Clinical significance of tumor-stroma ratio in head and neck cancer: a systematic review and meta-analysis

Abstract Background The clinical significance of tumor-stroma ratio (TSR) has been examined in many tumors. Here we systematically reviewed all studies that evaluated TSR in head and neck cancer. Methods Four databases (Scopus, Medline, PubMed and Web of Science) were searched using the term tumo(u)r-stroma ratio. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) were followed. Results TSR was studied in nine studies of different subsites (including cohorts of nasopharyngeal, oral, laryngeal and pharyngeal carcinomas). In all studies, TSR was evaluated using hematoxylin and eosin staining. Classifying tumors based on TSR seems to allow for identification of high-risk cases. In oral cancer, specifically, our meta-analysis showed that TSR is significantly associated with both cancer-related mortality (HR 2.10, 95%CI 1.56–2.84) and disease-free survival (HR 1.84, 95%CI 1.38–2.46). Conclusions The assessment of TSR has a promising prognostic value and can be implemented with minimum efforts in routine head and neck pathology.

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Predictive factors in advanced head and neck cancer treated by radio-chemotherapy and hypoxia modification

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.6085 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 6085-6085

Author(s):

B. Clavo ◽

F. Robaina ◽

A. Ruiz ◽

M. Lloret ◽

D. Macias ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Tumor Hypoxia ◽

Disease Free Survival ◽

Tumor Oxygenation ◽

Free Survival ◽

Stage Ivb ◽

Radio Chemotherapy ◽

Disease Free

6085 Background: Anemia and tumor hypoxia are known factors for resistance to radio-chemotherapy (RT-CT). In a previous report we have suggested that spinal cord stimulation (SCS) can modify tumor oxygenation and regional blood flow in head and neck cancer (HNC). The aim of the present prospective study was to test the predictive value of pO2 measurement in HNC treated by RT-CT and hypoxia modification using SCS. Methods: Twelve male patients with advanced HNC were analyzed. Stage IVb-IVa: 8–4; mean age 58 + 7.6 years (46–70). Scheduled therapy was hyperfractionated RT (120 cGy/fraction, two fractions/day, total dose 81.6 Gy) from a Co- 60 source, and tegafur 800 mg/day. SCS devices were placed before RT-CT under local anesthesia. During treatment, SCS was connected from 20–30 min before to 20–30 min after each radiotherapy session. Before treatment, they were assessed: Hemoglobin levels and tumor oxygenation pre-SCS and pos-SCS (measured by a polarographic probe system ‘pO2 Histograph‘), expressed as median-pO2, and the fraction of pO2 values less than 5 mmHg (HF5) and less than 2.5 mmHg (HF2.5). Correlations were assessed using Pearson and Spearman tests, and actuarial survival using Kaplan-Meier estimates and Log-rank test. Results: Hemoglobin levels were correlated with oxygenation pre-SCS and pos-SCS: median-pO2 (p=0.005 and p=0.011), HF5 (p=0.048 and p=0.005) respectively. Anemia was associated with more advanced stage (IVb vs IVa, p=0.022), higher HF5 pos-SCS (p=0.028) and lower disease-free survival (p=0.019). The HF2.5 pos-SCS was adversely correlated with the 2 years actuarial: disease-free survival (p=0.027), cause-specific survival (p=0.008) and overall survival (p=0.008). HF2.5 was also correlated with hematocrit (p=0.044). Conclusions: Low hemoglobin levels and anemia are associated with more hypoxic and more advanced tumors. Pre-treatment tumor hypoxia (assessed by the fraction of pO2 values less than 2.5 mmHg during-SCS) is a strong predictive factor for survival in advanced HNC. Patients with highly hypoxic tumors should be selected for more aggressive treatments. Partially supported by: Grant ‘FUNCIS: PI 31–98‘. Scientific supervision was carried out by GICOR. No significant financial relationships to disclose.

