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PURPOSE: To examine the role age plays in the treatment and prognosis of locally advanced head and neck cancer (LAHNC) treated definitively with radiation alone or combined modality therapy. METHODS: A retrospective analysis was performed of three NRG/RTOG trials examining either radiation alone or combined radiation and systemic therapy for LAHNC. The effect of age (≥70 yrs.) on cause-specific survival (CSS), overall survival (OS), and toxicity was evaluated. RESULTS: A total of 2688 patients were analyzed, of whom 309 patients (11.5%) were ≥ 70. For all studies combined, the hazard ratio (HR) for CSS for patients age ≥ 70 vs. those <70 was 1.33 (95%CI: 1.14-1.55, p < 0.001). For OS, the HR for patients age ≥ 70 vs. those <70 for all studies combined was 1.55 (95% CI 1.35-1.77, p < 0.001). After adjustment for all covariates, age ≥ 70 was associated with worse OS regardless of adjustment for smoking and p16 status. The survival difference was more pronounced in those receiving combined radiation and systemic therapy. Hematologic and renal toxicities were increased in combined modality trials in patients ≥70 years old. CONCLUSIONS: Patients age ≥ 70 with LAHNC were underrepresented in these clinical trials. Their CSS and OS proved inferior to patients <70 years old.
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Quimioradioterapia , Neoplasias de Cabeza y Cuello , Anciano , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Pronóstico , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
BACKGROUND: Is posttreatment functional status prognostic of overall survival in patients with head and neck cancer (HNC). METHODS: In an HNC clinical trial, 495 patients had two posttreatment functional assessments measuring diet, public eating, and speech within 6 months. Patients were grouped by impairment (highly, moderately, modestly, or not impaired) and determined if they improved, declined, or did not change from the first assessment to the second. Multivariable Cox models estimated overall mortality. RESULTS: Across all three scales, the change in posttreatment patient function strongly predicted overall survival. In diet, patients who declined to highly impaired had three times the mortality of patients who were not impaired at both assessments (hazard ratio [HR] = 3.60; 95% confidence interval, 2.02-6.42). For patients improving from highly impaired, mortality was statistically similar to patients with no impairment (HR = 1.38; 95% CI, 0.82-2.31). CONCLUSIONS: Posttreatment functional status is a strong prognostic marker of survival in patients with HNC.
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Dieta , Ingestión de Alimentos/psicología , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/fisiopatología , Recuperación de la Función/fisiología , Anciano , Femenino , Neoplasias de Cabeza y Cuello/terapia , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Calidad de Vida , Análisis de Supervivencia , Tasa de Supervivencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
PURPOSE: Previous studies indicate that the benefit of therapy depends on patients' risk for cancer recurrence relative to noncancer mortality (ω ratio). We sought to test the hypothesis that patients with head and neck cancer (HNC) with a higher ω ratio selectively benefit from intensive therapy. EXPERIMENTAL DESIGN: We analyzed 2,688 patients with stage III-IVB HNC undergoing primary radiotherapy (RT) with or without systemic therapy on three phase III trials (RTOG 9003, RTOG 0129, and RTOG 0522). We used generalized competing event regression to stratify patients according to ω ratio and compared the effectiveness of intensive therapy as a function of predicted ω ratio (i.e., ω score). Intensive therapy was defined as treatment on an experimental arm with altered fractionation and/or multiagent concurrent systemic therapy. A nomogram was developed to predict patients' ω score on the basis of tumor, demographic, and health factors. Analysis was by intention to treat. RESULTS: Decreasing age, improved performance status, higher body mass index, node-positive status, P16-negative status, and oral cavity primary predicted a higher ω ratio. Patients with ω score ≥0.80 were more likely to benefit from intensive treatment [5-year overall survival (OS), 70.0% vs. 56.6%; HR of 0.73, 95% confidence interval (CI): 0.57-0.94; P = 0.016] than those with ω score <0.80 (5-year OS, 46.7% vs. 45.3%; HR of 1.02, 95% CI: 0.92-1.14; P = 0.69; P = 0.019 for interaction). In contrast, the effectiveness of intensive therapy did not depend on risk of progression. CONCLUSIONS: Patients with HNC with a higher ω score selectively benefit from intensive treatment. A nomogram was developed to help select patients for intensive therapy.
