Hospital factors determining overall survival in cancer patients undergoing curative treatment.

BACKGROUND: In oncology, overall survival (OS) and quality of life (QoL) are key indicators. The factors that affect OS and QoL include tumor-related characteristics (stage and grade), patient-related factors (performance status and comorbidities), and cancer-directed therapy (CDT)-related aspects. In addition, external factors such as governance or policy (e.g., inaccessibility to CDT, increased distance to service, poor socioeconomic status, lack of insurance), and hospital-related factors (e.g., facility volume and surgeon volume) can influence OS and QoL. MATERIALS AND METHODS: The primary objective of this narrative review was to identify hospital-related factors that affect OS and QoL in patients receiving curative CDT. The authors defined extrinsic factors that can be modified at the hospital level as "hospital-related" factors. Only factors supported by randomized controlled trials (RCT), systematic reviews (SR) and/or meta-analyses (MA), and population database (PDB) analyses that address the relationship between OS and hospital factors were considered. RESULTS: The literature review found that high hospital or oncologist volume, adherence to evidence-based medicine (EBM), optimal time-to-treatment initiation (TTI), and decreased overall treatment time (OTT) increase OS in patients undergoing curative CDT. The use of case management strategies was associated with better symptom management and treatment compliance, but had a mixed effect on QoL. The practice of enhanced recovery after surgery (ERAS) in cancer patients did not result in an increase in OS. There was insufficient evidence to support the impact of factors such as teaching or academic centers, hospital infrastructure, and treatment compliance on OS and QoL. CONCLUSION: The authors conclude that hospital policies should focus on increasing hospital and oncologist volume, adhering to EBM, optimizing TTI, and reducing OTT for cancer patients receiving curative treatment.

A comparison of conventional and accelerated hypofractionated radiotherapy in definitive chemoradiation for locally advanced head and neck carcinoma: a retrospective cohort study.

PURPOSE: The study evaluates accelerated hypofractionated radiotherapy (AHRT) compared to conventional fractionation radiotherapy (CFRT) in patients with locally advanced head and neck cancer (LAHNC) receiving definitive chemoradiation therapy. MATERIALS AND METHODS: The study includes a retrospective cohort analysis of 120 patients. CFRT arm (n = 65) received 2 Gy per fraction to a dose of 70 Gy over 7 weeks in a three-volume approach, whereas the AHRT arm (n = 55) received 2.2 Gy per fraction to a dose of 66 Gy in 6 weeks with a two-volume approach. The primary outcome was overall survival (OS). RESULTS: With a median follow-up of 18.9 months, 23 patients died in the AHRT arm, and 45 deaths in the CFRT arm. The median OS was 23.4 and 37.63 months in the CFRT and AHRT arms, respectively (hazard ratio [HR] = 0.709; 95% confidence interval [CI], 0.425-1.18; p = 0.189). The median time to loco-regional control was 33.3 months in the CFRT arm and was not reached in the patient group receiving AHRT (HR = 0.558; 95% CI, 0.30-1.03; p = 0.065). The median progression-free survival was 15.9 months in the CFRT arm and 26.9 months in the AFRT arm (HR = 0.801; 95% CI, 0.49-1.28; p = 0.357). Out of 11 acute toxic deaths, eight were in the CFRT arm. CONCLUSION: The study showed a trend towards benefit in terms of locoregional control in the AHRT arm and similar OS. A longer follow-up of patients receiving AHRT is required to assess the benefit.

Volumetric image guidance for intravaginal brachytherapy: A dosimetric and clinical study.

