Joseph Wee

Randomized Trial of Radiotherapy Versus Concurrent Chemoradiotherapy Followed by Adjuvant Chemotherapy in Patients With American Joint Committee on Cancer/International Union Against Cancer Stage III and IV Nasopharyngeal Cancer of the Endemic Variety

PURPOSE The Intergroup 00-99 Trial for nasopharyngeal cancer (NPC) showed a benefit of adding chemotherapy to radiotherapy. However, there were controversies regarding the applicability of the results to patients in endemic regions. This study aims to confirm the findings of the 00-99 Trial and its applicability to patients with endemic NPC. PATIENTS AND METHODS Between September 1997 and May 2003, 221 patients were randomly assigned to receive radiotherapy (RT) alone (n = 110) or chemoradiotherapy (CRT; n = 111). Patients in both arms received 70 Gy in 7 weeks using standard RT portals and techniques. Patients on CRT received concurrent cisplatin (25 mg/m2 on days 1 to 4) on weeks 1, 4, and 7 of RT and adjuvant cisplatin (20 mg/m2 on days 1 to 4) and fluorouracil (1,000 mg/m2 on days 1 to 4) every 4 weeks (weeks 11, 15, and 19) for three cycles after completion of RT. All patients were analyzed by intent-to-treat analysis. The median follow-up time was 3.2 years. RESULTS Distant metastasis occurred in 38 patients on RT alone and 18 patients on CRT. The difference in 2-year cumulative incidence was 17% (95% CI, 14% to 20%; P = .0029). The hazard ratio (HR) for disease-free survival was 0.57 (95% CI, 0.38 to 0.87; P = .0093). The 2- and 3-year overall survival (OS) rates were 78% and 85% and 65% and 80% for RT alone and CRT, respectively. The HR for OS was 0.51 (95% CI, 0.31 to 0.81; P = .0061). CONCLUSION This report confirms the findings of the Intergroup 00-99 Trial and demonstrates its applicability to endemic NPC. This study also confirms that chemotherapy improves the distant metastasis control rate in NPC.

The Simons Genome Diversity Project: 300 genomes from 142 diverse populations

Here we report the Simons Genome Diversity Project data set: high quality genomes from 300 individuals from 142 diverse populations. These genomes include at least 5.8 million base pairs that are not present in the human reference genome. Our analysis reveals key features of the landscape of human genome variation, including that the rate of accumulation of mutations has accelerated by about 5% in non-Africans compared to Africans since divergence. We show that the ancestors of some pairs of present-day human populations were substantially separated by 100,000 years ago, well before the archaeologically attested onset of behavioural modernity. We also demonstrate that indigenous Australians, New Guineans and Andamanese do not derive substantial ancestry from an early dispersal of modern humans; instead, their modern human ancestry is consistent with coming from the same source as that of other non-Africans.

Prognostic factors in 677 patients in Singapore with nondisseminated nasopharyngeal carcinoma.

The objective of the current study was to describe the survival of nasopharyngeal carcinoma (NPC) patients in Singapore, verify the prognostic value of the revised 1997 TNM staging system, and develop a multivariate prognostic model for NPC. In addition, the authors also examined the prognostic value of characteristics of lymph node spread and parapharyngeal involvement.

Treatment of Nasopharyngeal Carcinoma using Intensity Modulated Radiotherapy - The National Cancer Centre, Singapore Experience

PURPOSE The aim of this study was to determine the efficacy and acute toxicity of our early experience with treating nasopharyngeal carcinoma (NPC) patients with intensity-modulated radiotherapy (IMRT). METHODS AND MATERIALS A review was conducted on case records of 195 patients with histologically proven, nonmetastatic NPC treated with IMRT between 2002 and 2005. MRI of the head and neck was fused with CT simulation images. All plans had target volumes at three dose levels, with a prescribed dose of 70 Gy to the gross disease, in 2.0-2.12 Gy/fraction over 33-35 fractions. Cisplatin-based chemotherapy was offered to Stage III/IV patients. RESULTS Median patient age was 52 years, and 69% were male. Median follow-up was 36.5 months. One hundred and twenty-three patients had Stage III/IV disease (63%); 50 (26%) had T4 disease. One hundred and eighty-eight (96%) had complete response; 7 (4%) had partial response. Of the complete responders, 10 (5.3%) had local recurrence, giving a 3-year local recurrence-free survival estimate of 93.1% and a 3-year disease-free survival of 82.1%. Fifty-one patients (26%) had at least one Grade 3 toxicity. CONCLUSIONS Results from our series are comparable to those reported by other centers. Acute toxicity is common. Local failure or persistent disease, especially in patients with bulky T4 disease, are issues that must be addressed in future trials.

