Alexander Tuan Falk

Radiation-enhanced cell migration/invasion process: a review.

Radiation therapy is a keystone treatment in cancer. Photon radiation has proved its benefits in overall survival in many clinical studies. However, some patients present local recurrences or metastases when cancer cells survive to treatment. Metastasis is a process which includes adhesion of the cell to the extracellular matrix, degradation of the matrix by proteases, cell motility, intravasation in blood or lymphatic vessels, extravasation in distant parenchyma and development of cell colonies. Several studies demonstrated that ionizing radiation might promote migration and invasion of tumor cells by intricate implications in the micro-environment, cell-cell junctions, extracellular matrix junctions, proteases secretion, and induction of epithelial-mesenchymal transition. This review reports various cellular pathways involved in the photon-enhanced cell invasion process for which potential therapeutic target may be employed for enhancing antitumor effectiveness. Understanding these mechanisms could lead to therapeutic strategies to counter the highly invasive cell lines via specific inhibitors or carbon-ion therapy.

The evolving locally-advanced non-small cell lung cancer landscape: Building on past evidence and experience

Lung cancer is a major public health concern worldwide. Progress in improving 5-year survival is lagging behind comparable survival rates in other common cancers. The majority of patients with locally advanced non-small cell lung cancer (NSCLC) are not suitable for surgical resection, hence the major role of radical radiotherapy. Advances in radiotherapy techniques allow targeted treatment of the disease, whilst minimizing the dose to organs at risk. Recent research into fractionation schedules, with hyperfractionated and accelerated radiotherapy regimens has been promising. Platinum-based chemotherapy has long been the standard of care for the initial treatment of advanced NSCLC. However, if radical radiotherapy remains the cornerstone of treatment for patients with unresectable advanced NSCLC either as single modality treatment or with concomitant chemotherapy, advances in understanding of tumor molecular biology and targeted drug development should bring targeted agents into the NSCLC management. The development of numerous therapeutic approaches has made the locally advanced NSCLC world change. An up-to-date overview of the current literature on updated chemotherapeutic agents, targeted therapy, immunotherapy, radiotherapy in stage III NSCLC is provided.

Bevacizumab: A dose review

Angiogenesis is a key process in cancer development and has been described has a hallmark of cancer. Two dose-intensities were approved for cancer treatment by the Food and Drug Administration and European Medicines Agency: 2.5mg/kg/week dose equivalent and 5mg/kg/week dose equivalent. While bevacizumab has shown its effectiveness in clinical trials, pharmacodynamics is not fully understood and a dose-effect relationship has not been proven in vivo. Direct trials comparing high or low doses are rare with potential dose-effect toxicity. Discordant data have been reported on the efficacy of doses. This review discusses the dose of bevacizumab via the analysis of studies that led to the approval of bevacizumab in clinical practice. Optimization of doses schemes could reduce potential dose-effect toxicities, potentiate synergetic effects with chemotherapy and permit the prescription to a larger population with a better cost-effectiveness ratio.

PD-L1 expression in basaloid squamous cell lung carcinoma: Relationship to PD-1 + and CD8 + tumor-infiltrating T cells and outcome

PD-1/PD-L1 inhibitors demonstrated durable clinical responses in patients with lung squamous cell carcinoma. However, the expression pattern of PD-L1 and the presence of CD8+ and PD-1+ tumor-infiltrating T cells in the basaloid variant of squamous cell carcinoma remain unknown. immunohistochemistry analysis of PD-L1 expression, with three recently validated monoclonal antibodies used in clinical trials (clones SP142, SP263, and 28-8), and detection of CD8+ and PD-1+ tumor-infiltrating T cells was performed on whole-tissue sections from 56 patients following surgery for basaloid squamous cell carcinoma. Data were correlated to clinicopathological parameters and outcome. Fair to poor concordance was observed between the SP142 vs SP263 clones, and SP142 vs 28-8 (κ range, 0.018–0.412), while the 28-8 and SP263 demonstrated a strong correlation in both the tumor cell and immune cell compartments (κ=0.883, and κ=0.721). Expression of PD-L1 correlated with a high content of CD8+ and PD-1+ tumor-infiltrating T cells when using SP142 (P=0.012; P=0.022), but not with SP263 or 28-8 (P=0.314; P=0.611). In the multivariate analysis, we found significantly better disease-free and overall survival rates for high PD-L1 expression with SP142, CD8+ and PD-1+ tumor-infiltrating T cells (P=0.003; P=0.007). No significant prognosis value was observed for SP263 and 28-8 clones, except a correlation between improved overall survival and SP263 in the univariate analysis (P=0.039), not confirmed in the multivariate model. In conclusion, we report that the expression of PD-L1 and the content of CD8+ and PD-1+ tumor-infiltrating T cells is an independent indicator of better outcome in basaloid squamous cell carcinoma patients, although the observed effect is dependent on the PD-L1 immunohistochemistry assay.

