Altered Fractionation Radiotherapy Research Articles

Organ-sparing radiation therapy for head and neck cancer

To improve locoregional tumor control and survival in patients with locally advanced head and neck cancer (HNC), therapy is intensified using altered fractionation radiation therapy or concomitant chemotherapy. However, intensification of therapy has been associated with increased acute and late toxic effects. The application of advanced radiation techniques, such as 3D conformal radiation therapy and intensity-modulated radiation therapy, is expected to improve the therapeutic index of radiation therapy for HNC by limiting the dose to critical organs and possibly increasing locoregional tumor control. To date, Review articles have covered the prevention and treatment of radiation-induced xerostomia and dysphagia, but few articles have discussed the prevention of hearing loss, brain necrosis, cranial nerve palsy and osteoradionecrosis of the mandible, which are all potential complications of radiation therapy for HNC. This Review describes the efforts to prevent therapy-related complications by presenting the state of the art evidence regarding advanced radiation therapy technology as an organ-sparing approach.

A Prospective Investigation of Swallowing, Nutrition, and Patient-rated Functional Impact Following Altered Fractionation Radiotherapy with Concomitant Boost for Oropharyngeal Cancer

Altered fractionation radiotherapy for head and neck cancer has been associated with improved locoregional control, overall survival, and heightened toxicity compared with conventional treatment. Swallowing, nutrition, and patient-perceived function for altered fractionation radiotherapy with concomitant boost (AFRT-CB) for T1-T3 oropharyngeal squamous cell carcinoma (SCC) have not been previously reported. Fourteen consecutive patients treated with AFRT-CB for oropharyngeal SCC were recruited from November 2006 to August 2009 in a tertiary hospital in Brisbane, Australia. Swallowing, nutrition, and patient-perceived functional impact assessments were conducted pretreatment, at 4-6weeks post-treatment, and at 6months post-treatment. Deterioration from pretreatment to 4-6weeks post-treatment in swallowing, nutrition, and functional impact was evident, likely due to the heightened toxicity associated with AFRT-CB. There was significant improvement at 6months post-treatment in functional swallowing, nutritional status, patient-perceived swallowing, and overall function, consistent with recovery from acute toxicity. However, weight and patient perception of physical function and side effects remained significantly worse than pretreatment scores. The ongoing deficits related to weight and patient-perceived outcomes at 6months revealed that this treatment has a long-term impact on function possibly related to the chronic effects of AFRT-CB.

Evidence‐based review of treatment options for patients with glottic cancer

Evidence-based medicine integrates the best available data in decision making, with the goal of minimizing physicians' and patients' subjectivity. In 2006, the American Society of Clinical Oncology edited clinical practice guidelines for the use of larynx preservation strategies. The objective of this review was to evaluate the current levels of evidence for glottic squamous cell carcinoma. Current guidelines for early stage glottic cancer are based on low-level evidence. Conservation surgery (open or transoral) and radiation therapy are all valid options for T1 and selected T2 lesions. For advanced lesions, surgery and combined chemotherapy and radiation are options. High-level evidence favors combined chemotherapy and radiation therapy or altered fractionation radiation therapy as nonsurgical strategies for organ preservation, compared with radiation therapy alone. The optimal combination of chemotherapy, targeted therapy, and radiation therapy remains to be demonstrated, however, and for high-volume tumors, total laryngectomy may still be warranted.

Hyperfractionated or accelerated radiotherapy for head and neck cancer.

