxicity or inability to receive at least 7 of the 10 drugs at ≥ 50% of the per-protocol doses at the end of the second treatment cycle.

Results
One patient was not evaluable for the primary endpoint (safety). All 9 evaluable patients met the primary endpoint. Ritonavir, temozolomide, captopril, and itraconazole were the drugs most frequently requiring dose modification or pausing. The most common adverse events were nausea, headache, fatigue, diarrhea, and ataxia. Progression-free survival at 12 months was 50%.

Conclusions
CUSP9v3 can be safely administered in patients with recurrent GBM under careful monitoring. A randomized phase II trial is in preparation to assess the efficacy of the CUSP9v3 regimen in GBM.

the free full text is available https://academic.oup.com/noa/article/3/1/vdab075/6308707

De-escalating cancer treatments during COVID 19 pandemic: Is metronomic chemotherapy a reasonable option?

2020-12-08T08:07:55Z

Palma Fedele, Valeria Sanna, Alessandro Fancellu, Antonella Marino, Nicola Calvani, and Saverio Cinierid from the Medical Oncology, Dario Camberlingo Hospital, Francavilla Fontana , the Medical Oncology, Hospital of Sassari, Sassari, the Department of Medical, Surgical and Experimental Sciences, Unit of General Surgery, University of Sassari, and the
Medical Oncology & Breast Unit, Antonio Perrino Hospital, Brindisi, Italy have published in Crit Rev Oncol Hematol. an opinion piece entitled : De-escalating cancer treatments during COVID 19 pandemic: Is metronomic chemotherapy a reasonable option?

The coronavirus disease 2019 (COVID-19) pandemic has forced healthcare systems to reorganize all the activities with the purpose of containing the virus infection. Medical resources have been concentrated on emergency departments and intensive care units while scheduled and non-urgent medical services have been suspended. The reorganization of the healthcare system has had an important impact on the management of cancer patients.
Cancer patients are considered at high risk of developing coronavirus infection and its severe complications, because of their illness and immunosuppressed status

Recommendations and guidelines on how to manage cancer patients during COVID 19 pandemic have been published. Oral administration of chemotherapy is recommended to limit the access of cancer patients to hospital facilities and in some cases to guarantee the continuum of care.
Low-dose metronomic administration of chemotherapy with different drugs and schedules has emerged in the last years as a possible alternative to conventional chemotherapy, due to its promising tumor control rates and excellent safety profiles. Moreover, given that many metronomic schedules use the oral route administration, it could represent a therapeutic strategy to ensure continuum of cancer care during COVID 19 pandemic.
In this review we have selected all the clinical studies that have used the metronomic strategy, especially with oral drugs, in order to identify the subgroups of cancer patients who can benefit most from a metronomic approach even during COVID 19 pandemic.

The full text is available here

metronomic temzolomide and propranol for refractory metastatic paraganglioma

2018-03-22T16:10:03Z

Miguel-Angel Díaz-Castellanos, Karina Villar Gómez de las Heras, Tamara Díaz-Redondo, Encarnación González-Flores, Virginia Albiñana and Luisa-María Botellafrom the PHEiPAS, Castellón de la Plana, Alianza VHL, Centro Cívico Rogelio Soto, Sabadell
Sanidad Castilla-La Mancha, Toledo, Servicio de Oncología, Hospital Universitario Carlos Haya, Málaga, Servicio de Oncología, and Hospital Universitario Virgen de las Nieves, Granada Centro de Investigaciones Biológicas, U-707 CIBERER, Madrid, Spain
have just published in F1000 RESEARCH a case report entitled : Propranolol increases the therapeutic response to temozolomide in a patient with metastatic paraganglioma

Introduction

Hereditary paraganglioma and pheochromocytoma syndromes (HPP) are characterized by rare tumors called pheochromocytomas (PHEOs) and paragangliomas (PGLs). These are highly vascularized catecholamine-secreting tumors of neural crest origin (chromaffin cells derived from the adrenal medulla – pheochromocytoma – or extra-adrenal paraganglia - paragangliomas), distributed symmetrically along the paravertebral axis. Although tumors are usually histologically benign, most of them hyper-secrete catecholamines, causing high cardiovascular morbidity and mortality1, and symptoms related to mass effect. If left untreated, a subset of these tumors will metastasize in bones, lungs, liver or lymph nodes2. These patients can develop other rare tumors too, such as renal cancer and gastrointestinal stromal tumors. However, tumorigenesis is rare in the first decade of life.

HPP syndromes are due to pathogenic variants of SDHx genes. Similarly to other autosomal-dominant hereditary cancer disease - von Hippel-Lindau (VHL) -paraganglioma–pheochromocytoma (PGL/PCC) syndrome is related to the hypoxia pathway. Hypoxia-inducible factor 1 (HIF1) regulates the cellular response according to oxygen levels. In lower oxygen cell environments, VHL recognition of HIF-1α is decreased, allowing HIF1 to promote cellular survival and growth. In cancer, the hypoxia pathway is switched by the tumoral cells leading to the tumor growth5. Pseudo-hypoxic states are those leading to the hypoxia-pathway gene expression, under normoxic conditions.

Germline mutations in the onco-suppressor gene, called Vhl leads to the autosomal-dominant hereditary cancer disease VHL. VHL disease is clinically characterized by retinal and CNS hemangioblastomas, RCC (renal clear cell carcinoma), PCC, neuroendocrine pancreatic tumors and pancreatic cystadenomas, endolymphatic sac tumors and broad ligament cystadenomas. Closely related to this disease are the mutations involving the succinate dehydrogenase genes (SDHx genes). The lack of function of SDHx genes leads to an inhibition of prolyl hydroxylases by alpha-ketoglutarate. These hydroxylases “target” HIF1/2-α by specific hydroxylation to be recognized and bound by VHL. In this way, hydroxylases cannot help in the degradation of HIF, and a state of pseudo-hypoxia is created.
Surveillance recommendations for both diseases (VHL disease and PHEO/PGL)2 are very similar. It is important to suspect, localize and resect these tumors.

