Clinical Outcomes of Several IMRT Techniques for Patients With Head and Neck Cancer: A Propensity Score-Weighted Analysis.

PURPOSE: The Advanced Radiotherapy Oto-Rhino-Laryngologie (ART-ORL) study (NCT02024035) was performed to prospectively evaluate the clinical and economic aspects of helical TomoTherapy and volumetric modulated arc therapy (RapidArc, Varian Medical Systems, Palo Alto, CA) for patients with head and neck cancer. METHODS AND MATERIALS: Fourteen centers participated in this prospective comparative study. Randomization was not possible based on the availability of equipment. Patients with epidermoid or undifferentiated nasopharyngeal carcinoma or epidermoid carcinoma of the oropharynx and oral cavity (T1-T4, M0, N0-N3) were included between February 2010 and February 2012. Only the results of the clinical study are presented in this report, as the results of the economic assessment have been published previously. Inverse probability of treatment weighting using the propensity score analysis was undertaken in an effort to adjust for potential bias due to nonrandomization. Locoregional control, cancer-specific survival, and overall survival assessed 18 months after treatment, as well as long-term toxicity and salivary function, were evaluated. RESULTS: The analysis included 166 patients. The following results are given after inverse probability of treatment weighting adjustment. The locoregional control rate at 18 months was significantly better in the TomoTherapy group: 83.3% (95% confidence interval [CI], 72.5%-90.2%) versus 72.7% (95% CI, 62.1%-80.8%) in the RapidArc group (P=.025). The cancer-specific survival rate was better in the TomoTherapy group: 97.2% (95% CI, 89.3%-99.3%) versus 85.5% (95% CI, 75.8%-91.5%) in the RapidArc group (P=.014). No significant difference was shown in progression-free or overall survival. TomoTherapy induced fewer acute salivary disorders (P=.012). Posttreatment salivary function degradation was worse in the RapidArc group (P=.012). CONCLUSIONS: TomoTherapy provided better locoregional control and cancer-specific survival than RapidArc treatment, with fewer salivary disorders. No significant difference was shown in progression-free and overall survival. These results should be explored in a randomized trial.

Photon iso-effective dose for cancer treatment with mixed field radiation based on dose-response assessment from human and an animal model: clinical application to boron neutron capture therapy for head and neck cancer.

Boron neutron capture therapy (BNCT) is a treatment modality that combines different radiation qualities. Since the severity of biological damage following irradiation depends on the radiation type, a quantity different from absorbed dose is required to explain the effects observed in the clinical BNCT in terms of outcome compared with conventional photon radiation therapy. A new approach for calculating photon iso-effective doses in BNCT was introduced previously. The present work extends this model to include information from dose-response assessments in animal models and humans. Parameters of the model were determined for tumour and precancerous tissue using dose-response curves obtained from BNCT and photon studies performed in the hamster cheek pouch in vivo models of oral cancer and/or pre-cancer, and from head and neck cancer radiotherapy data with photons. To this end, suitable expressions of the dose-limiting Normal Tissue Complication and Tumour Control Probabilities for the reference radiation and for the mixed field BNCT radiation were developed. Pearson's correlation coefficients and p-values showed that TCP and NTCP models agreed with experimental data (with r > 0.87 and p-values >0.57). The photon iso-effective dose model was applied retrospectively to evaluate the dosimetry in tumours and mucosa for head and neck cancer patients treated with BNCT in Finland. Photon iso-effective doses in tumour were lower than those obtained with the standard RBE-weighted model (between 10% to 45%). The results also suggested that the probabilities of tumour control derived from photon iso-effective doses are more adequate to explain the clinical responses than those obtained with the RBE-weighted values. The dosimetry in the mucosa revealed that the photon iso-effective doses were about 30% to 50% higher than the corresponding RBE-weighted values. While the RBE-weighted doses are unable to predict mucosa toxicity, predictions based on the proposed model are compatible with the observed clinical outcome. The extension of the photon iso-effective dose model has allowed, for the first time, the determination of the photon iso-effective dose for unacceptable complications in the dose-limiting normal tissue. Finally, the formalism developed in this work to compute photon-equivalent doses can be applied to other therapies that combine mixed radiation fields, such as hadron therapy.

Estimation of whole-body radiation exposure from brachytherapy for oral cancer using a Monte Carlo simulation.