Several trials have studied the role of altered fractionation radiotherapy in head and neck squamous cell carcinoma, but the effect of such treatment on survival is not clear. The aim of this individual patient data (IPD) meta-analysis was to assess whether this type of radiotherapy could improve survival. We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; CENTRAL (2010, Issue 3); PubMed; EMBASE; CINAHL; Web of Science; BIOSIS Previews; Cambridge Scientific Abstracts; ISRCTN and additional sources for published and unpublished trials. The date of the most recent search was 8 August 2010. We identified randomised trials comparing conventional radiotherapy with hyperfractionated or accelerated radiotherapy, or both, in patients with non-metastatic head and neck squamous cell carcinomas and grouped trials into three pre-specified treatment categories: hyperfractionated, accelerated and accelerated with total dose reduction. Trials were eligible if they began recruitment after 1969 and ended before 1998. We obtained updated individual patient data. Overall survival was the main outcome measure. The secondary outcome measures were local or regional control rates (or both), distant control rates and cause-specific mortality. We included 15 trials with 6515 patients. The median follow up was six years. Tumour sites were mostly oropharynx and larynx; 5221 (74%) patients had stage III-IV disease (UICC 2002). There was a significant survival benefit with altered fractionation radiotherapy, corresponding to an absolute benefit of 3.4% at five years (hazard ratio (HR) 0.92, 95% CI 0.86 to 0.97; P = 0.003). The benefit was significantly higher with hyperfractionated radiotherapy (8% at five years) than with accelerated radiotherapy (2% with accelerated fractionation without total dose reduction and 1.7% with total dose reduction at five years, P = 0.02). There was a benefit in locoregional control in favour of altered fractionation versus conventional radiotherapy (6.4% at five years; P < 0.0001), which was particularly efficient in reducing local failure, whereas the benefit on nodal control was less pronounced. The benefit was significantly higher in the youngest patients (under 50 year old) (HR 0.78, 95% CI 0.65 to 0.94), 0.95 (95% CI 0.83 to 1.09) for 51 to 60 year olds, 0.92 (95% CI 0.81 to 1.06) for 61 to 70 year olds, and 1.08 (95% CI 0.89 to 1.30) for those over 70 years old; test for trends P = 0.007). Altered fractionation radiotherapy improves survival in patients with head and neck squamous cell carcinoma. Comparison of the different types of altered radiotherapy suggests that hyperfractionation provides the greatest benefit. An update of this IPD meta-analysis (MARCH 2), which will increase the power of this analysis and allow for other comparisons, is currently in progress.

Interventions for the treatment of oral cavity and oropharyngeal cancer: radiotherapy.

The management of advanced oral cavity and oropharyngeal cancers is problematic and has traditionally relied on surgery and radiotherapy, both of which are associated with substantial adverse effects. Radiotherapy has been in use since the 1950s and has traditionally been given as single daily doses. This method of dividing up the total dose, or fractionation, has been modified over the years and a variety of approaches have been developed with the aim of improving survival whilst maintaining acceptable toxicity. To determine which radiotherapy regimens for oral cavity and oropharyngeal cancers result in increased overall survival, disease free survival, progression free survival and locoregional control. The following electronic databases were searched: the Cochrane Oral Health Group's Trials Register (to 28 July 2010), CENTRAL (The Cochrane Library 2010, Issue 3), MEDLINE via OVID (1950 to 28 July 2010) and EMBASE via OVID (1980 to 28 July 2010). There were no restrictions regarding language or date of publication. Randomised controlled trials where more than 50% of participants had primary tumours of the oral cavity or oropharynx, and which compared two or more radiotherapy regimens, radiotherapy versus other treatment modality, or the addition of radiotherapy to other treatment modalities. Data extraction and assessment of risk of bias was undertaken independently by two or more authors. Study authors were contacted for additional information as required. Adverse events data were collected from published trials. 30 trials involving 6535 participants were included. Seventeen trials compared some form of altered fractionation (hyperfractionation/accelerated) radiotherapy with conventional radiotherapy; three trials compared different altered fractionation regimens; one trial compared timing of radiotherapy, five trials evaluated neutron therapy and four trials evaluated the addition of pre-operative radiotherapy. Pooling trials of any altered fractionation radiotherapy compared to a conventional schedule showed a statistically significant reduction in total mortality (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.76 to 0.98). In addition, a statistically significant difference in favour of the altered fractionation was shown for the outcome of locoregional control (HR 0.79, 95% CI 0.70 to 0.89). No statistically significant difference was shown for disease free survival.No statistically significant difference was shown for any other comparison. Altered fractionation radiotherapy is associated with an improvement in overall survival and locoregional control in patients with oral cavity and oropharyngeal cancers. More accurate methods of reporting adverse events are needed in order to truly assess the clinical performance of different radiotherapy regimens.