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Quimioradioterapia/mortalidad , Neoplasias de Cabeza y Cuello/mortalidad , Recurrencia Local de Neoplasia/mortalidad , Nomogramas , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/terapia , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: Radiation Therapy Oncology Group (RTOG)-0129 recursive partitioning analysis was the basis for risk-based therapeutic intensification trials for oropharyngeal cancer (OPC). To the authors' knowledge, the question of whether RTOG-0129 overall survival (OS) estimates for low-risk, intermediate-risk, and high-risk groups are similar in other data sets or applicable to progression-free survival (PFS) is unknown. Therefore, the authors evaluated whether survival differences between RTOG-0129 risk groups persist at 5 years, are reproducible in an independent clinical trial, and are applicable to PFS, and whether toxicities differ across risk groups. METHODS: Prospective randomized clinical trials were analyzed retrospectively. RTOG-0129 evaluated standard versus accelerated fractionation radiotherapy concurrent with cisplatin. RTOG-0522 compared the combination of cisplatin and accelerated fractionation with or without cetuximab. Patients with OPC with available p16 status and tobacco history were eligible. RESULTS: There was a total of 260 patients and 287 patients, respectively, from RTOG-0129 and RTOG-0522, with median follow-ups for surviving patients of 7.9 years (range, 1.7-9.9 years) and 4.7 years (range, 0.1-7.0 years), respectively. Previous OS differences in RTOG-0129 persisted at 5 years. In RTOG-0522, the 5-year OS rates for the low-risk, intermediate-risk, and high-risk groups were 88.1%, 69.9%, and 45.1%, respectively (P for trend, <.001). The 5-year PFS rates for the same 3 groups were 72.9%, 56.1%, and 42.2%, respectively. In RTOG-0522 among a subgroup of patients considered to be at very good risk (p16-positive disease, smoking history of ≤10 pack-years, and classified with T1-T2 disease with ipsilateral lymph nodes measuring ≤6 cm or T3 disease without contralateral or >6 cm lymph nodes), the 5-year OS and PFS rates were 93.8% and 82.2%, respectively. Overall rates of acute and late toxicities were similar by risk group. CONCLUSIONS: RTOG-0129 risk groups persisted at 5 years and were reproducible in RTOG-0522. However, there was variability in the estimates. These data underscore the importance of long-term follow-up and appropriate patient selection in therapeutic deintensification trials.
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Carcinoma de Células Escamosas/mortalidad , Quimioradioterapia/mortalidad , Ensayos Clínicos como Asunto/normas , Neoplasias Orofaríngeas/mortalidad , Infecciones por Papillomavirus/complicaciones , Selección de Paciente , Medición de Riesgo/métodos , Adulto , Anciano , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/virología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/patología , Neoplasias Orofaríngeas/terapia , Neoplasias Orofaríngeas/virología , Papillomaviridae/aislamiento & purificación , Infecciones por Papillomavirus/virología , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
PURPOSE: Severe late toxicity is common after re-irradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck. However, many patients experience complications from tumor progression before manifesting late effects. We constructed a nomogram to examine this relationship between late toxicity and competing risks. METHODS AND MATERIALS: Patients with RSP squamous carcinoma originating in a field previously irradiated to ≥40â¯Gy and treated with IMRT-based re-irradiation to ≥40â¯Gy were collected. Grade ≥3 late toxicity developing ≥90â¯days after re-irradiation was collected. A multivariable competing-risk model was fit to the actuarial risk of late toxicity with progression or death as the competing risk. The final bootstrap optimized model was converted into a nomogram. RESULTS: From 9 institutions, 505 patients were included. The 2-year incidence of grade ≥3 late toxicity was 16.7% (95% CI 13.2-20.2%) whereas progression or death was 64.2% (95% CI 59.7-68.8%). The median freedom from late toxicity, progression or death was 10.7, 5.5 and 3.2â¯months for RPA class I-III patients respectively, whereas the median OS was 44.9, 15.9 and 7.9â¯months, respectively. The final model included six clinical factors. Notably, dose, volume and fractionation did not significantly impact toxicity. CONCLUSIONS: After re-irradiation, the risk of progression or death is approximately four times the risk of radiation-related severe late toxicity. The risk of late toxicity may be more dependent on patient and disease factors than modifiable treatment factors. This model is useful for patient selection, pre-treatment consent and post-treatment survivorship following re-irradiation.