Early stage oral cancer can be cured with oral brachytherapy, but whole-body radiation exposure status has not been previously studied. Recently, the International Commission on Radiological Protection Committee (ICRP) recommended the use of ICRP phantoms to estimate radiation exposure from external and internal radiation sources. In this study, we used a Monte Carlo simulation with ICRP phantoms to estimate whole-body exposure from oral brachytherapy. We used a Particle and Heavy Ion Transport code System (PHITS) to model oral brachytherapy with 192Ir hairpins and 198Au grains and to perform a Monte Carlo simulation on the ICRP adult reference computational phantoms. To confirm the simulations, we also computed local dose distributions from these small sources, and compared them with the results from Oncentra manual Low Dose Rate Treatment Planning (mLDR) software which is used in day-to-day clinical practice. We successfully obtained data on absorbed dose for each organ in males and females. Sex-averaged equivalent doses were 0.547 and 0.710 Sv with 192Ir hairpins and 198Au grains, respectively. Simulation with PHITS was reliable when compared with an alternative computational technique using mLDR software. We concluded that the absorbed dose for each organ and whole-body exposure from oral brachytherapy can be estimated with Monte Carlo simulation using PHITS on ICRP reference phantoms. Effective doses for patients with oral cancer were obtained.

Objective assessment of trismus in oral and oropharyngeal cancer patients treated with intensity-modulated radiation therapy (IMRT).

PURPOSE: The aim of this study was to estimate the prevalence of trismus in oral and oropharyngeal cancer patients (OOPC) treated with intensity-modulated radiation therapy (IMRT) and to identify the role of risk factors in patients who developed trismus. MATERIALS AND METHODS: A retrospective cohort study of OOPC treated with IMRT in our institution from 2009 to 2014 was performed. Patients eligible for this study had pre-RT and post-RT maximal inter-incisal opening (MIO) measurements at 6-48 months post-RT, treated with high-dose radiation (≥60 Gy) and pre-RT MIO ≥36 mm. A descriptive analysis to identify the incidence of trismus, with trismus stated as MIO ≤35 mm at or after 6 months post-RT measurement was performed. The role of risk factors such as age, gender, tumor site, tumor size (T), tumor stage, pre-RT MIO measurements and radiation dose to the tumor were assessed using Fisher exact test and the radiation doses to the ipsilateral muscles of mastication in patients who developed trismus were assessed by matching with control (non-trismus) patients using Wilcoxon Signed Rank test. RESULTS: The study consisted of 54 patients with a median age of 55 years and 81% were males. The median follow-up time was 10 months. The prevalence of trismus was 14.8%. Patients with pre-RT MIO measurements ≤40 mm were at risk of developing trismus (P < 0.001). In trismus patients, the average mean radiation dose to the masseter and medial pterygoid muscles was numerically higher but not significantly different (P = 0.08; P = 0.22, respectively) to matched control patients. Age, gender, radiation dose to the tumor, tumor site, size (T) and stage were also found to be not significant. CONCLUSION: Pre-RT MIO measurement was a significant risk factor for the development of trismus. However, this is a non-modifiable factor. Limiting radiation dose to the muscles of mastication could prevent this complication.

High-dose-rate interstitial brachytherapy in oral cancer-Its impact on quality of life.

PURPOSE: The aim of the study was to assess the impact of high-dose-rate (HDR) interstitial brachytherapy on quality of life (QOL) in oral cancer. METHODS AND MATERIALS: Thirty-two patients of oral cancer treated at our institute from January 2010 to December 2014 with radical radiotherapy (external beam radiotherapy + brachytherapy) were included for analysis; 30 patients received external beam radiotherapy (50-54 Gy) and HDR brachytherapy boost (18-24.5 Gy); 2 patients received radical HDR brachytherapy (31.5 Gy). Quality of life (QOL) was assessed by Telugu, Hindi, and English versions of EORTC Quality of Life Core-30 and EORTC Quality of Life Head and Neck Module (QLQ H&N35) before treatment, at 3 months, 6 months, 1 year, and 2 years after treatment. RESULTS: Of the 32 patients, 2 patients died and 1 patient progressed on followup; 2 patients were re-irradiation cases. On excluding these cases, 27 patients were available for analysis. The followup duration was 6-55 months. At the time of analysis, 91% (29) patients were disease free, 3% (1) progressed, and 6% (2) died. At the end of 2 years, none of the QLQ-C30 functional scores fell below the baseline. Pain, swallowing, sensory, speech, social contact, and social eating worsened at 3 months but improved over 2 years (p < 0.001). Sexuality and financial status showed delayed improvement (p < 0.001). Among the head and neck parameters, dry mouth and sticky saliva were significant determinants of QOL with delayed improvement (p < 0.001). The impact of age, sex, and tumor stage and on QOL was analyzed. Women reported a poorer QOL for physical and emotional parameters, social eating, weight loss, and fatigue. Tumor stage significantly affected QOL, with early stages showing a better QOL. CONCLUSIONS: Almost all patients regained normal function after treatment and reported an excellent QOL at 2 years. However, tumor stage significantly affected the QOL.

