Anil D’Cruz

Preferred reporting of case series in surgery; the PROCESS guidelines

INTRODUCTION Case series have been a long held tradition within the surgical literature and are still frequently published. Reporting guidelines can improve transparency and reporting quality. No guideline exists for reporting case series, and our recent systematic review highlights the fact that key data are being missed from such reports. Our objective was to develop reporting guidelines for surgical case series. METHODS A Delphi consensus exercise was conducted to determine items to include in the reporting guideline. Items included those identified from a previous systematic review on case series and those included in the SCARE Guidelines for case reports. The Delphi questionnaire was administered via Google Forms and conducted using standard Delphi methodology. Surgeons and others with expertise in the reporting of case series were invited to participate. In round one, participants voted to define case series and also what elements should be included in them. In round two, participants voted on what items to include in the PROCESS guideline using a nine-point Likert scale to assess agreement as proposed by the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) working group. RESULTS In round one, there was a 49% (29/59) response rate. Following adjustment of the guideline with incorporation of recommended changes, round two commenced and there was an 81% (48/59) response rate. All but one of the items were approved by the participants and Likert scores 7-9 were awarded by >70% of respondents. The final guideline consists of an eight item checklist. CONCLUSION We present the PROCESS Guideline, consisting of an eight item checklist that will improve the reporting quality of surgical case series. We encourage authors, reviewers, editors, journals, publishers and the wider surgical and scholarly community to adopt these.

Three-dimensional conformal radiotherapy (3D-CRT) versus intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the head and neck: A randomized controlled trial

PURPOSE To compare three-dimensional conformal radiotherapy (3D-CRT) with intensity modulated radiation therapy (IMRT) in curative-intent irradiation of head-neck squamous cell carcinoma (HNSCC). METHODS Previously untreated patients with biopsy-proven squamous carcinoma of oropharynx, larynx, or hypopharynx (T1-3, N0-2b) were randomly assigned using computer-generated permuted-block design to either 3D-CRT or IMRT, with incidence of physician-rated Radiation Therapy Oncology Group (RTOG) grade 2 or worse acute salivary gland toxicity as primary end-point. RESULTS Between 2005 and 2008, 60 patients randomly allocated to either 3D-CRT (n=28 patients) or IMRT (n=32) were included and analyzed on an intention-to-treat basis. The proportion [95% confidence intervals (CI)] of patients with RTOG grade 2 or worse acute salivary gland toxicity was significantly lesser in the IMRT arm [19 of 32 patients (59%, 95%CI: 42-75%)] as compared to 3D-CRT [25 of 28 patients (89%, 95%CI: 72-97%; p=0.009)]. Late xerostomia and subcutaneous fibrosis were also significantly lesser with IMRT. There was significant recovery of salivary function over time in patients treated with IMRT (p-value for trend=0.0036). At 3-years, there were no significant differences in loco-regional control or survival between the two arms. CONCLUSION IMRT significantly reduces the incidence and severity of xerostomia compared to 3D-CRT in curative-intent irradiation of HNSCC.

Verrucous carcinoma of the oral cavity: A clinical and pathological study of 101 cases

This paper studies the clinical and pathological predictors of local recurrence and disease-free survival (DFS) in patients with oral verrucous carcinoma (OVC) treated surgically, through a retrospective chart review. Three hundred and two patients with OVC were identified from January 1990 to December 2000, of which, 101 surgically treated patients who fulfilled our inclusion criteria were analyzed. A univariate analysis (UVA) of important prognostic factors, patterns of recurrence, and DFS is reported. Seventy-nine patients were male (M:F ratio, 3.6:1) and the mean age at presentation was 53.9 years (range, 23-90 years). The median follow up was 4.61 years (range, 0.51-14.3 years). The incidence of tobacco chewing, smoking, and alcohol intake was 77%, 42%, and 10%, respectively. Thirty-four patients (33.7%) had either leukoplakia or submucous fibrosis (SMF) on oral cavity examination. Early-stage tumors accounted for 39.7%; while 60.4% were late-stage tumors. On UVA, tumor location, presence of a premalignant lesion, smoking, and positive margins were statistically significant. Sixty-eight percent (19/28) recurred locally. The salvage rate for recurrent tumors was 66.7% (16/28) with a median post-recurrence survival of 16 months (range, 10-83 months). The five year DFS with surgical therapy was 77.6%. OVC has an excellent prognosis with surgical treatment. The significance of positive margins emphasizes the need for adequate surgical resection. Additionally, the presence of either leukoplakia or SMF and tumor location in the upper alveolar-palatal complex is associated with worse outcomes. Neck dissection, if considered, may be limited to a supra-omohyoid neck dissection (SOHND).

Hypofractionated, palliative radiotherapy for advanced head and neck cancer.