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Neoplasias de Cabeza y Cuello/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Neoplasias Primarias Secundarias/radioterapia , Nomogramas , Radioterapia de Intensidad Modulada/efectos adversos , Reirradiación/efectos adversos , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Fraccionamiento de la Dosis de Radiación , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Traumatismos por Radiación/mortalidad , Radioterapia de Intensidad Modulada/mortalidad , Reirradiación/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Tasa de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab-an antibody against the epidermal growth factor receptor-can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity. METHODS: RTOG 1016 was a randomised, multicentre, non-inferiority trial at 182 health-care centres in the USA and Canada. Eligibility criteria included histologically confirmed HPV-positive oropharyngeal carcinoma; American Joint Committee on Cancer 7th edition clinical categories T1-T2, N2a-N3 M0 or T3-T4, N0-N3 M0; Zubrod performance status 0 or 1; age at least 18 years; and adequate bone marrow, hepatic, and renal function. We randomly assigned patients (1:1) to receive either radiotherapy plus cetuximab or radiotherapy plus cisplatin. Randomisation was balanced by using randomly permuted blocks, and patients were stratified by T category (T1-T2 vs T3-T4), N category (N0-N2a vs N2b-N3), Zubrod performance status (0 vs 1), and tobacco smoking history (≤10 pack-years vs >10 pack-years). Patients were assigned to receive either intravenous cetuximab at a loading dose of 400 mg/m2 5-7 days before radiotherapy initiation, followed by cetuximab 250 mg/m2 weekly for seven doses (total 2150 mg/m2), or cisplatin 100 mg/m2 on days 1 and 22 of radiotherapy (total 200 mg/m2). All patients received accelerated intensity-modulated radiotherapy delivered at 70 Gy in 35 fractions over 6 weeks at six fractions per week (with two fractions given on one day, at least 6 h apart). The primary endpoint was overall survival, defined as time from randomisation to death from any cause, with non-inferiority margin 1·45. Primary analysis was based on the modified intention-to-treat approach, whereby all patients meeting eligibility criteria are included. This study is registered with ClinicalTrials.gov, number NCT01302834. FINDINGS: Between June 9, 2011, and July 31, 2014, 987 patients were enrolled, of whom 849 were randomly assigned to receive radiotherapy plus cetuximab (n=425) or radiotherapy plus cisplatin (n=424). 399 patients assigned to receive cetuximab and 406 patients assigned to receive cisplatin were subsequently eligible. After median follow-up duration of 4·5 years, radiotherapy plus cetuximab did not meet the non-inferiority criteria for overall survival (hazard ratio [HR] 1·45, one-sided 95% upper CI 1·94; p=0·5056 for non-inferiority; one-sided log-rank p=0·0163). Estimated 5-year overall survival was 77·9% (95% CI 73·4-82·5) in the cetuximab group versus 84·6% (80·6-88·6) in the cisplatin group. Progression-free survival was significantly lower in the cetuximab group compared with the cisplatin group (HR 1·72, 95% CI 1·29-2·29; p=0·0002; 5-year progression-free survival 67·3%, 95% CI 62·4-72·2 vs 78·4%, 73·8-83·0), and locoregional failure was significantly higher in the cetuximab group compared with the cisplatin group (HR 2·05, 95% CI 1·35-3·10; 5-year proportions 17·3%, 95% CI 13·7-21·4 vs 9·9%, 6·9-13·6). Proportions of acute moderate to severe toxicity (77·4%, 95% CI 73·0-81·5 vs 81·7%, 77·5-85·3; p=0·1586) and late moderate to severe toxicity (16·5%, 95% CI 12·9-20·7 vs 20·4%, 16·4-24·8; p=0·1904) were similar between the cetuximab and cisplatin groups. INTERPRETATION: For patients with HPV-positive oropharyngeal carcinoma, radiotherapy plus cetuximab showed inferior overall survival and progression-free survival compared with radiotherapy plus cisplatin. Radiotherapy plus cisplatin is the standard of care for eligible patients with HPV-positive oropharyngeal carcinoma. FUNDING: National Cancer Institute USA, Eli Lilly, and The Oral Cancer Foundation.
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Antineoplásicos/uso terapéutico , Cetuximab/uso terapéutico , Cisplatino/uso terapéutico , Neoplasias Orofaríngeas/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Cetuximab/administración & dosificación , Cetuximab/efectos adversos , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Esquema de Medicación , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/complicaciones , Radioterapia de Intensidad Modulada/efectos adversos , Radioterapia de Intensidad Modulada/métodos , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Resultado del TratamientoRESUMEN
AIM: We assessed the role of adjuvant interferon on relapse-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS) in node-positive melanoma patients. METHODS: We retrospectively reviewed 385 node-positive patients without distant metastatic disease treated from 1998 to 2015. The surgery was therapeutic lymph node dissection (LND, n = 86) or sentinel lymph node biopsy ± completion LND (n = 270). 128 patients (33.2%) received adjuvant interferon. RESULTS: After a median follow-up of 70 months, interferon was associated with improved RFS (hazard ratio [HR]: 0.55; p < 0.001), DMFS (HR: 0.59; p < 0.001) and OS (HR: 0.61; p = 0.003), controlling for tumor and nodal stage, node size, sex, primary site, adjuvant therapy and extracapsular extension. In an exploratory age-matched comparison of patients treated with (n = 67) and without (n = 233) adjuvant immunotherapy, interferon still showed improved RFS, DMFS and OS. CONCLUSION: Adjuvant interferon appears to improve OS among node-positive melanoma patients in a modern experience, providing context for comparison in the adjuvant therapy landscape.
