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Introduction: Nasopharyngeal carcinoma (NPC) is an endemic malignancy in Southeast Asia, particularly Southern China. The classical non-keratinising cell type is almost unanimously associated with latent Epstein-Barr virus (EBV) infection. Circulating plasma EBV DNA can be a useful biomarker in various clinical aspects, but comprehensive recommendations and international guidelines are still lacking. We conducted a systematic review of all original articles on the clinical application of plasma EBV DNA for NPC; we further evaluated its strengths and limitations for consideration as standard recommendations. Methods: The search terms 'nasopharyngeal OR nasopharynx', and 'plasma EBV DNA OR cell-free EBV OR cfEBV' were used to identify full-length articles published up to December 2020 in the English literature. Three authors independently reviewed the article titles, removed duplicates and reviewed the remaining articles for eligibility. Results: A total of 81 articles met the eligibility criteria. Based on the levels of evidence and grades of recommendation assessed, it is worth considering the inclusion of plasma EBV DNA in screening, pre-treatment work-up for enhancing prognostication and tailoring of treatment strategy, monitoring during radical treatment, post-treatment surveillance for early detection of relapse, and monitoring during salvage treatment for recurrent or metastatic NPC. One major limitation is the methodology of measurement requiring harmonisation for consistent comparability. Conclusions: The current comprehensive review supports the inclusion of plasma EBV DNA in international guidelines in the clinical aspects listed, but methodological issues must be resolved before global application. 2021 Elsevier Ltd. All rights reserved.

Background The primary goal of treatment in advanced laryngeal cancer is to achieve optimal oncologic outcomes while preserving function and quality of life. Combination of chemotherapy and radiation has been popularized as an alternative to surgery for patients facing total laryngectomy. However, survival analyses from large, population-based databases have not duplicated results reported from randomized trials. Methods A comprehensive literature review was undertaken to try to better understand the reasons why results differ among randomized trials and population cohort studies. Results A variety of reasons are discussed, including differences in patient staging, selection bias, complexity bias, inconsistent terminology, patient compliance and treatment expertise. Conclusions Personalized treatment considering all factors is critical for optimal outcomes. In general, evidence supports total laryngectomy for patients with T4 cancers. Definitive chemoradiotherapy strategies are acceptable alternatives for T3 cancers, provided that all resources for the administration of the treatment, follow-up and surgical salvage are available.

Purpose Toxicity, pathologic complete response, and long-term outcomes are reported for the neoadjuvant therapies assessed in a randomized phase 2 Eastern Cooperative Oncology Group and American College of Radiology Imaging Network trial for operable esophageal adenocarcinoma, staged as II-IVa by endoscopy/ultrasonography (EUS). Methods and Materials A total of 86 eligible patients began treatment. For arm A, preoperative chemotherapy was cisplatin, 30 mg/m 2 , and irinotecan, 50 mg/m 2 , on day 1, 8, 22, 29 during 45 Gy radiation therapy (RT), 1.8 Gy per day over 5 weeks. Adjuvant therapy was cisplatin, 30 mg/m 2 , and irinotecan, 65 mg/m 2 day 1, 8 every 21 days for 3 cycles. Arm B therapy was cisplatin, 30 mg/m 2 , and paclitaxel, 50 mg/m 2 , day 1, 8, 15, 22, 29 with RT, followed by adjuvant cisplatin, 75 mg/m 2 , and paclitaxel, 175 mg/m 2 , day 1 every 21 days for 3 cycles. Stratification included EUS stage and performance status. Results In arm A, median overall survival was 35 months, and 5-, 6-, and 7-year survival rates were 46%, 39%, and 35%, respectively, whereas for arm B, they were 21 months and 27%, 27%, and 23%, respectively. Median progression- or recurrence-free survival (PFS) was 39.8 months with a 3-year PFS of 50% for arm A and 12.4 months ( P =.046) with 3-year PFS of 28% for arm B. Eighty percent of the observed incidents of progression occurred within 19 months. Survival did not differ significantly by EUS and performance status strata. Conclusions Long-term survival was similar for both arms and did not appear superior to results achieved with other standard regimens.