Background: The present retrospective dosimetric and clinical study aims to explore the subset of patients who will benefit from volumetric image guidance in intravaginal brachytherapy (IVBT). Materials and Methods: Sixty-three consecutive patients who underwent IVBT using single-channel intravaginal cylinder were analyzed. The most common IVBT dose protocol was 1100 cGy in two fractions (with external beam radiotherapy [EBRT]) and 2200 cGy in four fractions (when used alone). The factors affecting the dose to organs at risk (OARs) (such as treated length, orientation of applicator, EBRT) and target volume were analyzed. Local control rate and late toxicities were reported. Results: There was a statistically significant increase in equivalent dose at 2 Gy per fraction (EQD2) doses of all OARs with the addition of EBRT. In 39.4%, EQD2 D2cc dose of rectum was more than 65 Gy. There was a statistically significant positive correlation with increasing treated length in D5cc (Gy) of rectum and D5cc (Gy) of urethra (Pearson's correlation coefficient of 0.375, P = 0.002 and Pearson's correlation coefficient of 0.394, P = 0.001, respectively). There was a statistically significant increase in D2cc and D5cc of rectum with posterior orientation. Air gaps were noted in 81% of applications. Median duration of follow-up was 30 months. One patient had vaginal recurrence in lower third of vagina. One patient was recorded with grade 2 hemorrhagic radiation proctitis. Conclusion: Computed tomography (CT)-based volumetric planning is an effective method to evaluate doses to OARs and confirm the adequacy of dose coverage, and we recommend routine use of the same. Image guidance is most beneficial in patients being treated with a combination of IVBT and EBRT, posterior orientation, and those who are treated for the entire length of vagina.

RhoC in association with TET2/WDR5 regulates cancer stem cells by epigenetically modifying the expression of pluripotency genes.

Emerging evidence illustrates that RhoC has divergent roles in cervical cancer progression where it controls epithelial to mesenchymal transition (EMT), migration, angiogenesis, invasion, tumor growth, and radiation response. Cancer stem cells (CSCs) are the primary cause of recurrence and metastasis and exhibit all of the above phenotypes. It, therefore, becomes imperative to understand if RhoC regulates CSCs in cervical cancer. In this study, cell lines and clinical specimen-based findings demonstrate that RhoC regulates tumor phenotypes such as clonogenicity and anoikis resistance. Accordingly, inhibition of RhoC abrogated these phenotypes. RNA-seq analysis revealed that RhoC over-expression resulted in up-regulation of 27% of the transcriptome. Further, the Infinium MethylationEPIC array showed that RhoC over-expressing cells had a demethylated genome. Studies divulged that RhoC via TET2 signaling regulated the demethylation of the genome. Further investigations comprising ChIP-seq, reporter assays, and mass spectrometry revealed that RhoC associates with WDR5 in the nucleus and regulates the expression of pluripotency genes such as Nanog. Interestingly, clinical specimen-based investigations revealed the existence of a subset of tumor cells marked by RhoC+/Nanog+ expression. Finally, combinatorial inhibition (in vitro) of RhoC and its partners (WDR5 and TET2) resulted in increased sensitization of clinical specimen-derived cells to radiation. These findings collectively reveal a novel role for nuclear RhoC in the epigenetic regulation of Nanog and identify RhoC as a regulator of CSCs. The study nominates RhoC and associated signaling pathways as therapeutic targets.

Late toxicities in locally advanced head and neck squamous cell carcinoma treated with intensity modulated radiation therapy.

PURPOSE: The study aims to report late toxicities in locally advanced head-and-neck squamous cell carcinoma (LAHNSCC) treated with intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: A retrospective study was conducted on 103 patients of LAHNSCC treated with IMRT. We analyzed the cumulative incidence of late xerostomia, dysphagia, and aspiration at an interval of 6-month, 1-year, 2-year, and 3-year from the start of IMRT. RESULTS: At a median follow up of 4.2 years (interquartile range, 3.5 to 6 years), the cumulative incidence of grade ≥2 late xerostomia was 5.5%, dysphagia was 6.9%, and aspiration was 11.1%. Logistic regression showed that Dmean of ≥26 Gy to parotids had higher risk of xerostomia (hazard ratio [HR] = 5.19; 95% confidence interval [CI], 1.90-14.22; p = 0.001). Late dysphagia was associated with Dmean of ≥45 Gy to pharyngeal constrictors (PC) (HR = 7; 95% CI, 1.84-26.61; p =0.004), ≥55 Gy to larynx (HR = 3.25; 95% CI, 1.15-9.11; p = 0.025), and adjuvant RT (HR = 5.26; 95% CI, 1.85-14.87; p = 0.002). Aspiration was associated with Dmean of ≥45 Gy to larynx (HR = 6.5; 95% CI, 1.93-21.88; p = 0.003), Dmean of ≥55 Gy to PC (HR = 3.54; 95% CI, 1.25-9.98; p = 0.017), and patients having late dysphagia (HR = 4.37; 95% CI, 1.55-12.31; p = 0.005). CONCLUSION: IMRT is a feasible radiation delivery technique in LAHNSCC with a decreased late toxicity profile.

