Hormones in the Treatment of Glioblastoma Multiforme
Here we are at the sixth episode of Ben Williams’ guide translation project on treatment options for Glioblastoma Multiforme. This is chapter 5 of the guide which talks about angiotensin-II receptor blockers, beta blockers, suppression of thyroid hormone T4, but also melatonin and vitamin D. The advice is still to use this information to discuss it with the medical team that is that is taking care of you. In case you can also point them to the supporting scientific references.
Before leaving you to the reading, I would like to point out this fund campaign that I launched on GoFund.me: Glioblastoma.it for CUSP-ND for Emanuele! I kindly ask you to share the link as Ben Williams and other survivors who have used the drug cocktail approach are behind the CUSP-ND! Enjoy the reading!
Unlike traditional anticancer chemotherapy, which kills cancer cells through directly cytotoxic mechanisms, a different approach can also be effective: manipulating the body’s balance of circulating hormones to obtain a more inhospitable environment for the growth of tumors.
Angiotensin II receptor blockers (ARBs)
Angiotensin-II is a peptide hormone produced by angiotensin-I, ie by the action of the angiotensin converting enzyme (ACE). The main effect of angiotensin II is vasoconstriction and a consequent increase in blood pressure. Therefore, ACE inhibitors and angiotensin II receptor antagonists are used as antihypertensive drugs, especially in heart disease. More recently, these drugs have been repurposed for use in some cancer studies.
A retrospective study published in 2012 (328) examined the steroid-sparing effects of angiotensin II inhibitors, including ACE inhibitors and angiotensin II receptor blockers (ARBs). Out of a total of 87 patients with newly diagnosed glioblastoma, 29 patients treated before radiotherapy for hypertension were identified. 18 of these were treated with ACE inhibitors (n = 3) or angiotensin II receptor blockers (n = 15).
Although no survival benefit was seen with angiotensin II inhibitors in this study, the 18 patients treated with an angiotensin II inhibitor used half the steroid dose compared to all other patients (mean dose of prednisolone of 29 mg per day versus 60 mg per day) and this difference remained significant in the multivariate analysis (p = 0.003).
A subsequent retrospective study by the same group published in January 2016 (329) focused specifically on the class of angiotensin II receptor blocking drugs and their effects on vasogenic edema in patients with glioblastoma. In this study, 11 patients taking angiotensin II receptor antagonists (ARBs) for hypertension were compared with 11 matching patients with similar age, size and tumor location, who were not taking drugs for hypertension. There was a significant 66% reduction in the FLAIR ratio in patients taking ARBs compared with corresponding patients not taking ARBs. Since the FLAIR signal can represent tumor infiltration or vasogenic edema, the nature of the peri-tumor FLAIR signal was evaluated with the mapping of the apparent diffusion coefficient (ADC). Nine evaluable patients who took ARBs had a 34% reduction in ADC ratios compared to matched controls who did not take ARBs, confirming the ability of this class of drugs to reduce peri-tumor edema.
A 2015 study, conducted by the same group of French researchers, suggests that angiotensin II inhibitors (including ACE inhibitors and ARBs) can also lead to superior survival outcomes (330). 81 patients with GBM were included in this study. Seven of these patients were taking ACE inhibitors and 19 were taking ARBs for hypertension. The 26 patients who used angiotensin II inhibitors had increased progression-free and overall survival (8.7 and 16.7 months) compared to patients who did not take these drugs (7.2 and 12.9 months). The use of angiotensin II inhibitors was a significant positive prognostic factor for both PFS and OS in the multivariate analysis.
A randomized phase 3 study in France (NCT01805453) has recently completed recruitment and is testing the influence of losartan (an ARB) compared to placebo on the dose of steroids needed to control edema on the last day of radiotherapy. Another drug of this class, telmisartan, has greater penetration into the central nervous system (331) and may therefore be a better choice.
See Chapter 13 for a discussion of angiotensin system inhibitors combined with Avastin.
Beta-blockers (especially propranolol) and the role of the sympathetic nervous system
Recently the role of the sympathetic nervous system in cancer progression and the potential role of beta-adrenergic antagonists (beta-blockers) have been brought into focus in some corners of the cancer research community. The first studies linking stress to increased rates of cancer progression have led to epidemiological studies showing lower rates of cancer in subjects taking beta-blockers. Beta blockers such as propranolol have recently entered controlled clinical trials in cancer.