The present case presents the clinical evolution and management of a patient with a hereditary paraganglioma syndrome. The combination of high doses of the beta blocker propranolol (3 mg/Kg/day) and the DNA intercalating agent, temozolomide, was been successful in the treatment of the SDHA metastatic paraganglioma.

Case description

A 53 year old man, with personal and family history of hypertension, was diagnosed with a 4 cm tumoral mass at costovertebral D6–D7 with a 21 max SUV, during a routine check-up in March 2010. The only manifestation of disease was elevated blood pressure. He was being treated at this time with irbesartan/hydrochlorothiazide (1250mg/12.5mg, respectively). After surgery, the pathology diagnosis was of PGL with a Ki67 around 5-8%, and synaptophysin and chromogranin positive. Genetic analysis found a mutation in the SDHA gene, leading to a heterozygous missense p.Ser445Leu change, defined as pathogenic8. The patient remained without treatment and symptom-free until August 2014, when a back pain appeared around the D10 region, with progressive worsening. In October, as the pain persisted, he underwent MRI and 18F-DG-PET scan and was diagnosed with several metastasis at: D6–D7, right acetabulum (3cm); vertebral hemi-body D10 (3cm); vertebral body of D12 (2cm); and left iliac crest (1cm). A scintigraphy with Indium-111 pentetreotide suggested metastatic disease of probably neuroendocrine origin. D10 lesion biopsy confirmed the diagnosis of PGL metastasis with a Ki67 around 15–20% (Figure 1A). The patient was treated with doxazosin (8 mg/day) and bisoprolol (10 mg/day).

In November 2014, the patient started on systemic treatment with denosumab (120 mg every 28 days) and lanreotide (120 mg every 14 days). After 4 months, a PET-TAC showed a metabolic stabilization of the disease, but with a slight growth of lesions according to MRI (Figure 1B). D6 and D10 lesions were then treated by radiotherapy (Cyberknife). To this purpose, in March/April 2015 the patient underwent SBRT with CiberKnife (24 Gy in D10, 15 Gy in D12 and 35 Gy in D6–7), and the pain disappeared. After 6 months, the D7 and D12 lesions were also irradiated and completed SBRT with CiberKnife (24 Gy in left iliac bone and 24 Gy to right acetabulum).

Response to radiotherapy was good, showing stability of lesions and decrease of max SUV. No new lesions appeared. In June 2015, a thermoablation and right acetabulum metastasis cementation was performed with good results.

At this moment, the anti-hypertensive bisoprolol was changed to propranolol(120mg/day), due to preliminary reports of propranolol's good results in VHL tumors9. During the following 11 months, the patient remained stable without disease progression (Figure 1C). Lanreotide dose was decreased to 120 mg every 3 weeks, due to side effects. Side effects included nausea, vomits, diarrhea and hyperglycaemia.

In May 2016, metanephrines and chromogranin were raised above normal levels, as follows: Chromogranin A, 106 ng/mL (normal level, <93); urine fractionated Norepinephrine, 196 mcg/24h (normal levels, 15–80); urine fractionated normetanephrine, 1316 mcg/24 h (normal levels, 128-484); urine total metanephephrine, 1394 mcg/24h (normal levels, 220-680). A 18FDG-PET-TAC revealed an important metastatic dissemination all over the skeleton, showing more than 40 small new lesions less than 2 cm, and with scarce or null Octreoscan and 123I-MIBG uptake (Figure 1D).

From this moment on, a combined treatment of metronomic temozolomide (75 mg/m² for 21 days every 28 days) and an increase of propranolol up to 3 mg/kg/day (240 mg/day) was prescribed. After the first cycle of temozolomide, results were evaluated in August 2016 at National Institutes of Health, where the previously detected metastatic dissemination was confirmed, although catecholamines and chromogranin levels were decreasing compared with the previous measures. Treatment was kept the same for 6 cycles of temozolomide. In December 2016, most of lesions had disappeared according to PET-TAC. The two remaining lesions had maximum SUV significantly decreased. In January 2017, lanreotide was retired due to adverse side effects (as before).

In July 2017, a new PET supported the previous results, showing the remaining two lesions but with maximum SUV lower (Figure 1F). Temozolomide was withdrawn because of side effects (lymphopenia and thrombopenia). In October 2017, 4 months since the last dose of temozolomide, and propranolol as the only treatment (240mg/day), the disease remains controlled according to the last PET-TAC (F18-FDG) (Figure 1G). This imaging study suggests the presence of two neoplastic bone lesions in the dorsal spine and right acetabulum; regarding the previous examination (July 2017), the lesions described in D6 and acetabulum persist without major changes, whereas that of vertebra D10 has disappeared.

Discussion
The present case report describes an impressive clinical and metabolic improvement of a patient suffering from a metastatic paraganglioma after using a combination of temozolomide and propranolol at high doses. The improvement has been kept even after 7 months of lanreotide removal (usually used as standard treatment).

We can only hypothesize about the reason for this spectacular result. However, there are some literature reports on the synergy between chemotherapeutic agents inducing DNA damage, and therefore blocking DNA replication (as it is here the case of temozolomide) and β-blockers, which have shown antiangiogenic and pro-apoptotic effects in tumoral cells.

Recent examples of these combinations found in the literature include the action of β-blockers increasing response to different chemotherapeutic agents. Pasquier et al. used a mouse model of neuroblastoma, where β-blockers were shown to increase treatment efficacy. Propranolol in combination with vinblastine (chemotherapeutic agent belonging to the group of vegetable alkaloids), proved to be a successful treatment for advanced angiosarcoma, with optimal results in seven patients following a clinical trial. Chow et al. showed the regression of a rapidly enlarging stage T2 angiosarcoma of the scalp and face, following combination therapy with propranolol hydrochloride, paclitaxel (other vegetable alkaloid), and radiotherapy. More recently, a prospective study using propranolol for off-label treatment of patients with melanoma, confirmed a significantly inversely association with recurrence of melanoma when propranolol was used at the time of diagnosis15. We could infer that propranolol seems to potentiate the anti-angiogenic effects and antitumor efficacy of chemotherapy.