Background The purpose of this article was to study the association of human papillomavirus (HPV) with clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). Patients and methods Archival baseline tumor specimens were obtained from patients treated on two clinical trials in recurrent or metastatic SCCHN: E1395, a phase III trial of cisplatin and paclitaxel versus cisplatin and 5-fluorouracil, and E3301, a phase II trial of irinotecan and docetaxel. HPV DNA was detected by in situ hybridization (ISH) with a wide-spectrum probe. p16 status was evaluated by immunohistochemistry. Clinical outcomes of interest were objective response, progression-free survival (PFS) and overall survival (OS). Results We analyzed 64 patients for HPV ISH and 65 for p16. Eleven tumors (17%) were HPV+, 12 (18%) were p16+, whereas 52 (80%) were both HPV- and p16-. The objective response rate was 55% for HPV-positive versus 19% for HPV-negative (P = 0.022), and 50% for p16-positive versus 19% for p16-negative (P = 0.057). The median survival was 12.9 versus 6.7 months for HPV-positive versus HPV-negative patients (P = 0.014), and 11.9 versus 6.7 months for p16-positive versus p16-negative patients (P = 0.027). After adjusting for other covariates, hazard ratio for OS was 2.69 (P = 0.048) and 2.17 (P = 0.10), favoring HPV-positive and p16-positive patients, respectively. The other unfavorable risk factor for OS was loss of ≥5% weight in previous 6 months (P = 0.0021 and 0.023 for HPV and p16 models, respectively). Conclusion HPV is a favorable prognostic factor in recurrent or metastatic SCCHN that should be considered in the design of clinical trials in this setting. Clinical Trial Identifier NCT01487733 Clinicaltrials.gov.

Purpose Previous analysis of this Intergroup trial demonstrated that with a median follow-up among surviving patients of 45.9 months, the concurrent postoperative administration of cisplatin and radiation therapy improved local-regional control and disease-free survival of patients who had high-risk resectable head-and-neck carcinomas. With a minimum of 10 years of follow-up potentially now available for all patients, these results are updated here to examine long-term outcomes. Methods and Materials A total of 410 analyzable patients who had high-risk resected head-and-neck cancers were prospectively randomized to receive either radiation therapy (RT: 60 Gy in 6 weeks) or identical RT plus cisplatin, 100 mg/m 2 i.v. on days 1, 22, and 43 (RT + CT). Results At 10 years, the local-regional failure rates were 28.8% vs 22.3% ( P =.10), disease-free survival was 19.1% vs 20.1% ( P =.25), and overall survival was 27.0% vs 29.1% ( P =.31) for patients treated by RT vs RT + CT, respectively. In the unplanned subset analysis limited to patients who had microscopically involved resection margins and/or extracapsular spread of disease, local-regional failure occurred in 33.1% vs 21.0% ( P =.02), disease-free survival was 12.3% vs 18.4% ( P =.05), and overall survival was 19.6% vs 27.1% ( P =.07), respectively. Conclusion At a median follow-up of 9.4 years for surviving patients, no significant differences in outcome were observed in the analysis of all randomized eligible patients. However, analysis of the subgroup of patients who had either microscopically involved resection margins and/or extracapsular spread of disease showed improved local-regional control and disease-free survival with concurrent administration of chemotherapy. The remaining subgroup of patients who were enrolled only because they had tumor in 2 or more lymph nodes did not benefit from the addition of CT to RT.

