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Efficacy of Induction Selection Chemotherapy vs Primary Surgery for Patients With Advanced Oral Cavity Carcinoma
Abstract
Importance
The University of Michigan has investigated the use of induction selection (IS) with chemoradiotherapy (CRT) for patients who respond to CRT and found this approach effective in the management of advanced laryngeal cancer. The IS approach was extended to oral cavity squamous cell carcinoma (OCSCC) to help understand whether organ preservation or survival benefit resulted.Objective
To evaluate the efficacy of an IS protocol vs primary surgical extirpation and selective postoperative radiotherapy for advanced OCSCC.Design and Setting
Retrospective matched cohort study at a tertiary care hospital.Participants
Nineteen patients with resectable stages III and IV OCSCC were enrolled into a phase 2 IS trial. Patients with a response of at least 50% underwent concurrent CRT; those with a response of less than 50% underwent surgical treatment and radiotherapy. A comparison cohort of patients treated with primary surgical extirpation during a similar time period was frequency matched for inclusion criteria and patient characteristics to those patients included from the phase 2 IS trial. No difference was noted in age, sex, pretreatment American Joint Committee on Cancer stage, T and N classifications, smoking status, alcohol consumption, or tumor subsite between the IS and surgical cohorts. Median follow-up was 9.4 years in the IS cohort and 7.1 years in the surgical cohort.Interventions
Induction selection and CRT vs primary surgical extirpation with or without postoperative radiotherapy.Main Outcomes and Measures
Overall and disease-specific survival and locoregional control.Results
The Kaplan-Meier estimate for overall survival at 5 years was 32% in the IS cohort and 65% in the surgical cohort. The Kaplan-Meier estimate for disease-specific survival at 5 years was 46% in the IS cohort and 75% in the surgical cohort. The Kaplan-Meier estimate for locoregional control at 5 years was 26% in the IS cohort and 72% in the surgical cohort. Multivariable analysis demonstrated significantly better overall and disease-specific survival and locoregional control outcomes (P = .03, P = .001, and P < .001, respectively) in the surgical cohort.Conclusions and Relevance
Primary surgical treatment showed significantly better survival and locoregional control compared with IS in this matched patient cohort. Despite success of organ preservation IS protocols in the larynx, comparative survival analysis of an IS protocol vs primary surgical extirpation for OCSCC demonstrates significantly better outcomes in the surgical cohort. These findings support surgery as the principal treatment for OCSCC.
... S. Chinn и соавт. [7] в работе, посвященной индукционной химиотерапии (ИХТ), сравнили отдаленные результаты лечения 2 групп пациентов. В 1-й группе (ИХТ + ЛТ ± операция) лечение начиналось с ИХТ по схеме PF (цисплатин и 5-фторурацил), далее, при эффекте лечения более 50 %, проводилась ЛТ до суммарной очаговой дозы (СОД) 70 Гр с одновременным введением цисплатина (100 мг/м 2 ) или карбоплатина (AUC = 6,0) 1 раз в 3 нед. ...
... Общая 5-летняя выживаемость составила 32 % в 1-й группе и 65 % во 2-й, а 5-летняя выживаемость без прогрессирования -46 % в 1-й группе и 75 % во 2-й. Достигнутые различия были статистически достоверны [7]. ...
... Так, по данным N. Al-Rajhi и соавт. [11], при лечении ранних стадий рака СОПР (T1-2N0M0) с хирургическим вмешательством на I этапе и применении послеоперационного облучения (при наличии отягчающих прогноз патоморфологических критериев) общая 5-летняя выживаемость равнялась 71 %, выживаемость без прогрессирования -63 % [7]. По данным I. Ganly и соавт. ...
Introduction. The issue of selecting treatment strategy for сT2N0M0 cancer of the oral mucosa remains relevant. Induction chemotherapy (applied in order to evaluate the possibility of organ-preserving chemoradiotherapy) is widely used in clinical practice. In this case, surgical treatment is performed only when chemotherapy (CT) is ineffective or a residual tumor is detected after chemoradiotherapy (CRT). However, many specialists recommend surgical treatment on the first stage of treatment.Objective: evaluation of the induction chemotherapy feasibility in the treatment of T2N0M0 cancer of the oral mucosa.Materials and methods. A total of 122 patients with primary Т2N0М0 cancer of oral mucosa without regional metastases (according to clinical examination) were included in the study.Results. In order to determine the best treatment strategy, we have compared treatment outcomes in three groups of patients. The most favorable outcomes were observed in the group of patients receiving combined treatment according to a scheme «surgery + radiotherapy (RT)/ CRT, where the overall 5-year survival rate and the progression-free 5-year survival rate were 70.4 % and 68.5 % respectively. Survival rate in this group was significantly higher (р < 0.05) than that in the group «induction CT (ICT) ± RT ± surgery» where these parameters comprised 42.2 % and 36.2 % respectively.Conclusion. Combined treatment with a surgery on the first stage followed by RT or CRT ensures better outcomes of the cancer of the oral mucosa than the strategies that include ICT.
... The answers were still not clear even after a lot of studies including randomized clinical trials and meta-analysis. [7][8][9][10][11] In addition, there are still few studies investigating the influence of NCT on the following surgery. Can we perform a limited surgery after NCT? Will it affect the surgical margins and prognosis? ...
... TPF regimen was reported with the highest good response rate as 94%. 7,8,13,14 A good response rate in this study was around 66% (21/32). In order not to affect the following surgery, the dosage of docetaxcel was reduced (60 mg/m 2 intravenously on day 1) to prevent from severe neutropenia. ...
Aim
The role of neoadjuvant chemotherapy (NCT) in the treatment of advanced oral squamous cell carcinoma (OSCC) is still controversial. Especially, there are still few studies investigating the influence of NCT on the following surgery. In this retrospective single-center attended cohort study, we investigated the oncological effect of NCT and its influence on the following surgery in patients with resectable locally advanced OSCC.
Method
The clinical data of 88 patients with locally advanced but resectable OSCC (T3/4) were reviewed retrospectively. NCT plus conservative surgery and radical surgery were compared. Five-year disease-specific survival (DSS) was observed as the main endpoint.
Results
Among 88 patients enrolled in this study, 56 patients received upfront radical surgery (non-NCT group) and 32 patients received NCT followed by surgery (NCT group). The patients in the non-NCT group had a statistically better DSS than the patients in the NCT group (P=0.041). Twenty-one out of 32 (65.6%) patients who received NCT were good responders including two patients (6.2%) had a complete response and 19 patients (59.4%) had a partial response. There was no statistical difference between good and poor responders in 5-year DSS (P=0.823). Eleven patients (34.4%) had conservative surgery without flap reconstruction and 21 patients had radical surgery with flap reconstruction after NCT. No statistical difference in surgical margins was found between the two types of surgery (P=0.519). There was also no statistical difference in 5-year DSS between the two types of surgery (P=0.652).
Conclusion
NCT plus surgery could not improve survival compared with upfront surgery. NCT could modify the surgical extent but would not affect the surgical margins. This conclusion should be explained cautiously, and randomized clinical trials with large sample size were needed to further answer the question.
... Although neoadjuvant therapy has been suggested, several induction chemotherapy protocols have shown no efficacy over surgery alone. [29][30][31] In contrast, more extensive resections and longer operation time may be required for patients that receive neoadjuvant chemotherapy. 32 In addition, neoadjuvant therapies may interfere with later chemotherapeutic agents. ...
A complete resection of tongue cancer is often difficult. We investigate the usefulness of administering G47Δ (teserpaturev), a triple-mutated oncolytic herpes simplex virus type 1, prior to resection. G47Δ exhibits good cytopathic effects and replication capabilities in all head and neck cancer cell lines tested. In an orthotopic SCCVII tongue cancer model of C3H/He mice, an intratumoral inoculation with G47Δ significantly prolongs the survival. Further, mice with orthotopic tongue cancer received neoadjuvant G47Δ (or mock) therapy with or without "hemilateral" resection, the maximum extent avoiding surgical deaths. Neoadjuvant G47Δ and resection led to 10/10 survival (120 days), whereas the survivals for G47Δ alone and resection alone were 6/10 and 5/10, respectively: all control animals died by day 11. Furthermore, 100% survival was achieved with neoadjuvant G47Δ therapy even when the resection area was narrowed to "partial," providing insufficient resection margins, whereas hemilateral resection alone caused death by local recurrence in half of the animals. G47Δ therapy caused increased number of tumor-infiltrating CD8+ and CD4+ cells, increased F4/80+ cells within the residual tongues, and increased expression of immune-related genes in and around the tumor. These results imply that neoadjuvant use of G47Δ is useful for preventing local recurrence after tongue cancer surgery.
... A 2017 National Cancer Database study comparing surgery followed by adjuvant therapy compared to concurrent chemoradiation showed better overall survival with the former treatment. [13] A 2014 study by Chinn et al. [14] compared IC followed by concurrent chemoradiation with surgery followed by adjuvant therapy. Improved overall survival, disease-specific survival, and locoregional control were associated with the latter. ...
Management of locally advanced OSCC is multimodal. No single therapy has been proved to be efficacious. However there is a trend towards surgical intervention in operable disease. In this review we appraise the various therapies used for the management of locally advanced OSCC. We review the literature with regards to the various treatment options for locally advanced OSCC. We categorically divided the manuscript into resectable, unresectable and technically unresectable disease. Surgery is the ideal treatment modality for resectable disease. For unresectable disease concurrent chemoradiation appears to improve survival compared to radiotherapy alone. Induction therapy might downstage tumors in the unresectable category. Targeted and Immunotherapy is reserved for recurrent, metastatic or platinum refractory OSCC. Management of locally advanced OSCC is multimodal with surgery playing the primary role. In the event where the tumor is in operable concurrent chemoradiotherapy is regarded as the best treatment modality. Induction chemotherapy currently cannot be recommended for resectable or even unresectable oral squamous cell carcinomas. However for technically unresectable disease it might play a role in improving respectability but it depends on the response of the tumor. Targeted therapy and immunotherapy is currently used for recurrent, metastatic and/or platinum refractory Head and Neck cancers. Currently it is not recommended for initial management of locally advanced disease.
... The annual rate of head and neck cancer (HNC) in the United States exceeds 66 000 cases resulting in over 14 000 associated deaths per year. 1 Surgery and/or radiotherapy remain principal management strategies for HNC. [2][3][4] However, despite optimal management, long-term survival rates remain low and prognosis is particularly poor in certain sociodemographic groups. Several social determinants of health have been independently associated with worse cancer control in HNC. ...