Focusing our attention to propranolol- an unspecific β-blocker - as an antitumoral agent, Albiñana and coworkers recently published the clinical and biomarker follow-up of a clinical trial conducted in seven VHL patients with retinal hemangioblastomas. These patients had no surgical option, and the tumors remained stable in size (with reabsorption of exudates) following 120 mg propranolol treatment for 12 months. This clinical trial led recently to the European Medicines Agency's designation of propranolol as Orphan drug for VHL disease.

The hypothesis supporting the antiangiogenic properties of propranolol relies on its proven effect on decreasing HIF-inducible transcription targets. Propranolol would decrease HIF protein levels, and therefore, the activation of the hypoxia program developed by the hypoxia target genes, among them, angiogenic factors, such as VEGF, FGF, PDGF, EPO, and metalloproteases, activated in tumors that favor migration and dissemination of cancer cells.

The advantages of the use of propranolol and temozolomide derive mainly from the long experience as therapeutic agents. Both are old drugs, and therefore, the safety profile and side effects are well known. In this context, we can state that if they are proven effective in tumoral cases difficult to manage, the therapeutic solution may be immediate from the bench to the patient. In our case, after 4 months taking propranolol as the only medication, the improvement is maintained, which would support the use of propranolol as a drug that significantly increases the progression-free survival in absence of temozolomide. If these results are confirmed in more studies, its use would represent an advantage, allowing - once the disease is in remission - periods of time for the marrow to recover from the adverse effects of chemotherapy with the alkylating agent.

The strengths of the treatment are the results and the absence of serious side effects for the propranolol in this particular case. The limitations of using propranolol derive from the anti-hypertensive effects. Hypotensive patients should take care with the treatment, and be always under cardiologist supervision.

For these rare diseases where therapeutic options are scarce and with not very successful results, outcomes like the one reported here have to be seriously considered if we want to improve the quality and life expectancy for these - in most cases - young patients

1 Lenders JW, Duh QY, Eisenhofer G, et al.: Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2014; 99(6): 1915–1942.

2. Rednam SP, Erez A, Druker H, et al.: Von Hippel-Lindau and hereditary pheochromocytoma/paraganglioma syndromes: Clinical features, genetics, and surveillance recommendations in childhood. Clin Cancer Res. 2017; 23(12): e68–e75.

3. Henegan JC Jr, Gomez CR: Heritable Cancer Syndromes Related to the Hypoxia Pathway. Front Oncol. 2016; 6: 68.

4. Semenza GL: Oxygen homeostasis. Wiley Interdiscip Rev Syst Biol Med. 2010; 2(3): 336–61.

5. Dhani N, Fyles A, Hedley D, et al.: The clinical significance of hypoxia in human cancers. Semin Nucl Med. 2015; 45(2): 110–21.

6. Taïeb D, Pacak K: New Insights into the Nuclear Imaging Phenotypes of Cluster 1 Pheochromocytoma and Paraganglioma. Trends Endocrinol Metab. 2017; 28(11): 807–817.

7. Selak MA, Durán RV, Gottlieb E: Redox stress is not essential for the pseudo-hypoxic phenotype of succinate dehydrogenase deficient cells. Biochim Biophys Acta - Bioenerg. 2006; 1757(5–6): 567–72.

8. Miettinen M, Killian JK, Wang ZF, et al.: Immunohistochemical loss of succinate dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol. 2013; 37(2): 234–40.

9. Albiñana V, Villar Gómez de Las Heras K, Serrano-Heras G, et al.: Propranolol reduces viability and induces apoptosis in hemangioblastoma cells from von Hippel-Lindau patients. Orphanet J Rare Dis. 2015; 10(1): 118.

10. Albiñana V, Recio-Poveda L, Zarrabeitia R, et al.: Propranolol as antiangiogenic candidate for the therapy of hereditary haemorrhagic telangiectasia. Thromb Haemost. 2012; 108(1): 41–53.

11. Pasquier E, Street J, Pouchy C, et al.: Β-Blockers Increase Response To Chemotherapy Via Direct Antitumour and Anti-Angiogenic Mechanisms in Neuroblastoma. Br J Cancer. 2013; 108(12): 2485–94.

12. Pasquier E, André N, Street J, et al.: Effective Management of Advanced Angiosarcoma by the Synergistic Combination of Propranolol and Vinblastine-based Metronomic Chemotherapy: A Bench to Bedside Study. EBioMedicine. 2016; 6: 87–95.

13. Jenkins K: Propranolol in Angiosarcoma: First Major Advance in Decades. Medscape. 2017. Reference Source

14. Chow W, Amaya CN, Rains S, et al.: Growth Attenuation of Cutaneous Angiosarcoma With Propranolol-Mediated β-Blockade. JAMA dermatology. 2015; 151(11): 1226–1229.

15. De Giorgi V, Grazzini M, Benemei S, et al.: Propranolol for Off-label Treatment of Patients With Melanoma Results From a Cohort Study. JAMA Oncol. 2017.

16. Albiñana V, Escribano RMJ, Soler I, et al.: Repurposing propranolol as a drug for the treatment of retinal haemangioblastomas in von Hippel-Lindau disease. Orphanet J Rare Dis. 2017; 12(1); 122.

Immunogenic chemotherapy: Dose and schedule dependence and combination with immunotherapy.

