The linear-quadratic model (LQ model) provides a biologically plausible and experimentally established method to quantitatively describe the dose-response to irradiation in terms of clonogenic survival. In the basic LQ formula, the clonogenic surviving fraction Sd/S₀ following a radiation dose d (Gy) is described by an inverse exponential approximation: Sd/S₀ = e-(αd+βd²), wherein α and β are experimentally derived parameters for the linear and quadratic terms, respectively. Radiation is often combined with other agents to achieve radiosensitisation. In this study, we reviewed radiation enhancement ratios of hyperthermia (HT), halogenated pyrimidines (HPs), various cytostatic drugs and poly(ADP-ribose) polymerase‑1 (PARP1) inhibitors expressed in the parameters α and β derived from cell survival curves of various mammalian cell cultures. A significant change in the α/β ratio is of direct clinical interest for the selection of optimal fractionation schedules in radiation oncology, influencing the dose per fraction, dose fractionation and dose rate in combined treatments. The α/β ratio may increase by a mutually independent increase of α or decrease of β. The results demonstrated that the different agents increased the values of both α and β. However, depending on culture conditions, both parameters can also be separately influenced. Moreover, it appeared that radiosensitisation was more effective in radioresistant cell lines than in radiosensitive cell lines. Furthermore, radiosensitisation is also dependent on the cell cycle stage, such as the plateau or exponentially growing phase, as well as on post-treatment plating conditions. The LQ model provides a useful tool in the quantification of the effects of radiosensitising agents. These insights will help optimize fractionation schedules in multimodality treatments.

/pdf/cell-survival-and-radiosensitisation-modulation-of-the-2ijvetqqqq.pdf

Cell survival and radiosensitisation: modulation of the linear and quadratic parameters of the LQ model (Review)

Metastatic lymphatic mapping in esophageal cancer is important to determine the optimal extent of the radiation field in case of neoadjuvant chemoradiotherapy and lymphadenectomy when esophagectomy is indicated. The objective of this review is to identify the distribution pattern of metastatic lymphatic spread in relation to histology, tumor location, and T-stage in patients with esophageal cancer. Embase and Medline databases were searched by two independent researchers. Studies were included if published before July 2019 and if a transthoracic esophagectomy with a complete 2- or 3-field lymphadenectomy was performed without neoadjuvant therapy. The prevalence of lymph node metastases was described per histologic subtype and primary tumor location. Fourteen studies were included in this review with a total of 8952 patients. We found that both squamous cell carcinoma and adenocarcinoma metastasize to cervical, thoracic, and abdominal lymph node stations, regardless of the primary tumor location. In patients with an upper, middle, and lower thoracic squamous cell carcinoma, the lymph nodes along the right recurrent nerve are often affected (34%, 24% and 10%, respectively). Few studies describe the metastatic pattern of adenocarcinoma. The current literature is heterogeneous in the classification and reporting of lymph node metastases. This complicates evidence-based strategies in neoadjuvant and surgical treatment.

https://www.mdpi.com/2072-6694/12/6/1592/pdf

Distribution of Lymph Node Metastases in Esophageal Carcinoma Patients Undergoing Upfront Surgery: A Systematic Review

The radio-sensitizing effects of several chemotherapeutic agents and hyperthermia have been investigated in several animal and human cell culture systems. Cells are first treated with Cisplatin, Gemcitabine, Halogenated pyrimidines or hyperthermia and thereafter irradiated with different dose of radiation up to 8 Gy. After treatment the clonogenic survival was determined and from the survival curves the values of the linear and quadratic parameters were determined using the formula S(D)/S(O)= exp-(αD+βD2).
An increase in the value of the linear parameter, α, was observed in most cases, which corresponds to an enhanced (potentially) direct lethal damage (PLD) at low doses. The quadratic parameter β, which is assumed to depend on the interaction of sublethal lesions (SLD), was rarely affected. Furthermore, it appeared that more radioresistant cell lines were more sensitised than the radiosensitive lines. Furthermore it can be concluded that radiosensitization is also dependent on cell cycle stage like plateau or exponentially growing phase or post treatment plating conditions.

