key: cord-1054418-qas0vzgn authors: Fedele, Palma; Sanna, Valeria; Fancellu, Alessandro; Marino, Antonella; Calvani, Nicola; Cinieri, Saverio title: De-escalating cancer treatments during COVID 19 pandemic: is metronomic chemotherapy a reasonable option? date: 2020-11-18 journal: Crit Rev Oncol Hematol DOI: 10.1016/j.critrevonc.2020.103148 sha: a704647ad435253c361908b0af7816224838392d doc_id: 1054418 cord_uid: qas0vzgn COVID 19 pandemic represents an emergency for public health services and containment measures to reduce the risk of infection have been promptly activated worldwide. The healthcare systems reorganization has had a major impact on the management of cancer patients who are considered at high risk of infection. 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 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. (1) In those countries where the spread of the pandemic is massive, specific measures have been taken to reduce access of cancer patients to hospitals. Elective surgeries, follow-up appointments J o u r n a l P r e -p r o o f and some types of cancer treatments have been cancelled or postponed to prioritize hospital beds and care for those who are seriously ill with COVID-19. (2) Consequently, medical oncologists must perform individual risk-benefit assessments in cancer patients before making any decision. For those patients who do not have an urgent need to start anticancer therapy, the treatment will be postponed. When the benefits for patients to undergo anticancer treatment outweigh the risks of being potentially exposed to the virus while travelling from home to the hospital and back, a new therapy will be initiated and in some cases the continuum of cancer care will be guaranteed. In this regard, recommendations and practical suggestions on how to implement cancer care have been published to guide medical oncologists in the difficult decision of prioritizing patients for cancer treatments. (3) (4) (5) (6) Since a priority of oncologists at this time is to minimize infection risks for cancer patients and encourage oral treatments to limit patients access to hospital facilities, we suggest to consider metronomic administration of chemotherapy as a reasonable therapeutic option to de escalate cancer treatments and to ensure the continuum of care of some cancer patients subgroups. Metronomic chemotherapy could allow the possibility of prolonged treatment with less side effects. It can allow the management of cancer patients at home and limit patients' dependence on hospitals and the possibility of infection in the hospital environment. Herein we analyze results from clinical trials that have evaluated the safety and efficacy of oral metronomic therapy in cancer patients, in order to identify the subgroups of cancer patients who are ideal candidates for metronomic chemotherapy. The earlier studies on MC were conducted in metastatic breast cancer (MBC) patients. Given that goals of care in MBC are to optimize both length and quality of life, MC strategies are attractive for their safe toxicity profile and good tumor control. Moreover, MC is delivered by the oral route that limits patients access to hospitals and represents the favorite route of chemotherapy administration for cancer patients. (12) The first clinical reports on MC examined the all oral combination of daily low dose of CM (cyclophosphamide 50 mg daily and methotrexate 2 days a week for a total dose of 10 mg a week) in pretreated or untreated MBC patients. (13) (14) (15) Subsequent studies have explored the efficacy and safety of the combination of CM with different other therapies (endocrine, anti Her2, targeted agents). The study by Aurilio et MeC was also tested in triple-drug chemotherapy combinations. In the phase II VEX trial the triple combination of metronomic oral vinorelbine 40 mg orally 3 times a week plus cyclophosphamide 50 mg daily and capecitabine 500 mg 3 times a day were explored in untreated metastatic triple-negative breast cancer patients. Median TTP was 6.4 months in 22/25 evaluable patients. The combination was well tolerated: most common grade 1-2 toxicities were nausea, diarrhea, leuko-/neutropenia and reversible liver enzyme alteration. Grade ≥ 3 adverse events were uncommon. (26) The multi-center, randomized phase II trial METEORA II is now investigating the metronomic regimen of cyclophosphamide 50 mg orally once daily continuously, capecitabine 500 mg, orally 3 times a day (1500 mg/day) continuously, vinorelbine 40 mg orally days 1, 3, 5 each week The phase II trial that investigated the combination of MeC 500 mg thrice daily plus cyclophosphamide 50 mg daily plus bevacizumab 15 mg/kg every 3 weeks and erlotinib 100 mg daily as first line treatment in HER2-negative, hormone receptor poor MBC reported a CBR of 75% (95% confidence interval [CI], 53%-90%). Median time to progression was 43 weeks (95% CI, 21-69). Toxicity was generally mild and grade 3 toxicity was rare: diarrhea (n = 1), thrombosis (n = 1), and hypertension (n = 2). (30) The multicenter, randomized phase III trial SAKK 24/09 compared bevacizumab with either paclitaxel or daily oral capecitabine 500 mg thrice daily plus and cyclophosphamide 50 mg daily as first-line treatment in patients with HER2-negative advanced breast cancer. No significant differences between treatment arms were reported in PFS that was 10.3 months (95 % CI 8.7-11.3) in the paclitaxel arm and 8.5 months in the metronomic arm (95 % CI 6.5-11.9). Less hair loss and numbness in metronomic arm were the only clinically and statistically significant differences. (31) More recently a phase II trial has explored a new metronomic regimen with cyclophosphamide 50 mg daily plus capecitabine 500 mg three times a day continuously in combination with trastuzumab in 60 HER-2 positive untreated MBC. The objective response rate that was the primary endpoint of the study was 56.7 % (95% CI, 44.1-68.4%) and CBR was 78.2%. Grade 3 and 4 toxicities were rare and the most commonly reported toxicities were G1 events (32) Metronomic therapy with oral vinorelbine has been explored in some MBC patient subgroups. In early breast cancer (EBC) the evidences currently reported show that the metronomic approach should be reserved for selected patients subgroups, such as triple negative, and as maintenance treatment. The first study that has explored efficacy and safety of oral MC is a randomized phase III trial that compared adjuvant tegafur/uracil (UFT) to classical CMF in node negative, high risk EBC patients. Survival results were similar in both arms, but the two different schedules differed in toxicity profiles. The quality of life scores were better for patients given UFT than those given CMF. (37) The open-label phase III trial, IBCSG 22-00 randomized 1,081 patients with ER and PGR negative EBC and any nodal status who have completed adjuvant chemotherapy to CM maintenance (cyclophosphamide 50 mg/d continuously and methotrexate 2.5 mg twice/d on days 1 and 2 of every week for 1 year) or to no CM. The metronomic CM maintenance therapy did not produce a significant reduction in DFS that was the primary endpoint of the study (DFS at 5 years was 78.1% in the CM group vs 74.7% in the no CM group (hazard ratio [HR] = 0.84, P = .14). There was a non statistically significant reduced HR (n = 340; HR, 0.72; 95% CI, 0.49 to 1.05) in the triple-negative, node-positive subgroup. Moreover, the CM maintenance chemotherapy was associated to grade 3 or 4 treatment-related adverse events that occurred in 14%. The most common side effect was elevated serum transaminases In preclinical studies MeC for colon cancer xenografts and colon cancer cells has proved to inhibit angiogenesis, decrease VEGF and microvessel density and increase antiangiogenic protein thrombospondin-1 (TSP-1). (44) The best clinical experience in colorectal cancer (CRC) derives from advanced disease where lowered but prolonged doses of standard chemotherapy have been used especially with the aim of targeting angiogenesis. The chemotherapeutic agents mostly studied for a metronomic approach in CRC are the fluoropyrimidines, predominantly capecitabine. Other agents evaluated in very few phase II studies are: tegafur/uracil (UFT), irinotecan, cyclophosphamide. The role of MeC has been particularly evaluated in phase II studies in the palliative setting of advanced pretreated patients and in one phase III trial in the maintenance therapy setting. Kidney cancer is usually thought to be resistant to standard chemotherapy and even targeted drugs seem to be only temporarily effective because of resistance. As target therapy and immunotherapy have improved the prognosis of metastatic renal cancer, the issues of quality of life and of pharmacologic tolerance are of paramount importance in this scenario. In particular, the resistance to these drugs still remains a problem. Further treatment strategy and MC could be an opportunity for renal cancer cure. Certainly, the manageability and low toxicity profile make MC particularly attractive also in kidney cancer. Table 2 reports safety details of the more significant phase II trials in kidney cancer. In ovarian cancer high level of response rate can be reached with debulking surgery and/or platinum based chemotherapy. However, relapse still occurs. In ovarian cancer, angiogenesis plays an important role, thus MC could be an interesting opportunity. (86) In most studies on ovarian cancer, MC has been used in relapsed/refractory ovarian carcinoma or in combination with standard chemotherapy to improve outcomes due to antiangiogenic effect with minimal toxicity. This frail population, generally heavily pretreated or unfit for iv chemotherapy because of complication of surgery, could have beneficial effects by continuous administration of low doses of chemotherapy. In animal models metronomic dosage of oral cyclophosphamide was proven to be safe in combination with