Assessment of predictive molecular variables in feline oral squamous cell carcinoma treated with stereotactic radiation therapy.

This study evaluated molecular characteristics that are potentially prognostic in cats with oral squamous cell carcinoma (SCC) that underwent stereotactic radiation therapy (SRT). Survival time (ST) and progression-free interval (PFI) were correlated with mitotic index, histopathological grades, Ki67 and epidermal growth factor receptor expressions, tumour microvascular density (MVD), and tumour oxygen tension (pO(2)). Median ST and PFI were 106 and 87 days, respectively (n = 20). Overall response rate was 38.5% with rapid improvement of clinical symptoms in many cases. Patients with higher MVD or more keratinized SCC had significantly shorter ST or PFI than patients with lower MVD or less keratinized SCC (P = 0.041 and 0.049, respectively). Females had significantly longer PFI and ST than males (P ≤ 0.016). Acute toxicities were minimal. However, treatment-related complications such as fractured mandible impacted quality of life. In conclusion, SRT alone should be considered as a palliative treatment. MVD and degree of keratinization may be useful prognostic markers.

Prospective quality of life assessment between treatment groups for oral cavity squamous cell carcinoma.

BACKGROUND: Postoperative radiation therapy (PORT) is frequently recommended to improve survival outcome. The effect of PORT-associated morbidity on patients' quality of life (QOL) is, however, not well established. This study assessed the effect of PORT on medium-term (ie, at 6 months) QOL in patients with oral cavity squamous cell carcinoma (SCC). METHODS: Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and Quality of Life Questionnaire Core Head and Neck 35 (QLQ-HN35) at initial presentation, and at 3-, 6-, and 12-month follow-up. Baseline QOL scores were adjusted for using analysis of covariance (ANCOVA). RESULTS: Global health status (mean difference = 13.3; p = .042) and xerostomia (mean difference = 35.4; p = .003) were significantly worse at 6 months in patients who received PORT compared to those treated with surgery alone. CONCLUSION: The survival advantage needs to be balanced against increased treatment toxicity. PORT is associated with reduced global health status, increased xerostomia, and marginally increased levels of fatigue at 6 months posttreatment for oral cavity cancer.

Support needs and quality of life in oral cancer: a systematic review.

PURPOSE: This review aims to systematically review the literature describing quality of life (QoL) outcomes and support needs in patients with oral cancer along the cancer trajectory. This is needed to form an evidence base for the design of interventions that enhance outcomes for this group. METHODS: Six electronic databases were searched. The results were screened for eligibility, and articles were included if they described patient-reported QoL outcomes that were translatable to support needs in patients with oral cancer. Data were extracted and synthesized according to the support needs identified and their relative impact on QoL. Methodological quality was assessed using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool. RESULTS: Thirty-one articles met the inclusion criteria. Support needs related to coping with the burden of radiotherapy in both psychosocial and physical aspects, swallowing dysfunction, dry mouth and oral functional deficits. Issues of depression, anxiety and malnutrition were identified as having a significant impact on QoL. CONCLUSIONS: Oral cancer support needs are highly subjective and varied in severity across the cancer continuum. Support needs that may warrant further investigation include management of changes to oral health and functioning, swallowing and nutritional compromise and psychological effects of cancer and treatment.

Supportive care needs in newly diagnosed oral cavity cancer patients receiving radiation therapy.