The sympathetic nervous system is a part of the autonomic nervous system, most often associated with “fight or flight” responses. The sympathetic nervous system is dependent on catecholamines, primarily adrenaline (adrenaline) and norepinephrine (noradrenaline), which activate two classes of adrenergic receptors in target tissues throughout the body: alpha and beta adrenergic receptors (which are further broken down into alpha-1, alpha-2, beta-1, beta-2 and beta-3 receptors).
Research and evidence regarding the link between the sympathetic nervous system and cancer progression has been more specifically limited to beta-adrenergic receptors and signaling. Animal studies in various cancer models have shown that stress contributed to tumor progression and these effects could be blocked with beta-blockers (333). The mechanisms studied are many and include the following downstream effects of beta-adrenergic signaling: stimulation of pro-inflammatory cytokines such as interleukin 6 and 8; increased recruitment of macrophages into tumors and increased macrophage expression of genes such as TGFB, VEGF, IL6, MMP9 and PTGS2 (which code for the COX-2 enzyme), which together promote angiogenesis, invasion and immunosuppression; inhibition of type 1 and 2 interferons, attenuation of cell-mediated anti-cancer immunity and reduced function of T lymphocytes and natural killer cells; activation of transcription factors that promote epithelial-mesenchymal transition, leading to tumor metastasis and invasion; and increased production of pro-angiogenic growth factors and cytokines, such as IL-6 and VEGF. A 2015 review summarizes the current evidence for the influence of the sympathetic immune system on cancer progression and the tumor microenvironment (334).
Clinical trials support the importance of beta-blockers in the treatment of cancer. An epidemiological study in Taiwan (335) reported that the incidence of cancer was significantly reduced (30-50%) in subjects using propranolol for at least six months, including the incidence of head and neck cancer and tumors. esophagus, stomach, colon, and prostate. The number of people with brain cancer was too low in both the propranolol group and the control group to achieve statistically significant results, although the risk of brain cancer was also lower in the propranolol group. Confirming these findings is a recent U.S. ovarian cancer clinical trial in which patients were divided into those not using beta blockers, those using older non-specific beta blockers (such as propranolol) and those using beta more recent selective and specific blockers for beta-1 adrenergic receptors. Ovarian cancer patients not using beta blockers had a median survival of 42 months, those using selective beta-1 agents had a median survival of 38 months, and those using nonselective beta blockers (e.g. propranolol) had a median survival of 38 months. median survival of 95 months (336).
Vicus Therapeutics, based in Morristown, New Jersey, is a company that develops a combination treatment called VT-122, which consists of a “chrono-modulated” formulation of propranolol (a beta blocker approved for the first time by the FDA in 1967) and etodolac (a non-steroidal anti-inflammatory drug first approved by the FDA in 1991). Both drugs are off-patent and available as generics. Vicus has three clinical trials listed on clinicaltrials.gov: one, as of 2007, tested VT-122 as a treatment for cachexia in patients with non-small cell lung cancer (NCT00527319); another, as of 2010, is testing VT-122 in combination with sorafenib for hepatocellular carcinoma (NCT01265576); a third, as of 2013, is testing VT-122 for progressive prostate cancer (NCT01857817).
Not listed on clinicaltrials.gov is a study presented in abstract form for the 2015 ASCO meeting, comparing low-dose temozolomide daily (20 mg twice daily) with or without VT-122 for recurrent glioblastoma. 20 patients took low-dose temozolomide alone and a further 21 patients took low-dose temozolomide and VT-122. Patient characteristics were not provided apart from the Karnofsky score, which was above 60 (median) in both groups. The most notable result was a median overall survival of 17.6 months in the low-dose TMZ and VT-122 group compared to only 9.2 months in the low-dose TMZ-only group. In the VT-122 group there were 5 complete responses (24%) and 12 responses in total (57%), compared to corresponding figures of 5% and 35% in the group that received TMZ alone. The one-year survival rate was 67% in the VT-122 group and 30% in the TMZ-only group. Rates of thrombocytopenia, neutropenia, and anemia were higher in the VT-122 group. Statistical tests for significance were not reported. Although this study misses very important information (enrollment criteria, patient characteristics, progression-free survival data, statistical significance, etc.), a median survival of 17.6 months for recurrent glioblastoma is interesting given that the median survival of 9.2 months in the low dose TMZ group is closer to the mean of the recurrent glioblastoma studies.