Treatment Outcomes of Locally Advanced Oropharyngeal Cancer: A Comparison Between Combined Modality Radio-Chemotherapy and Two Variants of Single Modality Altered Fractionation Radiotherapy

To compare outcomes in patients with locally advanced oropharyngeal cancer treated with radio-chemotherapy (RT-CT), accelerated fractionation radiotherapy (AccRT), or hypofractionated radiotherapy (HypoRT). Subjects were 321 consecutive patients with newly diagnosed oropharyngeal cancer, Stage III or IVA/B, treated between January 2001 and December 2005 at the BC Cancer Agency with RT-CT (n = 157), AccRT (n = 57), or HypoRT (n = 107). Outcomes examined were disease-specific survival (DSS), locoregional control (LRC), overall survival (OS), rate of G-tube use, and rate of hospitalization for acute complications. Median follow-up was 3.4 years. Three-year Kaplan-Meier DSS with RT-CT, AccRT, and HypoRT were 80%, 81%, and 74%, respectively (p = 0.219). Cox regression analysis identified treatment modality as a significant factor affecting DSS (p = 0.038). Compared with RT-CT, the hazard ratio (HR) for DSS was 1.0 with AccRT and 2.0 with HypoRT (p = 0.021). Kaplan-Meier pairwise comparisons found no significant difference in LRC and OS between RT-CT and AccRT. HypoRT was associated with significantly lower LRC (p = 0.005) and OS (p = 0.008) compared with RT-CT. There were significant differences in the rates of G-tube use (p < 0.001) and of hospitalization (p = 0.036) among the three treatment groups, with the most frequent rates observed in the RT-CT group. In patients with locally advanced oropharyngeal cancer, AccRT conferred DSS, LRC, and OS comparable to that of RT-CT. Patients treated with RT-CT experienced higher rates of treatment-related acute toxicities. HypoRT was associated with the least favorable outcomes.

Concomitant weekly cisplatin and altered fractionation radiotherapy in locally advanced head and neck cancer

Both concomitant chemotherapy and altered fractionation radiotherapy (RT) have been shown to improve outcomes for patients with locoregionally advanced head and neck squamous cell carcinomas. However, both strategies also increase acute toxicity, and it is questionable whether the 2 can be safely combined. Traditional concomitant chemotherapy regimens include high-dose cisplatin given at 100 mg/m2 every 3 weeks. The authors' purpose was to report efficacy and toxicity after weekly cisplatin (30 mg/m2/wk) concurrent with altered fractionation RT. One hundred twenty-one patients with American Joint Committee on Cancer stages II (3%), III (13%), or IV (84%) squamous cell carcinomas of the oropharynx (70%), hypopharynx (20%), or larynx (10%) were treated between 2000 and 2006 at the University of Florida with hyperfractionated RT (55 patients) or concomitant boost RT (66 patients) and concomitant cisplatin (30 mg/m2/wk). Median follow-up was 2.9 years; median follow-up on survivors was 3.6 years. Seventy-nine percent of patients completed ≥6 cycles of chemotherapy; 94% received ≥7200 centigrays. Seven (6%) patients changed from cisplatin to carboplatin because of bone marrow toxicity. Gastrostomy tube feeding was required in 54% of patients either before (16%) or during RT (38%). Two (1.6%) patients died from therapy-related complications. The 5-year outcomes were: local control, 83%; locoregional control, 79%; distant metastasis-free survival, 88%; cause-specific survival, 76%; and overall survival, 59%. Seven (6%) patients had severe late complications. Three (3%) patients required a permanent gastrostomy tube. Concomitant weekly cisplatin with altered fractionation RT is a safe and effective treatment regimen.

Cetuximab in the management of locoregionally advanced head and neck cancer: Expanding the treatment options?