Background:
Despite the importance of immune response and environmental stress on head and neck cancer (HNC) outcomes, no current pre-clinical stress model includes a humanized immune system.
Methods:
We investigated the effects of chronic stress induced by social isolation on tumor growth and human immune response in subcutaneous HNC tumors grown in NSG-SGM3 mice engrafted with a human immune system.
Results:
Tumor growth (p < 0.0001) and lung metastases (p = 0.035) were increased in socially isolated versus control animals. Chronic stress increased intra-tumoral CD4+ T-cell infiltrate (p = 0.005), plasma SDF-1 (p < 0.0001) expression, and led to tumor cell dedifferentiation toward a cancer stem cell phenotype (CD44+ /ALDHhigh , p = 0.025).
Conclusions:
Chronic stress induced immunophenotypic changes, increased tumor growth, and metastasis in HNC in a murine model with a humanized immune system. This model system may provide further insight into the immunologic and oncologic impact of chronic stress on patients with HNC.
... Chinn et al reported their Phase II experience: those who responded were treated with induction chemotherapy followed by definite simultaneous CRT, and those who did not respond were subsequently excised. 46 Outcomes in this induced-selection cohort proved to be poor compared to patient cohort who underwent early surgery and appropriate adjuvant RT /CRT. Patil reported that induction chemotherapy before reassessment for surgery could be a suitable replacement of concurrent chemoradiation in borderline resectable or technically unresectable oral cancers. ...
Objective:
We aimed to identify new prognostic factors of oral squamous cell carcinoma (OSCC) among platelet-related parameters, establish a survival prediction model to predict the survival status of OSCC patients, and analyze the therapeutic effect of neoadjuvant chemotherapy on OSCC patients on the basis of real-world data.
Materials and methods:
The real-world data of patients with OSCC confirmed by pathologic examination at Cancer Hospital from January 2011 to January 2015 and May 2017 to January 2020 were collected. We analyzed clinicopathologic factors using a Cox regression analysis, the Kaplan-Meier method, and propensity score matching (PSM).
Results:
The multivariate Cox regression analysis of not only validated the traditional prognostic factors such as tumor site, neural invasion, poor differentiation, and tumor-node-metastasis (TNM) stage but also identified a new prognostic factor, preoperative mean platelet volume (MPV) for overall survival (OS, HR, 0.47; 95% CI: 0.25-0.89, P = 0.020). A nomogram was created to predict the probability of 3-year and 5-year OS. We found that neoadjuvant chemotherapy improved OS in patients with OSCC.
Conclusion:
Preoperative MPV, being associated with female, neoadjuvant chemotherapy, and advanced stage (Stage III and IV), may be a new prognostic factor for OS of patients with OSCC. The nomograms provided useful prediction for OS in OSCC patients. Neoadjuvant chemotherapy may improve the OS of patients with OSCC.
... The major causative factors are smokeless tobacco and betel nut in Asian population whereas cigarette smoking and alcohol in Western population [3,4]. Surgery is the mainstay of treatment for early stage cancers [5]. ...
Background:
Nimotuzumab is a monoclonal antibody against epidermal growth factor receptor which can be combined with chemotherapy and radiotherapy for the treatment of locally advanced unresectable squamous cell carcinoma of head-and-neck region and its role has already been established in India.
Aim:
The aim of this case report is to show the role of nimotuzumab in carcinoma hypopharynx.
Methods:
We report a patient with Stage III carcinoma of hypopharynx, who received radiotherapy along with weekly nimotuzumab due to his comorbidities. The patient had tolerated the treatment very well without any major side effects.
Results:
The patient is on regular follow-up with a complete response (CR) of the disease and with the disease-free interval (DFI) of 7 months.
Conclusions:
Nimotuzumab along with radiotherapy can be safely given in the patients with carcinoma hypopharynx, who are ineligible for chemotherapy.
Relevance for patients:
Nimotuzumab can be added with radiotherapy to the patients with head-and-neck malignancies who are ineligible for chemotherapy to improve the clinical outcome with minimal toxicity.
... In patients who respond to initial induction chemotherapy, definitive CCRT would avoid and preserve the use of surgical treatment. However, only a single contemporary study was included in this review 47 , which did not demonstrate survival benefit with the use of induction chemoselection. While over half of patients receiving induction chemoselection had an initial response, this strategy was associated with worse survival than definitive surgery with risk informed adjuvant treatment. ...
Objective: Surgery is the preferred treatment modality for oral squamous cell carcinoma (OSCC). However, due to limited resources, re-assessment of treatment paradigms in the wake of the Coronavirus Disease 2019 (COVID-19) pandemic is urgently required. In this rapid review, we described contemporary oncological outcomes for OSCC using non-surgical modalities.
Methods: A systematic literature search was conducted for articles published between January 1, 2010 and April 1, 2020 on MEDLINE and Cochrane CENTRAL. Studies were included if they contained patients with OSCC treated with either neoadjuvant, induction, or definitive radiotherapy, chemotherapy, immunotherapy, or combination thereof, and an outcome of overall survival.
Results: In total, 36 articles were identified. Definitive radiotherapy or chemoradiotherapy were the focus of 18 articles and neoadjuvant chemotherapy or chemoradiotherapy were the focus of the other 18 articles. In early stage OSCC, definitive radiotherapy, with or without concurrent chemotherapy, was associated with a significantly increased hazard of death compared to definitive surgery (HR: 2.39, 95% CI: 1.56 - 3.67, I2: 63%). The hazard of death was non-significantly increased with definitive chemoradiotherapy in studies excluding early disease (HR: 1.98, 95% CI: 0.85 - 4.64, I2: 84%). Two recent randomized control trials have been conducted, demonstrating no survival advantage to neoadjuvant chemotherapy.
Conclusion: This review suggests that primary radiotherapy and chemoradiotherapy are inferior to surgical management for OSCC. Strategies for surgical delay warranting consideration are sparse, but may include several neoadjuvant regimens, recognizing these regimens may not offer a survival benefit over definitive surgery alone.
... 7 Up-front surgery for oral cavity cancer has a substantial survival benefit compared to radiation-based treatment in a small randomized trial 8 and a single-institution retrospective study. 9 Despite known racial disparities in survival and the likelihood of being recommended surgery for oral cavity cancer specifically, [2][3][4] no studies, to our knowledge, have examined whether racial disparities exist in actual treatment received. The purpose of this study was to evaluate contemporary racial disparities in both management recommendations for surgery and actual treatment received for oral cavity SCCs alone in the context of overall survival (OS) using the National Cancer Database (NCDB). ...
Background
Definitive surgery is recommended for oral cavity squamous cell carcinoma (SCC). The purpose of this study was to present our assessment of the disparities in treatment selection for oral cavity SCC.
Methods
Non‐Hispanic white and non‐Hispanic black patients with oral cavity SCC were identified in the National Cancer Database (NCDB). Regression models were used to estimate relative risk (RR) of receiving surgery and absolute difference between non‐Hispanic white and non‐Hispanic black patients.
Results
There were 82.3% of non‐Hispanic white patients who received surgery, compared to 64.2% of non‐Hispanic black patients (P < .001). The non‐Hispanic black patients were less likely to receive surgery than non‐Hispanic white patients (RR 0.87) with an absolute difference of 10.9%. The non‐Hispanic black patients were significantly more likely to not be offered surgery (RR 1.42) and to refuse recommended surgery (RR 1.38) but not have a contraindication to surgery (RR 1.17).
Conclusion
The non‐Hispanic black patients are less likely to receive or be recommended surgery for oral cavity SCC and are more likely to refuse surgery. Further study is needed to identify strategies to close this disparity.
... Few retrospective studies evaluated the results of the OCC cohorts from these trials showing similar efficacy in terms of survival when compared to surgery followed by perioperative RT or CRT, with PFS and OS rates ranging from 50% to 80% and 35% to 70% at 5 years, respectively [55][56][57]. Efficacy was maintained across stage III and IV and in patients with cartilage or bone invasion [55,61], but acute Table 2 Summary of recommendations for OPC and OCC. and late toxicity across the studies was remarkable, especially ORN, with rates ranging between 10% and 20% [53,54,62]. In two phase III trials, ICT did not improve rates of survival or distant metastases when compared to surgery plus postoperative CRT [60,61], but responders had improved outcomes, and some patients with T4 tumors might avoid total glossectomy [58,59]. ...
Head and neck cancer is one of the most frequent malignances worldwide. Despite the site-specific multimodality therapy, up to half of the patients will develop recurrence. Treatment selection based on a multidisciplinary tumor board represents the cornerstone of head and neck cancer, as it is essential for achieving the best results, not only in terms of outcome, but also in terms of organ-function preservation and quality of life. Evidence-based international and national clinical practice guidelines for head and neck cancer not always provide answers in terms of decision-making that specialists must deal with in their daily practice. This is the first Expert Consensus on the Multidisciplinary Approach for Head and Neck Squamous Cell Carcinoma (HNSCC) elaborated by the Spanish Society for Head and Neck Cancer and based on a Delphi methodology. It offers several specific recommendations based on the available evidence and the expertise of our specialists to facilitate decision-making of all health-care specialists involved.
... ic, treatment, and survival data in their study.Chinn et al.[15] studied 19 patients with resectable stages III and IV of OSCC. They determined age, gender, pretreatsion was carried out in all patients. ...
Statement of the problem:
Neoadjuvant chemotherapy (NCH) is controversial in the treatment of oral squamous cell carcinoma (OSCC).
Purpose:
The aim of this study was to evaluate the efficacy of NCH on OSCC prognosis.
Materials and method:
In this retrospective cohort study, 94 patients were studied in two groups. The patients in group 1 received NCH before the surgery, and those in group 2 underwent resection without any chemotherapy prior to surgery. The employed NCH agents consisted of cisplatin in combination with 5-fluorouracil in two treatment courses. Tumor size, lymph node involvement, age, and follow-up time were considered as variable factors of the study. Local recurrence (LR) and distant metastasis (DM) were outcomes of the study.
Results:
Comparison of LR and DM in various tumor sizes demonstrated no significant difference between the two groups (p> 0.05). Analysis of the data did not show any statistically significant difference between the groups for LR in subjects with N0, N1 and N2. Each one-year increase in age was associated with 10% increase in the hazard ratio (HR) (HR distance metastasis Y/N = 1.10, p= 0.05). In the same analysis, when considering LR as a dependent factor, LR risk in N2 was 3 times more than in N1 (p= 0.02). LR risk in N3 was 5 times more than in N1 [HR local recurrence (p= 0.006).