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BACKGROUND: Studies suggest treatment outcomes may vary between high (HVC)- and low-volume centers (LVC). Radiation therapy (RT) for head and neck cancer (HNC) requires weeks of treatment, the inconvenience of which may influence a patient's choice for treatment location. We hypothesized that receipt of RT for HNC at a HVC would influence outcomes compared to patients evaluated at a HVC, but who chose to receive RT at a LVC. METHODS: From 1998 to 2011, 1930 HNC patients were evaluated at a HVC and then treated with RT at either a HVC or LVC. Time-to-event outcomes and treatment factors were compared. RESULTS: Median follow-up was 34 months. RT was delivered at a HVC for 1368 (71%) patients and at a LVC in 562 (29%). Patients were more likely to choose HVC-RT if they resided in the HVC's county or required definitive RT (all P < 0.001). HVC-RT was associated with a significant improvement in 3-year LRC (84% vs 68%), DFS (68% vs 48%), and OS (72% vs 57%) (all P < 0.001). On multivariate analysis (MVA), HVC-RT independently predicted for improved LRC, DFS, and OS (all P < 0.05). CONCLUSIONS: In patients evaluated at a HVC, the choice of RT location was primarily influenced by their residing distance from the HVC. HVC-RT was associated with improvements in LRC, DFS, and OS in HNC. As treatment planning and delivery are technically demanding in HNC, the choice to undergo treatment at a HVC may result in more optimal delivered dose, RT duration, and outcome.
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Neoplasias de Cabeza y Cuello/radioterapia , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Hospitales de Alto Volumen , Hospitales de Bajo Volumen , Humanos , Masculino , Persona de Mediana Edad , Prioridad del Paciente , Selección de Paciente , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
PURPOSE: Limited data exist to guide the treatment technique for reirradiation of recurrent or second primary squamous carcinoma of the head and neck. We performed a multi-institution retrospective cohort study to investigate the effect of the elective treatment volume, dose, and fractionation on outcomes and toxicity. METHODS AND MATERIALS: Patients with recurrent or second primary squamous carcinoma originating in a previously irradiated field (≥40 Gy) who had undergone reirradiation with intensity modulated radiation therapy (IMRT); (≥40 Gy re-IMRT) were included. The effect of elective nodal treatment, dose, and fractionation on overall survival (OS), locoregional control, and acute and late toxicity were assessed. The Kaplan-Meier and Gray's competing risks methods were used for actuarial endpoints. RESULTS: From 8 institutions, 505 patients were included in the present updated analysis. The elective neck was not treated in 56.4% of patients. The median dose of re-IMRT was 60 Gy (range 39.6-79.2). Hyperfractionation was used in 20.2%. Systemic therapy was integrated for 77.4% of patients. Elective nodal radiation therapy did not appear to decrease the risk of locoregional failure (LRF) or improve the OS rate. Doses of ≥66 Gy were associated with improvements in both LRF and OS in the definitive re-IMRT setting. However, dose did not obviously affect LRF or OS in the postoperative re-IMRT setting. Hyperfractionation was not associated with improved LRF or OS. The rate of acute grade ≥3 toxicity was 22.1% overall. On multivariable logistic regression, elective neck irradiation was associated with increased acute toxicity in the postoperative setting. The rate of overall late grade ≥3 toxicity was 16.7%, with patients treated postoperatively with hyperfractionation experiencing the highest rates. CONCLUSIONS: Doses of ≥66 Gy might be associated with improved outcomes in high-performance patients undergoing definitive re-IMRT. Postoperatively, doses of 50 to 66 Gy appear adequate after removal of gross disease. Hyperfractionation and elective neck irradiation were not associated with an obvious benefit and might increase toxicity.
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Carcinoma de Células Escamosas/radioterapia , Fraccionamiento de la Dosis de Radiación , Neoplasias de Cabeza y Cuello/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Neoplasias Primarias Secundarias/radioterapia , Radioterapia de Intensidad Modulada/métodos , Reirradiación/métodos , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/virología , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/virología , Humanos , Estimación de Kaplan-Meier , Modelos Logísticos , Irradiación Linfática , Masculino , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/virología , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/virología , Hipofraccionamiento de la Dosis de Radiación , Traumatismos por Radiación/etiología , Radioterapia de Intensidad Modulada/efectos adversos , Reirradiación/efectos adversos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
PURPOSE: The therapeutic ratio of reirradiation for recurrent or second primary (RSP) squamous carcinoma of the head and neck may be improved in the intensity modulated radiation therapy (IMRT) era. However, patient selection for reirradiation remains challenging. We performed a multi-institution cohort study to investigate modern outcomes after IMRT-based reirradiation and to identify prognostic subgroups. PATIENTS AND METHODS: Patients with RSP squamous carcinoma originating in a previously irradiated field (≥40 Gy) who underwent reirradiation with IMRT (≥40 Gy re-IMRT) were included. Locoregional failure and late toxicity were calculated using the Gray competing risk method. Cox proportional hazards regression was used to identify factors associated with overall survival (OS). Factors associated with OS were entered into a recursive partitioning analysis (RPA) for OS. RESULTS: From 7 institutions, 412 patients were included. The median dose of re-IMRT was 60 Gy, and the median time between RT courses was 2.4 years. Chemotherapy was used in 76% of patients. The rates of grade ≥3, grade ≥4, and grade 5 acute toxicities were 19%, 4.4%, and 1.2%, respectively. The 2-year cumulative incidence of grade ≥3 late toxicity adjusted for the competing risks of recurrence or death was 14.2%. RPA identified 3 prognostic subgroups with distinct and homogenous OS (P<.001): class I included patients >2 years from their initial course of RT with resected tumors (2-year OS, 61.9%); class II included patients >2 years with unresected tumors or those ≤2 years and without feeding tube or tracheostomy dependence (2-year OS, 40.0%), and the remaining patients formed class III (2-year OS, 16.8%). Fifty-nine percent of class III patients underwent postoperative re-irradiation. CONCLUSIONS: This study informs outcomes and expectations with IMRT-based reirradiation. The RPA classification identifies 3 distinct subgroups, which can guide patient selection for therapy and clinical trial design. RPA class III patients are not ideal candidates for protracted chemoradiation regardless of resection status.