2018-02-26T09:39:27Z

In a recent review entitled : Immunogenic chemotherapy: Dose and schedule dependence and combination with immunotherapy, Junjie Wu and David Waxman from the Department of Biology, Division of Cell and Molecular Biology, Boston University, Boston USA review the data about metronomic chemotherapy (MC) and its impact on immunity

Indeed, some anti-cancer chemotherapeutic drugs, such as doxorubicin, mitoxantrone, and cyclophosphamide, can kill tumor cells by an immunogenic cell death pathway. In turn it activates both innate and adaptive anti-tumor immune responses
More specifically, dose and schedule of administration of MC can impact on anti-tumor immune responses. Strategy for effective immunogenic chemotherapy that rely on a modified metronomic schedule for drug delivery are proposed: medium-dose intermittent chemotherapy (MEDIC). Striking responses have been seen in preclinical cancer models using MEDIC, where an immunogenic cancer chemotherapeutic agent is administered intermittently and at an intermediate dose, designed to impart strong and repeated cytotoxic damage to tumors, and on a schedule compatible with activation of a sustained anti-tumor immune response, thereby maximizing anti-cancer activity. Of MEDIC can be then used for developing strategies for combination chemo-immunotherapy are explored.

The full text is available in the Cancer Letters Website here

Metronomic delivery of cyclophosphamide is less detrimental to granulosa cell viability, ovarian function, and fertility than MTD

2017-10-19T05:56:38Z

Dynes J, Osz K, Hooper A and Petrik J. from the Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada. have just published an article entitled Low Dose Metronomic Delivery of Cyclophosphamide is Less Detrimental to Granulosa Cell Viability and Ovarian Function Than Maximum Tolerated Dose Delivery in the Mouse in Biology of Reproduction.
In this article they show using mice model that metronomic cyclophosphamide induces less follicule atresia than MTD cyclophosphamide suggesting it might minimize tlong term effect of alkylating agents on fertility.

Abstract

Chemotherapy can cause early menopause or infertility in women and have a profound negative impact on the quality of life of young female cancer survivors. Various factors are known to influence the risk of chemotherapy-induced ovarian failure, including the drug dose and treatment duration; however, the scheduling of dose administration has not yet been evaluated as an independent risk factor. We hypothesized that Low-Dose Metronomic (LDM) chemotherapy scheduling would be less detrimental to ovarian function than the traditional Maximum-Tolerated Dose (MTD) strategy. In vitro, MTD cyclophosphamide exposure resulted in decreased proliferation and increased granulosa cell apoptosis, while cells treated with LDM cyclophosphamide were not different from untreated controls. Treatments of MTD cyclophosphamide induced high levels of follicle atresia and enhanced follicle recruitment in mice. In contrast, LDM delivery of an equivalent dose of cyclophosphamide reduced growing follicle numbers, but was not associated with higher levels of follicle atresia or recruitment. MTD cyclophosphamide induced significant vascular disruption and DNA damage in vivo, while LDM chemotherapy with equal cumulative amounts of cyclophosphamide were not different from controls. MTD chemotherapy also had a negative effect on mouse fertility outcomes. Our findings suggest that LDM scheduling could potentially minimize the long-term effects of cyclophosphamide on female fertility by preventing follicle depletion from enhanced activation.

You can access full text here.

Special section on Metronomic Chemotherapy in Cancer Letters

2017-04-02T12:44:39Z

Special section on Metronomic Chemotherapy, Guest Edited by Ravi Kumar and A.K. Sood from the Department of Pharmaceutical Sciences, Texas A&M University, College Station, TX, USA and the Frank McGraw Memorial Chair in Cancer Research, The University of Texas MD Anderson Cancer Center, Houston, TX, USA has been published in Cancer Letters.

This special section is a collection 14 pieces that covers a wide variety topics related to the potential of metronomic therapy: ranging from potential use in a given disease (colon cancer, pancreatic cancer, esophageal and gastroesophageal cancer, breast cancer, head & neck cancer), mechanism of action (imunnity, resistance) and new emerging fields (mathematical modelization, nanotechnologies) and results from clinical trial (breast cancer) or preclinical work (S1 & colon cancer).
It is great for the field of metronomic chemotherapy that a journal such as Cancer Letters initiate such an initiative. Nevertheless, not a single piece dedicated to low and middle income countries or children.... maybe next time ?

– The potential clinical promise of ‘multimodality' metronomic chemotherapy revealed by preclinical studies of metastatic disease

Robert S. Kerbel, Yuval Shaked
We present a rationale for further clinical development and assessment of metronomic chemotherapy on the basis of unexpected results obtained in translational mouse models of cancer involving treatment of advanced metastatic disease. Historically, mouse cancer therapy models have been dominated by treating established primary tumors or early stage low volume microscopic disease. Treatment of primary tumors is also almost always the case when using genetically engineered mouse models (GEMMs) of cancer or patient-derived xenografts (PDXs). Studies using such models, and others including transplanted cell lines, often yield highly encouraging results which are seldom recapitulated in the clinic, especially when assessed in randomized phase III clinical trials. While there are likely many different reasons for this discrepancy, one is likely the failure to recapitulate treatment of advanced visceral metastatic disease in mice. With this gap in mind, we have developed a number of models of metastatic human tumor xenografts (and more recently, of mouse tumors in syngeneic immunocompetent mice). A pattern of response we have observed with various targeted agents, e.g. VEGF pathway targeting antiangiogenic drugs or trastuzumab, is effective when treating primary tumors in contrast to a complete or severely reduced lack of such efficacy when treating advanced metastatic disease. Interestingly, an exception to this pattern has been observed using various continuous low-dose metronomic chemotherapy regimens, where counterintuitively, superior responses are observed in the metastatic setting, as well as superiority or equivalence of metronomic chemotherapy over standard maximum tolerated dose (MTD) chemotherapy, with lesser toxicity. The basis for these encouraging results may be related to the multiple mechanisms responsible for the anti-tumor effects and longer duration of metronomic chemotherapy regimens made possible by lesser toxicity. These include antiangiogenesis, stimulation of the immune system, stromal cell targeting in tumors, and possibly direct tumor cell targeting, including targeting cancer stem cells (CSCs). In addition, metronomic chemotherapy regimens minimize or even eliminate the problem of chemotherapy-induced host responses that may actually secondarily promote tumor growth and malignancy after causing an initial and beneficial anti-tumor response. We suggest that future preclinical studies of metronomic chemotherapy should be concentrated in the following areas: i) further comparative assessment of anti-tumor efficacy in primary vs metastatic treatment settings; ii) rigorous comparative assessment of conventional MTD chemotherapy vs metronomic chemotherapy using the same agent; iii) assessment of potential predictive biomarkers for metronomic chemotherapy, and methods to determine optimal biologic dose and schedule; and iv) a further detailed assessment of the potential of different chemotherapy drugs administered using MTD or metronomic regimens on stimulating or suppressing components of the innate or adaptive immune systems.