Surgery and adjuvant radiotherapy vs concurrent chemoradiotherapy in stage III/IV nonmetastatic squamous cell head and neck cancer: a randomised comparison

We compared concurrent combination chemotherapy and radiotherapy with surgery and adjuvant radiotherapy in patients with stage III/IV nonmetastatic squamous cell head and neck cancer. Patients with non-nasopharyngeal and nonsalivary resectable squamous cell head and neck cancer were randomised to receive either surgery followed by adjuvant radiotherapy (60 Gy over 30 fractions) or concurrent combination chemotherapy and radiotherapy (66 Gy in 33 fractions). Combination chemotherapy comprised two cycles of i.v. cisplatin 20 mg m− 2 day− 1 and i.v. 5-fluorouracil 1000 mg m− 2 day− 1, both to run over 96 h given on days 1 and 28 of the radiotherapy. A total of 119 patients were randomised. At a median follow-up of 6 years, there was no significant difference in the 3-year disease-free survival rate between the surgery and concurrent chemoradiotherapy (50 vs 40% respectively). The overall organ preservation rate or avoidance of surgery to primary site was 45%. Those with laryngeal/hypopharyngeal disease subsite had a higher organ-preservation rate than the rest (68 vs 30%). Combination chemotherapy and concurrent irradiation with salvage surgery was not superior to conventional surgery and postoperative radiotherapy for resectable advanced squamous cell head and neck cancer. However, this form of treatment schedule with a view to organ-preservation can be attempted especially for those with laryngeal/hypopharyngeal and possibly oropharyngeal disease subsites.

Global diversity, population stratification, and selection of human copy-number variation.