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Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Neoplasias Primarias Secundarias/radioterapia , Selección de Paciente , Radioterapia de Intensidad Modulada/métodos , Reirradiación , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Causas de Muerte , Estudios de Cohortes , Árboles de Decisión , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Primarias Secundarias/mortalidad , Radioterapia de Intensidad Modulada/efectos adversos , Reirradiación/efectos adversos , Análisis de Regresión , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: Two modern methods of reirradiation, intensity modulated radiation therapy (IMRT) and stereotactic body radiation therapy (SBRT), are established for patients with recurrent or second primary squamous cell carcinoma of the head and neck (rSCCHN). We performed a retrospective multi-institutional analysis to compare methods. METHODS AND MATERIALS: Data from patients with unresectable rSCCHN previously irradiated to ≥40 Gy who underwent reirradiation with IMRT or SBRT were collected from 8 institutions. First, the prognostic value of our IMRT-based recursive partitioning analysis (RPA) separating those patients with unresectable tumors with an intertreatment interval >2 years or those with ≤2 years and without feeding tube or tracheostomy dependence (class II) from other patients with unresected tumors (class III) was investigated among SBRT patients. Overall survival (OS) and locoregional failure were then compared between IMRT and SBRT by use of 2 methods to control for baseline differences: Cox regression weighted by the inverse probability of treatment and subset analysis by RPA classification. RESULTS: The study included 414 patients with unresectable rSCCHN: 217 with IMRT and 197 with SBRT. The unadjusted 2-year OS rate was 35.4% for IMRT and 16.3% for SBRT (P<.01). Among SBRT patients, RPA classification retained an independent association with OS. On Cox regression weighted by the inverse probability of treatment, no significant differences in OS or locoregional failure between IMRT and SBRT were demonstrated. Analysis by RPA class showed similar OS between IMRT and SBRT for class III patients. In all class II patients, IMRT was associated with improved OS (P<.001). Further subset analysis demonstrated comparable OS when ≥35 Gy was delivered with SBRT to small tumor volumes. Acute grade ≥4 toxicity was greater in the IMRT group than in the SBRT group (5.1% vs 0.5%, P<.01), with no significant difference in late toxicity. CONCLUSIONS: Reirradiation both with SBRT and with IMRT appear relatively safe with favorable toxicity compared with historical studies. Outcomes vary by RPA class, which informs clinical trial design. Survival is poor in class III patients, and alternative strategies are needed.
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Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Recurrencia Local de Neoplasia/radioterapia , Neoplasias Primarias Secundarias/radioterapia , Radiocirugia , Radioterapia de Intensidad Modulada , Reirradiación/métodos , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/mortalidad , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Linfoma/radioterapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Neoplasias Primarias Secundarias/mortalidad , Radiocirugia/efectos adversos , Radioterapia de Intensidad Modulada/efectos adversos , Reirradiación/efectos adversos , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: Evaluate the prognostic and predictive impact of HPV-associated p16-expression and assess the combined prognostic impact of p16 and smoking on altered fractionated radiotherapy (AFRT) for oropharyngeal cancer (OPC) within the frames of the update of the Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH). MATERIALS AND METHODS: Patients with OPC, known tumor p16-status and smoking history were identified from the MARCH update, resulting in a dataset of 815 patients from four randomized trials (RTOG9003, DAHANCA6&7, RTOG0129, ARTSCAN). Analysis was performed using a Cox model stratified by trial and adjusted on gender, age, T-stage, N-stage, type of radiotherapy fractionation, p16, smoking. Primary endpoint was progression-free survival (PFS). RESULTS: In total, 465 patients (57%) had p16-positive tumors and 350 (43%) p16-negative. Compared to p16-negative, p16-positive patients had significantly better PFS (HRâ¯=â¯0.42 [95% CI: 0.34-0.51], 28.9% absolute increase at 10â¯years) and OS (HRâ¯=â¯0.40 [0.32-0.49], 32.1% absolute increase at 10â¯years). No interaction between p16-status and fractionation schedule was detected. Smoking negatively impacted outcome; in the p16-positive subgroup, never smokers had significantly better PFS than former/current smokers (HRâ¯=â¯0.49 [0.33-0.75], 24.2% survival benefit at 10â¯years). CONCLUSIONS: No predictive impact of p16-status on response to AFRT could be detected but the strong prognostic impact of p16-status was confirmed and especially p16-positive never smoking patients have superior outcome after RT.