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The Association between Metformin and Survival of Head and Neck Cancer: A Systematic Review and Meta-Analysis of 7 Retrospective Cohort Studies

Current Pharmaceutical Design ◽

10.2174/1381612826666200218095310 ◽

2020 ◽

Vol 26 (26) ◽

pp. 3161-3170 ◽

Cited By ~ 3

Author(s):

Yongbo Wang ◽

Tao Fu ◽

Yu Liu ◽

Guifang Yang ◽

Chuanhua Yu ◽

...

Keyword(s):

Head And Neck Cancer ◽

Cohort Studies ◽

Head And Neck ◽

Neck Cancer ◽

Retrospective Cohort ◽

Cancer Survival ◽

Meta Analysis ◽

Disease Free Survival ◽

Cochrane Library ◽

Retrospective Cohort Studies

Background: Metformin has been associated with improved survival outcomes in various malignancies. However, observational studies in head and neck cancer are inconsistent. Objective: The study aimed to summarize and quantify the relationship between metformin use and the survival of head and neck cancer. Methods: A meta-analysis based on cohort studies was systematically conducted (published up to Jan 18, 2020), identified from PubMed, Embase, Web of Science, Cochrane Library, Google Scholar, and Scopus databases. Summary hazard ratios (HR) and 95% confidence intervals (CI) were calculated using a random-effects model. Results: Seven retrospective cohort studies including 3,285 head and neck cancer patients were included. The association between the use of metformin and cancer survival was not statistically significant: summarized HR of 0.89 (95% CI 0.66-1.18, P=0.413, I2=64.0%) for overall survival, summarized HR of 0.65 (95% CI 0.31-1.35, P=0.246, I2=60.3%) for disease-free survival, and summarized HR of 0.69 (95% CI 0.40-1.20, P=0.191, I2=73.1%) for disease-specific survival. Conclusion: In this meta-analysis of 7 retrospective cohort studies, there was not a statistically significant association between the use of metformin and better survival for head and neck cancer. However, the analysis may have been underpowered. More studies of prospective designs with larger sample sizes are needed to investigate the effect of metformin on the survival of head and neck cancer.

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Use of tumor volume as measured on F18FDG-PET/CT scan as a predictive biomarker for head and neck cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e17019 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e17019-e17019

Author(s):

Y. Choi ◽

M. Song ◽

Y. Seol ◽

B. Kwon ◽

H. Shin ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Treatment Response ◽

Neck Cancer ◽

Tumor Volume ◽

Disease Free Survival ◽

Metabolic Tumor Volume ◽

Free Survival ◽

Pet Ct ◽

Disease Free

e17019 Background: Functional imaging, PET and its fusion with anatomical modalities, PET/CT promise to improve detection and characteristic disease. The objective of this study was to evaluate metabolic tumor volume as measured on F-18 FDG-PET/CT and its association with treatment response and prognosis in patients with head and neck cancer. Methods: The study population consisted of patients received neoadjuvant chemotherapy for a maximum of three cycles followed by radiation therapy. Before treatment patients were taken FDG-PET/CT scan, SUVmax, tumor volume, metastasis were recorded. Results: We enrolled 59 patients with stage III ann IV head and neck cancer. The median age was 66 years (range 47–81). There were 32 patients with stage III and 27 with stage IV. The mean SUVmax was 8.8 (range, 1.478). The mean tumor volume was 21.3 cm3 (range, 0.2–170). There was no correlation between tumor volume and SUVmax (correlation coefficient 0.295). Higher SUVmax was not associated with an increased risk of lymph node and distant metastasis at diagnosis (p = 0.968). But higher tumor volume was associated with an increased risk of lymph node and distant metastasis at diagnosis (p = 0.063). The metabolic tumor volume as measured on PET/CT scans was predictor of treatment response and disease -free survival. The response rate were 84% (21/25) for an SUVmax <5.5, 55% (19/34) for an SUVmax > 5.5 (p = 0.038). The disease free survival were 31.1month for an SUVmax <5.5, 4.6months for an SUVmax > 5.5 (p = 0.025). Conclusions: The metabolic tumor volume as measured on F-18FDG-PET/CT is a predictive biomarker of treatment response and disease free survival for patients with head and neck cancer. No significant financial relationships to disclose.