Purpose Concurrent chemoradiation therapy (CCRT) for squamous cell carcinoma of the head and neck (SCCHN) increases local tumor control but at the expense of increased toxicity. We recently showed that several clinical/pretreatment factors were associated with the occurrence of severe late toxicity. This study evaluated the potential relationship between radiation dose delivered to the pharyngeal wall and toxicity. Methods and Materials This was an analysis of long-term survivors from 3 previously reported Radiation Therapy Oncology Group (RTOG) trials of CCRT for locally advanced SCCHN (RTOG trials 91-11, 97-03, and 99-14). Severe late toxicity was defined in this secondary analysis as chronic grade 3-4 pharyngeal/laryngeal toxicity and/or requirement for a feeding tube ≥2 years after registration and/or potential treatment-related death (eg, pneumonia) within 3 years. Radiation dosimetry (2-dimensional) analysis was performed centrally at RTOG headquarters to estimate doses to 4 regions of interest along the pharyngeal wall (superior oropharynx, inferior oropharynx, superior hypopharynx, and inferior hypopharynx). Case-control analysis was performed with a multivariate logistic regression model that included pretreatment and treatment potential factors. Results A total of 154 patients were evaluable for this analysis, 71 cases (patients with severe late toxicities) and 83 controls; thus, 46% of evaluable patients had a severe late toxicity. On multivariate analysis, significant variables correlated with the development of severe late toxicity, including older age (odds ratio, 1.062 per year; P =.0021) and radiation dose received by the inferior hypopharynx (odds ratio, 1.023 per Gy; P =.016). The subgroup of patients receiving ≤60 Gy to the inferior hypopharynx had a 40% rate of severe late toxicity compared with 56% for patients receiving >60 Gy. Oropharyngeal dose was not associated with this outcome. Conclusions Severe late toxicity following CCRT is common in long-term survivors. Age is the most significant factor, but hypopharyngeal dose also was associated.

Purpose The Head and Neck Intergroup conducted a Phase III randomized trial to determine whether the addition weekly cisplatin to daily radiation therapy (RT) would improve survival in patients with unresectable squamous cell head-and-neck carcinoma. Methods and Materials Eligible patients were randomized to RT (70 Gy at 1.8–2 Gy/day) or to the identical RT with weekly cisplatin dosed at 20 mg/m 2 . Failure-free survival (FFS) and overall survival (OS) curves were estimated with the Kaplan-Meier method and compared with the log rank test. Results Between 1982 and 1987, 371 patients were accrued, and 308 patients were found eligible for analysis. Median follow-up was 62 months. The median FFS was 6.5 and 7.2 months for the RT and RT + cisplatin groups, respectively ( p = 0.30). The p value for the treatment difference was p = 0.096 in multivariate modeling of FFS (compared to a p = 0.30 in univariate analysis). Expected acute toxicities were significantly increased with the addition of cisplatin except for in-field RT toxicities. Late toxicities were not significantly different except for significantly more esophageal (9% vs. 3%, p = 0.03) and laryngeal (11% vs. 4%, p = 0.05) late toxicities in the RT + cisplatin group. Conclusion The addition of concurrent weekly cisplatin at 20 mg/m 2 to daily radiation did not improve survival, although there was evidence of activity. Low-dose weekly cisplatin seems to have modest tumor radiosensitization but can increase the risk of late swallowing complications.

Summary A rise in incidence of oropharyngeal squamous cell cancer—specifically of the lingual and palatine tonsils—in white men younger than age 50 years who have no history of alcohol or tobacco use has been recorded over the past decade. This malignant disease is associated with human papillomavirus (HPV) 16 infection. The biology of HPV-positive oropharyngeal cancer is distinct with P53 degradation, retinoblastoma RB pathway inactivation, and P16 upregulation. By contrast, tobacco-related oropharyngeal cancer is characterised by TP53 mutation and downregulation of CDKN2A (encoding P16). The best method to detect virus in tumour is controversial, and both in-situ hybridisation and PCR are commonly used; P16 immunohistochemistry could serve as a potential surrogate marker. HPV-positive oropharyngeal cancer seems to be more responsive to chemotherapy and radiation than HPV-negative disease. HPV 16 is a prognostic marker for enhanced overall and disease-free survival, but its use as a predictive marker has not yet been proven. Many questions about the natural history of oral HPV infection remain under investigation. For example, why does the increase in HPV-related oropharyngeal cancer dominate in men? What is the potential of HPV vaccines for primary prevention? Could an accurate method to detect HPV in tumour be developed? Which treatment strategies reduce toxic effects without compromising survival? Our aim with this review is to highlight current understanding of the epidemiology, biology, detection, and management of HPV-related oropharyngeal head and neck squamous cell carcinoma, and to describe unresolved issues.