Conclusion:
Based on our results, neoadjuvant chemotherapy with combination of cisplatin and 5-fluorouracil may not improve prognosis of OSCC. However, further studies are suggested to assess other neoadjuvant chemotherapy protocols in OSCC patients.
... HNSCC is the principal histologic subtype of this disease, accounting for >90% of all cases [3]. For patients in early stage of HNSCC, the principal treatment is survey [4]. However, approximately two-thirds of HNSCC patients suffer loco-regionally advanced disease and untreatable by surgery. ...
Purpose:
Brachytherapy is a form of targeted radiation therapy and has shown good short-term efficacy in clinical practice. The purpose of this clinical trial was to determine the feasibility and safety of radioactive iodine 125 seeds implantation concomitantly with chemotherapy with docetaxel, cisplatin, 5-fluorouracil (TPF) in patients with head and neck squamous cell carcinoma (HNSCC).
Methods:
A total of 23 previously untreated patients with histologically documented advanced unresectable HNSCC underwent percutaneous interstitial implantation of radioactive iodine 125 seeds, and simultaneously received 3 cycles of chemotherapy every 21 days (75 mg/m(2) docetaxel D1, 75 mg/m(2) cisplatin D1, and 750 mg/m(2) 5-fluorouracil D2-5). The treatment efficacy was evaluated based on tumor size and clinical symptoms of the patients.
Results:
The overall response rate was 78.3%. No acute complications and treatment-related radiation damages occurred. Two-year progression-free survival (PFS) 60.9% and overall survival (OS) 52.2% were achieved. Four patients (17.4%) died of cardiovascular causes and local disease recurrence.
Conclusion:
Brachytherapy based on iodine 125 seeds implantation given concomitantly with chemotherapy is a mildly invasive, effective and safe therapeutic approach for advanced HNSCC.
... In Taiwan, the smoking and betel nut chewing are the most key factors for oral cancer development ( Lin et al., 2014;Kao and Lim, 2015). The treatments of SCC consist of surgery, radiation and chemotherapy for clinical patients but the overall survival rate has not been better significantly in the last several decades ( Chinn et al., 2014). Cisplatin is the major chemotherapy for SCC but severe side effects and drug resistance are increasing in oral cancer after the cisplatin treatment ( Yamano et al., 2010;Pendleton and Grandis, 2013). ...
Epigallocatechin gallate (EGCG) is a green tea polyphenol that presents anticancer activities in multiple cancer cells, but no available report was addressed for the underling molecular mechanism of cytotoxic impacts on drug-resistant oral squamous cell carcinoma cells. In the present study, the inhibitory effects of EGCG were experienced on cisplatin-resistant oral cancer CAR cells. EGCG inhibited cell viability in a time- and concentration-dependent manner by a sulforhodamine B (SRB) assay. EGCG induced CAR cell apoptosis and autophagy by 4',6-diamidino-2-phenylindole (DAPI) dye, acridine orange (AO) staining and green fluorescent protein (GFP)-tagged LC3B assay, respectively. EGCG also significantly enhanced caspase-9 and caspase-3 activities by caspase activity assay. EGCG markedly increased the protein levels of Bax, cleaved caspase-9, cleaved caspase-3, Atg5, Atg7, Atg12, Beclin-1, and LC3B-II, as well as significantly decreased the expression of Bcl-2, phosphorylated AKT (Ser473) and phosphorylation of STAT3 on Tyr705 by western blotting in CAR cells. Importantly, the protein and gene expression of multidrug resistance 1 (MDR1) were dose-dependently inhibited by EGCG. Overall, downregulation of MDR1 levels and alterations of AKT/STAT3 signaling contributed to EGCG-induced apoptosis and autophagy in CAR cells. Based on these results, EGCG has the potential for therapeutic effect on oral cancer and may be useful for long-term oral cancer prevention in the future. © 2016 Wiley Periodicals, Inc. Environ Toxicol, 2016.
... The role of chemoradiation is limited in OCSCC and this need to be emphasized to the patients as well as to their immediate family members. A study by Chinn et al. comparing the induction chemotherapy versus primary surgical extirpation for advanced OCSCC demonstrated that primary surgical extirpation group had better overall survival, disease specific survival and less locoregional recurrence than the induction chemotherapy group [10]. Furthermore, the induction chemotherapy also tends to cause multiple Complementary and Alternative Medicine (CAM) not only widely practice in low and middle income countries but also in developed countries such as Australia, USA, France and Canada. ...
Introduction: Oral cavity carcinoma is a common tumor of head and neck with tongue carcinoma is the main site of involvement in South East Asia region. Majority of patients present late and prognosis is dismal despite optimal treatment.
To compare and evaluation of surgical operability with and without induction chemotherapy in locally advanced head and neck squamous cell carcinoma. Head and neck malignancy grossly refers to squamous cell carcinomas of head and neck (HNSCC) have multiple treatment modalities and strategies, when opted in an appropriate manner renders tumours curable. The aim of this study is to compare and evaluation of surgical operability with and without induction chemotherapy in locally advanced head and neck squamous cell carcinoma. A prospective observational study involving 50 patients of histologically proven squamous cell carcinoma of head and neck region. Patients were categorized into two major groups, group-1 patients included resectable tumour stage and group-2 included unresectable tumour stage. Both groups were compared after appropriate chemotherapy and surgical intervention. There were a total of 78% males and 22% females with majority of patients in age group of 41–60 years. 54% patients had ulcerative type of growth pattern and most patients had primary site of lesion in oral cavity. 50% patients had moderately differentiated squamous cell carcinoma. Induction chemotherapy was considered in 70% of patients, while majority of patients were belonging to T4N2M0 stage. In this study, we recommend that the borderline category of patients who are initially in an unresectable tumour stage can undergo induction chemotherapy to downstage and shrink the tumour to a resectable stage following which the appropriate surgical intervention should be done with a close monitoring and sustained follow up to prevent recurrence.
Head and neck cancer therapies often require multidisciplinary approaches. The cutting edge of treatment algorithms involve the intersection of surgery, radiotherapy, chemotherapies, and next-generation targeted therapies. As we develop new techniques, new applications for old technologies, and novel treatment approaches, treatments continue to evolve. We discuss several of these modalities, including primary surgery for oropharynx squamous cell carcinoma, the management of oligometastatic disease, evolving combination algorithms using immunotherapies, organ preservation techniques in advanced oral cavity cancer, and emerging uses for induction chemotherapy.KeywordsMultidisciplinary careTORSInduction chemotherapyImmunotherapyTargeted therapySABROligometastases
Objectives
The role of surgery for conventionally “unresectable” (cT4b) oral cavity squamous cell carcinoma is unclear. We analyzed factors associated with overall survival in cT4b relative to cT4a oral cavity squamous cell carcinoma.
Methods
We identified 6830 cT4a and 522 cT4b oral cavity squamous cell carcinoma chemoradiation or surgery + adjuvant therapy patients in the National Cancer Data Base from 2004 to 2016. The main outcome was overall survival. Statistical analysis was performed using chi-squared tests, univariable and multivariable regression analysis.
Results
The cT4b group had a higher rate of positive margins (30.4% vs 21.3%, P = .009) and downstaging (41.2% vs 13.1%; P < .001) compared to cT4a, while only 1.7% were upstaged. cT4b surgery + chemoradiation patients had similar survival to cT4a surgery + radiation (HR 0.93; 95% CI, 0.70-1.25) and cT4a surgery + chemoradiation patients (HR, 0.92; 95% CI, 0.69-1.23), while cT4b surgery + radiation patients had worse OS (HR, 1.55; 95% CI, 1.05-1.47).
Conclusions
Clinical T4b staging is a poor predictor of pathologic staging given a high rate of downstaging on final pathology. Surgical resection with adjuvant chemoradiation is an option in select cT4b oral cavity squamous cell carcinoma patients.
Lip and oral cavity squamous cell carcinoma (SCC) develop from progressive dysplasia of these mucosal structures. The cancers are often preceded by premalignant lesions, and any nonhealing ulcers of the lip or oral cavity should be biopsied. Some risk factors for these 2 subsites overlap and include tobacco use, alcohol use, and an immunocompromised state. Lip and oral cavity SCC are clinically staged based on physical examination and imaging. The 5-year overall survival for early-stage lip and oral cavity SCC is around 70% to 90% but decreases to about 50% for late-stage disease.
Background
Surgery with adjuvant radiotherapy is the accepted standard for treatment of advanced oral cavity squamous cell carcinoma (OCSCC); however, alternative evidence suggests that definitive (chemo)radiotherapy may have similar outcomes.
Methods
Systematic review was performed to assess the therapeutic value of radiotherapy or chemoradiotherapy as a primary modality for treating OCSCC. Meta-analysis of outcomes was performed between articles comparing radiotherapy and primary surgical treatment.
Results
Meta-analysis showed less favorable results of radiotherapy compared to surgery: overall survival at 3-years (odds ratio [OR] = 0.51; 95% confidence interval [CI] = 0.34–0.77) and 5-years (OR = 0.42; 95% CI = 0.29–0.60); disease-specific survival at 3-years (OR = 0.55; 95% CI = 0.32–0.96) and 5-years (OR = 0.55; 95% CI = 0.32–0.96). Odds of feeding tube dependency were higher in primary radiotherapy group (OR = 2.67; 95% CI = 1.27–5.64).
Conclusions
Results of this study support the current perspective favoring primary surgical treatment for OCSCC in the absence of surgical contraindications.
Background:
Patients with locoregionally advanced oral cavity squamous cell carcinoma (OCSCC) have a poor survival outcome. Treatment involves extensive surgery, adjuvant radiation, or chemoradiation and results in high morbidity. In this study, the authors' objective was to evaluate their experience with induction chemotherapy (IC) in the treatment of locoregionally advanced OCSCC.
Methods:
A retrospective review of the medical records of all patients with locoregionally advanced (stage III and IV) OCSCC who received IC followed by definitive local therapy was conducted. Outcomes included response to IC and survival.
Results:
In total, 120 patients were included in the study. The overall stage was stage IV in 79.2% of patients. After 2 cycles of IC, 76 patients (63.3%) achieved at least a partial response, including 13 who had a complete response. Stable disease was observed in 30 patients (25%), and 14 patients (11.7%) had progressive disease. Among responders, 16 patients received definitive chemoradiation or radiation therapy, and 60 underwent surgical resection, of whom 15 had less extensive surgery than was originally planned. Overall, organ preservation was achieved in 40.8% of patients who had a favorable response to IC. The 5-year overall and disease-specific survival rates were 51.4% and 66.9%, respectively. Patients who had at least a partial response had better 5-year overall survival (60.1%) and disease-specific survival (78.5%) compared with nonresponders (33.8% and 46.4%, respectively).