irinotecan or pazopanib, with modest lowering of white blood cells and weight loss. Table 3 shows main toxicity reported with metronomic chemotherapy in ovarian cancer Although the introduction of immunotherapy has changed the prognosis of lung cancer, it remains Table 4 shows main toxicities reported with metronomic chemotherapy in lung cancer In patients with head and neck cancer (HNC) there are only limited management options due to the very frailty of this group of patients. MC may have a role for its good safety profile, as shown in table 5. Low-dose, continuous metronomic drugs were particularly studied in the contest of platinum-refractory patients and the commonest adverse event was fatigue ( G2-G3), while no febrile neutropenia was reported. (123) MC in recurrent HNC has shown good disease-control rates with effective palliation, minimal toxicity and preserved quality of life. (124, 125) In oral cancer methotrexate per os was evaluated with celecoxib with a significant beneficial of 15%; disease free survival was 13 months. (126,127) Besides, as the progression-free survival duration is prolonged, the risk of treatment resistance increases. It was shown that angiogenesis has an impact in melanoma, so it can be postulated that also MC has a role in this setting. (128) In MM the main experience with MC is in the use of alkylating agents. The first study of MC in MM explored the combinations of metronomic paclitaxel and celecoxib, but the toxicity was higher compared with oral regimen in other cancers and may be correlated to iv paclitaxel. (129) In a group of unfit elderly patients, treatment with cyclophosphamide reached an overall survival of 8 months, ranging from 4 to 37 (130) Similar results were reported also with cyclophosphamide combined with dendritic cell vaccine and a COX-2 inhibitor. (131) A different trial showed a good tolerance using temozolamide in association with cisplatin; the combination resulted in an overall survival of 50 weeks. (132) Glioblastoma is the most common malignant brain tumor. Standard therapy for glioblastoma includes surgery, radiotherapy and temozolamide. Few therapies are approved for recurrent disease and the prognosis is very poor. A metronomic approach for glioblastoma can be useful, because low dose chemotherapy could be well tolerated in a very frail population. Several clinical trials have studied the use of temozolamide, etoposide and cyclophosphamide which have the advantage of being manageable also in the outpatient setting, although no benefits in survival rate have been demonstrated. (133) Temozolamide was safe with radiotherapy and the overall survival was about 7 months (134); moreover, metronomic temozolamide was active for those patients who are refractory to standard cyclic treatment. (135) (136) The addition of bevacizumab has conflicting results. Bevacizumab used with a low dose temozolamide schedule seems to get a worse response (137) There are suggestions that MeC and bevacizumab could be used with success (138) In 2013 Chen conducted a metanalysis comparing metronomic and standard temozolamide regimens; no statistically significant difference was found between metronomic and standard schedules for response rate and no difference for overall survival at six and 12 months were reported. (139) In association with antinflammatory colecoxib, temozolamide had a very good safety profile without any G3/4 toxicity. (140) In a different study with temozolamide and bevacizumab and etoposide, only 1 episode of G4 neutropenia was seen. (141, 142) Zustovich et al. studied another tyrosine kinase inhibitor, sorafenib, twice daily with metronomic temozolamide; 6-month PFS was 26% and median OS was 7.4 months. (143). Table 6 shows main toxicities reported with metronomic chemotherapy in patients with brain tumors. Data reported so far have shown that oral metronomic regimens could be a reasonable treatment option in cancer patients. The low toxicity profile supports the chronic administration of the treatment especially in metastatic and pretreated patients and it could ensure the continuum of cancer care, preserving the prognosis of cancer patients also during COVID 19 pandemic. Low Nonetheless, the results are encouraging for the use of metronomic drugs in a population presenting various poor prognosis factors, such as age, comorbidities, pre-treatment lymphopenia and unfitness for usual chemotherapy. The metronomic schema seems to be a good alternative treatment, because of its safety and easy oral taking, enabling patients to stay at home longer. Further prospective randomized studies are needed to confirm more accurately the efficacy of specific metronomic regimens. 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Metronomic chemotherapy with daily low-dose temozolomide and celecoxib in elderly patients with newly diagnosed glioblastoma multiforme: a retrospective analysis We thank Antonio Guadalupi for his assistance with the manuscript.