OBJECTIVE: This study aimed to examine changes in physical symptom severity, functional status, supportive care needs, and related factors in oral cavity cancer patients during 6 months after beginning radiation therapy (RT) or concurrent chemotherapy and radiation therapy (CCRT). METHODS: A prospective longitudinal study was conducted involving oral cavity cancer patients from an RT clinic at a medical center in northern Taiwan. Patients were assessed for supportive care needs and physical symptoms at five time points: before the beginning of RT or CCRT and at 1, 2, 3, and 6 months after beginning RT or CCRT. The generalized estimating equation was used to identify predictors of overall needs as well as six specific dimensions of needs. RESULTS: A total of 82 patients completed the 6 months of follow-up. Patients had moderate to high levels of supportive care needs over the 6 months. Although the highest information need was at the pretreatment phase, in general, the peak for overall and individual care needs was at 2 months since first receiving RT or CCRT. Patients without religious beliefs as well as those with higher educational level, functional level, overall physical symptom severity, and baseline anxiety reported more supportive care needs. Anxiety level before treatment was the most common factor across most supportive care needs. Individual physical symptoms, including fatigue, swallowing difficulty, and oral mucositis, were significantly related to higher physical and daily living needs. CONCLUSIONS: A systematic clinical assessment to detect patients' care needs is necessary to improve the provision of timely cancer care and meet patients' healthcare needs.

Comparison of external beam radiation therapy and radioactive implants in the management of nonmetastatic oral squamous cell cancer: an analysis of the surveillance epidemiology and end results database.

OBJECTIVE: Radiotherapy in oral squamous cell carcinoma (OSCC) could be either through external beam (EBRT) or brachytherapy (BT). In third-world countries, access to novel treatment like BT is limited. This study aimed to compare survival in patients with OSCC treated with EBRT with BT recipients. METHODS: We examined cases of nonmetastatic OSCC between January 1, 1987, and December 31, 2007, in the surveillance epidemiology and end results (SEER) registry. A Cox proportional hazards model was used to determine the adjusted relationship between radiation type and survival. RESULTS: There was no significant difference in survival (adjusted) between patients who were treated with BT and those treated with EBRT (P = .330). However, combining EBRT + BT was associated with significantly better survival compared with EBRT alone (hazard ratios [HR] = 0.61, P < .001) or BT alone (HR = 0.70, P = .024). CONCLUSIONS: The effect of BT on survival was not significantly different from EBRT.

Evaluating the impact of patient, tumor, and treatment characteristics on the development of jaw complications in patients treated for oral cancers: a SEER-Medicare analysis.

BACKGROUND: Jaw complications, including osteoradionecrosis, are significant sequelae of radiation therapy (RT) for oral cancers. This study identifies the impact of patient, tumor, and treatment characteristics on the development of jaw complications in patients treated with RT. METHODS: The Surveillance, Epidemiology, and End Results (SEER)-Medicare database was used to identify patients treated with RT for oral cancers from 1999 to 2007. Jaw complications were identified by International Classification of Diseases 9th revision (ICD-9) diagnosis codes and/or related procedures using Current Procedural Terminology (CPT) and ICD-9 codes. RESULTS: A total of 1848 patients were identified. With a median follow-up of 2.5 years, 297 patients (16.1%) developed jaw complications: 226 patients had a diagnosis, 41 patients had a procedure, and 30 patients had both. On multivariate analysis, female sex, lack of chemotherapy use, and fewer comorbidities were associated with a statistically significant increase in jaw complications. CONCLUSIONS: Even with modern techniques, jaw complications are a notable and potentially devastating side effect of RT for oral cancers.

Assessment of changes in vascularity and blood volume in canine sarcomas and squamous cell carcinomas during fractionated radiation therapy using quantified contrast-enhanced power Doppler ultrasonography: a preliminary study.