Suppression of thyroid hormone T4 (thyroxine)
Based on observations of the relationship between hypothyroid status (depressed thyroid function) and improved outcomes in cancer patients dating back to at least 1988, Aleck Hercbergs and colleagues at the Cleveland Clinic conducted a clinical study, published in 2003, in which 22 gliomas high-grade patients were treated with propylthiouracil to induce chemical hypothyroidism and high-dose tamoxifen (349). 15 of the patients had a diagnosis of glioblastoma and the remainder were grade 3 gliomas. Half of the patients (11 of 22) achieved hypothyroid status, although no clinical symptoms of hypothyroidism were observed. A survival analysis determined that the median survival in the 11 hypothyroid patients was 10.1 months, while the median survival in the non-hypothyroid group was only 3.1 months. After an adjustment of the results to take into account the lower age of hypothyroid patients, survival was even longer in the hypothyroid group, with borderline statistical significance (p = 0.08).
Subsequently, in 2005, the discovery of cell surface receptors for thyroid hormones on integrins αvβ3 (alphaVbeta3), provided an explanatory mechanism for their cancer-promoting effects (350). This particular integrin tends to be overexpressed on cancer cells and the stimulation of this integrin by thyroid hormones leads to an increase in angiogenesis, proliferation of cancer cells and resistance to apoptosis (351).
Following the publication of the 2003 study, many cancer physicians and cancer patients contacted Hercbergs and a group of 23 advanced cancer patients were informally treated with thyroid suppression therapy in addition to standard treatments (351). Patients who were taking synthetic T4 for pre-existing hypothyroidism switched abruptly to synthetic T3 (Cytomel), and three of these patients experienced rapid and lasting tumor remission in combination with standard treatments. In the remaining patients, methimazole was used to lower T4 levels below the reference range and the patients again received the synthetic T3 hormone (Cytomel). The reason for this is that even though T3 is the active form of thyroid hormone, the affinity for T4 to the thyroid hormone receptor on integrin is greater than for T3 and T4 is a stronger inducer of proliferation. of cancer cells. It is therefore believed that the suppression of T4 and integration with T3 (Cytomel) reduces the main cancer-promoting effect of thyroid hormones, avoiding the clinical symptoms of hypothyroidism, such as fatigue.
Four patients with glioblastoma were included in this study, including a 67-year-old male with KPS of 70 and partial resection who survived 36 months (3 years) and a 64-year-old male with KPS of 60 who had only done a biopsy and lived for 48 months (4 years). Both of these patients had an expected survival of 10 months. A third female patient with glioblastoma, aged 68, had a low KPS of 40 and survived for 8 months.
Several patients who failed to achieve free T4 depletion or who voluntarily discontinued treatment (possibly due to a perception of lack of benefit or an actual lack of benefit) were excluded from the study. Therefore, the 100% response rate observed in this study is perhaps an exaggeration, although the long survival of two out of four patients with advanced GBM certainly suggests a treatment effect, as standard treatments alone rarely lead to such positive outcomes. Furthermore, Hercbergs et al. published a case report of a 64-year-old patient with optic glioma, progressive after standard treatments, who responded to T4 depletion with propylthiouracil followed by carboplatin chemotherapy with a 2.5-year remission period and overall survival 4.5 years old (352).
A Phase 2 clinical trial to test T4 suppression with methimazole and Cytomel (synthetic T3) in addition to standard treatment for newly diagnosed glioblastoma began recruitment in Tel-Aviv, Israel in early 2016 (NCT02654041) .
This is a natural hormone secreted by the pineal gland that regulates the body’s daytime rhythm. It is commonly used for the treatment of jet lag and for insomnia. It is readily available at any health food store and most drugstores. Its role in the treatment of cancer has been based on the assumption that it strengthens the immune system, with the current hypothesis that it increases the activity of T helper cells. It has also recently been shown to inhibit angiogenesis (225). Melatonin can also have direct cytotoxic effects on some types of cancer cells, particularly melanoma cells. It has no known toxic side effects.