The treatment of locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) has evolved in recent years as a consequence of a better understanding of the potential benefits associated with altered radiation fractionation regimens, concurrently administered chemotherapy and radiotherapy (chemoradiotherapy) and induction chemotherapy. Concurrent chemoradiotherapy is a treatment option for technically resectable disease, where functional morbidity precludes the use of surgery. Induction chemotherapy followed by radiotherapy may also be used in this setting, and has been validated for larynx preservation. Concurrent chemoradiotherapy is a standard treatment approach for medically fit patients with locoregionally advanced unresectable disease. However, the toxicity burden of additional chemotherapy in both the concurrent chemoradiotherapy and induction chemotherapy settings can have implications for treatment compliance and may impede the administration of chemotherapy and/or radiotherapy to schedule. The epidermal growth factor receptor (EGFR)-targeted IgG1 monoclonal antibody, cetuximab (Erbitux®), has shown significant clinical benefits in the treatment of both locoregionally advanced and recurrent and/or metastatic SCCHN. A phase III study in locoregionally advanced disease demonstrated significant improvements in locoregional control and progression-free and overall survival with cetuximab plus radiotherapy compared with radiotherapy alone, and overall survival benefits were maintained at 5 years. The addition of cetuximab to concurrent chemoradiotherapy has been shown to be feasible in phase II trials and is being investigated in phase III trials. Preliminary evidence suggests that cetuximab could be incorporated into induction management strategies. Taken together, these data support an important role for cetuximab in the treatment paradigm for locoregionally advanced SCCHN.

Hyperfractionated radiation therapy and concurrent chemotherapy for advanced head and neck cancer.

5566 Background: Extensive clinical research aimed at improving locoregional tumor control as well as functional outcome of patients with locally advanced head and neck cancer, using altered radiation fractionation schemes and combination with chemotherapy. We investigated the feasibility of combining hyperfractionated radiotherapy with concomitant chemotherapy, and to assessed its toxicity, in those patients. Progression-free survival, and overall survival, were set as secondary end points. Methods: Between November 2003 and November of 2007, 48 patients with stage III and IV HNC who met the eligibility criteria were enrolled in the study. All the patients had unresectable disease. Hyperfractionated Radiation consisted of 120 cGy twice daily, 6 hours apart, for a total of 69.6 Gys in 58 fractions over 6 weeks. Three cycles of concurrent chemotherapy (cisplatin and 5-fluorouracil) were delivered during weeks 1, 4, and 6 of irradiation. Results: The treatment was delivered in a median overall period of 54 days, with a recorded median delay of 7 days. Grade 4 skin toxicity was experienced by 4.1% of patients only. Therapy was well tolerated (grade 3 mucositis in 21%, grade 4 in 26%, grade 3 leukopenia in 10%). Weight loss more than 10 kg was reported in 10 (16.7%) of the cases. The most common late toxicity was mild to moderate xerostomia which was encountered in 34 (70.8%) cases and improved thereafter. Hypothyroidism was encountered in 7 (14.6%) of the cases. Complete response (CR) was observed in 40 (83.3%) of patients. Partial response (PR) was achieved in the remaining 8 (16.7%) patients. Disease relapse occurred in 9 (18.8%) patients after complete responce. 3 patients relapsed locally, 5 patients developed distant metastasis, and one patient developed both local and distant metastasis. 2 patients (4.1%) died of treatment complications, 8 patients (16.7%) died with progressive locoregional, and metastatic disease. The 2- year disease free survival was 77%. Conclusions: Hyperfractionated radiotherapy and concurrent chemotherapy is tolerable. Results regarding LC and OS are encouraging as compared to conventional radiotherapy and concurrent chemotherapy. No significant financial relationships to disclose.

Concurrent radiochemotherapy in advanced hypopharyngeal cancer

BackgroundConcurrent platinum-based radiochemotherapy has been recommended as a standard of care in patients with locally advanced squamous cell head and neck carcinomas. Unfortunately, there is a lack of level one evidence on best treatment approach for advanced hypopharyngeal cancer. This report aims to summarize the results of our study on concurrent radiochemotherapy in patients with advanced hypopharyngeal cancer.MethodsA retrospective analysis of 41 patients with stage III-IV hypopharyngeal cancer was performed. All patients were treated with three dimensional conformal radiotherapy and received 70 Gy in 35 fractions (2 Gy per fraction, 5 fractions per week). In dependence of the period when radiotherapy was realized, two different treatment techniques were used. Concurrent chemotherapy consisted of cisplatin 30 mg/m2 given on a weekly basis.ResultsThe median age was 52 years (range 29-70). Stage IV disease was recognized in 73.2% of the patients. Complete response rates at the primary site and at the metastatic neck lymph nodes were 68.3% and 36.6%, respectively. A complete composite response was present in 27 patients (65.9%). Median follow-up was 13 months (range 7-36). Distant metastases as initial failure occurred in 7 patients (46.7%). The 2-year local relapse-free survival and regional relapse-free survival rates were 55.2% and 75.8%, respectively. The 2-year locoregional relapse-free survival rate was 51.3%. The 2-year disease-free survival and overall survival rates were 29.3% and 32.8%, respectively. Confluent mucositis was developed in 46.3% of patients. Leucopenia grade 1 was the most frequent hematological toxicity. The median weight loss at the end of treatment was 12% (range 5-21). The worst grade of late toxicity was most commonly pronounced in the skin and in the subcutaneous tissue.ConclusionsBased on unsatisfactory results in our study we suggest that the use of sequential radiochemotherapy or chemotherapy given concomitantly with altered fractionation radiotherapy with the implementation of intensity-modulated radiotherapy as radiotherapy technique could represent treatment approaches able to improve outcome in patients with advanced hypopharyngeal cancer.