Conclusions:
The results demonstrate a response rate to IC in patients with advanced OCSCC similar to what has been observed in patients with cancer in other head and neck subsites. Patients who achieved at least a partial response to IC had a more favorable outcome, with ensuing organ preservation. Further studies are warranted.
Introduction and objectives
With the goal of achieving functional preservation, one of the treatment strategies for patients with locally advanced squamous cell carcinomas of the head and neck is to initiate treatment with induction chemotherapy (CT) and decide the second therapeutic manoeuvre depending on the response. The objective of this study is to evaluate organ preservation capacity based on this therapeutic approach in patients with tumours of the oral cavity and oropharynx.
Methods
A retrospective study of 246 patients with locally advanced carcinomas of the oral cavity or oropharynx (cT3-T4) initially treated with induction CT.
Results
After induction CT 28% of patients achieved a complete response of the primary location of the tumour, 43.1% a partial response greater than 50%, and 28.9% a reduction less than 50% or persistence. After the induction CT treatment 70 patients (28.5%) underwent surgical treatment, and 176 (71.5%) radiotherapy (RT) or chemoradiotherapy (CRT). Considering the patients treated non-surgically (n = 176), organ preservation for patients with a complete response (n = 66) was 65.2%, for those patients with a partial response greater than 50% (n = 75) it was 30.7%, and for patients with a partial response less than 50% or persistence (n = 35) it was 14.3%.
Conclusion
The response to treatment with induction CT has prognostic value in patients with locally advanced carcinomas of the oral cavity and oropharynx. Patients who are candidates for conservative treatment with RT or CRT would be those who achieve a complete response after induction treatment.
Resumen
Introducción y objetivos
Con el objetivo de conseguir la preservación funcional, una de las estrategias de tratamiento para los pacientes con carcinomas localmente avanzados de cabeza y cuello consiste en iniciar el tratamiento con quimioterapia (QT) de inducción y decidir la segunda maniobra terapéutica en función de la respuesta. El objetivo del presente estudio es evaluar la capacidad de preservación de órgano basada en esta estrategia terapéutica en pacientes con tumores de cavidad oral y orofaringe.
Métodos
Estudio retrospectivo de 246 pacientes con carcinomas de cavidad oral u orofaringe localmente avanzados (cT3-T4) tratados inicialmente con QT de inducción.
Resultados
Tras la QT de inducción el 28% de los pacientes consiguieron una respuesta completa de la localización primaria del tumor, el 43,1% una respuesta parcial superior al 50% y el 28,9% una reducción inferior al 50% o persistencia. Tras el tratamiento de QT de inducción 70 pacientes (28,5%) recibieron tratamiento quirúrgico y 176 (71,5%) radioterapia (RT) o quimiorradioterapia (QRT). Considerando a los pacientes tratados de forma no quirúrgica (n = 176), la preservación de órgano para los pacientes con una respuesta completa (n = 66) fue del 65,2%, para los pacientes con una respuesta parcial superior al 50% (n = 75) fue del 30,7% y para los pacientes con una respuesta inferior al 50% o persistencia (n = 35) fue del 14,3%.
Conclusión
La respuesta al tratamiento con QT de inducción cuenta con capacidad pronóstica en los pacientes con carcinomas localmente avanzados de cavidad oral y orofaringe. Los pacientes candidatos a tratamiento conservador con RT o QRT serían aquellos que consiguen una respuesta completa tras la administración del tratamiento de inducción.
Objective
To dynamically estimate conditional survival (CS) probabilities for patients with oral squamous cell carcinoma (OSCC) after surgical resection.
Method
A large-scale prospective study was performed involving 1147 eligible OSCC patients from December 2002 to June 2018. Follow-up was completed on January 8, 2019. Cox proportional hazards models were utilized to assess prognostic factors related to overall survival (OS). Three-year CS (CS3) of patients who had already survived x years was calculated as the formula CS3 = OS(x+3)/OS(x).
Results
CS3 estimates at the time of 0, 1, 3, 5-year survival demonstrated a tendency increase over time, and improved from 78.47% to 82.25%, while the postoperative actuarial OS decreased from 78.47% at 3 years to 57.12% at 8 years. Moreover, the differences between CS3 and actuarial OS were more obvious among patients with unfavorable tumor characteristics. Disparities in CS3 across all subgroups of tumor features illustrated more prominent at baseline (d range: 0.24 to 0.40), while the gaps would narrow if those patients have already survived 5 years (d range: −0.01 to 0.18).
Conclusion
Our findings suggest that survival profiles of OSCC patients evolve and increase over time following resection, especially for those with unfavorable tumor features at initial diagnosis. CS estimates may provide more accurate prediction and guide surveillance schedules.
Of central concern to both the patient and the clinician, once the diagnosis of oral cancer has been made, is the question “Will the patient survive?” There are many factors that might influence the prognosis for the patient, some of which include choice of treatment modality by the surgeon/oncologist treating the patient. Some of them may be beyond anyone’s control (e.g., age, gender, genetic profile of the tumor, extent of disease at diagnosis). Some the patient may be able to influence (e.g., does it matter if I continue to smoke or drink alcohol?). Some may reside within the surgical skills of the surgeon. Some factors may appear to be influential following univariate analysis and “disappear” following multivariate analysis. This chapter seeks to arrive at a consensus view upon the relative significance of a number of demographic, pathological, and clinical factors that may influence the prognosis for the patient.
Contemporary diagnostic imaging have a huge impact on detecting, planning and monitoring the treatment of patients with oral squamous cell carcinoma. Imaging studies are performed to detect malignancies, assess staging (primary tumour size and localisation) metastases in regional lymph nodes and distant metastases, response to radiotherapy or chemotherapy and detect recurrence and disease dissemination. Computed tomography and magnetic resonance imaging are referred to as the “gold standard” for imaging oral cancer. The images are evaluated along with clinical and histopathological data. An optimal combination of preoperative examination methods to predict bone invasion is necessary for the planning of definitive therapy for oral cancer patients.
The treatment of locally advanced oral cavity cancer is often multimodal, involving surgical resection, radiotherapy (RT), and chemotherapy. Systemic therapy is the mainstay of treatment for recurrent/metastatic disease. While the concurrent use of cisplatin with post-operative RT is well established in patients with high risk features of extranodal extension and/or positive surgical margins following resection, the role of chemotherapy in other curative settings is not clear. Studies reporting success of induction chemotherapy or definitive chemoradiotherapy in absence of primary resection include all anatomic sites of head and neck cancer, and oral cavity cancer subset is rarely reported as a separate analysis, thus limiting the interpretation of results. This article will focus on the use of systemic therapy for locoregionally advanced oral cavity cancer.
Background:
Racial disparities in squamous cell carcinoma of the head and neck (HNSCC) negatively affect non-Hispanic black (NHB) patients. This study was aimed at understanding how treatment is prescribed and received across all HNSCC subsites.
Methods:
With the National Cancer Database, patients from 2004 to 2014 with surgically resectable HNSCCs, including tumors of the oral cavity (OC), oropharynx (OP), hypopharynx (HP), and larynx (LX), were studied. The treatment received was either upfront surgery or nonsurgical treatment. Treatment patterns were compared according to race and subsite, and how these differences changed over time was evaluated.
Results:
NHB patients were less likely than non-Hispanic white (NHW) patients to receive surgery across all subsites (relative risk [RR] for OC, 0.87; RR for OP, 0.75; RR for HP, 0.73; RR for LX, 0.87; all P values <.05). They were also more likely to refuse a recommended surgery (RR for OC, 1.50; RR for OP, 1.23; RR for HP, 1.23; RR for LX, 1.34), and this difference was significant except for HP. NHB patients were more likely to not be offered surgery across all subsites (RR for OC, 1.38; RR for OP, 1.07; RR for HP, 1.05; RR for LX, 1.03; all P values <.05). Rates of surgery increased and rates of not being offered surgery declined for both NHB and NHW patients from 2004 to 2014, but the absolute disparities persisted in 2014.
Conclusions:
Across all HNSCC subsites, NHB patients were less likely than NHW patients to be recommended for and receive surgery and were more likely to refuse surgery. These differences have closed over time but persist. Enhanced shared decision making may improve these disparities.
Oropharynx cancer has a markedly high prevalence in eastern countries. This cancer leads to complexity and persistence of dysfunction in breathing, speech, swallowing and chewing, accompanied by long-lasting and often permanent disability. In order to achieve a cure and preserve the function, we have actively performed surgical reconstruction following multidisciplinary treatment for oropharynx cancer at our institution. This is a clinical case of a 53-year-old male patient identified as having stage III squamous cell carcinoma of the right lateral tongue. Given the large size of the tongue tumor, neoadjuvant chemotherapy was particularly useful prior to surgery and radiotherapy. In addition, in cases of advanced tongue tumor, primary surgery followed by adjuvant chemotherapy is recommended for a better disease control and survival. We used an infrahyoid myocutaneous island flap for reconstruction of tongue defects after cancer resection. The infrahyoid island flap, harvested from the infrahyoid muscles, is based on the superior thyroid vessels. This thin and pliable flap provided a skin island of about 7 cm from the central part of the anterior neck in our patient. This flap was reliable and achieved primary closure of the tongue defect. The donor site was closed primarily without difficulties. The present report includes a review of the etiology, diagnosis, and contemporary methods of treating oropharyngeal cancer.
Background
The 2017 National Comprehensive Cancer Network Clinical Practice Guidelines recommend surgical resection or definitive radiation therapy for early-stage oral cavity malignancies, and surgical resection or multimodality clinical trials for late-stage disease. Few studies have been conducted to identify predictors of choice of treatment modality for oral cavity malignancies.
Methods
All patients in the National Cancer Data Base (NCDB) diagnosed with oral cavity squamous cell carcinoma (OCSCC) between 1998 and 2011 were identified. Chi-square and binary logistic regression were used to identify factors predictive of surgical or nonsurgical treatment; multiple imputation was used for missing data. Cox proportional hazards models were generated to identify associations between treatment modality and overall survival (OS).