Clinical research on the use of melatonin for cancer has been mainly conducted in Italy, where it has been used both as a single agent after radiotherapy, and in combination with various chemotherapy or immunotherapy regimens, most frequently with interleukin-2. . Part of the rationale for such combinations is that they decrease the side effects of chemotherapy, especially with regards to blood counts. In one of the clinical trials (226) 30 patients with GBM were randomly assigned to receive radiotherapy alone (n = 16) or concomitant radiotherapy with melatonin 20 mg / day (n = 14). Melatonin was continued after completion of radiotherapy. Survival was significantly greater for subjects who received melatonin. In terms of one-year survival rates, 6/14 patients who received melatonin were alive, while only 1/16 of the patients who did not receive melatonin were still alive.
This GBM study involved a relatively small number of patients, so the effects should be considered temporary until a larger study is conducted. However, comparable effects were reported in a similar project for the use of melatonin with advanced lung cancer (227). Again, as in the GBM study, there was a substantial improvement in the survival rate for patients who took melatonin.
To date, there have been at least a dozen Phase 2 clinical trials using melatonin alone or in combination with other agents and five Phase 3 trials involving random assignment of subjects to melatonin versus some type of group of control. In most of these studies, the population considered was relatively small and involved patients in the terminal stages of the disease, which is why these studies were probably largely ignored by oncologists.
However, some studies have been much larger and seem to leave little doubt that melatonin significantly increases the effectiveness of chemotherapy. One of the largest randomized clinical trials involved 250 patients with advanced metastatic carcinoma of various types (228). Patients were randomly assigned to either chemotherapy alone (using different chemotherapies for different cancers) or chemotherapy plus 20 mg of melatonin per day. Objective tumor regression occurred in 42 (including 6 complete regressions) of 124 patients who received melatonin but only in 19/126 (with zero complete regressions) of control patients. A comparable difference occurred in the survival rate: 63/124 of those who received melatonin were alive after one year versus only 29/126 who received chemotherapy alone. A different study involved 100 patients with metastatic non-small cell lung cancer (229) comparing chemotherapy alone with chemotherapy in combination with melatonin. With chemotherapy alone, 9 of the 51 patients achieved partial tumor regression, while 17 of the 49 chemotherapy patients who also took melatonin achieved complete (n = 2) or partial (n = 15) regression. Twenty percent of chemotherapy patients survived for one year and none for two years, while the corresponding numbers for melatonin-associated chemo were 40% and 30%. Melatonin not only increased the effectiveness of chemotherapy, but also significantly reduced its toxicity.
The largest report included 370 patients, divided into three different types of cancer: lung cancer (non-small cell), colorectal cancer and gastric cancer (230). The aggregate of all three types, the response rate (percentage of patients with tumor regression) was 36% for patients treated with chemotherapy and melatonin, compared to 20% for patients treated with chemotherapy alone. The corresponding two-year survival rates were 25% versus 13%. The benefits of melatonin have occurred for all three types of cancer. Additionally, patients who received melatonin experienced fewer side effects. These studies leave little doubt about the clinical significance of the effects of melatonin. Furthermore, a recent study has shown that the use of multiple components of the secretions of the pineal gland instead of melatonin alone further increases the clinical efficacy (231). A caveat about the use of melatonin is that a recent randomized study compared radiation treatment for metastatic brain cancer with and without melatonin and found no benefit for melatonin (232). Given that almost all the evidence supporting the use of melatonin derives from its addition to chemotherapy, it is possible that it does not offer any benefit when added to radiation alone, perhaps due to its strong antioxidant properties.
Many laboratory studies have shown that vitamin D is highly cytotoxic to cancer cells, due to several mechanisms (although labeled as a vitamin, vitamin D could more properly be considered a hormone). Although most research has focused on its ability to activate genes that cause cancer cells to differentiate into mature cells, other effects have also been identified, including cell cycle regulation, inhibition of growth factor-like insulin and inhibition of angiogenesis (246). However, the calcitriol form of vitamin D is not readily usable for cancer treatments because dosages that produce anti-cancer effects also cause hypercalcemia, which can be life-threatening (Vitamin D’s primary function is to regulate absorption and reabsorption of calcium from bones and teeth).