BACKGROUND A significant proportion of advanced stage head and neck cancer patients are incurable and have a limited life expectancy. This study reports a single institution experience with a hypofractionated radiotherapy regimen for palliation of loco-regionally advanced and incurable HNSCC. MATERIALS AND METHODS Between 2000 and 2005, 110 patients of unresectable HNSCC were treated with a palliative radiotherapy (40Gy in 16 fractions). Distressing symptoms were assessed before treatment. Patients with good objective regression with acceptable toxicity received further escalation of dose till 50Gy. We made three strata to compare symptomatic improvement namely percentage relief <50%, between 50-75% and >75% as compared to baseline. RESULTS Most common baseline distressing complaints were pain in 109 (99%) patients and dysphagia in 97 (88%) patients. Eleven patients (10%) had complete response (CR) and 80 (73%) patients had complete and partial response (PR). At completion of radiotherapy 26%, 57%, and 17% of patients had <50%, 50-75%, and >75% symptomatic relief, respectively. The overall PFS (defined as either complete disappearance of the disease or non-progression in the irradiated field) at 12 months was 55.1% (95% CI, 40.3%-69.9%). On multivariate analysis weight >50kg (p=0.049) and radiotherapy dose of more than 40Gy (p=0.012) were found to be significant for PFS. Acute and late reactions were acceptable. CONCLUSIONS The hypofractionated radiotherapy regimen evaluated is an effective treatment modality for sustained symptoms relief with good response rates and acceptable toxicity.

Gefitinib plus cisplatin and radiotherapy in previously untreated head and neck squamous cell carcinoma: a phase II, randomized, double-blind, placebo-controlled study.

BACKGROUND AND PURPOSE To assess the efficacy and safety of gefitinib given concomitantly and/or as maintenance therapy to standard cisplatin/radiotherapy for previously untreated, unresected, stage III/IV non-metastatic SCCHN. MATERIALS AND METHODS In this phase II, double-blind, study, 226 patients were randomized to gefitinib 250mg/day, 500mg/day or placebo in two phases: a concomitant phase (gefitinib or placebo with chemoradiotherapy), followed by a maintenance phase (gefitinib or placebo alone). Primary endpoint was local disease control rate (LDCR) at 2years; secondary endpoints were LDCR at 1year, objective response rate, progression-free survival, overall survival, and safety and tolerability. RESULTS Gefitinib (250 and 500mg/day) did not improve 2-year LDCR compared with placebo either when given concomitantly with chemoradiotherapy (32.7% vs. 33.6%, respectively; OR 0.921, 95% CI 0.508, 1.670 [1-sided p=0.607]) or as maintenance therapy (28.8% vs. 37.4%, respectively; OR 0.684, 95% CI 0.377, 1.241 [1-sided p=0.894]). Secondary efficacy outcomes were broadly consistent with the 2-year LDCR results. In both doses, gefitinib was well-tolerated and did not adversely affect the safety and tolerability of concomitant chemoradiotherapy. CONCLUSION Gefitinib was well-tolerated, but did not improve efficacy compared with placebo when given concomitantly with chemoradiotherapy, or as maintenance therapy alone.

BRAF V600E mutation in papillary thyroid carcinoma: significant association with node metastases and extra thyroidal invasion.

B-Raf (BRAF) is the strongest activator in the downstream of MAP kinase signaling. The somatic point mutation of BRAF gene (V600E) is the most common and specific event in papillary thyroid carcinoma (PTC). However, its prevalence is variable among different studies and its association with clinico-pathological features is controversial. This study tests the prevalence of BRAFV600E mutation in thyroid cancer patients in Indian subcontinental population. We analyzed 140 thyroid tumor specimens for BRAF gene mutation at codon 600 using mutant-allele-specific amplification, single-strand conformation polymorphism, Mutector assay, and DNA sequencing of the PCR-amplified exon 15. BRAF mutation at codon 600 was detected in 46 of 86 PTC patients (53.4%) from Indian subcontinental cohort. Frequency of mutation varied across the subtypes of PTCs. BRAFV600E mutation was more common in the conventional PTC (38 out of 62; 61%) than in the follicular variant of PTC (2 out of 17; 11.7%). None of the 8 follicular thyroid adenomas, 14 follicular thyroid carcinomas, 16 medullary thyroid carcinomas, and 16 benign hyperplasia patients showed any exon 15 mutation. We found significant correlation between BRAF mutation status and extra-thyroidal invasion, lymph node metastasis, and tumor stage. However no correlation was observed with gender, age, and tumor size of the patients. Thus our findings suggest that BRAFV600E is a prevalent genetic alteration in adult sporadic PTCs in Indian cohort and it may be responsible for the progression of classic variant of PTC to metastatic and poorly differentiated subtype and likely to have significant impact on its diagnostic and prognostic management.

Factors affecting the quality of voice in the early glottic cancer treated with radiotherapy.

AIMS To prospectively analyze the objective voice quality before and after radiotherapy (RT) for early glottic cancer and to evaluate the role of different factors that may affect it. METHODS Patients with T1-T2N0M0 glottic cancer underwent voice quality assessment before treatment and after radical RT. Post-RT voice quality was compared to the voice at diagnosis and the voice of healthy individuals used as controls. A comprehensive set of voice parameters were measured. The effects of age, smoking history, T stage, anterior commissure (AC) involvement, radiation dose, fractionation and volumes on pre-treatment and post-treatment voice quality were analyzed. RESULTS The voice quality data of 50 patients were analyzed. Following treatment, there was a significant improvement in the majority of measured parameters. However, perturbation and HNR remained inferior compared to controls. A history of smoking, AC involvement and larger RT volumes resulted in poorer voice parameters following RT. There was no significant impact of age alone. T2 tumors had an inferior voice quality before treatment, but did not remain inferior following RT. Hypofractionated RT did not show any negative impact. CONCLUSIONS There is a considerable improvement of voice quality following RT. Several factors may have specific effects on pre-treatment and post-treatment voice.