– Metronomic chemotherapy: A potent macerator of cancer by inducing angiogenesis suppression and antitumor immune activation

Eirini Biziota, Leonidas Mavroeidis, Eleftheria Hatzimichael, Periklis Pappas
Metronomic chemotherapy is a low dosing treatment strategy that attracts growing scientific and clinical interest. It refers to dense and uninterrupted administration of low doses of chemotherapeutic agents (without prolonged drug free intervals) over extended periods of time. Cancer chemotherapy is conventionally given in cycles of maximum tolerated doses (MTD) with the aim of inducing maximum cancer cell apoptosis. In contrast, the primary target of metronomic chemotherapy is the tumor's neovasculature. This is relevant to the emerging concept that tumors exist in a complex microenvironment of cancer cells, stromal cells and supporting vessels. In addition to its anti-angiogenetic properties, metronomic chemotherapy halts tumor growth by activating anti-tumor immunity, thus decreasing the acquired resistance to conventional chemotherapy. Herein, we present a review of the literature that provides a scientific basis for the merits of chemotherapy when administered on a metronomic schedule.

– Safety and efficacy study of metronomic vinorelbine, cyclophosphamide plus capecitabine in metastatic breast cancer: A phase II trial

Emilia Montagna, Antonella Palazzo, Patrick Maisonneuve, Giuseppe Cancello, Monica Iorfida, Angela Sciandivasci, Angela Esposito, Anna Cardillo, Manuelita Mazza, Elisabetta Munzone, Antonella Lai, Aron Goldhirsch, Marco Colleoni
In a phase II study we assessed the safety and efficacy of metronomic oral chemotherapy with vinorelbine, cyclophosphamide capecitabine in patients with metastatic breast cancer, either as first-line (naïve group) or second-line or greater therapy (pre-treated group). Eligible patients had histologically or cytologically proven, hormone-receptor positive metastatic breast cancer. The primary end point was median time to progression (TTP). A total of 43 patients in the naïve group and 65 in the pre-treated group were enrolled. The median TTP was 25.1 months in the naïve group and 11.2 months in the pre-treated group. The most frequently reported grade 2 treatment-related adverse events were leukopenia and hand and foot syndrome. Metronomic combination of cyclophosphamide, capecitabine and vinorelbine showed significant activity and good tolerability in patients hormonal receptor positive, metastatic breast cancer patients.

– Metronomic S-1 dosing and thymidylate synthase silencing have synergistic antitumor efficacy in a colorectal cancer xenograft model

Amr S. Abu Lila, Naoto Moriyoshi, Masakazu Fukushima, Cheng-Long Huang, Hiromi Wada, Tatsuhiro Ishida
Metronomic chemotherapy is currently considered an emerging therapeutic option in clinical oncology. S-1, an oral formulation of Tegafur (TF), a prodrug of 5-fluorouracil (5-FU), is designed to improve the antitumor activity of 5-FU in tandem with reducing its toxicity. Clinically, metronomic S-1 dosing has been approved for the standard first- and second-line treatment of metastatic or advanced stage of colorectal (CRC). However, expression of intratumor thymidylate synthase (TS), a significant gene in cellular proliferation, is associated with poor outcome to 5-FU-based chemotherapeutic regimens. In this study, therefore, we examined the effect of a combination of TS silencing by an RNA interfering molecule, chemically synthesized short hairpin RNA against TS (shTS), and 5-FU on the growth of human colorectal cancer cell (DLD-1) both in vitro and in vivo. The combined treatment of both shTS with 5-FU substantially inhibited cell proliferation in vitro. For in vivo treatments, the combined treatment of metronomic S-1 dosing with intravenously injected polyethylene glycol (PEG)-coated shTS-lipoplex significantly suppressed tumor growth, compared to a single treatment of either S-1 or PEG-coated shTS-lipoplex. In addition, the combined treatment increased the proportion of apoptotic cells in the DLD-1 tumor tissue. Our results suggest that metronomic S-1 dosing combined with TS silencing might represent an emerging therapeutic strategy for the treatment of patients with advanced CRC.

– Tackling pancreatic cancer with metronomic chemotherapy

Adriana Romiti, Rosa Falcone, Michela Roberto, Paolo Marchetti
Pancreatic tumours, the majority of which arise from the exocrine pancreas, have recently shown an increasing incidence in western countries. Over the past few years more and more new selective molecules directed against specific cellular targets have become available for cancer therapy, leading to significant improvements. However, despite such advances in therapy, prognosis of pancreatic cancer remains disappointing. Metronomic chemotherapy (MCT), which consists in the administration of continuous, low-dose anticancer drugs, has demonstrated the ability to suppress tumour growth. Thus, it may provide an additional therapeutic opportunity for counteracting the progression of the tumour. Here we discuss evidence arising from preclinical and clinical studies regarding the use of MCT in pancreatic cancer. Good results have generally been achieved in preclinical studies, particularly when MCT was combined with standard dose chemotherapy or antinflammatory, antiangiogenic and immunostimolatory agents. The few available clinical experiences, which mainly refer to retrospective data, have reported good tolerability though mild activity of metronomic schedules. Further studies are therefore awaited to confirm both preclinical findings and the preliminary clinical data.