Objective We hypothesized that most relapses in patients with esophageal cancer having neoadjuvant chemoradiation therapy would occur outside of the surgical and radiation fields. Methods Recurrence patterns, time to recurrence, and median survival were examined in 267 patients who had esophagectomy after neoadjuvant chemoradiation therapy at Johns Hopkins over 19 years. Results Of 267 patients, 82 (30.7%) showed complete response to neoadjuvant therapy, with 108 (40.4%) and 77 (28.8%) showing partial response or no response, respectively. Recurrence developed in 84 patients (patients with complete response 18/82, 21.4%; patients with partial response 39/108, 36.1%; patients with no response 27/77, 35.1%; P = .055, respectively). Most patients had recurrences at distant sites (65/84;77.4%) regardless of pathologic response, and subsequent survival was brief (median 8.37 months). Median disease-free survival was short (10 months) and did not differ based on recurrence site for patients with partial response or no response, but was longer for patients with complete response with distant recurrence, whose median disease-free survival was 27.3 months (P = .008). By multivariate analysis, no other factor except for pathologic response to neoadjuvant therapy was associated with disease recurrence or death. Patients with partial response or no response were 1.97 and 2.23 times more likely to have recurrence than patients with complete response (P = .024 and P = .012, respectively). Conclusions Most esophageal cancer recurrences after neoadjuvant therapy and surgery are distant, and survival time after recurrence is short regardless of pathologic response. Fewer patients achieving complete response had recurrences, and distant recurrences in these patients manifest later than in patients showing partial response and those showing no response. Only pathologic response is significantly associated with disease recurrence, suggesting that tumor biology and chemosensitivity are critical in long-term patient outcome.

Summary The addition of a planned neck dissection after radiotherapy has traditionally been considered standard of care for patients with positive neck-nodal disease. With the acceptance of chemoradiotherapy as the new primary treatment for patients with locally advanced squamous-cell head and neck cancers, and the increasing numbers of patients who achieve a complete response, the role of planned neck dissection is now being questioned. The accuracy and availability of a physical examination or of different imaging modalities to identify true complete responses adds controversy to this issue. This consensus statement will address some of the controversies surrounding the role of neck dissection following chemoradiotherapy for squamous-cell carcinomas of the head and neck, with particular reference to patients in Asia.

To assess the risk of ipsilateral subclinical neck nodal involvement for early T-stage/node-positive oropharyngeal squamous cell carcinoma.Patients undergoing multilevel upfront neck dissection (ND) at Johns Hopkins Hospital within the last 10 years for early clinical T-stage (cT1-2) node-positive (cN+) oropharyngeal squamous cell carcinoma were identified. Pathologic involvement of Levels IB-V was determined. For each nodal level, the negative predictive value of imaging results was computed by using sensitivity/specificity data for computed tomography (CT). This was used to calculate 1 - negative predictive value, or the risk that a negative level on CT harbors subclinical disease.One hundred three patients met the criteria. Radical ND was performed in 14.6%; modified radical ND, in 70.9%; and selective ND, in 14.6%. Pathologic positivity rates were 9.5%, 91.3%, 40.8%, 18.0%, and 3.3% for Levels IB-V, respectively. Risks of subclinical disease despite negative CT imaging results were calculated as 3.1%, 76.3%, 17.5%, 6.3%, and 1.0% for Levels IB-V, respectively.Levels IB and V are at very low (5%) risk of involvement, even with ipsilateral to pathologically proven neck disease; this can guide radiation planning. Levels II and III should be included in high-risk volumes regardless of imaging results, and Level IV should be included within the lowest risk volume.

