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Concurrent treatment with everolimus (RAD001) and hormonoradiotherapy in high-risk locally advanced prostate cancer: Results of a phase I trial.
Abstract
150 Background: Everolimus is able to stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving everolimus together with hormonotherapy and radiation therapy may kill more tumor cells. Methods: We conducted a phase I trial to evaluate the impact of everolimus (RAD001), an mTOR inhibitor, in patients treated concurrently with radiotherapy (RT) and ablative androgen treatment in high-risk locally advanced prostate cancer. Inclusion criteria were high-risk locally advanced non metastatic prostate cancer defined as clinical stage ≥ T3 or Gleason score ≥ 8 or PSA ≥ 20. The week before the beginning of RT, RAD001 was administered at different dose levels, twice daily, until the last day of irradiation. A nonsteroid antiandrogen was also given for 1 month at the beginning of RT. Prostate and seminal vesicle were irradiated up to 74Gy in 37 fractions of 2Gy with concomitant long-term LHRH analogue. The starting dose of RAD001 was 5mg/d wi...
... A phase-I clinical trial of 15 patients with locally advanced PC conducted by Azria et al. demonstrated that combined treatment with mTORC1 inhibitor everolimus, hormonal therapy and radiotherapy was feasible [61]. The MTD of everolimus was 7.5 mg/day. ...
... Several of these early clinical trials used mTOR inhibitors. Frequent side effects of the most commonly used mTOR inhibitor everolimus included mucositis, cutaneous rash and diarrhoea [61,62]. mTOR inhibitors were found to be safe in combination with chemotherapy and/or radiotherapy in cervical cancer, PC and rectal cancer. ...
Radiotherapy is routinely used as a neoadjuvant, adjuvant or palliative treatment in various cancers. There is significant variation in clinical response to radiotherapy with or without traditional chemotherapy. Patients with a good response to radiotherapy demonstrate better clinical outcomes universally across different cancers. The PI3K/AKT/mTOR pathway upregulation has been linked to radiotherapy resistance. We reviewed the current literature exploring the role of inhibiting targets along this pathway, in enhancing radiotherapy response. We identified several studies using in vitro cancer cell lines, in vivo tumour xenografts and a few Phase I/II clinical trials. Most of the current evidence in this area comes from glioblastoma multiforme, non-small cell lung cancer, head and neck cancer, colorectal cancer, and prostate cancer. The biological basis for radiosensitivity following pathway inhibition was through inhibited DNA double strand break repair, inhibited cell proliferation, enhanced apoptosis and autophagy as well as tumour microenvironment changes. Dual PI3K/mTOR inhibition consistently demonstrated radiosensitisation of all types of cancer cells. Single pathway component inhibitors and other inhibitor combinations yielded variable outcomes especially within early clinical trials. There is ample evidence from preclinical studies to suggest that direct pharmacological inhibition of the PI3K/AKT/mTOR pathway components can radiosensitise different types of cancer cells. We recommend that future in vitro and in vivo research in this field should focus on dual PI3K/mTOR inhibitors. Early clinical trials are needed to assess the feasibility and efficacy of these dual inhibitors in combination with radiotherapy in brain, lung, head and neck, breast, prostate and rectal cancer patients.
... Concurrent administration of other targeted agents including alpelisib and everolimus with radiation has not been studied in breast cancer. Extrapolation from other tumor types suggests safety, but this finding must be validated in larger populations of doses used in breast cancer 52,53 . ...
Endocrine therapy (ET) remains the mainstay of treatment for steroid hormone receptor-positive, human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC). Tumor resistance to hormone therapy has led to the development of novel endocrine drug combinations, transforming the landscape of MBC management. The options for ET are expanding, with promising agents in the pipeline. Although MBC remains incurable, many patients can enjoy years of survival with good quality of life by cycling through the many available agents. With the plethora of available agents and rapid approvals, clinicians look to evidence-based guidelines to assist in treatment selection to maximize patient well-being. In this review, we provide a contemporary review of the advances in ET and a suggested algorithm to guide clinicians in daily management of patients with hormone receptor-positive, HER2-negative MBC. We will discuss landmark trials and highlight their impact in reshaping treatment approaches. Finally, we will provide a glimpse into advances on the horizon and the promise they bring to improve outcomes in patients with advanced breast cancer.