But like many vitamins / hormones, the generic designation does not refer to a specific chemical structure but to a family of related molecules that can have different properties. For vitamin D, many of these variants (commonly referred to as analogs) have been shown to effectively inhibit the growth of cancer cells but without the same degree of toxic hypercalcemia. In a 2002 article in the Journal of Neuro-oncology (247), 10 patients with glioblastoma and one with a grade III anaplastic astrocytoma received a form of vitamin D called alfacalcidol in a dosage of 0.04 micrograms / kg each day, a dosage that did not produce significant hypercalcaemia. Median survival was 21 months and three of the eleven survived long-term (more than 5 years). Although the percentage of patients who responded to treatment was not high, the fact that any relatively non-toxic treatment can produce a number of long-term survivors is remarkable. There is also strong reason to believe that vitamin D is synergistic with retinoids such as accutane (248). Its effectiveness is also increased in the presence of dexamethasone (249) and a variety of antioxidants, in particular carnosic acid, but also lycopene, curcumin, silibinin and selenium (250).
Alfacalcidol is not available in the United States, but is available in Europe and Canada. For US residents, it can be obtained from various online retailers. It should also be noted that many other vitamin D analogues are available, which also have very little hypercalcemic effects. One of these, paricalcitol, which was developed for the treatment of a parathyroid gland disorder and has recently been the subject of numerous experimental studies (251, 252, 253) which have shown high cytotoxicity for many different types of cancer . Given that other forms of vitamin D have been shown to be highly cytotoxic to glioblastoma cells and that glioma cells are known to have vitamin D receptors, it seems likely that paricalcitol may also be effective for glioblastoma multiforme. Unfortunately, its routine use is complicated by the fact that it is only available in a form that requires an intravenous injection.
The most common version of vitamin D3 found in health food stores is cholecalciferol, which is the precursor of calcitriol, the form of vitamin D used by the body. A recent cholecalciferol study with prostate cancer patients who had progressed after standard therapy (254) suggests that this common form of vitamin D3 may be clinically beneficial. Fifteen patients who failed standard treatments received 2000 IU per day. PSA levels were reduced or remained the same for nine patients, and there was a reliable decrease in the rate of PSA rise for the rest of the patients. No side effects of the treatment were reported by any of the patients. Since it has recently been shown that serum levels of vitamin D are inversely related to the incidence of cancer, the toxic dosage has recently been discussed at length. Doses of up to 5000-10,000 IU per day appear to be safe. Recently, it has become common for women suffering from osteoporosis with low vitamin D levels to receive up to 50,000 IU / day for short periods of time. However, it is important to note that all forms of vitamin D can occasionally produce dangerous serum levels of calcium, partly because there is great variability in their effects between individuals. It is therefore important to monitor blood calcium levels, especially while a non-toxic dosage is being established.
(225) Lissoni, P., et al. Anti-angiogenic activity of melatonin in advanced cancer patients. Neuroendocrinology Letters, 2001, Vol. 22, 45-47.
(226) Lissoni, P., et al. Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone. Oncology, 1996, Vol. 53, pp. 43-46.
(227) Lissoni, P., et al. Randomized study with the pineal hormone melatonin versus supportive care alone in advanced non-small cell lung cancer resistant to a first-line chemotherapy containing cisplatin. Oncology, 1992, Vol. 49, pp. 336-339.
(228) Lissoni, P., et al. Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumor patients with poor clinical status. European Journal of Cancer, 1999, Vol. 35, pp. 1688-1692.
(229) Lissoni, P. et al. Five year survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: a randomized trial. Journal of Pineal Research, 2003, Vol. 35, 12-15.
(230) Lissoni, P., Biochemotherapy with standard chemotherapie plus the pineal hormone melatonin in the treatment of advanced solid neoplasms. Pathologie Biologie, 2007, 55, 201-204.
(231) Lissoni, P., et al. Total pineal endocrine substitution therapy (TPEST) as a new neuroendocrine palliative treatment of untreatable metastatic solid tumor patients: a phase II study. Neuroendocrinology Letters, 2003, 24, 259-262.
(246) Van den Bemd, G. J., & Chang, G. T. Vitamin D and Vitamin D analogues in cancer treatment. Current Drug Targets, 2002, Vol. 3, 85-94.