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Carcinoma de Células Escamosas/epidemiología , Carcinoma de Células Escamosas/radioterapia , Inhibidor p16 de la Quinasa Dependiente de Ciclina/biosíntesis , Neoplasias de Cabeza y Cuello/epidemiología , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias Orofaríngeas/epidemiología , Neoplasias Orofaríngeas/radioterapia , Papillomaviridae/metabolismo , Infecciones por Papillomavirus/epidemiología , Fumar/epidemiología , Anciano , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virología , Supervivencia sin Enfermedad , Fraccionamiento de la Dosis de Radiación , Femenino , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/virología , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Orofaríngeas/metabolismo , Neoplasias Orofaríngeas/virología , Infecciones por Papillomavirus/metabolismo , Infecciones por Papillomavirus/patología , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Riesgo , Fumar/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello , Resultado del TratamientoRESUMEN
BACKGROUND: The Meta-Analysis of Radiotherapy in squamous cell Carcinomas of Head and neck (MARCH) showed that altered fractionation radiotherapy is associated with improved overall and progression-free survival compared with conventional radiotherapy, with hyperfractionated radiotherapy showing the greatest benefit. This update aims to confirm and explain the superiority of hyperfractionated radiotherapy over other altered fractionation radiotherapy regimens and to assess the benefit of altered fractionation within the context of concomitant chemotherapy with the inclusion of new trials. METHODS: For this updated meta-analysis, we searched bibliography databases, trials registries, and meeting proceedings for published or unpublished randomised trials done between Jan 1, 2009, and July 15, 2015, comparing primary or postoperative conventional fractionation radiotherapy versus altered fractionation radiotherapy (comparison 1) or conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone (comparison 2). Eligible trials had to start randomisation on or after Jan 1, 1970, and completed accrual before Dec 31, 2010; had to have been randomised in a way that precluded prior knowledge of treatment assignment; and had to include patients with non-metastatic squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing first-line curative treatment. Trials including a non-conventional radiotherapy control group, investigating hypofractionated radiotherapy, or including mostly nasopharyngeal carcinomas were excluded. Trials were grouped in three types of altered fractionation: hyperfractionated, moderately accelerated, and very accelerated. Individual patient data were collected and combined with a fixed-effects model based on the intention-to-treat principle. The primary endpoint was overall survival. FINDINGS: Comparison 1 (conventional fractionation radiotherapy vs altered fractionation radiotherapy) included 33 trials and 11â423 patients. Altered fractionation radiotherapy was associated with a significant benefit on overall survival (hazard ratio [HR] 0·94, 95% CI 0·90-0·98; p=0·0033), with an absolute difference at 5 years of 3·1% (95% CI 1·3-4·9) and at 10 years of 1·2% (-0·8 to 3·2). We found a significant interaction (p=0·051) between type of fractionation and treatment effect, the overall survival benefit being restricted to the hyperfractionated group (HR 0·83, 0·74-0·92), with absolute differences at 5 years of 8·1% (3·4 to 12·8) and at 10 years of 3·9% (-0·6 to 8·4). Comparison 2 (conventional fractionation radiotherapy plus concomitant chemotherapy versus altered fractionation radiotherapy alone) included five trials and 986 patients. Overall survival was significantly worse with altered fractionation radiotherapy compared with concomitant chemoradiotherapy (HR 1·22, 1·05-1·42; p=0·0098), with absolute differences at 5 years of -5·8% (-11·9 to 0·3) and at 10 years of -5·1% (-13·0 to 2·8). INTERPRETATION: This update confirms, with more patients and a longer follow-up than the first version of MARCH, that hyperfractionated radiotherapy is, along with concomitant chemoradiotherapy, a standard of care for the treatment of locally advanced head and neck squamous cell cancers. The comparison between hyperfractionated radiotherapy and concomitant chemoradiotherapy remains to be specifically tested. FUNDING: Institut National du Cancer; and Ligue Nationale Contre le Cancer.