Results
Of 23,459 patients, 4139 (17.6%) underwent primary nonsurgical treatment. Among NCDB-registered facilities, there has been a decrease in use of nonsurgical treatment for OCSCC (OR 0.97, p < 0.001). Older age, non-white race, Medicaid insurance, low income, low education, and later-stage disease were associated with nonsurgical therapy, while patients at academic/research programs were more likely to undergo surgery (OR 0.38, p < 0.001). Nonsurgical treatment was associated with decreased OS (HR = 2.02, p < 0.001); this was upheld on subgroup analysis of early- and late-stage disease.
Conclusions
Use of primary nonsurgical treatment for OCSCC has decreased over time among NCDB-registered facilities and is associated with factors related to access to care. Surgical resection for the primary treatment of oral cavity cancer may be associated with improved OS, though conclusions regarding survival are limited by the non-randomized nature of the data.
Background:
Inoperable oral cavity squamous cell carcinoma (SCC) is a highly invasive disease associated with the extensive destruction of locoregional tissues and a dismal prognosis. Management strategies for these patients are limited.
Methods:
This study was a single arm, prospective, open-label phase II trial. A regimen consisting of cetuximab-docetaxel, cisplatin, and fluorouracil (C-TPF) followed by bio-chemoradiotherapy (bio-CRT) with cisplatin and cetuximab was administered to patients who responded to induction chemotherapy. The objective response rate to C-TPF was the primary endpoint.
Results:
Forty-three patients were enrolled in this study. The objective response rate of C-TPF was 88.4%; 88.9% (32/36) of the responders completed the full bio-CRT course, and the objective response rate of bio-CRT was 64.7%. The most common grade 3/4 adverse events for induction chemotherapy were leucopenia (32.6%) and febrile neutropenia (14.0%). The 1-year progression-free survival (PFS) and overall survival (OS) rates were 43% and 68%, respectively.
Conclusion:
C-TPF is an effective and tolerable induction chemotherapy regimen for inoperable oral cavity SCC.
Integration and optimization of active systemic agents and radiosensitizers into the therapeutic regimen for head and neck cancer remains a topic of active investigation. Recent trials have not consistently supported the use of induction chemotherapy. There are several clinical scenarios in which there is a strong rationale for induction chemotherapy, such as larynx preservation, unfavorable sites and bulky locally advanced disease. The increasing prevalence of HPV-positive malignancies, impacts both interpretation of clinical research and the design of future trials. In the broad spectrum of this disease the prognosis is often dismal, with substantial room for improvement over current therapy. In the face of conflicting clinical data, we address the question of whether there remains a role for induction chemotherapy.
The Southwest Oncology Group designed a phase II trial for patients with base of tongue or hypopharyngeal cancer to evaluate the complete histologic response rate at the primary site after induction chemotherapy followed by chemoradiotherapy for responders. Secondary end points were the rate of organ preservation and the need for salvage surgery.
Fifty-nine eligible patients were enrolled; 37 had base of tongue cancer, and 22 had hypopharynx cancer. Forty-two percent had stage III disease, and 58% had stage IV disease. Induction chemotherapy was two cycles of cisplatin 100 mg/m(2) and fluorouracil 1,000 mg/m(2)/d for 5 days. Patients who had a greater than 50% response at the primary site were treated with radiation 72Gy and concurrent cisplatin 100 mg/m(2) for three cycles. Patients with less than partial response at the primary had immediate salvage surgery.
Forty-five patients (76%) had a greater than 50% response at the primary after induction chemotherapy; 43 went on to receive definitive chemoradiotherapy. Thirty-two patients (54%) achieved a histologic complete response at the primary site, and an additional nine patients had a complete clinical response, but biopsy was not done. Seventy-five percent of patients did not require surgery at the primary tumor site. The 3-year overall survival was 64%. The 3-year progression-free survival with organ preservation was 52%.
Patients with base of tongue or hypopharyngeal cancer treated with this regimen of induction chemotherapy followed by definitive chemoradiotherapy have a good rate of organ preservation without compromise of survival.
Cisplatin-based neoadjuvant chemotherapy (NAC) has been reported to increase survival of patients with nasopharyngeal carcinoma, and organ preservation in those with laryngeal carcinoma, but its efficacy for other head and neck carcinomas is still controversial. We examined the effects of NAC for patients with stage III-IV squamous cell carcinoma of the oral cavity. The patients were divided into two groups; 9 patients who underwent NAC consisting of one course of cisplatin (CDDP), docetaxel (TXT) and 5-fluorouracil (5FU) followed by surgery (NAC group), and 18 patients who underwent surgery alone (control group). Complete response (CR) was not observed, but partial response (PR) was obtained in 6 of 9 patients (33%) of the NAC group. The 3-year survival rate was 29.6% in the NAC group and 81.5% in the control group. Although any valid conclusions could not be drawn because of the small number of patients examined here, NAC with CDDP, TXT and 5FU offered no advantages over standard treatment for advanced oral cancer in terms of survival.
To test induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CRT) or surgery/radiotherapy (RT) for advanced oropharyngeal cancer and to assess the effect of human papilloma virus (HPV) on response and outcome.
Sixty-six patients (51 male; 15 female) with stage III to IV squamous cell carcinoma of the oropharynx (SCCOP) were treated with one cycle of cisplatin (100 mg/m(2)) or carboplatin (AUC 6) and with fluorouracil (1,000 mg/m(2)/d for 5 days) to select candidates for CRT. Those achieving a greater than 50% response at the primary tumor received CRT (70 Gy; 35 fractions with concurrent cisplatin 100 mg/m(2) or carboplatin (AUC 6) every 21 days for three cycles). Adjuvant paclitaxel was given to patients who were complete histologic responders. Patients with a response of 50% or less underwent definitive surgery and postoperative radiation. Pretreatment biopsies from 42 patients were tested for high-risk HPV.
Fifty-four of 66 patients (81%) had a greater than 50% response after IC. Of these, 53 (98%) received CRT, and 49 (92%) obtained complete histologic response with a 73.4% (47 of 64) rate of organ preservation. The 4-year overall survival (OS) was 70.4%, and the disease-specific survival (DSS) was 75.8% (median follow-up, 64.1 months). HPV16, found in 27 of 42 (64.3%) biopsies, was associated with younger age (median, 55 v 63 years; P = .016), sex (22 of 30 males [73.3%] and five of 12 females [41.7%]; P = .08), and nonsmoking status (P = .037). HPV titer was significantly associated with IC response (P = .001), CRT response (P = .005), OS (P = .007), and DSS (P = .008).
Although the numbers in this study are small, IC followed by CRT is an effective treatment for SCCOP, especially in patients with HPV-positive tumors; however, for patients who do not respond to treatment, alternative treatments must be developed.
Background.
We performed a prospective, randomized study in patients with previously untreated advanced (Stage III or IV) laryngeal squamous carcinoma to compare the results of induction chemotherapy followed by definitive radiation therapy with those of conventional laryngectomy and postoperative radiation.
Methods.
Three hundred thirty-two patients were randomly assigned to receive either three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy. The clinical tumor response was assessed after two cycles of chemotherapy, and patients with a response received a third cycle followed by definitive radiation therapy (6600 to 7600 cGy). Patients in whom there was no tumor response or who had locally recurrent cancers after chemotherapy and radiation therapy underwent salvage laryngectomy.
Results.
After two cycles of chemotherapy, the clinical tumor response was complete in 31 percent of the patients and partial in 54 percent. After a median follow-up of 33 months, the estimated 2-year survival was 68 percent (95 percent confidence interval, 60 to 76 percent) for both treatment groups (P = 0.9846). Patterns of recurrence differed significantly between the two groups, with more local recurrences (P = 0.0005) and fewer distant metastases (P = 0.016) in the chemotherapy group than in the surgery group. A total of 59 patients in the chemotherapy group (36 percent) required total laryngectomy. The larynx was preserved in 64 percent of the patients overall and 64 percent of the patients who were alive and free of disease.
Conclusions.
These preliminary results suggest a new role for chemotherapy in patients with advanced laryngeal cancer and indicate that a treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx in a high percentage of patients, without compromising overall survival. (N Engl J Med 1991; 324:1685–90.)
Matching is a common method of adjustment in observational studies. Currently, matched samples are constructed using greedy heuristics (or “stepwise” procedures) that produce, in general, suboptimal matchings. With respect to a particular criterion, a matched sample is suboptimal if it could be improved by changing the controls assigned to specific treated units, that is, if it could be improved with the data at hand. Here, optimal matched samples are obtained using network flow theory. In addition to providing optimal matched-pair samples, this approach yields optimal constructions for several statistical matching problems that have not been studied previously, including the construction of matched samples with multiple controls, with a variable number of controls, and the construction of balanced matched samples that combine features of pair matching and frequency matching. Computational efficiency is discussed. Extensive use is made of ideas from two essentially disjoint literatures, namely statistical matching in observational studies and graph algorithms for matching. The article contains brief reviews of both topics.
Background
Local-regional recurrence of disease remains the major obstacle to cure of advanced head and neck cancers.Methods
This investigation reviewed data derived from Radiation Therapy Oncology Group (RTOG) protocols #85-03 and #88-24 to identify characteristics of tumors that predicted local-regional recurrence of disease following surgery and postoperative radiotherapy (RT).ResultsThe presence of tumor in two or more lymph nodes, and/or extracapsular spread of nodal disease, and/or microscopic-size tumor involvement of the surgical margins of resection imparts a high risk of local-regional (L-R) relapse. Our data also support the hypothesis that, following surgery, the concurrent addition of chemotherapy (CT) to RT may increase the likelihood of L-R control of disease for patients who have these high-risk characteristics.ConclusionA prospective trial of surgery followed by concurrent RT and CT is warranted for patients who have high-risk characteristics found at surgery. © 1998 John Wiley & Sons, Inc. Head Neck 20: 588–594, 1998.
One hundred fourteen patients with carcinomas of the oral tongue and floor of mouth were treated with high-dose megavoltage radiation at Stanford University from 1956 to 1970. Actuarial 5-year survival for 56 patients with oral tongue lesions was: T1, 73%; T2,37%; and T3, 19%. Similarly, for 58 patients with lesions of the floor of mouth, 5-year survival was: T1 73%; T2,37%; and T3,25%. Local control of the primary was obtained in oral tongue T1 lesions 10 of 11 times; T2, 5 of 8; and T3, 13 of 36 times. For floor of mouth, local control was: T1, 22 of 26; T2, 7 of 14; and T3, 3 of 15. There was an indication that better control was obtained if interstitial therapy was a planned part of the treatment. Dose for local control when external radiation alone was utilized was usually over 1900 rets. Patients with initially clinically negative nodes (TxNO) who had a low radiation dose to primary echelon lymph nodes developed later cervical lymph node metastases 38% of the time. In no case did late metastatic disease appear in patients whose necks were treated prophylactically.