Optimal time management on linear accelerator: A logical model to reduce patient waiting time.

INTRODCTION: Optimal time management is of utmost importance in the radiotherapy department. Inappropriate allocation of time slots leads to prolonged waiting times and decreased patient satisfaction during external beam radiotherapy. The present study tests a logical model to improve the waiting time for the patients. MATERIALS AND METHODS: The treatment time, waiting time, and causes of delay were studied from November 4, 2014, to July 24, 2015. New rules were framed for treatment slot allocation from December 26, 2014. The treatment slots were classified based on the treatment technology (three-dimensional conformal radiotherapy and intensity-modulated radiotherapy) with inclusion of "buffer slots" and patient education. The results were compared before and after rules. RESULTS: A total of 1032 time slots were analyzed, of which 225 "before rules" and 807 "after rules," respectively. There was a significant reduction in the average waiting time for treatment in on-time patients (median [interquartile range (IQR)] of 25.2 min [31.75] vs. 3 min [3.5]; P< 0.00001) as well as in late-coming patients (median [IQR] of 38.2 min [13.795] vs. 21.11 min [12.75]; P= 0.00006). 59.7% (71 patients) of the treatment was delayed "before rules" as opposed to 32.2% (137 patients) "after rules" in on-time patients. Due to better patient education, there was a significant improvement in the patient punctuality toward the allotted time. CONCLUSION: The treatment slots classified based on the teletherapy technique with buffer slots, and patient education helps in better time management on linear accelerator. This methodology significantly reduces waiting time and thereby the number of patients having delay in the treatment.

Toxicity syndrome and early competing deaths in head-and-neck cancer undergoing radiation therapy: Observation and hypothesis.

Radiotherapy (RT) and/or concurrent chemoradiation (CRT) is the mainstay for the treatment of locally advanced head-and-neck cancer (LAHNC). Sepsis remains a poorly understood and unrecognized event in head-and-neck cancer. The study aims to hypothesize a 'toxicity syndrome' leading to sepsis and subsequent sepsis-related deaths. A retrospective audit of all 125 LAHNC patients treated radically from January 2013 to June 2017 was conducted. A total of fifteen toxic deaths were reported. Thirteen deaths were attributed to sepsis. Individual toxicity for death was ascertained only for three cases. A toxicity syndrome namely 'mucositis-dysphagia-aspiration-sepsis (MDAS) complex' was proposed as the cause of death in the rest ten cases. The authors recommend the surveillance of the 'MDAS complex' for the prevention of early toxicity-related deaths in patients with LAHNC undergoing RT or CRT.

RhoC regulates radioresistance via crosstalk of ROCK2 with the DNA repair machinery in cervical cancer.