ACR Appropriateness Criteria ® Nonsurgical Treatment for Non-Small-Cell Lung Cancer: Good Performance Status/Definitive Intent

The optimal strategy for the non-surgical definitive treatment of patients with good performance status non-small cell lung cancer (mostly with locally advanced disease) has dramatically evolved over time. This article presents evidence-based data to review this literature. Several decades ago, the standard treatment for most stage III inoperable NSCLC was definitive radiation therapy alone. Randomized trials have since shown superior results with sequential chemotherapy and radiation, and more recently with concurrent chemoradiation, the current standard of care. Studies suggest a limited role for induction or adjuvant systemic therapy in addition to concurrent chemoradiation. The role of altered radiation fractionation techniques, such as hyperfractionation for locally advanced disease or hypofractionation for early stage disease is also discussed. More recently, the application of more advanced radiation techniques has been explored, including intensity modulated radiation therapy (IMRT) and proton beam radiation. Finally, various case variants are presented as examples of state-of-the-art treatment approaches.

Definitive Altered Fractionation Radiotherapy and Concomitant Weekly Cisplatin for Locally Advanced Head and Neck Cancer

The purpose of this study was to determine the efficacy and toxicities of single-agent weekly cisplatin for patients with squamous cell carcinoma of the head and neck treated definitively with radiation therapy (RT). Thirty-five patients with American Joint Committee of Cancer stage II (3%), stage III (14%), or stage IV (83%) squamous cell carcinoma of the oropharynx, larynx, or hypopharynx treated from June 2000 to November 2003 at the University of Florida were retrospectively reviewed. Subjects received radiation therapy (RT; median, 74.4 Gy) and cisplatin, 30 mg/m2/wk. Altered fractionation was used in 34 of 35 (97%) patients. The endpoints were best response, percentage of grade III or IV toxicities, local-regional control, disease-free survival, cause-specific survival, and overall survival. The median number of cycles of cisplatin administered was 6. Grade III or IV toxicities were: anemia, 11%; thrombocytopenia, 6%; leukopenia, 26%; and mucositis, 23%. No patients had renal failure and 1 patient (3%) died because of therapy-related complications. Responses to therapy included 71% complete response, 17% partial response, and 6% stable disease. Median follow-up for all patients was 1.8 years (range, 0.1-7.8 years); median follow-up for living patients was 4.4 years (range, 2.6-7.8 years). The 3-year outcomes were: local-regional control, 85%; disease-free survival, 56%; cause-specific survival, 59%; and overall survival, 40%. Concomitant weekly CDDP with definitive RT is feasible, tolerable, highly active, and comparable with more complex, costly, and toxic regimens. Intercurrent disease was a significant contributor to mortality in our population. Our regimen is an attractive alternative to sequential chemoradiotherapy programs.

Chemotherapy Alone for Laryngeal Preservation—Is It Possible?