– Metronomic chemotherapy and immunotherapy in cancer treatment

Yu-Li Chen, Ming-Cheng Chang, Wen-Fang Cheng
Systemic chemotherapy given at maximum tolerated doses (MTD) has been the mainstay of cancer treatment for more than half a century. In some chemosensitive diseases such as hematologic malignancies and solid tumors, MTD has led to complete remission and even cure. The combination of maintenance therapy and standard MTD also can generate good disease control; however, resistance to chemotherapy and disease metastasis still remain major obstacles to successful cancer treatment in the majority of advanced tumors. Metronomic chemotherapy, defined as frequent administration of chemotherapeutic agents at a non-toxic dose without extended rest periods, was originally designed to overcome drug resistance by shifting the therapeutic target from tumor cells to tumor endothelial cells. Metronomic chemotherapy also exerts anti-tumor effects on the immune system (immunomodulation) and tumor cells. The goal of immunotherapy is to enhance host anti-tumor immunities. Adding immunomodulators such as metronomic chemotherapy to immunotherapy can improve the clinical outcomes in a synergistic manner. Here, we review the anti-tumor mechanisms of metronomic chemotherapy and the preliminary research addressing the combination of immunotherapy and metronomic chemotherapy for cancer treatment in animal models and in clinical setting.

– Metronomic chemotherapy in metastatic colorectal cancer

In Sook Woo, Yun Hwa Jung
Overall survival and quality of life of patients with metastatic colorectal cancer (mCRC) have improved due to the development of standard systemic treatment. However, many patients are still suffering from the eventual progression of cancer, treatment-related toxicities, and the economic burden of new drugs. Salvage or maintenance therapy, which consistently controls or stabilizes tumor progression without debilitating quality of life, is required. Recently, metronomic capecitabine maintenance therapy after disease control using conventional chemotherapy with maximal tolerated doses has demonstrated beneficial results in a phase III trial. Metronomic chemotherapy has been known to control tumors through antiangiogenesis and immunomodulation as well as a direct effect on tumor-initiating cells. It has the characteristics of being minimally toxic, inexpensive, and durable for maintaining disease stabilization. Therefore, patients with mCRC, who tend to be elderly and frail and have been previously treated, might be suitable for metronomic therapeutic strategies. Furthermore, antiangiogenic therapy has been an important component in treating mCRC, but the schedules and doses of metronomic chemotherapy have not yet been established. Here we review translational and clinical research on metronomic chemotherapy in colorectal cancer (CRC).

– Metronomics in the neoadjuvant and adjuvant treatment of breast cancer

Elisabetta Munzone, Marco Colleoni
The concept of metronomic chemotherapy (MC) has evolved from a descriptive preclinical phenomenon encompassing inhibition of angiogenesis to a clinically validated treatment concept involving multiple potential mechanisms of action. Clinicians are progressively more incline to consider MC as a component of mainstream medical oncology practice in advanced breast cancer. However, more recently MC has been tested even in the adjuvant/neoadjuvant setting, taking the opportunity to obtain tumor specimens and blood samples, in order to identify tumor-specific or patient-specific biomarkers for personalizing treatments. In addition, the antiangiogenic and pro-immune nature of metronomic chemotherapy made triple negative breast cancer (TNBC) a good candidate for exploring low-dose maintenance treatment in the adjuvant setting or in combination with immunomodulatory drugs. The potential development of MC in breast cancer pass through the research to identify biomarkers and individual tumor characteristics that can better address the use of this treatment strategy in the future. Finally, the subjective attitude of patients represents one of the major factors that influence the choice and acceptance of a therapeutic program. Personal preference and considerations about quality of life should guide the treatment choice eventually prioritizing the use of MC. Nevertheless, more robust data from randomized phase III trials are needed in the future, in order to make clinicians more confident in using metronomic strategies.

– Metronomic chemotherapy for advanced breast cancer patients

Marina Elena Cazzaniga, Maria Rita Dionisio, Francesca Riva
Metronomic chemotherapy refers to the minimum biologically effective dose of a chemotherapy agent given as a continuous dosing regimen with no prolonged drug-free breaks that leads to antitumor activity. This schedule seems to have not only a direct cytotoxicity on cancer cells but also an effect on the tumor microenvironment by inhibiting tumor angiogenesis and modulating immune response.
Metronomic chemotherapy was widely investigated in patients with breast cancer. The results of these studies showed that this strategy is not only effective but has a low toxicity profile too, proposing as a promising strategy for breast cancer patients. In this review we summarize the results of Phase II and III studies evaluating metronomic therapy in metastatic breast cancer.

– Potential role of metronomic chemotherapy in the treatment of esophageal and gastroesophageal cancer

Vanita Noronha, Vijay M. Patil, Amit Joshi, Anuradha Chougule, Shripad Banavali, Kumar Prabhash
Patients with esophagogastric cancer have poor prognoses in spite of the best available therapies. Patients are debilitated and may not tolerate, or may progress, on standard cytotoxic chemotherapy regimens. Metronomic chemotherapy is an attractive treatment option due to its very low reported toxicity, modest efficacy, low cost and ease of administration. Capecitabine is the most common drug used in metronomic scheduling; other drugs include cyclophosphamide and paclitaxel. Dosing of capecitabine can range from 1000 mg orally daily for 4 weeks on and 1 week off to a continuous dosing schedule of 1500 mg orally daily. Reported toxicities, including neutropenia, mucositis and hand-foot syndrome, occur in <10% of patients. As there is a lack of well-conducted, randomized clinical trials evaluating the role of metronomic chemotherapy in esophagogastric cancer, it cannot be recommended as the standard of care; however, it can be considered to be a therapeutic option, especially in elderly patients with relapsed disease for whom other therapeutic options are limited.

– Metronomic chemotherapy in head and neck cancer

Francesca De Felice, Ilaria Benevento, Angela Musella, Daniela Musio, Vincenzo Tombolini
Head neck cancer (HNC) is generally treated with a multimodality approach. Loco-regional-distant control is often worst, due to the advantage stage disease at diagnosis and the optimal treatment option remains an unresolved issue. Metronomic chemotherapy (MCHT) is an emerging therapeutic option in clinical oncology and it may prove useful in HNC patients.