Since its start as the Eastern Cooperative Cancer Chemotherapy Group in 1955, the Eastern Cooperative Oncology Group (ECOG) has been at the vanguard of adult cancer clinical research in the United States, and for more than 50 years its research findings have influenced cancer care worldwide. While the cancer clinical research milieu has changed considerably since its inception, the ECOG, through sound leadership and a committed membership, has maintained its pioneering roles in scientific discovery and defining standards of cancer care for all adult cancers.

We aimed to examine deficiencies in established methods of summarising adverse events, and to create a new reporting system (TAME) for summarising the toxicity burden of cancer treatment. TAME consolidates traditional adverse-event data into three risk domains: short-term (acute) Toxicity (T), Adverse long-term (late) effects (A), and Mortality risk (M) generated by a treatment programme (E=End results); and assigns treatments to risk classes for each risk domain.We examined formally an established method for summarising adverse events (the max-grade method) in five trials of patients with head and neck cancer done between September, 1991, and August, 2000, by the Radiation Therapy Oncology Group (RTOG) that involved 13 treatment groups (2304 patients). We calculated TAME summary metrics that included time and multiplicity factors in the same patient groups. We compared relative T values with relative values for toxic effects from the max-grade approach. We also calculated the range of individual patient T scores in two groups from one of the trials (the laryngeal-preservation trial).The max-grade method systematically excluded 29-70% of total reported high-grade (grade 3-4) acute adverse events, contained progressive bias, and favoured higher toxicity programmes. Relative T values in the 13 treatment programmes tested showed an increase of almost 500% in acute toxicity burden (100-590) between treatment groups compared with a 170% increase (100-270) between treatment groups by use of the max-grade method. The difference between these two summary systems was statistically significant (mean difference -102 [95% CI -167 to -37], p=0.005, t test for paired differences). Four risk classes were designated for acute and relative late effects: low (100-140), moderate (150-390), high (400-490), and extreme (or=500). The distribution of individual patient T scores showed that 82 (60%) patients who received concurrent platinum-radiotherapy for larynx preservation reported two or more high-grade events, and 34 (20%) reported four or more high-grade events; these findings differed significantly from the distribution of individual patient T scores for patients who received radiotherapy alone, in which 32 (19%) reported two or more high-grade events and 3 (3%) reported four or more high-grade events (p0.0001). The max-grade method also systematically excluded 26-48% of high-grade (grade 3-4) late adverse events. However, less variation was noted in the relative risk of late events (100-270) by the TAME method for late effects.Traditional methods for summarising adverse events systematically exclude important data, giving an inaccurate impression of the toxicity burden in complex multimodality trials. By contrast, T values use data on all high-grade adverse events. T values are proportional to the intensity of treatment, showing a 500% increase between treatment groups in acute toxicity burden in RTOG trials of head and neck cancer done during this study interval. TAME reporting provides a concise and uniform method to compare relative risk among treatment options. Future studies should include testing the performance of the TAME system in additional datasets (from different research organisations and disease sites), prospective correlation of TAME endpoints with predefined outcome measures, and assessment of its usefulness in clinical decision making.

The optimal regimen for organ preservation for laryngeal cancer remains an area of active investigation. Multiple organ-preservation strategies have been explored, including radiation therapy alone, induction chemotherapy followed by radiation therapy, and concomitant chemoradiotherapy. Until recently, induction chemotherapy followed by radiation therapy was the standard of care for organ preservation in the United States. However, recent data from the Intergroup Trial, R 91-11 has placed concomitant chemoradiotherapy in the forefront as the standard of care for organ preservation. Newer strategies are being investigated and include the use of induction chemotherapy before concomitant chemoradiotherapy and the integration of novel biological agents. It remains to be seen whether such interventions can improve on the excellent locoregional control shown in the landmark Intergroup trial.