Radiosensitization with Chemotherapeutic Agents and Hyperthermia: Effects on Linear-quadratic Parameters of Radiation Cell Survival Curves

Objective We sought to determine the extent of lymphadenectomy that optimizes staging and survival in patients with locally advanced esophageal adenocarcinoma (EAC) treated with neoadjuvant chemoradiotherapy followed by esophagectomy. Summary background data Several studies have found that a more extensive lymphadenectomy leads to better disease-specific survival in patients treated with surgery alone. Few studies, however, have investigated whether this association exists for patients treated with neoadjuvant chemoradiotherapy. Methods We examined our prospective database and identified patients with EAC treated with neoadjuvant chemoradiotherapy followed by esophagectomy between 1995 and 2017. Overall survival (OS) and disease-free survival (DFS) were estimated using Kaplan-Meier methods, and a multivariable Cox proportional hazards model was used to identify independent predictors of OS and DFS. The relationship between the total number of nodes removed and 5-year OS or DFS was plotted using restricted cubic spline functions. Results In total, 778 patients met the inclusion criteria. The median number of excised nodes was 21 (interquartile range, 16-27). A lower number of excised lymph nodes was independently associated with worse OS and DFS (OS: hazard ratio [HR], 0.98; confidence interval [CI], 0.97-1.00; P = 0.013; DFS: HR, 0.99; CI, 0.98-1.00; P = 0.028). Removing 25 to 30 lymph nodes was associated with a 10% risk of missing a positive lymph node. Both OS and DFS improved with up to 20 to 25 lymph nodes removed, regardless of treatment response. Conclusions The optimal extent of lymphadenectomy to enhance both staging and survival following chemoradiotherapy, regardless of treatment response, is approximately 25 lymph nodes.

A More Extensive Lymphadenectomy Enhances Survival Following Neoadjuvant Chemoradiotherapy in Locally Advanced Esophageal Adenocarcinoma.

Mapping of Lymph Node Metastasis From Thoracic Esophageal Cancer: A Retrospective Study

The distribution of lymph node metastases in esophageal adenocarcinoma following neoadjuvant chemoradiation (nCRTx) is unclear, but may have consequences for radiotherapy and surgery. The aim of this study was to define the distribution of lymph node metastases and relation to the radiation field in patients following nCRTx and esophagectomy. Between April 2014 and August 2015 esophageal adenocarcinoma patients undergoing transthoracic esophagectomy with 2-field lymphadenectomy following nCRTx were included in this prospective observational study. Lymph node stations according to AJCC 7 were separately investigated. The location of lymph node metastases in relation to the radiation field was determined. The primary endpoint was the distribution of lymph node metastases and relation to the radiation field, the secondary endpoints were high-risk stations and risk factors for lymph node metastases and relation to survival. Fifty consecutive patients were included. Lymph node metastases were found in 60% of patients and most frequently observed in paraesophageal (28%), left gastric artery (24%), and celiac trunk (18%) stations. Fifty-two percent had lymph node metastases within the radiation field. The incidence of lymph node metastases correlated significantly with ypT-stage (p = 0.002), cT-stage (p = 0.005), lymph angioinvasion (p = 0.004), and Mandard (p = 0.002). The number of lymph node metastases was associated with survival in univariable analysis (HR 1.12, 95% CI 1.068–1.173, p < 0.001). Esophageal adenocarcinoma frequently metastasizes to both the mediastinal and abdominal lymph node stations. In this study, more than half of the patients had lymph node metastases within the radiation field. nCRTx is therefore not a reason to minimize lymphadenectomy in patients with esophageal adenocarcinoma.

Distribution of lymph node metastases in esophageal adenocarcinoma after neoadjuvant chemoradiation therapy: a prospective study.

acknowledged that partial laryngectomy, which in a broad sense includes TLM, is a form of larynx preservation (1). However, it is simply not feasible to consider a trial to test the efficacy and functional outcome of surgical techniques against other larynx-preserving therapies prospectively until head and neck surgical oncologists can put together a group of devoted contributors to determine and prioritize which surgical technique to bring forward for headto-head comparison, to introduce training and quality assurance programs for the surgical experimental arm, and to enroll predefined numbers of patients. Christiansen et al. are well-known, experienced proponents of TLM. The real challenge facing them is their ability to assemble a group of colleagues who are truly committed to putting TLM into rigorous scientific testing, as has been done for nonsurgical therapies, and proving their devotion by completing patient enrollment into a multi-institutional Phase II trial. Until such an effort is successfully completed, the recommendation for including TLM in future cooperative group Phase III trials represents a pie in the sky.

Quantification of the contribution of hyperthermia to results of cervical cancer trials: in regard to Plataniotis and Dale (Int J Radiat Oncol Biol Phys 2009;73:1538-1544).

QUANTIFICATION OF THE CONTRIBUTION OF HYPERTHERMIA TO RESULTS OF CERVICAL CANCER TRIALS: IN REGARD TO PLATANIOTIS AND DALE. Authors' reply

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Distribution of lymph node metastases in esophageal adenocarcinoma after neoadjuvant chemoradiation therapy: a prospective study.

Quantification of the contribution of hyperthermia to results of cervical cancer trials: in regard to Plataniotis and Dale (Int J Radiat Oncol Biol Phys 2009;73:1538-1544).

QUANTIFICATION OF THE CONTRIBUTION OF HYPERTHERMIA TO RESULTS OF CERVICAL CANCER TRIALS: IN REGARD TO PLATANIOTIS AND DALE. Authors' reply