Purpose:
Reporting long-term toxicities in trials of chemoirradiation (CRT) of head-and-neck cancer (HNC) has mostly been limited to observer-rated maximal Grades >or=3. We evaluated this reporting approach for dysphagia by assessing patient-reported dysphagia (PRD) and objective swallowing dysfunction through videofluoroscopy (VF) in patients with various grades of maximal observer-reported dysphagia (ORD).
Methods and materials:
A total of 62 HNC patients completed quality-of-life questionnaires periodically through 12 months post-CRT. Five PRD items were selected: three dysphagia-specific questions, an Eating-Domain, and "Overall Bother." They underwent VF at 3 and 12 months, and ORD (Common Terminology Criteria for Adverse Events) scoring every 2 months. We classified patients into four groups (0-3) according to maximal ORD scores documented 3-12 months post-CRT, and assessed PRD and VF summary scores in each group.
Results:
Differences in ORD scores among the groups were considerable throughout the observation period. In contrast, PRD scores were similar between Groups 2 and 3, and variable in Group 1. VF scores were worse in Group 3 compared with 2 at 3 months but similar at 12 months. In Group 1, PRD and VF scores from 3 through 12 months were close to Groups 2 and 3 if ORD score 1 persisted, but were similar to Group 0 in patients whose ORD scores improved by 12 months.
Conclusions:
Patients with lower maximal ORD grades, especially if persistent, had similar rates of PRD and objective dysphagia as patients with highest grades. Lower ORD grades should therefore be reported. These findings may have implications for reporting additional toxicities besides dysphagia.
Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. A total of 1,596,670 new cancer cases and 571,950 deaths from cancer are projected to occur in the United States in 2011. Overall cancer incidence rates were stable in men in the most recent time period after decreasing by 1.9% per year from 2001 to 2005; in women, incidence rates have been declining by 0.6% annually since 1998. Overall cancer death rates decreased in all racial/ethnic groups in both men and women from 1998 through 2007, with the exception of American Indian/Alaska Native women, in whom rates were stable. African American and Hispanic men showed the largest annual decreases in cancer death rates during this time period (2.6% and 2.5%, respectively). Lung cancer death rates showed a significant decline in women after continuously increasing since the 1930s. The reduction in the overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of about 898,000 deaths from cancer. However, this progress has not benefitted all segments of the population equally; cancer death rates for individuals with the least education are more than twice those of the most educated. The elimination of educational and racial disparities could potentially have avoided about 37% (60,370) of the premature cancer deaths among individuals aged 25 to 64 years in 2007 alone. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population with an emphasis on those groups in the lowest socioeconomic bracket.
To report outcomes of oral cavity cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy (chemoIMRT).
Between 2001 and 2004, 21 patients with oral cavity squamous cell carcinoma underwent definitive chemoIMRT. Sites included were oral tongue (n = 9), floor of mouth (n = 6), buccal mucosa (n = 3), retromolar trigone (n = 2), and hard palate (n = 1). Most had stage III-IV disease (n = 20). The most common regimen was 5 days infusional 5-fluorouracil (600 mg/m(2)/d × 5 days), hydroxyurea (500 mg, PO BID), and 1.5 Gy twice-daily irradiation to 72 to 75 Gy.
The median follow-up for surviving patients was 60 months. Treatment failure occurred as follows: local-1, regional-1, and distant metastases-2. The 2- and 5-year estimates of locoregional progression-free survival, disease-free survival, and overall survival were 90% and 90%, 71% and 71%, and 76% and 76%, respectively. Late complications included osteoradionecrosis (3 patients, 14%).
Concurrent chemoIMRT results in promising locoregional control for oral cavity squamous cell carcinomas with acceptable toxicity.
The optimal management of oral cavity squamous cell carcinoma (OCSCC) typically involves surgical resection followed by adjuvant radiotherapy or chemoradiotherapy (CRT) in the setting of adverse pathologic features. Intensity-modulated radiation therapy (IMRT) is frequently used to treat oral cavity cancers, but published IMRT outcomes specific to this disease site are sparse. We report the Dana-Farber Cancer Institute experience with IMRT-based treatment for OCSCC.
Retrospective study of all patients treated at Dana-Farber Cancer Institute for OCSCC with adjuvant or definitive IMRT between August 2004 and December 2009. The American Joint Committee on Cancer disease stage criteria distribution of this cohort included 5 patients (12%) with stage I; 10 patients (24%) with stage II (n = 10, 24%); 14 patients (33%) with stage III (n = 14, 33%); and 13 patients (31%) with stage IV. The primary endpoint was overall survival (OS); secondary endpoints were locoregional control (LRC) and acute and chronic toxicity.
Forty-two patients with OCSCC were included, 30 of whom were initially treated with surgical resection. Twenty-three (77%) of 30 surgical patients treated with adjuvant IMRT also received concurrent chemotherapy, and 9 of 12 (75%) patients treated definitively without surgery were treated with CRT or induction chemotherapy and CRT. With a median follow-up of 2.1 years (interquartile range, 1.1-3.1 years) for all patients, the 2-year actuarial rates of OS and LRC following adjuvant IMRT were 85% and 91%, respectively, and the comparable results for definitive IMRT were 63% and 64% for OS and LRC, respectively. Only 1 patient developed symptomatic osteoradionecrosis, and among patients without evidence of disease, 35% experienced grade 2 to 3 late dysphagia, with only 1 patient who was continuously gastrostomy-dependent.
In this single-institution series, postoperative IMRT was associated with promising LRC, OS, and lower late toxicity rates, and chemoradiotherapy was a successful treatment for patients with high-risk disease. In contrast, outcomes of radiation-based treatment for patients with inoperable locally advanced disease were markedly less successful.
Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data regarding cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,529,560 new cancer cases and 569,490 deaths from cancer are projected to occur in the United States in 2010. Overall cancer incidence rates decreased in the most recent time period in both men (1.3% per year from 2000 to 2006) and women (0.5% per year from 1998 to 2006), largely due to decreases in the 3 major cancer sites in men (lung, prostate, and colon and rectum [colorectum]) and 2 major cancer sites in women (breast and colorectum). This decrease occurred in all racial/ethnic groups in both men and women with the exception of American Indian/Alaska Native women, in whom rates were stable. Among men, death rates for all races combined decreased by 21.0% between 1990 and 2006, with decreases in lung, prostate, and colorectal cancer rates accounting for nearly 80% of the total decrease. Among women, overall cancer death rates between 1991 and 2006 decreased by 12.3%, with decreases in breast and colorectal cancer rates accounting for 60% of the total decrease. The reduction in the overall cancer death rates translates to the avoidance of approximately 767,000 deaths from cancer over the 16-year period. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, geographic area, and calendar year. Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years. Further progress can be accelerated by applying existing cancer control knowledge across all segments of the population and by supporting new discoveries in cancer prevention, early detection, and treatment.
Patients with advanced oral cavity cancer (OCC) typically have not been enrolled in clinical trials utilizing contemporary multimodality strategies. There exist dogmatic expectations of inferior outcome in OCC patients secondary to ineffectiveness of treatment and unacceptable toxicity. The purpose of this study was to analyze survival, swallowing function, and incidence of osteoradionecrosis (ORN) of patients with stage III/IV OCC who have undergone primary concomitant chemoradiotherapy (CRT).
All advanced OCC patients who were enrolled in University of Chicago concomitant CRT protocols from 1994 to 2008 were reviewed. One hundred eleven newly diagnosed advanced OCC patients were evaluated. We performed a subset analysis of 27 additional advanced OCC patients who underwent surgery followed by postoperative CRT. Swallowing function was assessed via oropharyngeal motility study, and a Swallowing Performance Status Scale score was assigned. Presence of clinically significant ORN was documented.
Median follow-up was 3.25 years. Five-year overall and progression-free survival was 66.9% and 65.9%, respectively. There was no difference in overall or progression-free survival when the surgery-first group was compared with the primary CRT group (P = .88 and P = .86 respectively). Function, without gastric tube requirement, was excellent, with 92.2% of patients able to maintain weight via oral route. Incidence of ORN was 18.4%, occurring in nine of 49 patients evaluated.
Our data support the use of primary CRT as a viable treatment option for patients with advanced OCC. Survival is high, and overall function for the majority of patients is satisfactory. Patients with T4 oral tongue cancer may be spared total glossectomy. The incidence of ORN may be considered acceptable, in light of the benefits of enduring life and function.
Background : As a general rule, surgery whenever possible, followed by irradiation is considered to be the standard treatment for cancer of the hypopharynx, thus sacrificing natural speech. In most patients, surgery includes removal of the larynx. Purpose : A prospective, randomized phase III study was conducted by the European Organization for Research and Treatment of Cancer (EORTC) starting in 1990 to compare a larynx-preserving treatment (induction chemotherapy plus definitive, radiation therapy in patients who showed a complete response or surgery in those who did not respond) with conventional treatment (total laryngectomy with partial pharyngectomy, radical neck dissection, and postoperative irradiation) in previously untreated and operable patients with histologically proven squamous cell carcinomas of the pyriform sinus or aryepiglottic fold, but free of other cancers. Methods : Patients were randomly assigned to one of two treatment arms: 1) immediate surgery with postoperative radiotherapy (50–70 Gy) or 2) induction chemotherapy (cisplatin [100 mg/m2] given as a bolus intravenous injection on day 1, followed by infusion of fluorouracil [1000 mg/m2 per day] on days 1–5). An endoscopic evaluation was performed after each cycle of chemotherapy. After two cycles, only partial and complete responders received a third cycle. Patients with a complete response after two or three cycles of chemotherapy were treated thereafter by irradiation (70 Gy); nonresponding patients underwent conventional surgery with postoperative radiation (50–70 Gy). Salvage surgery was also performed when patients relapsed after chemotherapy and irradiation. The trial was designed to test the equivalence of the two treatment arms; i.e., the induction chemotherapy treatment would be judged equivalent to immediate surgery if the relative risk of death for induction chemotherapy compared with immediate surgery was significantly less than 1.43 using a one-sided hypothesis test at the.05 level of significance. Results : Two hundred two patients entered the trial and were randomly assigned; only 194 were eligible for treatment (94 in the immediate-surgery arm and 100 in the induction-chemotherapy arm). In the induction-chemotherapy arm, complete response was seen in 52 (54%) of 97 patients with local disease (primary tumor) and in 31 (51%) of 61 patients with regional disease (involvement of the neck). Treatment failures at local, regional, and second primary sites occurred at approximately the same frequencies in the immediate-surgery arm (12%, 19%, and 16%, respectively) and in the induction-chemotherapy arm (17%, 23%, and 13%, respectively). In contrast, there were fewer failures at distant sites in the induction-chemotherapy arm than in the immediate-surgery arm (25% versus 36%, respectively; P =.041). The median duration of survival was 25 months in the immediate-surgery arm and 44 months in the induction-chemotherapy arm and, since the observed hazard ratio was 0.86 (logrank test, P =.006), which was significantly less than 1.43, the two treatments were judged to be equivalent. The 3- and 5-year estimates of retaining a functional larynx in patients treated in the induction chemotherapy arm were 42% (95% confidence interval = 31%-53%) and 35% (95% confidence interval = 22%-48%), respectively. Conclusions and Implications : Larynx preservation without jeopardizing survival appears feasible in patients with cancer of the hypopharynx. On the basis of these observations, the EORTC has now accepted the use of induction chemotherapy followed by radiation as the new standard treatment in its future phase III larynx preservation trials. [J Natl Cancer Inst 1996; 88: 890–9]
Our previous individual patient data (IPD) meta-analysis showed that chemotherapy improved survival in patients curatively treated for non-metastatic head and neck squamous cell carcinoma (HNSCC), with a higher benefit with concomitant chemotherapy. However the heterogeneity of the results limited the conclusions and prompted us to confirm the results on a more complete database by adding the randomised trials conducted between 1994 and 2000.