To assess the long-term survival results after cisplatin, protracted infusion 5-fluorouracil, and concurrent radiotherapy (RT) followed by surgical resection of esophageal cancer.Ninety-two patients with esophageal cancer (65 with adenocarcinoma and 27 with squamous cell carcinoma) were treated in two sequential protocols of preoperative chemoradiotherapy. The patients had tumor confined to the esophagus and regional nodes, including celiac nodes for middle and distal lesions. In trial A (1989-1994), 50 patients were treated with 44 Gy RT (2 Gy/d) along with concurrent 5-fluorouracil 300 mg/m(2)/d given by protracted venous infusion on Days 1-30 and cisplatin 26 mg/m(2) on Days 1-5 and 26-30. In trial B (1995-1997, 42 patients), the chemotherapy dosages during RT were reduced to 5-fluorouracil 225 mg/m(2)/d protracted venous infusion and cisplatin 20 mg/m(2)/d on Days 1-5 and 16-30; three cycles of paclitaxel 135 mg/m(2)and cisplatin 75 mg/m(2) were given postoperatively. Surgery generally occurred 4-6 weeks after completion of the planned preoperative therapy. Transhiatal resection was performed whenever possible.Of the 92 patients, 86 (93%) underwent surgery (1 refused, 2 died preoperatively, and 3 developed evidence of metastatic disease). Of the 92 patients, 80 (87%) had complete resections with negative margins (3 had positive margins and 3 had distant metastases discovered at surgery). The pathologic complete response rate was 33% (30 of 92). The median follow-up was 63.5 months. The median survival and disease-specific survival for all enrolled patients was 35 and 59 months, respectively. The 5-year survival and disease-specific survival rate was 40% and 49%, respectively. Patients with a pathologic complete response had a 67% survival rate at 5 years (median not reached), and the remainder of patients had a 5-year survival rate of 27% (median 21 months; p0.001). For 21 patients alive after 5 years (60-121 months), 2 died of their disease and all others were disease free. Eight patients with pathologic Stage I tumor at the time of surgery had survival similar to those with a complete response to preoperative therapy. The median survival for patients with pathologic Stage IIA, IIB, III, and IV disease at the time of surgery was 22, 13.5, 18, and 4.9 months, respectively. The pattern of initial failure was local/regional alone in 6% (5 of 90), local/regional plus distant in 3% (3 of 90), and distant alone in 47% (42 of 90). No differences were noted in survival or response rate between those with adenocarcinoma or squamous cell carcinoma.The promising 5-year survival results and low rate of late cancer-related deaths suggest that these regimens of intensive neoadjuvant therapy may improve the overall cure rate. The pathologic stage after neoadjuvant therapy is an important predictor of survival and may be useful in selecting patients for novel adjuvant therapies. Isolated local failure is uncommon, indicating that efforts to improve the therapeutic outcome should focus on optimizing systemic therapy rather than intensifying the RT. Additional randomized data are needed to assess the benefits of this therapeutic approach fully.

Organ-preservation strategies include definitive radiation therapy alone, induction chemotherapy followed by radiotherapy, and concurrent chemoradiotherapy. Over the past decade, induction chemotherapy followed by radiotherapy has been the standard for the nonsurgical management of advanced laryngeal cancer. Over this same period, however, other nonsurgical strategies have been under evaluation. These approaches include radiotherapy with concurrent chemotherapy to take advantage of the radiosensitizing properties of most cytotoxic drugs with activity against squamous cell cancer, altered fractionation radiotherapy, and the incorporation of molecularly targeted therapeutics into multimodality treatment.

Beta-catenin plays important roles in both intercellular adhesion and signal transduction. Mutations in the beta-catenin or adenomatous polyposis coli (APC) gene can alter the degradation of beta-catenin and cause aberrant accumulation of beta-catenin result in increased transcription of target genes. The dysregulated APC/beta-catenin pathway has been recently discovered as an important mechanism of tumorigenesis in various cancers, but its role in esophageal adenocarcinomas is not clear. Therefore, we studied the beta-catenin gene mutation, allelic loss of chromosome 5q, and APC gene mutation in esophageal and esophagogastric junction adenocarcinomas. Two (2%) somatic mutations in exon 3 of the beta-catenin gene, encompassing the region for glycogen synthase kinase-3beta phosphorylation, were detected from 109 adenocarcinomas. Chromosomal allelic loss on 5q was frequent in 45.3% (44/97) of tumors. Only one missense mutation in the mutation cluster region of the APC gene was detected from 38 esophageal and esophagogastric junction adenocarcinomas with the 5q allelic loss. Our results based on partial screening mutational analyses indicate that mutations of APC/beta-catenin pathway, unlike in colorectal carcinoma, involve only a small subset of esophageal and esophagogastric junction adenocarcinoma.