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Pretreatment prognostic nutritional index as a prognostic marker in head and neck cancer: a systematic review and meta-analysis

Scientific Reports ◽

10.1038/s41598-021-96598-9 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Chih-Wei Luan ◽

Yao-Te Tsai ◽

Hsin-Yi Yang ◽

Kuan-Yin Chen ◽

Po-Hsien Chen ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Predictive Value ◽

Meta Analysis ◽

Prognostic Nutritional Index ◽

Cochrane Library ◽

Cancer Site ◽

Free Survival ◽

Nutritional Index

AbstractThe predictive value of the pretreatment prognostic nutritional index (PNI) for head and neck cancer (HNC) remains controversial. We conducted a meta-analysis to assess the predictive value of PNI in HNC patients. A systematic search through internet databases including PubMed, Embase, and Cochrane Library for qualified studies estimating the association of PNI with HNC patient survival was performed. Overall survival (OS), progression-free survival (PFS), disease-specific survival (DSS), disease-free survival (DFS) and distant metastasis-free survival (DMFS) data were collected and evaluated. A random-effects model was used to calculate the pooled hazard ratios (pHRs) and corresponding 95% confidence intervals (CIs). A total of 7815 HNC patients from 14 eligible studies were involved. Pooled analysis showed that low pretreatment PNI was correlated with poor OS (pHR: 1.93, 95% CI 1.62–2.30, p < 0.001), PFS (pHR: 1.51, 95% CI 1.19–1.92, p = 0.008), DSS (pHR: 1.98, 95% CI 1.12–3.50, p < 0.001), DFS (pHR: 2.20, 95% CI 1.66–2.91, p < 0.001) and DMFS (pHR: 2.04, 95% CI 1.74–2.38, p < 0.001). Furthermore, low pretreatment PNI was correlated with poor OS despite variations in the cancer site, sample size, PNI cut-off value, analysis method (multivariate analysis or univariate analysis) and treatment modality in subgroup analysis. Elevated pretreatment PNI is correlated with a superior prognosis in HNC patients and could be used as a biomarker in clinical practice for prognosis prediction and treatment stratification.

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Efficacy of adjuvant chemotherapy for patients with resectable head and neck cancer: a subset analysis of the Head and Neck Contracts Program.

Journal of Clinical Oncology ◽

10.1200/jco.1990.8.5.838 ◽

1990 ◽

Vol 8 (5) ◽

pp. 838-847 ◽

Cited By ~ 103

Author(s):

C Jacobs ◽

R Makuch

Keyword(s):

Head And Neck Cancer ◽

Adjuvant Chemotherapy ◽

Head And Neck ◽

Induction Chemotherapy ◽

Neck Cancer ◽

Standard Therapy ◽

Disease Free Survival ◽

Free Survival ◽

N2 Disease ◽

Disease Free

To evaluate the efficacy of adjuvant chemotherapy for patients with advanced head and neck squamous cancer, the Head and Neck Contracts Program conducted a three-arm study comparing standard surgery and radiation, induction chemotherapy (cisplatin and bleomycin) plus standard therapy, and induction chemotherapy plus standard therapy followed by maintenance cisplatin for 6 months. As previously reported, this trial of 462 patients demonstrated no significant difference in disease-free survival or survival, but a significantly lower metastatic rate in the maintenance arm. To determine whether particular subgroups may have benefited from adjuvant therapy, we evaluated results based on primary site, and tumor (T) and node (N) stage. Of the 192 patients with oral cavity cancer, those on the maintenance arm had a significantly improved 3-year disease-free survival (67%) compared with the standard arm (49%) or induction arm (44%) (overall P = .05). For hypopharyngeal and laryngeal cancers there was no marked overall benefit. For the 106 patients with T1 plus T2 disease, there was marginal improvement in disease-free survival for the maintenance group (72%) compared with the standard group (47%) or induction group (43%) (overall P = .09). There was no advantage for patients with T3 and T4 disease. There was superior disease-free survival for patients with N1 disease on the maintenance arm (70%) compared with the standard arm (42%) (P = .024). The same was true for disease-free survival in 109 patients with N2 disease: standard (52%), induction (30%), maintenance (84%) (overall P less than .001). There was no benefit for N3 disease. A significant survival advantage with maintenance chemotherapy was only seen for N2 disease (overall P = .04). Since head and neck cancer patients are a heterogeneous group, there may be particular sites and stages for which adjuvant chemotherapy would be advantageous, and subset analysis can help indicate directions for new trials.