Holsinger et al 1 report the results of a phase II trial testing chemotherapy alone as definitive treatment for preservation of the larynx in selected patients with stages II to IV laryngeal cancer. This study is the first of its kind in the United States, even though the approach has been tried in France by Laccourreye et al 2,3 in patients with T1 to T3N0 glottic cancers. In their study, Holsinger et al were careful to select patients with T2 to T4 cancers of the glottic or supraglottic larynx who could be treated with conservation laryngeal surgery. Using a regimen of cisplatin plus ifosfamide plus paclitaxel (TIP), chemotherapy alone proved successful, with no local or regional failures in 10 patients (32%) demonstrating biopsy-confirmed complete response (CR) out of 31 patients enrolled. These results are important because they underscore the sensitivity of squamous cell cancer of the larynx to cisplatin-based chemotherapy, the potential for chemotherapy as a single-modality treatment option in selected patients with laryngeal cancer, conservation laryngeal surgery as an organ-preserving option for appropriate patients selected by an experienced team, and the importance of a multidisciplinary care team in the evaluation, management, and follow-up of patients with head and neck cancer. Seven years were required for the accrual of nine patients with T3 or T4, N0 or N1 cancers suitable for conservation laryngeal surgery, in addition to the 22 patients with T2N0 or N1 cancers who were identified as being at high risk for recurrence with altered fractionation radiotherapy, and who were also candidates for conservation laryngeal surgery. These 31 patients, all of whom had excellent performance status, received either three or four cycles of TIP followed by response assessment. All patients achieved either a CR or partial response to TIP. If a CR was determined on the basis of imaging, endoscopic examination, and negative biopsy, additional cycles of TIP were administered (up to a maximum of six cycles), after which patients were rigorously monitored. Patients with less than a biopsy-proven CR underwent appropriate laryngeal surgery, with or without neck dissection and radiation, as indicated. A high rate of laryngeal preservation was achieved (83%; 95% CI, 65 to 94), significantly better than the rate of 60%, which had been determined— on the basis of previous studies 4,5 of stage III and IV laryngeal cancers treated for organ preservation in patients in whom total laryngectomy would otherwise have been required— sufficient for declaring the treatment a success. Clearly, the bar had been set too low for this patient group, in which stage II disease was predominant, and which was suitable for conservation laryngeal surgery from the outset. The estimated survival outcomes at 5 years were an overall survival of 83% (95% CI, 70 to 98) and a recurrence-free survival (deaths not resulting from study cancer were censored) of 73% (95% CI, 58 to 91), suggesting that the treatment approach was not detrimental. Standard of care management of laryngeal cancer varies with

Radiotherapy for the management of locally advanced squamous cell carcinoma of the head and neck

Squamous cell carcinomas of the head and neck (SCCHN) affect approximately 35 000 people in the United States yearly. Although survival has improved with advances in therapy, patients with advanced stages of SCCHN continue to have a poor prognosis. An understanding of rationale for treatment selection, newer developments in therapy, and treatment toxicity is critical. Standard methods of treating locally advanced SCCHN are reviewed. Advances in medical and radiotherapeutic management are discussed and the toxicities of therapy are described. Postoperative chemoradiation is used in patients with high-risk characteristics. Induction chemotherapy and altered fractionation radiation treatment have been evaluated as alternatives to definitive chemo-radiotherapy. Targeted agents such as cetuximab may prove to increase survival with minimal increase in toxicity profile. Technological improvements such as the use of intensity-modulated radiation treatment have proven to decrease some debilitating side effects from radiation treatment. Locally advanced SCCHN continues to present a therapeutic challenge. Survival, local control, and quality of life are all goals of treatment. The optimal method of treating locally advanced SCCHN is the subject of ongoing research. Long-term side effects can be minimized with the use of newer technologies and with careful treatment planning.

Radiation induced oral mucositis.

Patients receiving radiotherapy or chemotherapy will receive some degree of oral mucositis The incidence of oral mucositis was especially high in patients: (i) With primary tumors in the oral cavity, oropharynx, or nasopharynx; (ii) who also received concomitant chemotherapy; (iii) who received a total dose over 5,000 cGy; and (iv) who were treated with altered fractionation radiation schedules. Radiation-induced oral mucositis affects the quality of life of the patients and the family concerned. The present day management of oral mucositis is mostly palliative and or supportive care. The newer guidelines are suggesting Palifermin, which is the first active mucositis drug as well as Amifostine, for radiation protection and cryotherapy. The current management should focus more on palliative measures, such as pain management, nutritional support, and maintenance, of good oral hygiene

Multidisciplinary Management of Locally Advanced SCCHN: Optimizing Treatment Outcomes

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.