The management of advanced cancers of the larynx and hypopharynx has become increasingly complex as different treatment modalities including surgery, radiation, and chemotherapy have been combined with the goal of improving local disease control and disease-specific survival. A union of 17 comprehensive cancer centers in the United States, the National Comprehensive Cancer Network (NCCN), was formed in 1995 to promote state-of-the-art cancer care. To achieve this goal, multidisciplinary panels of experts from member institutions have created disease-specific practice guidelines for the evaluation and treatment of cancer patients, including head and neck cancers. 47 These guidelines, intended to help clarify and standardize care of patients with head and neck cancers, were based, where possible, on the findings of multicenter randomized, controlled trials. Many decision points in patient management have not been evaluated to date in such trials, however, and therefore data from phase II trials and case series also influenced the treatment guidelines. Although detailed analysis of surgical methods and radiation techniques is beyond the scope of this article, the evolving laryngeal preservation strategies for patients with advanced, resectable hypopharyngeal or laryngeal (including supraglottic and glottic) cancers are reviewed, using the relevant sections of the NCCN practice guidelines as a framework for discussion. Until recently in the United States, the conventional therapy given patients with locally advanced laryngeal (T3 or T4) or hypopharyngeal (T2, T3, or T4) cancers has been total laryngectomy with neck dissection followed by postoperative radiation therapy. 54 Unfortunately, patients treated with laryngectomy suffer a complete loss of voice and sometimes impairment of swallowing function, leading to decreased overall quality of life in many aspects, including nutrition, social functioning, and personal hygiene. These problems motivated the development of laryngeal-preservation approaches. Organ-preservation approaches have included induction chemotherapy followed in responding patients by radiation and primary radiation therapy alone with surgery reserved for treatment failures. After resectable, advanced laryngeal or hypopharyngeal cancer has been diagnosed, patients and their treating physicians must choose among three primary treatment modalities that are currently available. The NCCN practice guidelines present these three options as surgery, induction chemotherapy, or definitive radiation therapy (Figs. 1, 2, and 3). Many factors contribute to the decision-making process, including patient preference, performance status, tumor location and stage, and the treatment practices of the patient's physicians. Recently, the Department of Veterans Affairs (VA) and the European Organization for Research and Treatment of Cancer (EORTC) reported two landmark randomized, controlled trials in patients with advanced, resectable laryngeal or hypopharyngeal cancer. These two large trials compared primary surgical management with a laryngeal preservation approach of induction chemotherapy followed by definitive radiation. The trials demonstrated that overall survival was comparable in the two treatment groups. 16,37 Moreover, laryngeal preservation was enjoyed by one half to two thirds of the surviving patients in the chemotherapy plus radiation therapy group but by none of the primary laryngectomy patients at 5 years. Given that data from these two important trials served as a foundation for the critical decision point of choosing primary therapy shown in the NCCN guidelines, an understanding of the treatment algorithms requires careful consideration of the findings in these two trials.

Over the past decade and a half, several strategies have been developed to improve the survival of patients with esophageal cancer. Two strategies employ either neoadjuvant chemotherapy or chemoradiotherapy followed by surgery to improve local-regional control and decrease the incidence of distant metastases. A third strategy uses nonsurgical therapy as definitive treatment for patients without metastatic disease. Single-institution pilot trials and randomized comparative trials have been conducted evaluating each approach. The rationale for these trials, results, and current recommendations are presented.