Asunto(s)
Carcinoma de Células Escamosas/radioterapia , Fraccionamiento de la Dosis de Radiación , Neoplasias de Cabeza y Cuello/radioterapia , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
Purpose Treatment of oropharyngeal squamous cell carcinoma (OPSCC) is evolving toward risk-based modification of therapeutic intensity, which requires patient-specific estimates of overall survival (OS) and progression-free survival (PFS). Methods To develop and validate nomograms for OS and PFS, we used a derivation cohort of 493 patients with OPSCC with known p16 tumor status (surrogate of human papillomavirus) and cigarette smoking history (pack-years) randomly assigned to clinical trials using platinum-based chemoradiotherapy (NRG Oncology Radiation Therapy Oncology Group [RTOG] 0129 and 0522). Nomograms were created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index. Nomograms were externally validated in a cohort of 153 patients with OPSCC randomly assigned to a third trial, NRG Oncology RTOG 9003. Results Both models included age, Zubrod performance status, pack-years, education, p16 status, and T and N stage; the OS model also included anemia and age × pack-years interaction; and the PFS model also included marital status, weight loss, and p16 × Zubrod interaction. Predictions correlated well with observed 2-year and 5-year outcomes. The uncorrected concordance index was 0.76 (95% CI, 0.72 to 0.80) for OS and 0.70 (95% CI, 0.66 to 0.74) for PFS, and bias-corrected indices were similar. In the validation set, OS and PFS models were well calibrated, and OS and PFS were significantly different across tertiles of nomogram scores (log-rank P = .003;< .001). Conclusion The validated nomograms provided useful prediction of OS and PFS for patients with OPSCC treated with primary radiation-based therapy.
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Carcinoma de Células Escamosas/mortalidad , Neoplasias de Cabeza y Cuello/mortalidad , Nomogramas , Neoplasias Orofaríngeas/mortalidad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/radioterapia , Quimioradioterapia , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Neoplasias Orofaríngeas/diagnóstico , Neoplasias Orofaríngeas/tratamiento farmacológico , Neoplasias Orofaríngeas/radioterapia , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Ensayos Clínicos Controlados Aleatorios como Asunto , Carcinoma de Células Escamosas de Cabeza y Cuello , Tasa de SupervivenciaRESUMEN
Background: Regional radiation therapy (RT) has been shown to reduce the risk of regional recurrence with node-positive cutaneous melanoma. However, risk factors for regional recurrence, especially in the era of sentinel lymph node biopsy (SLNB), are less clear. Our goals were to identify risk factors associated with regional recurrence and to determine whether a radiosensitivity index (RSI) gene expression signature (GES) could identify patients who experience a survival benefit with regional RT. Methods: A single-institution, Institutional Review Board-approved study was performed including 410 patients treated with either SLNB with or without completion lymph node dissection (LND; n=270) or therapeutic LND (n=91). Postoperative regional RT was delivered to the involved nodal basin in 83 cases (20.2%), to a median dose of 54 Gy (range, 30-60 Gy) in 27 fractions (range, 5-30). Primary outcomes were regional control and overall survival by RSI GES status. Results: Median follow-up was 69 months (range, 13-180). Postoperative regional RT was associated with a reduced risk of regional recurrence among all patients on univariate (5-year estimate: 95.0% vs 83.3%; P=.036) and multivariate analysis (hazard ratio[HR], 0.15; 95% CI, 0.05-0.43; P<.001). Among higher-risk subgroups, regional RT was associated with a lower risk of regional recurrence among patients with clinically detected lymph nodes (n=175; 5-year regional control: 94.1% vs 69.5%; P=.003) and extracapsular extension (ECE) present (n=138; 5-year regional control: 96.7% vs 62.2%; P<.001). Among a subset of radiated patients with gene expression data available, a low RSI GES (radiosensitive) tumor status was associated with improved survival compared with a high RSI GES (5-year: 75% vs 0%; HR, 10.68; 95% CI, 1.24-92.14). Conclusions: Regional RT was associated with a reduced risk of regional recurrence among patients with ECE and clinically detected nodal disease. Gene expression data show promise for better predicting radiocurable patients in the future. In the era of increasingly effective systemic therapies, the value of improved regional control potentially takes on greater significance.
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Melanoma/patología , Melanoma/radioterapia , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/radioterapia , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor , Estudios de Cohortes , Terapia Combinada , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica/métodos , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Melanoma/genética , Melanoma/mortalidad , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Radioterapia Adyuvante/métodos , Retratamiento , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/mortalidad , Insuficiencia del Tratamiento , Resultado del Tratamiento , Adulto Joven , Melanoma Cutáneo MalignoRESUMEN
PURPOSE: To present evidence-based guidelines for the treatment of oropharyngeal squamous cell carcinoma (OPSCC) with definitive or adjuvant radiation therapy (RT). METHODS AND MATERIALS: The American Society for Radiation Oncology convened the OPSCC Guideline Panel to perform a systematic literature review investigating the following key questions: (1) When is it appropriate to add systemic therapy to definitive RT in the treatment of OPSCC? (2) When is it appropriate to deliver postoperative RT with and without systemic therapy following primary surgery for OPSCC? (3) When is it appropriate to use induction chemotherapy in the treatment of OPSCC? (4) What are the appropriate dose, fractionation, and volume regimens with and without systemic therapy in the treatment of OPSCC? RESULTS: Patients with stage IV and stage T3 N0-1 OPSCC treated with definitive RT should receive concurrent high-dose intermittent cisplatin. Patients receiving adjuvant RT following surgical resection for positive surgical margins or extracapsular extension should be treated with concurrent high-dose intermittent cisplatin, and individuals with these risk factors who are intolerant of cisplatin should not routinely receive adjuvant concurrent systemic therapy. Induction chemotherapy should not be routinely delivered to patients with OPSCC. For patients with stage IV and stage T3 N0-1 OPSCC ineligible for concurrent chemoradiation therapy, altered fractionation RT should be used. CONCLUSION: The successful management of OPSCC requires the collaboration of radiation, medical, and surgical oncologists. When high-level data are absent for clinical decision-making, treatment recommendations should incorporate patient values and preferences to arrive at the optimal therapeutic approach.