Radiation therapy does not only target tumour cells but also affects tumour vascularity. In the present study, changes in tumour vascularity and blood volume were investigated in five grade 1 oral fibrosarcomas, eight other sarcomas (non-oral soft tissue and bone sarcomas) and 12 squamous cell carcinomas in dogs during fractionated radiation therapy (total dose, 45-56 Gy). Contrast-enhanced power Doppler ultrasound was performed before fraction 1, 3, 6, 8, 10, 12, 14 and 15 or 16 (sarcomas) or 17 (squamous cell carcinomas). Prior to treatment, median vascularity and blood volume were significantly higher in squamous cell carcinomas (P=0.0005 and 0.001), whereas measurements did not differ between oral fibrosarcomas and other sarcomas (P=0.88 and 0.999). During the course of radiation therapy, only small, non-significant changes in vascularity and blood volume were observed in all three tumour histology groups (P=0.08 and P=0.213), whereas median tumour volume significantly decreased until the end of treatment (P=0.04 for fibrosarcomas and other sarcomas, P=0.008 for squamous cell carcinomas). It appeared that there was a proportional decrease in tumour volume, vascularity and blood volume. Doppler measurements did not predict progression free interval or survival in any of the three tumour groups (P=0.06-0.86). However, the number of tumours investigated was small and therefore, the results can only be considered preliminary.

Dental needs in Brazilian patients subjected to head and neck radiotherapy.

In spite of its recognized benefits in the treatment of malignant tumors, radiation therapy have several side effects in the head and neck region. The evaluation of oral conditions by a dentist is important to prevent or minimize these problems. The aim of this retrospective review was to analyze the dental needs in 357 patients who received radiotherapy in the head and neck region and were treated at Orocentro/FOP/UNICAMP, between January 1990 and December 2004. Review of patient files showed that dental examination before radiotherapy was not performed in 148 patients (41.5%) and was done in 209 patients (58.5%). From the total of examined patients, 94 (45%) did not require dental procedures at the moment of examination, while 115 (55%) presented some sort of dental need. Following the patients after the radiotherapy, it was observed that the group of patients that was evaluated before radiation presented less need of restorations, root canal filling and dental extractions than those who were not evaluated. The results of this study confirm that the evaluation of oral conditions prior to radiotherapy is essential to minimize the dental needs, emphasizing the importance of the dentist in the multidisciplinary team that treats cancer patients.

First-year quality of life assessment of an intra-arterial (RADPLAT) versus intravenous chemoradiation phase III trial.

BACKGROUND: We report the results of a multicenter randomized phase III study, assessing quality of life (QOL) in intra-arterial (IA) versus standard intravenous (IV) chemoradiation in advanced head and neck cancer. METHODS: Two hundred seven patients with inoperable stage IV disease-152 men and 55 women; mean age, 55 years-were included in this study. The patients were treated with standard radiotherapy with 4 weekly IA or 3 weekly IV cisplatin infusions. The QOL assessments carried out were EORTC-C30, H&N35, and trial-specific questionnaires. RESULTS: Overall QOL deteriorated in all patients during treatment, is gradually improving over 1 year. IA patients showed significantly less nausea and vomiting at week 7 (p <.001). IV patients were significantly more fatigued (p <.006). At 1 year, no significant difference in tube feeding was found. Voice quality slightly exceeded the pretreatment values at 1 year. Forty-two of 62 employed patients returned to work. CONCLUSION: During treatment, significantly fewer problems with nausea and vomiting occurred in IA than in IV patients. Both groups showed improved voicing and oral intake during follow-up, often exceeding pretreatment values at 1 year.

Bone healing after dental extractions in irradiated patients: a pilot study on a novel technique for volume assessment of healing tooth sockets.

The aim of this study was to evaluate longitudinally the bone-healing process by measuring volumetric changes of the extraction sockets in head and neck cancer patients undergoing radiotherapy after tooth extraction. A total group of 15 patients (nine males, six females) undergoing tooth extraction at the Department of Periodontology (University Hospital KULeuven) were enrolled after giving informed consent. In seven patients, teeth presenting a risk for complications and eventual radionecrosis were extracted prior to the radiotherapeutical procedure. Monitoring of bone healing was performed by evaluating the volumetric changes of the alveoli by cone beam CT scanning (CBCT) at extraction and after 3 and 6 months. In parallel, a similar longitudinal evaluation of extraction sites was done in a control group of eight patients. Within this pilot-study, a total of 15 healing extraction sockets were evaluated and followed up. There was a significant difference in volumetric fill up of extraction sockets in test group vs. control group at three (37.1 +/- 7.9%) vs. (54.6 +/- 4.0%) and 6 months (47.2 +/- 8.8%) vs. (70.0 +/- 7.3%), respectively. The present pilot study demonstrated the clinical usefulness of CBCT for evaluation of extraction socket healing. The study objectively demonstrates the delayed bone healing after tooth extraction in irradiated head and neck cancer patients. Considering the limitations of this pilot study, a potential effect of radiotherapy on further jaw bone healing after pre-therapeutic tooth extractions should be further explored.