BACKGROUND: Radioresistance remains a challenge to the successful treatment of various tumors. Intrinsic factors like alterations in signaling pathways regulate response to radiation. RhoC, which has been shown to modulate several tumor phenotypes has been investigated in this report for its role in radioresistance. In vitro and clinical sample-based studies have been performed to understand its contribution to radiation response in cervical cancer and this is the first report to establish the role of RhoC and its effector ROCK2 in cervical cancer radiation response. METHODS: Biochemical, transcriptomic and immunological approaches including flow cytometry and immunofluorescence were used to understand the role of RhoC and ROCK2. RhoC variants, siRNA and chemical inhibitors were used to alter the function of RhoC and ROCK2. Transcriptomic profiling was performed to understand the gene expression pattern of the cells. Live sorting using an intracellular antigen has been developed to isolate the cells for transcriptomic studies. RESULTS: Enhanced expression of RhoC conferred radioprotection on the tumor cells while inhibition of RhoC resulted in sensitization of cells to radiation. The RhoC overexpressing cells had a better DNA repair machinery as observed using transcriptomic analysis. Similarly, overexpression of ROCK2, protected tumor cells against radiation while its inhibition increased radiosensitivity in vitro. Further investigations revealed that ROCK2 inhibition abolished the radioresistance phenotype, conferred by RhoC on SiHa cells, confirming that it is a downstream effector of RhoC in this context. Additionally, transcriptional analysis of the live sorted ROCK2 high and ROCK2 low expressing SiHa cells revealed an upregulation of the DNA repair pathway proteins. Consequently, inhibition of ROCK2 resulted in reduced expression of pH2Ax and MRN complex proteins, critical to repair of double strand breaks. Clinical sample-based studies also demonstrated that ROCK2 inhibition sensitizes tumor cells to irradiation. CONCLUSIONS: Our data primarily indicates that RhoC and ROCK2 signaling is important for the radioresistance phenotype in cervical cancer tumor cells and is regulated via association of ROCK2 with the proteins of DNA repair pathway involving pH2Ax, MRE11 and RAD50 proteins, partly offering insights into the mechanism of radioresistance in tumor cells. These findings highlight RhoC-ROCK2 signaling involvement in DNA repair and urge the need for development of these molecules as targets to alleviate the non-responsiveness of cervical cancer tumor cells to irradiation treatment.

Burden of acute toxicities in head-and-neck radiation therapy: A single-institutional experience.

INTRODUCTION: Combined modality therapy is the standard of care in locally advanced head-and-neck cancer (HNC). The incidence of acute toxicities increases with additional therapy. The present study investigated the incidence and patterns of mucositis, dysphagia, aspiration, feeding tube use, admission for supportive care, and treatment compliance in patients with HNC treated curatively with radiation therapy (RT) with or without chemotherapy. METHODS AND MATERIAL: A retrospective review of 164 consecutive HNC patients treated with RT at St. John's Medical College Hospital, Bengaluru, from January 2013 to June 2017 was done. RESULTS: A total of 148 HNC patients were treated with a curative intent and 122 (82.4%) were locally advanced HNC. Combined Modality treatment was received by 119 (80.4%) patients. Eighty-four (56.7%) patients were treated by concurrent chemo-radiation. IMRT technique was used in 125 (84.5%) patients. The incidence of grade 3-4 mucositis, dysphagia and aspiration was 25%, 46%, and 10%, respectively. Nasogastric tube feeding was necessitated in 18.9% (n=28) and 27% (n = 40) required inpatient admission for supportive care. Twenty-nine (19.6%) patients did not complete planned RT dose and 46 (31%) patients had unscheduled RT break (>2days). Fifty-six (66.7%) patients did not receive planned chemotherapy. CONCLUSIONS: Acute toxicity due to RT in HNC remains a challenge despite using modern techniques. A significant proportion of patients require supportive therapy for more than 12 weeks and did not complete the scheduled treatment.

Immobilization versus no immobilization for pelvic external beam radiotherapy.