Integrating genomics in head and neck cancer treatment: Promises and pitfalls.

Head and neck squamous cell carcinomas (HNSCC) represent a multifactorial disease of poor prognosis. They have lagged behind other cancers in terms of personalized therapy. With expansion and high throughput sequencing methods, recent landmark exonic studies and Cancer Genome Atlas data have identified genes relevant to carcinogenesis and cancer progression. Mutational profiles and rates vary widely depending on exposure to carcinogens, anatomic subsites and human papilloma virus (HPV) infection. Tumors may exhibit specific, tissue-specific, not exclusively HPV-related, gene alterations, such those observed in oral cavity cancers in Asia or Occident. Except for the PI3K pathway, the rate of mutations in HPV+ cancers is much lower than in tobacco/alcohol-related cancers. Somatic driver mutation analyses show that relatively few driver genes are druggable in HNSCC and that tumor suppressor gene alterations prevail. More mature for therapeutic applications is the oncogenic PI3K pathway, with preclinical human xenograft models suggesting that PI3KCA pathway mutations may be used as predictive biomarkers and clinical data showing efficacy of mTOR/Akt inhibitors. Therapeutic guidance, to date, relies on classical histoprognostic factors, anatomic subsite and HPV status, with integration of hierarchized supervised mutational profiling to provide additional therapeutic options in advanced HNSCC in a near future. Unsupervised controlled genomic analyses remain necessary to unravel potentially relevant genes.

Concomitant cervical and transperineal parametrial high-dose-rate brachytherapy boost for locally advanced cervical cancer.

Purpose There is no consensus for parametrial boost technic while both transvaginal and transperineal approaches are discussed. A prototype was developed consisting of a perineal template, allowing transperineal needle insertion. This study analyzed acute toxicity of concomitant cervical and transperineal parametrial high-dose-rate brachytherapy (HDRB) boost for locally advanced cervical cancer. Material and methods From 01.2011 to 12.2014, 33 patients (pts) presenting a locally advanced cervical cancer with parametrial invasion were treated. After the first course of external beam radiation therapy with cisplatinum, HDRB was performed combining endocavitary and interstitial technique for cervical and parametrial disease. Post-operative delineation (CTV, bladder, rectum, sigmoid) and planification were based on CT-scan/MRI. HDRB was delivered in 3-5 fractions over 2-3 consecutive days. Acute toxicities occurring within 6 months after HDRB were retrospectively reviewed. Results Median age was 56.4 years (27-79). Clinical stages were: T2b = 23 pts (69.7%), T3a = 1 pt (3%), T3b = 6 pts (18.2%), and T4a = 3 pts (9.1%). Median HDRB prescribed dose was 21 Gy (21-27). Median CTVCT (16 pts) and HR-CTVMRI (17 pts) were 52.6 cc (28.5-74.3), 31.9 cc (17.1-58), respectively. Median EQD2αβ10 for D90CTV and D90HR-CTV were 82.9 Gy (78.2-96.5), 84.8 Gy (80.6-91.4), respectively. Median EQD2αβ3 (CT/MRI) for D2cc bladder, rectum and sigmoid were 75.5 Gy (66.6-90.9), 64.4 Gy (51.9-77.4), and 60.4 Gy (50.9-81.1), respectively. Median follow-up was 14 months (ranged 6-51). Among the 24 pts with MFU = 24 months, 2-year LRFS rate, RRFS, and OS were 86.8%, 88.8%, and 94.1%, respectively. The rates of acute genitourinary and gastrointestinal toxicities were 36% (G1 dysuria = 8 pts, G2 infection = 2 pts, G3 infection = 2 pts), and 27% (G1 diarrhea = 9 pts), respectively. One patient presented vaginal bleeding at the time of applicator withdrawal (G3-blood transfusion); no bleeding was observed due to the parametrial implant. Conclusions Concomitant cervical and transperineal parametrial HDRB boost for locally advanced cervical cancer appears feasible and safe with no specific acute toxicity compare to cervical HDRB alone. Longer follow-up and larger patient cohort will be needed.

Treating metastatic sarcomas locally: a paradoxe, a rationale, an evidence?

PURPOSE The mainstay of first line treatment in metastatic sarcomas is chemotherapy with response rates of ≈25% but the optimal management of further events is debated. We assessed the benefit of local metastatic treatment in metastatic sarcomas. RESULTS Local control of local treatment strategies (≈85%) is excellent but highly institution-dependent and subject to selection biases. Formal evidence of an improvement of survival with local ablative treatments has been limited to retrospective studies. On the other hand, some chemotherapy trials are inconclusive because about 20% of patients receive local metastatic ablation as it is considered unethical to omit local treatment in these patients. Further, technology has made surgery, stereotactic irradiation and radiofrequency ablation highly effective on local control with limited morbidity. CONCLUSION The benefit on survival of metastatic ablation deserves prospective studies integrating quality of life, cost effectiveness and patient-reported outcomes assessment.