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Adaptive Radiotherapy for Head and Neck Cancer

Technology in Cancer Research & Treatment ◽

10.1177/1533034616662165 ◽

2016 ◽

Vol 16 (2) ◽

pp. 218-223 ◽

Cited By ~ 22

Author(s):

Murat Surucu ◽

Karan K. Shah ◽

John C. Roeske ◽

Mehee Choi ◽

William Small ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Tumor Volume ◽

Reduction Rate ◽

Disease Free Survival ◽

Volume Reduction ◽

Free Survival ◽

Original Plan ◽

Tumor Volume Reduction

Objective: To investigate the effects of adaptive radiotherapy on dosimetric, clinical, and toxicity outcomes for patients with head and neck cancer undergoing chemoradiotherapy with intensity-modulated radiotherapy. Methods: Fifty-one patients with advanced head and neck cancer underwent definitive chemoradiotherapy with the original plan optimized to deliver 70.2 Gy. All patients were resimulated at a median dose of 37.8 Gy (range, 27.0-48.6 Gy) due to changes in tumor volume and/or patient weight loss (>15% from baseline). Thirty-four patients underwent adaptive replanning for their boost planning (21.6 Gy). The dosimetric effects of the adaptive plan were compared to the original plan and the original plan copied on rescan computed tomography. Acute and late toxicities and tumor local control were assessed. Gross tumor volume reduction rate was calculated. Results: With adaptive replanning, the maximum dose to the spinal cord, brain stem, mean ipsilateral, and contralateral parotid had a median reduction of −4.5%, −3.0%, −6.2%, and −2.5%, respectively (median of 34 patients). Median gross tumor volume and boost planning target volume coverage improved by 0.8% and 0.5%, respectively. With a median follow-up time of 17.6 months, median disease-free survival and overall survival was 14.8 and 21.1 months, respectively. Median tumor volume reduction rate was 35.2%. For patients with tumor volume reduction rate ≤35.2%, median disease-free survival was 8.7 months, whereas it was 16.9 months for tumor volume reduction rate >35.2%. Four patients had residual disease after chemoradiotherapy, whereas 64.7% (20 of 34) of patients achieved locoregional control. Conclusion: Implementation of adaptive radiotherapy in head and neck cancer offers benefits including improvement in tumor coverage and decrease in dose to organs at risk. The tumor volume reduction rate during treatment was significantly correlated with disease-free survival and overall survival.

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Postoperative Bio-Chemoradiotherapy Using Cetuximab and Docetaxel in Patients With Cis-Platinum�Intolerant Core High-Risk Head and Neck Cancer: Protocol of a Phase 2 Nonrandomized Clinical Trial (Preprint)

10.2196/preprints.11003 ◽

2018 ◽

Author(s):

Goshi Nishimura ◽

Hiromitsu Hatakeyama ◽

Osamu Shiono ◽

Masataka Taguri ◽

Masanori Komatsu ◽

...