Factors Associated With Long-Term Dysphagia After Definitive Radiotherapy for Locally Advanced Head-and-Neck Cancer

The use of altered fractionation radiotherapy (RT) regimens, as well as concomitant chemotherapy and RT, to intensify therapy for locally advanced head-and-neck cancer can lead to increased rates of long-term dysphagia. We identified 122 patients who had undergone definitive RT for locally advanced head-and-neck cancer, after excluding those who had been treated for a second or recurrent head-and-neck primary, had Stage I-II disease, developed locoregional recurrence, had <12 months of follow-up, or had undergone postoperative RT. The patient, tumor, and treatment factors were correlated with a composite of 3 objective endpoints as a surrogate for severe long-term dysphagia: percutaneous endoscopic gastrostomy tube dependence at the last follow-up visit; aspiration on a modified barium swallow study or a clinical diagnosis of aspiration pneumonia; or the presence of a pharyngoesophageal stricture. A composite dysphagia outcome occurred in 38.5% of patients. On univariate analysis, the primary site (p = 0.01), use of concurrent chemotherapy (p = 0.01), RT schedule (p = 0.02), and increasing age (p = 0.04) were significantly associated with development of composite long-term dysphagia. The use of concurrent chemotherapy (p = 0.01), primary site (p = 0.02), and increasing age (p = 0.02) remained significant on multivariate analysis. The addition of concurrent chemotherapy to RT for locally advanced head-and-neck cancer resulted in increased long-term dysphagia. Early intervention using swallowing exercises, avoidance of nothing-by-mouth periods, and the use of intensity-modulated RT to reduce the dose to the uninvolved swallowing structures should be explored further in populations at greater risk of long-term dysphagia.

A multidisciplinary approach to squamous cell carcinomas of the head and neck: an update

The treatment of locally advanced squamous cell carcinoma of the head and neck has improved with the addition of chemotherapy to radiotherapy. Other approaches are being investigated to improve the clinical benefit at an acceptable level of toxicity. The present review summarizes recently published data on the treatment of locally advanced squamous cell carcinoma of the head and neck. Altered radiation fractionation regimens have been shown to increase efficacy, and induction chemotherapy may offer clinical benefits. One of the most important advances in this setting has been the demonstration that addition of the epidermal growth factor receptor-targeted monoclonal antibody, cetuximab, to radiotherapy improves locoregional control and overall survival compared with radiotherapy alone. The survival benefit of this combination appears to be of at least the same magnitude as that seen with chemoradiotherapy, but the combination is not associated with the high level of toxicity that characterizes chemoradiotherapy. The use of more sensitive instruments for adverse event recording may provide a better picture of the toxicity burden. Although the further modification of radiotherapy and chemotherapy within chemoradiotherapy regimens is unlikely to offer major clinical benefits, it is likely that any significant advances will be made with the incorporation of novel agents into treatment regimens. The combination of cetuximab and radiotherapy forms a new standard for the treatment of locally advanced squamous cell carcinoma of the head and neck.

Concurrent Chemoradiotherapy in the Management of Squamous Cell Cancer of the Oropharynx: Current Standards and Future Directions