AIM: To identify the most reproducible technique of patient positioning and immobilization during pelvic radiotherapy. BACKGROUND: Radiotherapy plays an important role in the treatment of pelvic malignancies. Errors in positioning of patient are an integral component of treatment. The present study compares two methods of immobilization with no immobilization with an aim of identifying the most reproducible method. MATERIALS AND METHODS: 65 consecutive patients receiving pelvic external beam radiotherapy were retrospectively analyzed. 30, 21 and 14 patients were treated with no-immobilization with a leg separator, whole body vacuum bag cushion (VBC) and six point aquaplast immobilization system, respectively. The systematic error, random error and the planning target volume (PTV) margins were calculated for all the three techniques and statistically analyzed. RESULTS: The systematic errors were the highest in the VBC and random errors were the highest in the aquaplast group. Both systematic and random errors were the lowest in patients treated with no-immobilization. 3D Systematic error (mm, mean ± 1SD) was 4.31 ± 3.84, 3.39 ± 1.71 and 2.42 ± 0.97 for VBC, aquaplast and no-immobilization, respectively. 3D random error (mm, 1SD) was 2.96, 3.59 and 1.39 for VBC, aquaplast and no-immobilization, respectively. The differences were statistically significant between all the three groups. The calculated PTV margins were the smallest for the no-immobilization technique with 4.56, 4.69 and 4.59 mm, respectively, in x, y and z axes, respectively. CONCLUSIONS: Among the three techniques, no-immobilization technique with leg separator was the most reproducible technique with the smallest PTV margins. For obvious reasons, this technique is the least time consuming and most economically viable in developing countries.

How common is hypothyroidism after external radiotherapy to neck in head and neck cancer patients?

PURPOSE: To identify the occurrence of clinical and subclinical hypothyroidism among head and neck cancer patients receiving radiation to the neck and to justify routine performing of thyroid function tests during follow-up. MATERIALS AND METHODS: This is a prospective nonrandomized study of 45 patients of head and neck cancer, receiving radiotherapy (RT). Thyroid stimulating hormone and T4 estimations were done at baseline and at 4 months and 9 months following RT. RESULTS: Of the 45 patients, 37(82.2 %) were males and eight (17.8 %) were females. All patients received radiation to the neck to a dose of >40Gy. 35.6% received concurrent chemotherapy. Two patients underwent prior neck dissection. Fourteen patients (31.1%) were found to have clinical hypothyroidism (P value of 0.01). Five (11.1%) patients were found to have subclinical hypothyroidism with a total 19 of 45 (42.2%) patients developing radiation-induced hypothyroidism. Nine of 14 patients with clinical hypothyroidism were in the age group of 51 to 60 years (P=0.0522). Five of 16 patients who received chemoradiation and nine of 29 who received RT alone developed clinical hypothyroidism. Above 40 Gy radiation dose was not a relevant risk factor for hypothyroidism. CONCLUSION: Hypothyroidism (clinical or subclinical) is an under-recognized morbidity of external radiation to the neck which is seen following a minimum dose of 40 Gy to neck. Recognizing hypothyroidism (clinical or subclinical) early and treating it prevents associated complications. Hence, thyroid function tests should be made routine during follow-up.

Crystalline maculopathy: a rare complication of tamoxifen therapy.

Tamoxifen is a selective estrogen receptor modulator widely used in the treatment of hormone-responsive breast cancer. Tamoxifen-induced ocular complications are very rare. A post-menopausal woman, diagnosed and treated case of carcinoma of left breast, on follow-up presented with history of gradual diminution of vision in both eyes of 3 months duration. Patient was on tamoxifen therapy 20 mg daily for the last 2 years. Fundus examination showed crystalline maculopathy. Fluorescein angiography, ocular coherence tomography confirmed the diagnosis. Tamoxifen therapy was discontinued. Although ocular toxicity is rare, careful evaluation of patients with visual symptoms on tamoxifen therapy is required.

Endometrioid endometrial adenocarcinoma in a premenopausal woman with multiple organ metastases.

Endometrial adenocarcinoma is the third common malignancy of the female genital tract occurring most often in the postmenopausal age group. High tumor grade, advanced surgical stage, and lymphovascular space invasion are implicated as poor prognostic factors for dissemination of disease. We present an unusual case of endometrial adenocarcinoma in a premenopausal woman with simultaneous metastases in brain, liver, skin and skeletal system, within one month of completion of treatment. The role of adjuvant/concurrent chemotherapy in addition to radiotherapy in high risk cases is discussed along with the review of literature.