Duplications and deletions in the human genome Duplications and deletions can lead to variation in copy number for genes and genomic loci among humans. Such variants can reveal evolutionary patterns and have implications for human health. Sudmant et al. examined copy-number variation across 236 individual genomes from 125 human populations. Deletions were under more selection, whereas duplications showed more population-specific structure. Interestingly, Oceanic populations retain large duplications postulated to have originated in an ancient Denisovan lineage. Science, this issue 10.1126/science.aab3761 Copy-number variation reveals how selection affects the human genome across the globe. INTRODUCTION Most studies of human genetic variation have focused on single-nucleotide variants (SNVs). However, copy-number variants (CNVs) affect more base pairs of DNA among humans, and yet our understanding of CNV diversity among human populations is limited. RATIONALE We aimed to understand the pattern, selection, and diversity of copy-number variation by analyzing deeply sequenced genomes representing the diversity of all humans. We compared the selective constraints of deletions versus duplications to understand population stratification in the context of the ancestral human genome and to assess differences in CNV load between African and non-African populations. RESULTS We sequenced 236 individual genomes from 125 distinct human populations and identified 14,467 autosomal CNVs and 545 X-linked CNVs with a sequence read-depth approach. Deletions exhibit stronger selective pressure and are better phylogenetic markers of population relationships than duplication polymorphisms. We identified 1036 population-stratified copy-number–variable regions, 295 of which intersect coding regions and 199 of which exhibit extreme signatures of differentiation. Duplicated loci were 1.8-fold more likely to be stratified than deletions but were poorly correlated with flanking genetic diversity. Among these, we highlight a duplication polymorphism restricted to modern Oceanic populations yet also present in the genome of the archaic Denisova hominin. This 225–kilo–base pair (kbp) duplication includes two microRNA genes and is almost fixed among human Papuan-Bougainville genomes. The data allowed us to reconstruct the ancestral human genome and create a more accurate evolutionary framework for the gain and loss of sequences during human evolution. We identified 571 loci that segregate in the human population and another 2026 loci of fixed-copy 2 in all human genomes but absent from the reference genome. The total deletion and duplication load between African and non-African population groups showed no difference after we account for ancestral sequences missing from the human reference. However, we did observe that the relative number of base pairs affected by CNVs compared to single-nucleotide polymorphisms is higher among non-Africans than Africans. CONCLUSION Deletions, duplications, and CNVs have shaped, to different extents, the genetic diversity of human populations by the combined forces of mutation, selection, and demography. Figure Global human CNV diversity and archaic introgression of a chromosome 16 duplication. (Left) The geographic coordinates of populations sampled are indicated on a world map (colored dots). The pie charts show the continental population allele frequency of a single ~225-kbp duplication polymorphism found exclusively among Oceanic populations and an archaic Denisova. (Right) The ancestral structure of this duplication locus (1) and the Denisova duplication structure (2) are shown in relation to their position on chromosome 16. We estimate that the duplication emerged ~440 thousand years ago (ka) in the Denisova and then introgressed into ancestral Papuan populations ~40 ka. In order to explore the diversity and selective signatures of duplication and deletion human copy-number variants (CNVs), we sequenced 236 individuals from 125 distinct human populations. We observed that duplications exhibit fundamentally different population genetic and selective signatures than deletions and are more likely to be stratified between human populations. Through reconstruction of the ancestral human genome, we identify megabases of DNA lost in different human lineages and pinpoint large duplications that introgressed from the extinct Denisova lineage now found at high frequency exclusively in Oceanic populations. We find that the proportion of CNV base pairs to single-nucleotide–variant base pairs is greater among non-Africans than it is among African populations, but we conclude that this difference is likely due to unique aspects of non-African population history as opposed to differences in CNV load.

Sensorineural Hearing Loss After Radiotherapy and Chemoradiotherapy: A Single, Blinded, Randomized Study

PURPOSE The synergistic ototoxicity of radiation and cisplatin (CDDP) has not been adequately studied. This study investigated whether the use of concurrent and postradiotherapy CDDP in patients with nasopharyngeal carcinoma (NPC) resulted in a difference in postradiotherapy sensorineural hearing when compared with the use of radiotherapy alone. PATIENTS AND METHODS Newly diagnosed patients were randomly assigned to the radiotherapy or chemoradiotherapy groups. Bone conduction hearing thresholds were performed before treatment and at 1 week, 6 months, 1 year, and 2 years after completion of radiotherapy. Statistical analysis was performed using the Mann-Whitney U test. RESULTS Hearing thresholds averaged over 0.5, 1, and 2 kHz were found to be poorer in the chemoradiotherapy group (58 patients) compared with the radiotherapy group (57 patients) at 1 year (P = .001) and 2 years (P = .03) after radiotherapy. Hearing thresholds at 4 kHz were significantly worse for patients in the chemoradiotherapy arm at all of the postradiotherapy time points studied and were more severely affected than the thresholds at lower speech frequencies. In the radiotherapy group, deterioration of median hearing thresholds, which occurred in the immediate post-treatment period, improved within the first year but deteriorated again at 2 years. In the chemoradiotherapy group, median hearing threshold deterioration, which started immediately after radiotherapy, stabilized by 1 year. CONCLUSION Patients with NPC who received radiotherapy and concurrent/adjuvant chemotherapy using CDDP experienced greater sensorineural hearing loss compared with patients treated with radiotherapy alone, especially to high-frequency sounds in the speech range. Normal inner ear tissue tolerance, which was once defined only for radiotherapy patients alone, should be redefined in chemoradiotherapy patients.