– Application of mathematical models to metronomic chemotherapy: What can be inferred from minimal parameterized models?

Urszula Ledzewicz, Heinz Schättler
Metronomic chemotherapy refers to the frequent administration of chemotherapy at relatively low, minimally toxic doses without prolonged treatment interruptions. Different from conventional or maximum-tolerated-dose chemotherapy which aims at an eradication of all malignant cells, in a metronomic dosing the goal often lies in the long-term management of the disease when eradication proves elusive. Mathematical modeling and subsequent analysis (theoretical as well as numerical) have become an increasingly more valuable tool (in silico) both for determining conditions under which specific treatment strategies should be preferred and for numerically optimizing treatment regimens. While elaborate, computationally-driven patient specific schemes that would optimize the timing and drug dose levels are still a part of the future, such procedures may become instrumental in making chemotherapy effective in situations where it currently fails. Ideally, mathematical modeling and analysis will develop into an additional decision making tool in the complicated process that is the determination of efficient chemotherapy regimens. In this article, we review some of the results that have been obtained about metronomic chemotherapy from mathematical models and what they infer about the structure of optimal treatment regimens.

– Metronomic chemotherapy and nanocarrier platforms

Amr S. Abu Lila, Tatsuhiro Ishida
The therapeutic concept of administering chemotherapeutic agents continuously at lower doses, relative to the maximum tolerated dose (MTD) without drug-free breaks over extended periods –known as “metronomic chemotherapy”– is a promising approach for anti-angiogenic cancer therapy. In comparison with MTD chemotherapy regimens, metronomic chemotherapy has demonstrated reduced toxicity. However, as a monotherapy, metronomic chemotherapy has failed to provide convincing results in clinical trials. Therapeutic approaches including combining the anti-angiogenic “metronomic” therapy with conventional radio-/chemo-therapy and/or targeted delivery of chemotherapeutic agents to tumor tissues via their encapsulation with nanocarrier-based platforms have proven to potentiate the overall therapeutic outcomes. In this review, therefore, we focused on the mutual contribution made by nanoscale drug delivery platforms to the therapeutic efficacy of metronomic-based chemotherapy. In addition, the influence that the dosing schedule has on the overall therapeutic efficacy of metronomic chemotherapy is discussed.

– Resistance to metronomic chemotherapy and ways to overcome it

Maria Riesco-Martinez, Karla Parra, Ronak Saluja, Giulio Francia, Urban Emmenegger
Therapeutic resistance is amongst the major determinants of cancer mortality. Contrary to initial expectations, antivascular therapies are equally prone to inherent or acquired resistance as other cancer treatment modalities. However, studies into resistance to vascular endothelial growth factor pathway inhibitors revealed distinct mechanisms of resistance compared to conventional cytotoxic therapy. While some of these novel mechanisms of resistance also appear to be functional regarding metronomic chemotherapy, herein we summarize available evidence for mechanisms of resistance specifically described in the context of metronomic chemotherapy. Numerous preclinically identified molecular targets and pathways represent promising avenues to overcome resistance and enhance the benefits achieved with metronomic chemotherapy eventually. However, there are considerable challenges to clinically translate the preclinical findings.

Role of vascular normalization in benefit from metronomic chemotherapy.

2017-02-09T09:43:54Z

FM Pekris, JW Baish , T. Stylianopoulos T, and RK Jain from the Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia , Cyprus, the Department of Biomedical Engineering, Bucknell University, Lewisburg, the Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia 1678, Cyprus and the Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, USA have just pubiseehd in the Proc Natl Acad Sci U S A. a article entitled : Role of vascular normalization in benefit from metronomic chemotherapy.

In this work, the authors integrate in a mathematical model the multiple mechanisms of metronomic chemotherapy , how these mechanisms are related to one another. They report that MC leads to an improved function of tumor vessels which turns out to be a key determinant of benefit from MC. Using multiple dosage schedules and incorporation interactions among cancer cells, stem-like cancer cells, immune cells, and the tumor vasculature, the authors have found that MC induces functional normalization of tumor blood vessels.
This normalization results in turn in improved tumor perfusion and cascade decreased hypoxia, reprogramming of the immunosuppressive tumor microenvironment toward immunostimulation and also improved drug delivery and ultimately therapeutic outcomes. This mathematical model has valuable biological translation and enables evaluation of the relative importance of these mechanisms, and suggests guidelines for the optimal use of MC.

Evidence implicating immunological host effects in the efficacy of metronomic low-dose chemotherapy.

2016-09-15T17:41:49Z

Y. Shaked and al. from the Israel Institute of Technology, The University of Texas M. D. Anderson Cancer Center and the Sunnybrook Research Institute have just published in Cancer Research an article entitled: Evidence implicating immunological host effects in the efficacy of metronomic low-dose chemotherapy where they show the impact of metronomic capecitabine on the immune system and their potential anti-tumoral effects.

Abstract

Background : Conventional chemotherapy drugs administered at a maximum tolerated dose (MTD) remains the backbone for treating most cancers. Low-dose metronomic (LDM) chemotherapy, which utilizes lower, less toxic, doses given on a close regular basis over prolonged periods, is an alternative and better tolerated potential strategy to improve chemotherapy. LDM chemotherapy has been evaluated preclinically and clinically and has shown therapeutic benefit, in both early and advanced stage metastatic disease, especially when used as a maintenance therapy. However, knowledge about the anti-tumor mechanisms by which LDM chemotherapy acts remain limited.

Material and Methods: Here we characterized the effects of LDM and MTD capecitabine therapy on tumor and host cells using high-throughput systems approaches involving mass spectrometry flow cytometry and automated cell imaging followed by in vivo analyses of such therapies.