Keyword(s):

Head And Neck Cancer ◽

High Risk ◽

Head And Neck ◽

Neck Cancer ◽

Disease Free Survival ◽

Positive Margin ◽

Phase 2 ◽

Free Survival ◽

Number Of Patients ◽

Disease Free

BACKGROUND We confirmed the safety of postoperative bio-chemoradiotherapy using cetuximab and docetaxel in a small number of patients with cis-platinum–intolerant core high-risk head and neck cancer. OBJECTIVE To assess treatment efficacy, we planned a phase 2 study of postoperative bio-chemoradiotherapy for patients with cis-platinum–intolerant core high-risk head and neck cancer and will compare the results to those of previously collected radiotherapy data. METHODS Patients who underwent definitive surgery for oral cavity, laryngeal, oropharyngeal, or hypopharyngeal advanced cancer, whose postoperative pathological results indicated core high risk for recurrence (eg, positive margin in the primary site or extranodal extension) and who were cis-platinum–intolerant, will undergo postoperative bio-chemoradiotherapy. The primary end point is 2-year disease-free survival. RESULTS The expected 2-year disease-free survival is set at 55%, and the calculated sample size is 35 patients, according to a statistical analysis based on previous reports. CONCLUSIONS This treatment method is expected to improve the survival rate of patients with severe head and neck cancer. CLINICALTRIAL UMIN Clinical Trials Registry UMIN000031835; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ ctr_view.cgi?recptno=R000036355 (Archived by WebCite at http://www.webcitation.org/71fejVjMr)

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Aberrant Epigenetic Regulation in Head and Neck Cancer Due to Distinct EZH2 Overexpression and DNA Hypermethylation

10.20944/preprints201810.0565.v1 ◽

2018 ◽

Author(s):

Daiki Mochizuki ◽

Yuki Misawa ◽

Hideya Kawasaki ◽

Atsushi Imai ◽

Shiori Endo ◽

...

Keyword(s):

Head And Neck Cancer ◽

Rna Interference ◽

Head And Neck ◽

Neck Cancer ◽

Univariate Analysis ◽

Disease Free Survival ◽

Rank Test ◽

Dna Hypermethylation ◽

Free Survival ◽

Disease Free

EZH2 overexpression is associated with tumor proliferation, metastasis, and poor prognosis. Targeting and inhibiting EZH2 may be an effective therapeutic strategy for head and neck squamous cell carcinoma (HNSCC). We previously analyzed EZH2 mRNA expression in a well-characterized dataset of 230 (110 original and 120 validation cohorts) human head and neck cancer samples. This study aimed to investigate the effects of inhibiting EZH2, either via RNA interference or via pharmacotherapy, on HNSCC growth. EZH2 upregulation was significantly correlated with recurrence (P < 0.001) and the methylation index of tumor suppressor genes (P < 0.05). DNMT3A was significantly upregulated upon EZH2 upregulation (P = 0.043). Univariate analysis revealed that EZH2 upregulation was associated with poor disease-free survival (log-rank test, P < 0.001). In multivariate analysis, EZH2 upregulation was evaluated as a significant independent prognostic factor of disease-free survival (hazard ratio: 2.085, 95% confidence interval: 1.390–3.127; P < 0.001). Cells treated with RNA interference and DZNep, an EZH2 inhibitor, showed the most dramatic changes in expression, accompanied with a reduction in the growth and survival of FaDu cells. These findings suggest that EZH2 upregulation is correlated with tumor aggressiveness and adverse patient outcomes in HNSCC. Evaluation of EZH2 expression might help predict the prognosis of HNSCC patients.