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Carcinoma de Células Escamosas/radioterapia , Neoplasias Orofaríngeas/radioterapia , Carcinoma de Células Escamosas/patología , Femenino , Humanos , Masculino , Neoplasias Orofaríngeas/patologíaRESUMEN
PURPOSE: Concurrent chemoradiotherapy (CRT) is the standard of care for many sites of locally advanced head and neck squamous cell carcinomas (LAHNC). However, on meta-analysis, the addition of chemotherapy did not improve survival for patients >70years. We hypothesized that elderly patients treated with CRT would have increased toxicity without similar improvements in survival. METHODS: A single-institution, IRB-approved retrospective study took place from 2005 to 2012 including 369 patients treated with CRT for LAHNC. Multivariate models for death at 3months and death over time were developed using logistic regression and Cox modeling, respectively. RESULTS: Patients ≥70years were treated less often with concurrent cisplatin dosed every 3weeks (25.5% vs. 71.4%, respectively) and more often with weekly carboplatin (31.9% vs. 3.4%) than patients <70years (n=322; p<0.001). Patients ≥70years experienced increased toxicity during treatment with more frequently hospitalizations (36.2% vs. 21.1%; p=0.02) and a lower rate of PEG removal at last follow-up or death (77.1% vs. 92.9%; p=0.004). A higher proportion of patients ≥70years died within 3months (12.8% vs. 2.8%; p=0.001) following CRT. Patients ≥70 had an increased risk of death at 3months following CRT (odds ratio 5.19, 95% CI 1.64-16.41; p=0.005) and worse survival over time (hazard ratio 2.30, 95% CI 1.34-3.93; p=0.002). CONCLUSIONS: Patients ≥70years were more often treated with less toxic chemotherapy, yet experienced higher rates of hospitalization during treatment and increased rates of acute mortality following CRT. The efficacy of chemoradiotherapy for elderly patients should be evaluated in a prospective setting.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Escamosas/terapia , Quimioradioterapia , Neoplasias de Cabeza y Cuello/terapia , Radioterapia de Intensidad Modulada/métodos , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Carboplatino/uso terapéutico , Carcinoma de Células Escamosas/mortalidad , Cisplatino/uso terapéutico , Trastornos de Deglución , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Hospitalización/estadística & datos numéricos , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Mortalidad , Análisis Multivariante , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Carcinoma de Células Escamosas de Cabeza y Cuello , Tasa de SupervivenciaRESUMEN
PURPOSE: To analyze the quality of life (QOL) and performance status (PS) (secondary outcome) in patients with stage III to IV head and neck cancer (HNC) enrolled on a prospective randomized phase 3 trial comparing radiation-cisplatin without cetuximab (CIS) or with cetuximab (CET/CIS). The QOL hypothesis proposed a between-arm difference in Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN) total score of ≥10% of the instrument range from baseline to 1 year. METHODS AND MATERIALS: Patients who gave consent to the QOL/PS study completed the FACT-HN, Performance Status Scale for HNC (PSS-HN), and EuroQol (EQ-5D) at baseline through to 5 years. The pretreatment QOL/PS scores were correlated with outcome and p16 status in patients with oropharyngeal cancer (OPC). RESULTS: Of 818 analyzable patients, the 1-year change from baseline score for FACT-HN total was -0.41 (CIS arm) and -5.11 (CET/CIS arm) (P=.016), representing a 3.2% between-arm change of the FACT-HN total score. The mean EQ-5D index and PSS-HN scores were not significantly different between arms. The p16-positive OPC patients had significantly higher baseline and 1-year scores for PSS-HN, FACT-HN total, physical and functional subscales, and 2-years for the EQ-5D index compared with p16-negative OPC patients. Higher pretreatment PSS-HN diet, PSS-HN eating, FACT-HN, and EQ-5D index scores were associated with better overall survival (OS) and progression-free (PFS) survival on multivariate analysis. Higher baseline FACT-HN total, functional, physical subscale, and EQ-5D index scores were associated with improved OS and PFS in p16-positive OPC patients but not in p16-negative and non-OPC patients. CONCLUSION: There was no clinically meaningful difference in QOL/PS between arms. The p16-positive OPC patients had significantly higher QOL/PS than did p16-negative patients. Pretreatment QOL/PS is a significant independent predictor of outcome in locally advanced HNC.