(247) Trouillas, P, et al. Redifferentiation therapy in brain tumors: long-lasting complete regression of glioblastomas and an anaplastic astrocytoma under long-term 1-alpha-hydroxycholecalciferol. Journal of Neuro-oncology, 51, 57-66.
(248) Bollag, W. Experimental basis of cancer combination chemotherapy with retinoids, cytokines, 1, 25-hydroxyvitamin D3, and analogs. Journal of Cellular Chemistry, 1994, Vol. 56, 427-435.
(249) Bernardi, R. J., et al. Antiproliferative effects of 1alpha, 25-dihydroxyvitamin D (3) and vitamin D analogs on tumor-derived endothelial cells. Endocrinology, 2002, Vol. 143, 2508-2514
(250) Danilenko, M., et al. Carnosic acid potentiates the antioxidant and pro-differentiation effects of 1-alpha, 25-dihydroxyvitamin D3 in leukemia cells but does not promote elevation of basal levels of intracellular calcium. Cancer Research, 2003, Vol. 63, 1325-1332. “(251) Chen, T. C., et al. The in vitro evaluation of 25-hydroxyvitamin D3 and 19-nor-1 alpha, 25-dihydroxyvitamin D2 as therapeutic agents for prostate cancer. Clinical Cancer Research, 2000, Vol. 6, 901-908.
(252) Kumagai, T., et al. Vitamin D2 analog 19-nor-1, 25-dihydroxyvitamin D2: antitumor activity against leukemia, myeloma and colon cancer cell lines. Journal of the National Cancer Institute, 2003, Vol. 95, 896-905.
(253) Molnar, I., et al. 19-nor-1alpha, 25-dihydroxyvitamin D (2) (paricalcitol): effects on clonal proliferation, differentiation, and apoptosis in human leukemia cell lines. Journal of Cancer Research and Clinical Oncology, 2003, Vol. 129, 35-42.
(254) Woo, T.C.S, et al. Pilot study: Potential role of Vitamin D (Cholecalciferol) in patients with PSA relapse after definitive therapy. Nutrition and Cancer, 2005, 51(1), 32-36.
(330) Januel, E et al. “Impact of renin-angiotensin system blockade on clinical outcome in glioblastoma.” European Journal of Neurology 22.9 (2015): 1304-1309.
(331) Michel, Martin C et al. “A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists.” Pharmacological reviews 65.2 (2013): 809-848.
(332) Huang, Jiayi et al. “A phase I study to repurpose disulfiram in combination with temozolomide to treat newly diagnosed glioblastoma after chemoradiotherapy.” Journal of neuro-oncology (2016): 1-8.
(333) Cole, Steven W, and Anil K Sood. “Molecular pathways: beta-adrenergic signaling in cancer.” Clinical cancer research 18.5 (2012): 1201-1206.
(334) Cole, Steven W et al. “Sympathetic nervous system regulation of the tumour microenvironment.” Nature Reviews Cancer 15.9 (2015): 563-572. (335) Chang, Ping-Ying et al. “Propranolol reduces Cancer risk: a population-based cohort study.” Medicine 94.27 (2015).
(336) Watkins, Jack L et al. “Clinical impact of selective and nonselective beta-blockers on survival in patients with ovarian cancer.” Cancer 121.19 (2015): 3444-3451.
(349) Hercbergs, Aleck A et al. “Propylthiouracil-induced chemical hypothyroidism with high-dose tamoxifen prolongs survival in recurrent high grade glioma: a phase I/II study.” Anticancer research 23.1B (2002): 617-626.
(350) Bergh, Joel J., Hung-Yun Lin, Lawrence Lansing, Seema N. Mohamed, Faith B. Davis, Shaker Mousa, and Paul J. Davis. “Integrin α V β 3 Contains a Cell Surface Receptor Site for Thyroid Hormone That Is Linked to Activation of Mitogen-Activated Protein Kinase and Induction of Angiogenesis.” Endocrinology 146.7 (2005): 2864-871.
(351) Hercbergs, Aleck et al. “Medically induced euthyroid hypothyroxinemia may extend survival in compassionate need cancer patients: an observational study.” The oncologist 20.1 (2015): 72-76.
Fine! I hope you enjoyed reading, I have been as faithful as possible. A new chapter very soon!