NGS analysis on tumor tissue and cfDNA for genotype-directed therapy in metastatic NSCLC patients. Between hope and hype?

ABSTRACT Introduction: The advent of genomic based precision medicine led to the implementation of biomarker testing in metastatic non-small cell lung cancer (NSCLC) patients. Next generation sequencing (NGS) has been recently implemented to routine diagnostic requirements in lung oncology. Areas covered: Two cases of patients with metastatic NSCLC for whom NGS analysis performed on both tumor and liquid biopsy has not improved the clinical course of their disease are reported. These cases illustrate the difficulty of the so-called ‘personalized or precision’ medicine in clinical routine practice for metastatic NSCLC. Expert commentary: Discovery and detection of critical cancer-gene alterations better indicates targeted therapies that must be administered to improve the care of NSCLC patients in the personalized medicine era. There has been much interest in the literature and the scientific community for NGS tailored therapies approach for patients. However, there may be a gap between this theoretical stratified medicine and clinical practice. The advantages and drawbacks of NGS on tumor tissue and cell-free DNA for metastatic NSCLC are discussed.

Intensity-modulated salvage radiotherapy with simultaneous integrated boost for local recurrence of prostate carcinoma: a pilot study on the place of PET-choline for guiding target volume delineation

OBJECTIVE The aim of this study was to report the first cases of salvage radiotherapy (RT) using the intensity-modulated radiotherapy (IMRT) with simultaneous integrated boost (SIB) targeted on choline positron emission tomography (PET) uptake in a local recurrent prostate cancer, after a radical prostatectomy. METHODS Four patients received salvage irradiation for biochemical relapse that occurred after the initial radical prostatectomy. The relapse occurred from 10 months to 6 years with PSA levels ranging from 2.35 to 4.86 ng ml(-1). For each patient, an (18)F-choline PET-CT showed a focal choline uptake in prostatic fossa, with standardized uptake value calculated on the basis of predicted lean body mass (SUL) max of 3.3-6.8. No involved lymph node or distant metastases were diagnosed. IMRT doses were of 62.7 Gy (1.9 Gy/fraction, 33 fractions), with a SIB of 69.3 Gy (2.1 Gy/fraction, 33 fractions) to a PET-guided target volume. RESULTS Acute toxicities were limited. We observed no gastrointestinal toxicity ≥grade 2 and only one grade 2 genitourinary toxicity. At 1-month follow-up evaluation, no complication and a decrease in PSA level (6.8-43.8% of the pre-therapeutic level) were reported. After 4 months, a decrease in PSA level was obtained for all the patients, ranging from 30% to 70%. At a median follow-up of 15 months, PSA level was controlled for all the patients, but one of them experienced a distant lymph node recurrence. CONCLUSION Salvage irradiation to the prostate bed with SIB guided by PET-CT is feasible, with biological efficacy and no major acute toxicity. ADVANCES IN KNOWLEDGE IMRT with PET-oriented SIB for salvage treatment of prostate cancer is possible, without major acute toxicity.

Chemotherapy Regimen in Nonagenarian Cancer Patients: A Bi-Institutional Experience

Background: The elderly population in Western countries is growing and constitutes a public health issue. Concomitantly, age-related diseases such as cancer increase. There are few data on the efficacy, tolerability and toxicity of specific anticancer therapy in the very elderly patients; therefore, their management is not standardized. Methods: In this bi-institutional study, we reviewed medical records of patients who received or continued specific anticancer therapy beyond the age of 90 years. Geriatric assessment was not reported for our patients. Twelve patients were enrolled. Their general health condition was good, and half of them were living in elderly institutions. Ten patients had a solid tumor and 2 were treated for hematological malignancies. Most were diagnosed with a locally advanced or metastatic disease, and the goal of treatment was curative for only 1 patient. Six patients received chemotherapy as first-line treatment, 4 patients received targeted therapy and 2 received concomitant chemoradiation. Four patients received a second-line treatment. Results: Despite a significant reduction in treatment posology in half of the patients, 8 acute grade 3/4 toxicities were reported and 2 patients died of treatment-related septic shock. Median duration of first-line treatment was 3.2 months, and progression-free survival ranged from 18 to 311 days. Overall survival ranged from 18 days to 11 years. Conclusion: Aging is a heterogeneous process, and management of elderly patients is a multidisciplinary approach. Geriatric assessment helps to identify older patients with a higher risk of morbidity/mortality and allows to assess the risks and benefits of specific anticancer therapy. The choice of treatment should be based primarily on the expected symptomatic benefit, and treatment should not compromise the quality of life.