The updated IPD meta-analysis included trials comparing loco-regional treatment to loco-regional treatment+chemotherapy in HNSCC patients and conducted between 1965 and 2000. The log-rank-test, stratified by trial, was used to compare treatments. The hazard ratios of death were calculated.
Twenty-four new trials, most of them of concomitant chemotherapy, were included with a total of 87 trials and 16,485 patients. The hazard ratio of death was 0.88 (p<0.0001) with an absolute benefit for chemotherapy of 4.5% at 5 years, and a significant interaction (p<0.0001) between chemotherapy timing (adjuvant, induction or concomitant) and treatment. Both direct (6 trials) and indirect comparisons showed a more pronounced benefit of the concomitant chemotherapy as compared to induction chemotherapy. For the 50 concomitant trials, the hazard ratio was 0.81 (p<0.0001) and the absolute benefit 6.5% at 5 years. There was a decreasing effect of chemotherapy with age (p=0.003, test for trend).
The benefit of concomitant chemotherapy was confirmed and was greater than the benefit of induction chemotherapy.
Patients with T4 oral cavity (OC) tumors are often treated with surgery followed by adjuvant chemoradiotherapy (CRT).
We performed a retrospective review of 4 multi-institutional phase II studies estimating long-term toxicity, locoregional control (LC), progression-free survival (PFS), and overall survival (OS) of primary CRT.
Thirty-nine subjects were identified; 16 (42%) with bony involvement. Median radiotherapy dose delivered to primary tumor was 74 Gy. Five-year OS, PFS, and LC rates were 56%, 51%, and 75%, respectively. Sixty-nine percent of subjects with bony involvement never relapsed. Seven subjects developed osteoradionecrosis. Bone involvement with primary tumor did not appear to be associated with increased risk of death, relapse, or long-term complication.
These data suggest that primary CRT is an effective treatment approach in patients with T4 OC tumors including those with bony involvement producing LC, survival, and complication rates comparable to historical series. Prospective clinical trials should evaluate primary surgical versus CRT treatment in these patients.
To determine if a rectangular template free tissue transfer is effective for the reconstruction of the hemiglossectomy defect.
Prospective case series.
Tertiary care academic medical center.
A total of 13 patients (male to female ratio, 8:5; mean age, 55 years) presenting with squamous cell carcinoma of the oral tongue from May 2000 to December 2002.
Of the 13 patients, 7 received postoperative radiotherapy and 2 received prior radiotherapy. The radial forearm was the donor site in 11 patients and the lateral arm and anterolateral thigh in 1 patient each. The mean flap area was 50 cm(2) (range, 24-80 cm(2)).
Major and minor complications, speech and swallowing assessment, oral cavity obliteration, premaxillary contact, tongue elevation, and tongue protrusion.
There were no major complications, and 2 of the 13 patients experienced minor complications. Of the 13 patients, 12 achieved the goals of oral cavity obliteration and premaxillary contact and resumed solid oral intake. One patient remained G-tube dependent owing to toxic effects from previous chemoradiation treatment. The mean tongue tip protrusion was 0.7 cm (range, 0-1.7 cm), and the mean elevation was 1.7 cm (range, 1-3 cm). Patients with protrusion greater than 0.8 cm had better swallowing scores for "range of solids" (5.8 of 6 vs 3.9 of 6; P = .045) and "eating in public" (4.6 of 5 vs 3.5 of 5; P = .10). The average patient resumed a full range of liquid and solid intake with minimal restrictions and believed that their speech was mostly understandable with occasional repetition.
The template-based rectangle tongue flap effectively restored speech and swallowing function in this group of patients. Tongue protrusion greater than 0.8 cm is associated with better swallowing results.
The management of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN) is highly complex. Data from recent clinical trials have altered the treatment landscape by refining the use of existing therapies, such as radiation therapy and chemotherapy, and providing new treatment options, such as cetuximab. Selecting the most appropriate treatment for an individual patient requires a multidisciplinary approach and careful assessment of the relative advantages and disadvantages of each treatment approach. Surgery is highly effective but can have debilitating long-term consequences. Chemoradiation and altered fractionation radiation therapy are more effective than conventional radiation therapy, but also more toxic; as a consequence of toxicity, suboptimal delivery of radiation may diminish, in practice, the efficacy observed in clinical trials of these strategies. Cetuximab plus radiation therapy is more effective than radiation alone and does not substantially increase radiation-related toxicity, or affect the delivery of planned radiotherapy. However, whether cetuximab plus radiation therapy is similar in efficacy to chemoradiation is unknown at this time. Ideally, multidisciplinary teams weigh all these factors when making individual treatment decisions. Data from current trials will help further optimize multimodality treatment for LA-SCCHN.
One hundred fourteen patients with carcinoma of the oral tongue and floor of mouth were treated with high-dose megavoltage radiation at Stanford University from 1956 to1970. Actuarial 5-year survival for 56 patients with oral tongue lesions was: T', 73; T', 37%; and T', 19%. Similarly, for 58 patients with lesions of the floor mouth, 5-year survival was: T', 73%; T', 37%; and T', 25%. Local control of the primary was obtained in oral tongue T' lesions 10 of 11 times; T', 5 of 8; and T', 13 of 36 times. For floor of mouth, local control was: T', 22 of 26;T', 7 of 14; andT', 3 of 15. There was an indication that better control was obtained if interstitialtherapy was a planned part of the treatment. Dose for local control when external radiation alone was utilized was usually over 1900 rets. Patients with initially clinicallynegative nodes (TXNO) who had a low radiation dose to primary echelon lymph nodes developed later cervical lymph node metastases 38% of the time. In no case did late metastatic disease appear in patients whose necks were treated prophylactically.
To test the efficacy of sequential chemotherapy as an adjuvant to surgery and postoperative radiotherapy for patients with locally-advanced but operable squamous cell cancers of the head and neck region, a randomized clinical trial was conducted under the auspices of the Head and Neck Intergroup (Radiation Therapy Oncology Group, Southwest Oncology Group, Eastern Oncology Group, Cancer and Leukemia Group B, Northern California Oncology Group, and Southeast Group). Eligible patients had completely resected tumors of the oral cavity, oropharynx, hypopharynx, or larynx. They were then randomized to receive either three cycles of cis-platinum and 5-FU chemotherapy followed by postoperative radiotherapy (CT/RT) or postoperative radiotherapy alone (RT). Patients were categorized as having either "low-risk" or "high-risk" treatment volumes depending on whether the surgical margin was greater than or equal to 5 mm, there was extracapsular nodal extension, and/or there was carcinoma-in-situ at the surgical margins. Radiation doses of 50-54 Gy were given to "low-risk" volumes and 60 Gy were given to "high-risk" volumes. A total of 442 analyzable patients were entered into this study with the mean-time-at-risk being 45.7 months at the time of the present analysis. The 4-year actuarial survival rate was 44% on the RT arm and 48% on the CT/RT arm (p = n.s.). Disease-free survival at 4 years was 38% on the RT arm compared to 46% on the CT/RT arm (p = n.s.). At 4 years the local/regional failure rate was 29% vs. 26% for the RT and CT/RT arms, respectively (p = n.s.). The incidence of first failure in the neck nodes was 10% on the RT arm compared to 5% on the CT/RT arm (p = 0.03 without adjusting for multiple testing) and the overall incidence of distant metastases was 23% on the RT arm compared to 15% on the CT/RT arm (p = 0.03). Treatment related toxicity is discussed in detail, but, in general, the chemotherapy was satisfactorily tolerated and did not affect the ability to deliver the subsequent radiotherapy. Implications for future clinical trials are discussed.
Radiation therapy alone, surgery alone, or the combination of these two modalities, remain the accepted treatments in the management of epidermoid carcinomas of the mucosa of the head and neck. These modalities of therapy produce comparable results; but, radiotherapy alone has the advantage that it can conserve anatomy and function. Irradiation with teletherapy techniques, at times supplemented by interstitial brachytherapy, with doses ranging from 6600 to 8000 cGy, results in satisfactory tumor response (CR). The CR of T1N0 and T2N0 lesions will be 99% and 90% respectively, but only 29% in T4N3 tumors treated with radiation only. To improve on the limited CR rate achieved in the advanced stages, surgery is combined pre or post-irradiation, or reserved for the salvage of failures. In the oral cavity and oropharynx, these possible options give comparable tumor control and survival, but in the supraglottic larynx post-operative irradiation is superior to pre-operative radiotherapy. Tumor recurrence rates in the head and neck range from 15 to 34% depending on initial site, stage and type of therapy. Cancer control activities that emphasize prevention and early diagnosis should present a better future for these patients.