Recommendations for screening and early detection of common cancers in India

Cancers of the breast, uterine cervix, and lip or oral cavity are three of the most common malignancies in India. Together, they account for about 34% of more than 1 million individuals diagnosed with cancer in India each year. At each of these cancer sites, tumours are detectable at early stages when they are most likely to be cured with standard treatment protocols. Recognising the key role that effective early detection and screening programmes could have in reducing the cancer burden, the Indian Institute for Cytology and Preventive Oncology, in collaboration with the US National Cancer Institute Center for Global Health, held a workshop to summarise feasible options and relevant evidence for screening and early detection of common cancers in India. The evidence-based recommendations provided in this Review are intended to act as a guide for policy makers, clinicians, and public health practitioners who are developing and implementing strategies in cancer control for the three most common cancers in India.

Intraoral adenoid cystic carcinoma: prognostic factors and outcome.

Intraoral (oral cavity and oropharynx) adenoid cystic carcinomas are uncommon cancers characterized by slow evolution, protracted clinical course, multiple and/or delayed recurrences, and late distant metastases. The molecular biology behind this enigmatic disease remains poorly characterized. To analyze and correlate prognostic factors with outcome in intraoral adenoid cystic carcinoma. Medical records of 76 patients with intraoral adenoid cystic carcinoma treated with definitive loco-regional therapy at the institute between 1992 and 2004 were retrospectively reviewed and analyzed.Majority (85.5%) of the patients had advanced stage disease. Seventy-four patients underwent surgery, of which 51 (68.9%) received adjuvant radiotherapy. The median dose of radiation was 56 Gy (range 44-66 Gy). Two patients with medical co-morbidities received radical radiotherapy. Perineural invasion, margin positivity and nodal positivity were present in 24 (32.4%); 27 (36.4%); and 15 (19.7%) patients, respectively. Ten (13.1%) patients developed local recurrence and 6 (7.8%) distant metastases. With a median follow-up of 20 months (range 1-137 months), the 5-year Kaplan-Meier estimates of local control and disease-free survival were 57.9% and 47.1%, respectively. On uni-variate analysis, perineural invasion (p=0.003), oropharyngeal primary (p=0.033), and advanced T-stage (p=0.047) were associated with increased local recurrences. Perineural invasion (p=0.05) and primary site (p=0.042) also predicted disease-free survival. On multivariate analysis, both perineural invasion and primary site retained significance for local control (p=0.007, p=0.011) and disease-free survival (p=0.018, p=0.014), respectively. Intraoral adenoid cystic carcinoma is an uncommon disease with an enigmatic clinical course. Perineural invasion, site of primary, and T-stage significantly impact upon local control and disease-free survival. The role of adjuvant radiotherapy remains controversial. Larger prospective studies with mature follow-up are needed to define the optimal treatment of intraoral adenoid cystic carcinoma.

A prospective randomized phase II study comparing metronomic chemotherapy with chemotherapy (single agent cisplatin), in patients with metastatic, relapsed or inoperable squamous cell carcinoma of head and neck.

BACKGROUND Cetuximab based treatment is the recommended chemotherapy for head and neck squamous cell cancers in the palliative setting. However, due to financial constraints, intravenous (IV) chemotherapy without cetuximab is commonly used in lesser developed countries. We believe that oral metronomic chemotherapy may be safer and more effective in this setting. METHODS We conducted an open label, superiority, parallel design, randomized phase II trial comparing oral MCT [daily celecoxib (200mg twice daily) and weekly methotrexate (15mg/m(2))] to intravenous single agent cisplatin (IP) (75mg/m(2)) given 3 weekly. Eligible patients had head and neck cancers requiring palliative chemotherapy with ECOG PS 0-2 and adequate organ functions who could not afford cetuximab. The primary end point was progression-free survival. RESULTS 110 Patients were recruited between July 2011 to May 2013, 57 randomized to the MCT arm and 53 to the IP arm. Patients in the MCT arm had significantly longer PFS (median 101 days, 95% CI: 58.2-143.7 days) compared to the IP arm (median 66 days, 95% CI; 55.8-76.1 days) (p=0.014). The overall survival (OS) was also increased significantly in the MCT arm (median 249 days, 95% CI: 222.5-275.5 days) compared to the IP arm (median 152 days, 95% CI: 104.2-199.8 days) (p=0.02). There were fewer grade 3/4 adverse effects with MCT, which was not significant. (18.9% vs. 31.4%, P=0.14). CONCLUSION Oral metronomic chemotherapy has significantly better PFS and OS than single agent platinum in the palliative setting.