During the past 25 years, the Radiation Therapy Oncology Group (RTOG) has played a major role in head and neck cancer clinical research. The major research themes for recent and currently active trials have been: (a) combined modality therapy, (b) altered fractionation radiotherapy, (c) hypoxic cell sensitizers, (d) organ preservation, (e) chemoprevention, and (f) clinical/laboratory correlations. For advanced operable disease, the RTOG showed improved local-regional control with postoperative radiotherapy as compared to preoperative radiotherapy for carcinoma of the supraglottic larynx and hypopharynx. This established the use of surgery followed by postoperative radiotherapy as the standard treatment in subsequent RTOG and Intergroup trials for operable disease. For advanced inoperable disease, the RTOG demonstrated the feasibility of testing altered fractionation radiotherapy in a multiinstitutional clinical trials setting. A Phase III trial comparing hyperfractionation and accelerated fractionation to conventional fractionation is now in progress. Phase I/II combined modality studies established the efficacy of concurrent high-dose cisplatin and radiotherapy in the treatment of advanced disease and provided the basis for further testing in Phase III trials for nasopharyngeal carcinoma, larynx preservation, and high-risk advanced operable disease. Analysis of the extensive RTOG Head and Neck Cancer database established the incidence of second malignancies and their adverse impact on patients whose initial tumors were cured by radiotherapy, and provided the basis for chemoprevention trials. Recursive partitioning analysis identified 6 distinct prognostically homogeneous patient groups based on pretreatment tumor or patient characteristics and/or treatment variables. Retrospective analysis identified tumor p105 antigen density as an independent prognostic indicator in patients irradiated for head and neck cancer. Future trials will continue to focus on the reduction of morbidity and mortality, and improvement of the quality of life of head and neck cancer patients through innovative radiotherapy delivery, multimodality approaches, use of chemical and biological modifiers, and other novel therapies, identification of clinical and biological prognostic indicators, and prevention or diminution of acute morbidity and late complications of the disease and its treatment.

Numerous studies have shown cisplatin-based chemotherapy to be effective in the treatment of head and neck cancer. Cisplatin/5-fluorouracil (5-FU) is the most frequently used combination regimen, but neurotoxicity, ototoxicity, and renal toxicity limit repeated dosing (for long-term treatment of responding patients) and dose intensification. In studies to date, the analogue carboplatin appears to have activity similar to cisplatin, the advantage of no significant neurotoxicity, ototoxicity, or renal toxicity, and less emetic potential. Two randomized trials have shown cisplatin/5-FU and carboplatin/5-FU superior in terms of response rate compared to single-agent therapy. Treatment with combinations of carboplatin/methotrexate and carboplatin/cisplatin is feasible, but myelosuppression is dose-limiting. As an induction regimen, carboplatin/5-FU yields response rates similar to cisplatin/5-FU. Overall, carboplatin has a more favorable toxicity profile for treating head and neck cancer patients who often have multiple medical problems when presenting for palliation of cancer. Reversible myelosuppression is dose-limiting. However, the availability of hematopoietic growth factors may allow investigators to safely intensify dosing, particularly in combined-modality curative treatment regimens for the newly diagnosed patient.

The incorporation of chemotherapy into a combined modality approach for treating newly diagnosed, advanced head and neck cancer has been under evaluation since the 1970s. In this review, the criteria for a well-designed prospective randomized trial are delineated based on prognostic factors determined from singleinstitution induction chemotherapy trials. The results of randomized controlled trials conducted from 1978 to the present are discussed with respect to their impact on survival, locoregional disease control, and the development of distant metastasis. Each study is then critiqued for its design, conduct, and interpretation. Organ preservation, improved locoregional control, and survival are important goals for future trials.

Conclusions: Women aged 40 or older diagnosed with breast cancer with an age-adjusted mammogram frequency on average at least annually were more often diagnosed with noninvasive stage 0 breast cancer than women with less frequent screening or no prior mammography. Women with any history of mammography prior to time of diagnosis also presented with earlier stage invasive disease and smaller tumor size. This was associated with greater eligibility for breast conservation and less frequent recommendation for mastectomy for women with prior mammogram screening. This study confirms the benefits of regular mammographic screening for women 40 years or older, and supports an annual interval for most often detecting the most curable stage 0 form of breast cancer.