Therapeutic implications of fibroblast growth factor receptor inhibitors in a combination regimen for solid tumors.

A number of novel drugs targeting the fibroblast growth factor receptor (FGFR) signaling pathway have been developed, including mostly tyrosine kinase inhibitors, selective inhibitors or monoclonal antibodies. Multiple preclinical and clinical studies have been conducted worldwide to ascertain their effects on diverse solid tumors. Drugs, such as lenvatinib, dovitinib and other non-specific FGFR inhibitors, widely used in clinical practice, have been approved by the Food and Drug Administration for cancer therapy, although the majority of drugs remain in preclinical tests or clinical research. The resistance to a single agent for FGFR inhibition with synthetic lethal action may be overcome by a combination of therapeutic approaches and FGFR inhibitors, which could also enhance the sensitivity to other therapeutics. Therefore, the aim of the present review is to describe the pharmacological characteristics of FGFR inhibitors that may be combined with other therapeutic agents and the preclinical data supporting their combination. Additionally, their clinical implications and the remaining challenges for FGFR inhibitor combination regimens are discussed.

CBCT evaluation of inter- and intra-fraction motions during prostate stereotactic body radiotherapy: a technical note.

BACKGROUND: In most clinical trials, gold fiducial markers are implanted in the prostate to tune the table position before each radiation beam. Yet, it is unclear if a cone-beam computed tomography (CBCT) should be performed before each beam to monitor a possible variation of the organs at risk (OARs) fullness, especially in case of recto-prostatic spacer implantation. The present study aimed at assessing the inter- and intra-fraction movements of prostate, bladder and rectum in patients implanted with a hyaluronic acid spacer and undergoing prostate stereotactic body radiotherapy (SBRT). METHODS: Data about consecutive patients undergoing prostate SBRT were prospectively collected between 2015 and 2019. Inter-and intra-fraction prostate displacements and volume variation of organs at risk (OARs) were assessed with CBCTs. RESULTS: Eight patients were included. They underwent prostate SBRT (37.5Gy, 5 fractions of 7.5Gy) guided by prostate gold fiducial markers. Inter-fraction variation of the bladder volume was insignificant. Intra-fraction mean increase of the bladder volume was modest (29 cc) but significant (p < 0.001). Both inter- and intra-fraction variations of the rectum volume were insignificant but for one patient. He had no rectal toxicity. The magnitude of table displacement necessary to match the prostate gold fiducial marker frequently exceeded the CTV/PTV margins (0.4 cm) before the first (35%) and the second arc (15%). Inter- and intra-fraction bladder and rectum volume variations did not correlate with prostate displacement. CONCLUSION: Major prostate position variations were reported. In-room kV fiducial imaging before each arc seems mandatory. Intra-fraction imaging of the OARs appears unnecessary. We suggest that only one CBCT is needed before the first arc. TRIAL REGISTRATION: NCT02361515, February 11th, 2015.

Chemoradiation and granulocyte-colony or granulocyte macrophage-colony stimulating factors (G-CSF or GM-CSF): time to think out of the box?

Concerns have been raised about potential toxic interactions when colony-stimulating factors (CSFs) and chemoradiation are concurrently performed. In 2006, the ASCO guidelines advised against their concomitant use. Nevertheless, with the development of modern radiotherapy techniques and supportive care, the therapeutic index of combined chemotherapy, radiotherapy, and CSFs is worth reassessing. Recent clinical trials testing chemoradiation in lung cancer let investigators free to decide the use of concomitant CSFs or not. No abnormal infield event was reported after the use of modern radiotherapy techniques and concomitant chemotherapy regimens. These elements call for further investigation to set new recommendations in favour of the association of chemoradiation and CSFs. Moreover, radiotherapy could induce anticancer systemic effects mediated by the immune system in vitro and in vivo. With combined CSFs, this effect was reinforced in preclinical and clinical trials introducing innovative radioimmunotherapy models. So far, the association of radiation with CSFs has not been combined with immunotherapy. However, it might play a major role in triggering an immune response against cancer cells, leading to abscopal effects. The present article reassesses the therapeutic index of the combination CSFs-chemoradiation through an updated review on its safety and efficacy. It also provides a special focus on radioimmunotherapy.

Comparison of chemoradiotherapy with and without brachytherapy as adjuvant therapy after radical surgery in early-stage cervical cancer with poor prognostic factors: An observational study.

This study aimed to determine whether the addition of intracavitary brachytherapy (ICBT) to chemoradiotherapy (CRT) improves outcome in patients with cervical cancer and poor prognostic factors. Patients with stage IB to IIA cervical cancer who had undergone radical hysterectomy and pelvic lymphadenectomy between August 2008 and December 2014 were retrospectively registered in this study. All patients received external beam radiation therapy (EBRT) + chemotherapy, and some patients additionally received ICBT. EBRT consisted of 45 to 50.4 Gy delivered to the standard pelvic field in 25 to 28 fractions. Chemotherapy consisted of 2 to 4 courses of weekly cisplatin-based treatment. ICBT was delivered in 1 to 3 insertions. Ninety-seven of 163 patients received CRT, and 66 patients additionally received ICBT. During a median follow-up period of 33 months, recurrence was detected in 38 patients. The 3-year locoregional control (LRC), disease-free survival (DFS), and overall survival (OS) rates did not differ significantly between patients who did and did not receive ICBT. In subgroup analyses, fewer recurrences were seen in patients with at least 1 high-risk factor who received ICBT than in those who did not, with a significant (62%) reduction in the risk of progression or death (hazard ratio 0.384, 95% confidence interval 0.151-0.978, P = .045). The difference in OS between the CRT and CRT + ICBT subgroups was marginal (P = .064). The addition of ICBT to CRT after radical surgery significantly improves LRC and DFS rates in women with cervical cancer and at least 1 high-risk factor.

Clinical outcomes and toxicity of postoperative intensity-modulated versus three-dimensional conformal radiation therapy in patients with cervical cancer.

AIM: To compare the clinical outcomes and toxicity of pelvic intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiation therapy (3D-CRT) as adjuvant postoperative treatment in patients with cervical cancer. METHODS: Between April 2008 and December 2013, 115 patients with International Federation of Gynecology and Obstetrics stages IA-IIB cervical cancer were initially treated with radical hysterectomy and underwent adjuvant pelvic external-beam radiation therapy (EBRT) without brachytherapy. The median postoperative pelvic EBRT dose was 50 Gy (range, 45-50 Gy). Twenty-six patients received IMRT and 89 patients underwent 3D-CRT. Chemotherapy consisted of two to four courses of platinum-based treatment. Locoregional control, disease-free survival (DFS), overall survival (OS) and treatment-related complications were compared between the two groups. No significant difference in clinical data was observed between groups. RESULTS: With a median follow-up of 28.6 months, 2-year OS rates were 90.3% in the 3D-CRT group and 91.6% in the IMRT group (P = 0.674), and DFS rates were 88.8% and 86.0%, respectively (P = 0.722). The rates of acute gastrointestinal (GI) and genitourinary (GU) toxicity were lower in the IMRT group than in the 3D-CRT group (GI, 50% vs 84.3%, P = 0.009; GU, 19.2% vs 56.2%, P = 0.007). CONCLUSION: Our results indicate that IMRT not only significantly reduced the rate of toxicity, but also provided good clinical outcomes consistent with those achieved with 3D-CRT. However, further studies with more patients and longer follow-up times are warranted to confirm the benefits of IMRT.