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Role of concurrent chemoradiotherapy in organ preservation for locally advanced head and neck cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.e17044 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. e17044-e17044

Author(s):

N. Savaraj ◽

V. Dinh ◽

L. Chua ◽

P. Bustillo ◽

K. Nissim

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Concurrent Chemoradiotherapy ◽

Locally Advanced ◽

Disease Free Survival ◽

Hypopharyngeal Cancer ◽

Advanced Head ◽

Free Survival ◽

Disease Free

e17044 Background: Optimal management for head and neck cancer is controversial. Standard of care has been surgery followed by radiotherapy, but is done with the risk of organ resection. The VA larynx study, EORTC 24891, and 91–11 US Intergroup trial have shown that chemoradiotherapy is comparable to surgery with radiotherapy in laryngeal cancers while preserving organ function. It is unclear, though, whether this could be accomplished in other tumor sites without sacrificing locoregional control and/or survival. Methods: We performed a retrospective chart review of patients who were treated at the Miami VA Medical Center with chemoradiotherapy for advanced staged head and neck cancers from 1996 to 2008. The majority of patients (84%) received 5FU and cisplatin. The choice of chemoradiotherapy was either determined by patients’ choice or their comorbidities, such as pulmonary disease and cardiac disease, precluded them from undergoing major surgery. Primary endpoints included death, relapse rates, and disease-free survival; secondary endpoints were toxicities associated with treatment and diminished organ function. Results: A total of 62 patients were included. Out of these patients, 52% had stage III disease and 50% had primary sites in the oropharynx; the remaining included larynx and hypopharynx. 20% of patients required salvage neck dissection. Complications included severe mucositis (69%), dysphagia (19% short term, 34% long term), hoarseness (13%), and dry mouth (24%). 27% had relapse of disease and median time for disease-free survival was 26 months. A total of 35 patients had died with a 2-year survival rate of 59.6%. Overall survival was best for laryngeal and oropharyngeal cancer (63 and 46 months, respectively) compared to hypopharyngeal cancer (22 months). Conclusions: Concurrent chemoradiotherapy is a valid option for treatment of locally advanced head and neck cancers especially for laryngeal and possibly oropharyngeal primaries with significant but tolerable toxicities. Although organ preservation is possible for the majority of patients with locally advanced head and neck cancer, however, the poor survival seen in hypopharyngeal cancer needs further investigation. No significant financial relationships to disclose.

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A randomized trial of adjuvant chemotherapy in head and neck cancer.

Journal of Clinical Oncology ◽

10.1200/jco.1985.3.5.672 ◽

1985 ◽

Vol 3 (5) ◽

pp. 672-679 ◽

Cited By ~ 95

Author(s):

S G Taylor ◽

E Applebaum ◽

J L Showel ◽

M Norusis ◽

L D Holinger ◽

...

Keyword(s):

Overall Survival ◽

Head And Neck Cancer ◽

Adjuvant Chemotherapy ◽

Head And Neck ◽

Induction Chemotherapy ◽

Neck Cancer ◽

Disease Free Survival ◽

Free Survival ◽

Regional Therapy ◽

Disease Free

Ninety-five patients with squamous cell carcinoma of the head and neck were entered into a randomized study testing a two-week course of induction chemotherapy with methotrexate and leucovorin given prior to regional therapy. In addition, following regional therapy, patients randomized to chemotherapy were to receive similar methotrexate courses every three months for one year. Poor tolerance to this regimen after radiation and surgery led to a change in the chemotherapy following regional therapy to a combination of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin every three weeks for four cycles after the first 35 patients had been entered. Nine cases were ineligible and four lacked any follow-up data, leaving 82 analyzable cases. Using Cox regression analysis, no differences in the percentage of patients achieving disease control, the relapse-free survival, or the overall survival were identified between any treatment group. As has been described in many pilot studies of induction chemotherapy of head and neck cancer, chemotherapy responders had a more favorable disease-free survival than chemotherapy nonresponders in the total group of patients receiving adjuvant chemotherapy. However, correcting for imbalances in the expected three year disease-free survival of these patients, based on their disease site and stage, erased this difference, indicating tumor response to this regimen of chemotherapy is not an independent factor affecting disease outcome. The division of patients into arbitrary prognostic categories based on the expected outcome for each specific tumor site and stage proved to be a useful method for balancing treatment groups, given the multiple site-stage combinations within the upper aerodigestive tract. The defined prognostic categories were the single most sensitive predictors of relapse-free and overall survival.

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