The use of radiotherapy and concurrent chemotherapy has been explored in the management of squamous cell head and neck cancer for more than 3 decades. Even the earliest phase II and phase III studies, which used conventional radiotherapy and single-agent chemotherapy with drugs such as fluorouracil, bleomycin, and cisplatin, suggested a survival benefit from this approach. Validation of concurrent chemoradiotherapy as a community standard occurred in 1996, with the initial report from INT 0099, a randomized trial comparing radiotherapy alone with concurrent radiation and single-agent cisplatin, followed by adjuvant fluorouracil and cisplatin in patients with advanced nasopharyngeal cancer (1). This study, subsequently published in 1998, demonstrated a highly significant progression-free and overall survival advantage for patients treated with the combinedmodality regimen, and this regimen was rapidly accepted as a standard of care for advanced nasopharyngeal cancer. Also in 1998 came a report from a large meta-analysis of updated, individual data assessing the role of chemotherapy in squamous cell head and neck cancer (2). Patients from randomized trials conducted between 1965 and 1993 were included. This analysis, subsequently published in 2000, reviewed results from 63 separate trials involving 10,741 patients, comparing locoregional treatment with or without chemotherapy. Although no overall survival benefit was seen for treatment schedules using either induction or adjuvant chemotherapy,ahighlysignificantsurvivalbenefitwasidentified for concomitant chemotherapy and radiation. A hazard ratio of 0.81 (95% Confidence Interval (CI), 0.76‐0.88) with a p value of <0.0001 and an 8% 5-year survival benefit was observed, even from these older studies. Although oropharynx cancer often predominated in these clinical trials, they were, in general, not site specific. Nonetheless, this meta-analysis further justified the use of concurrent chemoradiotherapy as a standard nonoperative treatment for this disease. Results from a North American Intergroup trial of chemoradiotherapy in patients with unresectable head-and-neck tumors were first presented in 2000 and were published in 2003 (3). This study compared radiotherapy alone with radiotherapy and single-agent cisplatin and a third arm using a split course of radiotherapy and concurrent combination fluorouracil and cisplatin. As seen in nasopharynx cancer, the concurrent chemoradiotherapy arm using single-agent cisplatin proved superior to radiotherapy alone, with a projected 3-year survival improvement from 23% to 37% and a median survival improvement from 12.6 to 19.1 months (p = 0.014). The third treatment arm, which used a split course of radiotherapy, did not prove to be statistically different from the other two arms, an observation attributed to the scheduled break in radiotherapy delivery on this arm of the trial. This Intergroup study firmly established concurrent chemoradiotherapy with single-agent cisplatin as a treatment standard for unresectable head and neck cancer. Although it was not a site-specific study, primary tumors in the oropharynx predominated in the study population. During this same period, several other smaller single- and multi-institution trials were also published, comparing various combinations of concurrent chemotherapy and radiotherapy with radiotherapy alone as definitive treatment for this disease. In general, they were also not site-specific studies. The results, however, were very consistent. The addition of concurrent chemotherapy to radiotherapy reproducibly improved both survival and locoregional control.

A Prospective Phase II Study of Induction Carboplatin and Vinorelbine followed by Concomitant Topotecan and Accelerated Radiotherapy (ART) in Locally Advanced Non-small Cell Lung Cancer (NSCLC)

Survival of locally advanced/unresectable non-small cell lung cancer (NSCLC) has improved with the use of concurrent radiation and chemotherapy over the past decades, but local and distant failure remain high. In addition, a key limiting factor in combining chemotherapy with accelerated radiotherapy (ART) is severe esophagitis. We investigated the toxicity, response rate, and overall survival (OS) with induction carboplatin and vinorelbine followed by concomitant topotecan and ART in patients with locally advanced/unresectable NSCLC. In this phase II trial, stage IIIA or IIIB NSCLC patients with a Karnofsky performance score >60 were eligible. Patients received induction carboplatin (area under the curve = 5.5) on days 1 and 22, and vinorelbine (25 mg/m2) on days 1, 8, 22, and 29. During the concurrent chemoradiation, patients received intravenous topotecan (0.5 mg/m2) on days 43 to 47, days 57 to 61, and days 71 to 75 before the morning radiotherapy (RT) fraction. RT was administered in an accelerated fashion at 2 Gy per fraction, twice daily for five consecutive days, every other week, to a cumulative dose of 60 Gy during a 5-week period. Thirty-seven patients were accrued; of these, 35 were evaluable. Overall response rate was 71% (14% complete response, 57% partial response). Six of 35 (17%) patients had stable disease. Four (11%) patients progressed during treatment. At a median follow-up of 45 months for surviving patients, the median survival based on Kaplan-Meier estimates is 17.9 months. OS at 1, 2, and 3 years is 62%, 41%, and 33%, respectively. Actuarial 5-year OS is 21%. The median time to first relapse is 12.2 months (9.1-24.7 months). There were no cases of grade 3 or 4 esophagitis. This combined-modality regimen yielded encouraging OS rates, with no severe esophagitis. Using four-dimensional RT treatment planning, we plan to further evaluate altered fractionation RT and chemotherapy for this group of patients.