Dental needs in brazilian patients subjected to head and neck radiotherapy

In spite of its recognized benefits in the treatment of malignant tumors, radiation therapy have several side effects in the head and neck region. The evaluation of oral conditions by a dentist is important to prevent or minimize these problems. The aim of this retrospective review was to analyze the dental needs in 357 patients who received radiotherapy in the head and neck region and were treated at Orocentro/FOP/UNICAMP, between January 1990 and December 2004. Review of patient files showed that dental examination before radiotherapy was not performed in 148 patients (41.5 percent) and was done in 209 patients (58.5 percent). From the total of examined patients, 94 (45 percent) did not require dental procedures at the moment of examination, while 115 (55 percent) presented some sort of dental need. Following the patients after the radiotherapy, it was observed that the group of patients that was evaluated before radiation presented less need of restorations, root canal filling and dental extractions than those who were not evaluated. The results of this study confirm that the evaluation of oral conditions prior to radiotherapy is essential to minimize the dental needs, emphasizing the importance of the dentist in the multidisciplinary team that treats cancer patients.

Apesar dos benefícios da radioterapia no tratamento de tumores malignos, vários são os seus efeitos colaterais na região de cabeça e pescoço. Sendo assim, a avaliação das condições bucais pelo cirurgião dentista é fundamental para prevenir e/ou minimizar estes danos. Este estudo retrospectivo teve como objetivo verificar as condições dentárias e as necessidades de tratamento odontológico dos 357 pacientes que receberam radioterapia na região de cabeça e pescoço, atendidos pelo Orocentro/ FOP/UNICAMP, no período de janeiro de 1990 a dezembro de 2004. Em 148 (41,5 por cento) do total dos pacientes a avaliação odontológica não foi realizada previamente à radioterapia. A avaliação odontológica pré-radioterápica foi realizada em 209 pacientes (58,5 por cento) dos quais 94 (45 por cento) não tinham necessidades de tratamento odontológico no momento da avaliação, enquanto 115 (55 por cento) apresentavam algum tipo de necessidade odontológica. O grupo de pacientes avaliados antes da radioterapia apresentou menores necessidades de restaurações, endodontias e exodontias que os pacientes não avaliados. Conclui-se que a avaliação das condições bucais previamente à radioterapia é essencial para diminuir as necessidades de tratamento odontológico enfatizando a importância da participação do cirurgião-dentista na equipe multidisciplinar que trata pacientes com câncer.

[Assessment of disease-free survival in patients with loco-regional recurrence of squamous cell carcinoma of the oral cavity and oropharynx submitted to salvage treatment]. / Avaliação da sobrevida livre de doença de pacientes com recidiva loco-regional de carcinoma epidermóide de cavidade bucal e orofaringe submetidos a tratamento de resgate.

OBJECTIVE: Salvage surgery is the first therapeutic option for recurrent tumors of the mouth and oropharynx, mainly in early stage tumors. This study intends to evaluate the disease free survival interval after salvage treatment for recurrent tumors of the mouth and oropharynx. METHODS: Retrospective analysis of 276 patients with squamous cell carcinoma of the mouth and oropharynx treated with surgery. One hundred and twenty seven patients developed loco-regional recurrence. Ninety-seven were staged as early tumors and 178 as advanced ones. The tumor site was the lip in 25 cases, oral cavity in 173 and oropharynx in 78. Postoperative radiotherapy was indicated in 121 cases with a mean dose of 60.8Gy. RESULTS: Eighty-nine patients underwent salvage treatment (surgery in 76 patients). Loco-regional recurrences were treated with salvage surgery in 65% of cases. Disease free survival after salvage surgery was 13% in cases with recurrences diagnosed up to 6 months and 48% in those who recurred after 12 months of follow-up (p=0.0009). Modality of salvage treatment and the disease free interval were independent variables of survival in the multivariate analysis. CONCLUSION: In cases clinically staged as I and II, the disease free survival in five years after salvage treatment was 70%.