Results: An increase in myeloid and T regulatory cells and a decrease in NK and T cytotoxic cells were found in MTD-capecitabine-treated tumors compared to LDM-capecitbine-treated tumors. Plasma from MTD capecitabine-treated mice induced a more tumorigenic and metastatic profile in both breast and colon carcinoma cells than plasma from mice treated with LDM capecitabine. These results correlated, in part, with in vivo studies using models of human or mouse advanced metastatic disease, where the therapeutic advantage of MTD capecitabine was limited despite a substantial initial anti-tumor activity found in the primary tumor setting.

Conclusion: Overall these results implicate a possible contribution of immunological host effects in accounting for the therapeutic limitations of MTD compared to LDM capecitabine.

Metronomic cyclophosphamide & anti-tumor immunity: tumor model & drug schedule dependence of gene responses and their regulators.

2016-08-21T08:58:02Z

In this recent preclinical work entitled Metronomic cyclophosphamide activation of anti-tumor immunity: tumor model, mouse host, and drug schedule dependence of gene responses and their upstream regulators published in BMC Cancer, the team from David Waxman, Division of Cell and Molecular Biology, Department of Biology and Bioinformatics Program, Boston University report on the pro-immune effect of metronomic cyclophosphamide using different cell lines and schedule of cyclophosphamide to unveil the mechanism of actions that could explain difference in response to treatment.

Abstract

BACKGROUND: Cyclophosphamide (CPA) can activate immunogenic tumor cell death, which induces immune-based tumor ablation and long-term anti-tumor immunity in a syngeneic C57BL/6 (B6) mouse GL261 glioma model when CPA is given on a 6-day repeating metronomic schedule (CPA/6d). In contrast, we find that two other syngeneic B6 mouse tumors, LLC lung carcinoma and B16F10 melanoma, do not exhibit these drug-induced immune responses despite their intrinsic sensitivity to CPA cytotoxicity.

METHODS: To elucidate underlying mechanisms, we investigated gene expression and molecular pathway changes associated with the disparate immune responsiveness of these tumors to CPA/6d treatment.

RESULTS: Global transcriptome analysis indicated substantial elevation of basal GL261 immune infiltration and strong CPA/6d activation of GL261 immune stimulatory pathways and their upstream regulators, but without preferential depletion of negative immune regulators compared to LLC and B16F10 tumors. In LLC tumors, where CPA/6d treatment is shown to be anti-angiogenic, CPA/6d suppressed VEGFA target genes and down regulated cell adhesion and leukocyte transendothelial migration genes. In GL261 tumors implanted in adaptive immune-deficient scid mice, where CPA/6d-induced GL261 regression is incomplete and late tumor growth rebound can occur, T cell receptor signaling and certain cytokine-cytokine receptor responses seen in B6 mice were deficient. Extending the CPA treatment interval from 6 to 9 days (CPA/9d) - which results in a strong but transient natural killer cell response followed by early tumor growth rebound - induced fewer cytokines and increased expression of drug metabolism genes.

CONCLUSIONS: These findings elucidate molecular response pathways activated by intermittent metronomic CPA treatment and identify deficiencies that characterize immune-unresponsive tumor models and drug schedules.

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Drug Repurposing in Oncology—patient and health systems opportunities

2016-06-27T11:09:00Z

The cost of cancer drugs is going through the roof. Reconsidering the large arsenal of drugs already available for other diseases as options for treating cancer is a unique opportunity for patients and for national healthcare systems.
The continuing reduction in the cost of DNA sequencing is paving the way for ‘precision medicine', and an increasing number of clinical trials are being designed specifically for patients with a certain genetic profile of their tumours. However, researchers and doctors are having to deal with a new and complex scenario.
Firstly, the few National Healthcare Systems (NHSs) who can afford new “targeted” cancer drugs can no longer bear the cost. The average cost of treatment with a new cancer drug rose from $100 per month in the 1990s to $10,000 per month in 2011. Unfortunately, there is no sign that this will improve over the short or medium term.
Secondly, the availability of new cancer genomic data has revealed a greater complexity than was anticipated, and this situation makes it even clearer that we need treatments based on a combination of therapies instead of simply using a single agent. However, this does not fit the traditional strategy of the pharmaceutical industry, whose agenda is centred around clinical trials designed to achieve registration and approval for the clinical use of one new drug for one indication at a time.
In light of this situation, in an article in Nature Reviews Clinical Oncology entitled “Drug repurposing in oncology—patient and health systems opportunities”, Francesco Bertolini of the European Institute of Oncology in Milan (Italy), Vikas Sukhatme of Harvard Medical School, Beth Israel Deaconess Medical Center and GlobalCures in Boston (USA), and Gauthier Bouche of the Anticancer Fund in Brussels (Belgium) propose a new way forward with the potential to deliver significant benefits to patients and NHSs alike.
There is a certain amount of drugs already available for clinical use in different diseases and which have the potential to be reused in oncology, a strategy known as "Drug Repurposing"; this presents unique opportunities for new combination therapies. Preclinical and clinical development will certainly be safer because the side effects are already known, but also faster and cheaper as existing knowledge about the drugs reduces the amount of work and time needed for further development. Clinical development can be supported by partnerships between governments, NHSs, and not-for-profit foundations, with obvious potential benefits for all partners. Success stories involving the repurposing strategy in oncology have so far been limited, but have had a big impact, exemplified by thalidomide, a drug made infamous for serious effects on unborn children in the sixties, and now used with great success to treat multiple myeloma. Good old aspirin is another successful case of repurposing, in light of the results of its role in preventing colon cancer.
The European Institute of Oncology, Global Cures and the Anticancer Fund are already actively pursuing repurposing on various fronts. Each of these organizations is running pre-clinical and clinical trials focusing on drugs with low-cost and low-toxicity. A commitment to this research is now required from governments, NHSs and other funding sources, as this would significantly facilitate this type of therapeutic approach with the potential for rapid and significant benefits for cancer patients worldwide.