... Everolimus in combination with radiation was studied during a phase-I clinical trial for the treatment of locally advanced prostate cancer. The study determined that MTD of everolimus is 7.5 mg/day, while due to the minor side effects (Dose-limiting toxicity occurred in two out of fifteen patients) the administration of a smaller dose (5 mg/day was) recommended [60]. In parallel with this study other reports also mentioned that everolimus is well tolerable below 10 mg/day (Table 2) [61]. ...
Introduction Radiotherapy is one of the most common types of cancer treatment modalities. Radiation can affect both cancer
and normal tissues, which limits the whole delivered dose. It is well documented that radiation activates phosphatidylinositol
3-kinase (PI3K) and AKT signaling pathway; hence, the inhibition of this pathway enhances the radiosensitivity of tumor
cells. The mammalian target of rapamycin (mTOR) is a regulator that is involved in autophagy, cell growth, proliferation,
and survival.
Conclusion The inhibition of mTOR as a downstream mediator of the PI3K/AKT signaling pathway represents a vital
option for more effective cancer treatments. The combination of PI3K/AKT/mTOR inhibitors with radiation can increase
the radiosensitivity of malignant cells to radiation by autophagy
Radiotherapy in combination with androgen deprivation therapy (ADT) is a standard treatment option for men with localized and locally advanced prostate cancer. However, emerging clinical evidence suggests that radiotherapy can be incorporated into multimodality therapy regimens beyond ADT, in combinations that include chemotherapy, radiosensitizing agents, immunotherapy and surgery for the treatment of men with localized and locally advanced prostate cancer, and those with oligometastatic disease, in whom the low metastatic burden in particular might be treatable with these combinations. This multimodal approach is increasingly recognized as offering considerable clinical benefit, such as increased antitumour effects and improved survival. Thus, radiotherapy is becoming a key component of multimodal therapy for many stages of prostate cancer, particularly oligometastatic disease.
Context:
Systemic therapies, combined with local treatment for high-risk prostate cancer, are recommended by the international guidelines for specific subgroups of patients; however, for many of the clinical scenarios, it remains a research field.
Objective:
To perform a systematic review, and describe current evidence and perspectives about the multimodal treatment of high-risk prostate cancer.
Evidence acquisition:
We performed a systematic review of PubMED, Embase, Cochrane Library, European Society of Medical Oncology/American Society of Clinical Oncology Annual proceedings, and clinicalTrial.gov between January 2010 and February 2018 following the Preferred Reporting Items for Systematic Reviews and Meta-analysis statement.
Evidence synthesis:
Seventy-seven prospective trials were identified. According to multiple randomized trials, combining androgen deprivation therapy (ADT) with external-beam radiotherapy (EBRT) outperforms EBRT alone for both relapse-free and overall survival. Neoadjuvant ADT did not show significant improvement compared with prostatectomy alone. The role of adjuvant ADT after prostatectomy in patients with high-risk disease is still debated, with lack of data from phase 3 trials in pN0 patients. Novel androgen pathway inhibitors have been tested only in early-phase trials in addition to primary treatment. GETUG 12, RTOG 0521, and nonmetastatic subgroup of the STAMPEDE trial showed improved relapse-free survival for docetaxel in patients treated with EBRT plus ADT, although mature metastasis-free survival data are still pending. Both the SPCG-12 and the VACSP#553 trial showed no improvement in relapse-free survival for adjuvant docetaxel after prostatectomy.
Conclusions:
In contrast to the clearly demonstrated survival benefits of long-term adjuvant ADT when used with EBRT, its role after prostatectomy remains unclear especially in pN0 patients. Adding docetaxel to EBRT-ADT improves relapse-free survival, with immature results on overall survival. Novel androgen receptor pathway inhibitors are currently being tested in the neoadjuvant and adjuvant setting.
Patient summary:
Treatment of high-risk prostate cancer is based on a multimodality approach that includes systemic treatments. The best treatment or therapy combination remains to be defined.
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