Randomized Double-Blind Trial of Combined Modality Treatment With or Without Amifostine in Unresectable Stage III Non–Small-Cell Lung Cancer

PURPOSE Greater toxicities have been recognized to be a consequence of combined chemotherapy and radiotherapy in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This study was designed to determine if the use of amifostine could reduce treatment-related toxicities associated with the use of paclitaxel plus carboplatin and thoracic radiotherapy. PATIENTS AND METHODS Sixty patients with unresectable stage III NSCLC were treated with two cycles of paclitaxel 175 mg/m2 and carboplatin (area under the time-concentration curve = 6), followed by thoracic radiotherapy (64 Gy) with concurrent weekly paclitaxel 60 mg/m2. Patients were randomly assigned to receive 740 mg/m2 of amifostine (arm A) or placebo (arm B) before each dose of paclitaxel and carboplatin. Treatment-related toxicities were evaluated at each visit and nerve conduction tests were performed before and after treatment for the objective assessment of neurotoxicity. RESULTS There was no significant difference between arms A and B in grade 3 to 4 neutropenia. In all 72 neurophysiological parameters measured, there was no significant difference between the two treatment arms, although there was a trend toward fewer patients showing deterioration in arm A for six of the parameters. Grade 2 to 3 esophagitis occurred in 43% of patients in arm A and in 70% of patients in arm B. The difference of -27% (95% confidence limit = -50%, 0.4%) was not statistically significant. Response rates and survival were also not significantly different between the two arms. CONCLUSION Pretreatment with amifostine showed a trend toward reducing the severity of esophagitis associated with concurrent chemoradiotherapy, but it did not reach statistical significance. There was no significant protective effect on hematologic or neurologic toxicities induced by paclitaxel and carboplatin.

Genomic analyses inform on migration events during the peopling of Eurasia

High-coverage whole-genome sequence studies have so far focused on a limited number of geographically restricted populations, or been targeted at specific diseases, such as cancer. Nevertheless, the availability of high-resolution genomic data has led to the development of new methodologies for inferring population history and refuelled the debate on the mutation rate in humans. Here we present the Estonian Biocentre Human Genome Diversity Panel (EGDP), a dataset of 483 high-coverage human genomes from 148 populations worldwide, including 379 new genomes from 125 populations, which we group into diversity and selection sets. We analyse this dataset to refine estimates of continent-wide patterns of heterozygosity, long- and short-distance gene flow, archaic admixture, and changes in effective population size through time as well as for signals of positive or balancing selection. We find a genetic signature in present-day Papuans that suggests that at least 2% of their genome originates from an early and largely extinct expansion of anatomically modern humans (AMHs) out of Africa. Together with evidence from the western Asian fossil record, and admixture between AMHs and Neanderthals predating the main Eurasian expansion, our results contribute to the mounting evidence for the presence of AMHs out of Africa earlier than 75,000 years ago.

Design of a prognostic index score for metastatic nasopharyngeal carcinoma

The survival outcome of patients with systemic cancer differs significantly between individuals even within the same tumour type. We set out to illustrate this by analysing the factors determining survival in patients with metastatic disease from nasopharyngeal carcinoma (NPC) and to design a scoring system based on these prognostic factors. Patients referred between January 1994 and December 1999 were retrospectively analysed. Factors analysed included patient (age group, gender, performance status (BS) at diagnosis of metastases), disease (number of metastatic sites, specific metastatic sites, disease-free interval (DFI), metastases at presentation, presence of locoregional recurrence), and laboratory factors (leucocyte count, haemoglobin level, albumin level). Univariate and multivariable analyses were performed using the Cox proportion hazards model. A numerical score was derived from the regression coefficients of each independent prognostic variable. The prognostic index score (PIS) of each patient was calculated by totalling up the scores of each independent variable. Independently significant, negative prognostic factors were liver metastasis, lung metastasis, anaemia, poor PS, distant metastasis at initial diagnosis, and a DFI of <6 months. Three prognostic groups based on the PIS were obtained: (i) good risk (PIS=0-6); (ii) intermediate risk (7-10); (iii) poor risk (>or=11). The median survivals for these groups were 19.5, 10, and 5.8, months, respectively, (log rank test: P<0.0001). The variable prognosis of patients with disseminated NPC can be assessed by using easily available clinical information (patient, disease and laboratory factors). The PIS system will need to be validated on prospectively collected data of another cohort of patients.