A retrospective review of 163 consecutive patients with biopsy-proven, invasive squamous cell carcinoma of the floor of the mouth who underwent inpatient treatment at the Massachusetts General Hospital during the 15-year period from January 1962 through December 1976 is presented. The stage at first presentation, clinical features of the disease, incidence of second primary tumors, analysis of therapeutic modalities, and survival statistics are compared with reports from other large centers. Floor of mouth tumors comprised 28%, (163/592) of oral squamous cell carcinomas seen at the Massachusetts General Hospital during that time period. Seventy-one per cent of floor of mouth tumors were in men and 29% in women; women tended to present earlier in the course of their disease. Thirty-seven patients (23%) developed a secondary primary malignancy, and four of these 37 patients developed two second primaries. Distant metastatic disease appeared in 6% of patients with Stage I, II, or III disease and 26% of patients with Stage IV disease. Radiation therapy alone and surgery alone resulted in equivalent long-term survival rates for early stage disease. In more advanced stages (III and IV), a combined approach utilizing surgery and radiation therapy obtained superior results for short-term survival than either modality alone. The importance of early diagnosis and treatment and suggestions for development of cooperative protocols in an attempt to improve salvage of patients with this disease is discussed.
As a general rule, surgery whenever possible, followed by irradiation is considered to be the standard treatment for cancer of the hypopharynx, thus sacrificing natural speech. In most patients, surgery includes removal of the larynx.
A prospective, randomized phase III study was conducted by the European Organization for Research and Treatment of Cancer (EORTC) starting in 1990 to compare a larynx-preserving treatment (induction chemotherapy plus definitive, radiation therapy in patients who showed a complete response or surgery in those who did not respond) with conventional treatment (total laryngectomy with partial pharyngectomy, radical neck dissection, and postoperative irradiation) in previously untreated and operable patients with histologically proven squamous cell carcinomas of the pyriform sinus or aryepiglottic fold, but free of other cancers.
Patients were randomly assigned to one of two treatment arms: 1) immediate surgery with postoperative radiotherapy (50-70 Gy) or 2) induction chemotherapy (cisplatin [100 mg/m2] given as a bolus intravenous injection on day 1, followed by infusion of fluorouracil [1000 mg/m2 per day] on days 1-5). An endoscopic evaluation was performed after each cycle of chemotherapy. After two cycles, only partial and complete responders received a third cycle. Patients with a complete response after two or three cycles of chemotherapy were treated thereafter by irradiation (70 Gy); nonresponding patients underwent conventional surgery with postoperative radiation (50-70 Gy). Salvage surgery was also performed when patients relapsed after chemotherapy and irradiation. The trial was designed to test the equivalence of the two treatment arms; i.e., the induction chemotherapy treatment would be judged equivalent to immediate surgery if the relative risk of death for induction chemotherapy compared with immediate surgery was significantly less than 1.43 using a one-sided hypothesis test at the .05 level of significance.
Two hundred two patients entered the trial and were randomly assigned; only 194 were eligible for treatment (94 in the immediate-surgery arm and 100 in the induction-chemotherapy arm). In the induction-chemotherapy arm, complete response was seen in 52 (54%) of 97 patients with local disease (primary tumor) and in 31 (51%) of 61 patients with regional disease (involvement of the neck). Treatment failures at local, regional, and second primary sites occurred at approximately the same frequencies in the immediate-surgery arm (12%, 19%, and 16%, respectively) and in the induction-chemotherapy arm (17%, 23%, and 13%, respectively). In contrast, there were fewer failures at distant sites in the induction-chemotherapy arm than in the immediate-surgery arm (25% versus 36%, respectively; P = .041). The median duration of survival was 25 months in the immediate-surgery arm and 44 months in the induction-chemotherapy arm and, since the observed hazard ratio was 0.86 (logrank test, P = .006), which was significantly less than 1.43, the two treatments were judged to be equivalent. The 3- and 5-year estimates of retaining a functional larynx in patients treated in the induction-chemotherapy arm were 42% (95% confidence interval = 31%-53%) and 35% (95% confidence interval = 22%-48%), respectively.
Larynx preservation without jeopardizing survival appears feasible in patients with cancer of the hypopharynx. On the basis of these observations, the EORTC has now accepted the use of induction chemotherapy followed by radiation as the new standard treatment in its future phase III larynx preservation trials.
Local-regional recurrence of disease remains the major obstacle to cure of advanced head and neck cancers.
This investigation reviewed data derived from Radiation Therapy Oncology Group (RTOG) protocols #85-03 and #88-24 to identify characteristics of tumors that predicted local-regional recurrence of disease following surgery and postoperative radiotherapy (RT).
The presence of tumor in two or more lymph nodes, and/or extracapsular spread of nodal disease, and/or microscopic-size tumor involvement of the surgical margins of resection imparts a high risk of local-regional (L-R) relapse. Our data also support the hypothesis that, following surgery, the concurrent addition of chemotherapy (CT) to RT may increase the likelihood of L-R control of disease for patients who have these high-risk characteristics.
A prospective trial of surgery followed by concurrent RT and CT is warranted for patients who have high-risk characteristics found at surgery.
When the complex structures of the upper aerodigestive tract are disrupted after resection of head and neck tumors, an appropriate reconstructive option should be chosen in an attempt to regain maximum function. Reconstructions using microvascular free tissue transfer offer unparalleled flexibility, both in tissue composition and in placement. This article will examine functional outcomes after free flap reconstruction of the upper aerodigestive tract.
With the maturation of free tissue transfer techniques, functional outcomes are being analyzed with increasing frequency. Recent reports show promising results for free flap reconstruction of oral cavity, oropharyngeal, and hypopharyngeal soft tissue defects, as well as for bony mandibular and maxillary defects.
For both soft tissue and bony defects of the upper aerodigestive tract, microvascular free flaps provide good functional outcomes. In the future, randomized studies are needed to compare the functional outcomes of microvascular free flaps with those of other reconstructive options.
Background:
In 2004, level I evidence was established for the postoperative adjuvant treatment of patients with selected high-risk locally advanced head and neck cancers, with the publication of the results of two trials conducted in Europe (European Organization Research and Treatment of Cancer; EORTC) and the United States (Radiation Therapy Oncology Group; RTOG). Adjuvant chemotherapy-enhanced radiation therapy (CERT) was shown to be more efficacious than postoperative radiotherapy for these tumors in terms of locoregional control and disease-free survival. However, additional studies were needed to identify precisely which patients were most suitable for such intense treatment.
Methods:
Both studies compared the addition of concomitant relatively high doses of cisplatin (on days 1, 22, and 43) to radiotherapy vs radiotherapy alone given after surgery in patients with high-risk cancers of the oral cavity, oropharynx, larynx, or hypopharynx. A comparative analysis of the selection criteria, clinical and pathologic risk factors, and treatment outcomes was carried out using data pooled from these two trials.
Results:
Extracapsular extension (ECE) and/or microscopically involved surgical margins were the only risk factors for which the impact of CERT was significant in both trials. There was also a trend in favor of CERT in the group of patients who had stage III-IV disease, perineural infiltration, vascular embolisms, and/or clinically enlarged level IV-V lymph nodes secondary to tumors arising in the oral cavity or oropharynx. Patients who had two or more histopathologically involved lymph nodes without ECE as their only risk factor did not seem to benefit from the addition of chemotherapy in this analysis.
Conclusions:
Subject to the usual caveats of retrospective subgroup analysis, our data suggest that in locally advanced head and neck cancer, microscopically involved resection margins and extracapsular spread of tumor from neck nodes are the most significant prognostic factors for poor outcome. The addition of concomitant cisplatin to postoperative radiotherapy improves outcome in patients with one or both of these risk factors who are medically fit to receive chemotherapy.
Primary chemoradiotherapy in patients with advanced laryngeal cancer can achieve high rates of organ preservation without sacrificing survival compared with radiation alone or conventional laryngectomy. Appropriate selection of patients for organ preservation approaches could enhance overall treatment outcome and quality of life. We conducted a phase II organ preservation trial for patients with stage III and IV larynx cancer to determine whether late salvage surgery rates could be decreased and survival improved by selecting patients for organ preservation based on response to a single cycle of induction chemotherapy.
The chemotherapy was cisplatin 100 mg/m2 on day 1 and fluorouracil 1,000 mg/m(2)/d for 5 days. Patients who achieved less than 50% response had immediate laryngectomy. Patients who achieved more than 50% response went on to concurrent chemoradiotherapy. Histologic complete responders after chemoradiotherapy received two more cycles of chemotherapy. Patients with residual disease after chemoradiotherapy had planned salvage surgery.
Of 97 eligible patients, 73 (75%) achieved more than 50% response and received chemoradiotherapy. A total of 29 patients (30%) had salvage surgery; 19 patients (20%) had early salvage surgery after the single cycle of induction chemotherapy, three patients (3%) had late salvage surgery after chemoradiotherapy, six patients (6%) eventually had salvage surgery for recurrence, and one patient had laryngectomy for chondroradionecrosis. The median follow-up time was 41.9 months. The overall survival rate at 3 years is 85%. The cause-specific survival rate was 87%. Larynx preservation was achieved in 69 patients (70%).
These results confirm excellent larynx preservation and improved overall survival rates compared with historical results.
Several techniques have been developed to reconstruct oral and pharyngeal defects following surgery, in order to restore function and cosmesis. These are primary closure, skin grafts, local transposition of skin, mucosa and/or muscle, regional flaps and free vascularized flaps. Because of the 'bulky', pedicled nature and problems with the donor area of locoregional flaps, and consequently frequently unsatisfactory functional results, free vascularized flaps have gained popularity during the last decade. The authors review the current options available to give physicians, who are not experienced in the field of reconstruction in the head and neck, an impression of the range of techniques available for reconstruction of oral and pharyngeal defects following tumor resection. For reconstruction of oral cavity and pharyngeal defects, fasciocutaneous (e.g. radial forearm and anterolateral thigh flaps) and myocutaneous free flaps (e.g. rectus abdominis and latissimus dorsi) have proven to be very reliable. Free vascularized osteocutaneous flaps (e.g. fibula and iliac crest) permit reconstructive options for bony defects of the mandible or maxilla that can be adapted to a variety of defects. Depending on the site, size and involved tissues of the surgical defect and patient factors, a variety of reconstructive options are available. For both soft tissue and bony defects of the upper aerodigestive tract, microvascular free flaps provide good functional outcomes.
Section of Biostatistics Technical Report 56. Mayo Foundation.; 1985. Computerized matching of controls
- Eakj Bergstralh
Bergstralh, EaKJ. Section of Biostatistics Technical Report 56. Mayo Foundation.; 1985.
Computerized matching of controls..