头颈部肿瘤自适应放疗的研究进展

调强放射治疗(intensity-modulated radiation therapy,IMRT)是头颈部恶性肿瘤的重要治疗方法之一。但在IMRT过程中,摆位误差、解剖结构的移位及变形、肿瘤退缩或进展及形状改变等,可导致靶区和危及器官的照射剂量和体积出现“偏差”,影响IMRT的精确性。图像引导的放射治疗(image-guidedradiotherapy,IGRT)可部分纠正摆位误差,从而提高放疗精度,但不能解决非刚性误差以及解剖结构变化带来的剂量差异。自适应放射治疗(adaptive radiation therapy,ART)是在IMRT和IGRT基础上出现的新型放疗技术,能修正IMRT和IGRT靶区和危及器官的偏差。通过患者图像、剂量等反馈信息对原治疗计划重新优化和调整,这是一种基于反馈控制理论的治疗策略。其目的是使放射治疗更加精确化、个体化。     

The impact of dose on parotid salivary recovery in head and neck cancer patients treated with radiation therapy

PURPOSE: A common side effect experienced by head and neck cancer patients after radiation therapy (RT) is impairment of the parotid glands' ability to produce saliva. Our purpose is to investigate the relationship between radiation dose and saliva changes in the 2 years after treatment. METHODS AND MATERIALS: The study population includes 142 patients treated with conformal or intensity-modulated radiotherapy. Saliva flow rates from 266 parotid glands are measured before and 1, 3, 6, 12, 18, and 24 months after treatment. Measurements are collected separately from each gland under both stimulated and unstimulated conditions. Bayesian nonlinear hierarchical models were developed and fit to the data. RESULTS: Parotids receiving higher radiation produce less saliva. The largest reduction is at 1-3 months after RT followed by gradual recovery. When mean doses are lower (e.g., <25 Gy), the model-predicted average stimulated saliva recovers to pretreatment levels at 12 months and exceeds it at 18 and 24 months. For higher doses (e.g., >30 Gy), the stimulated saliva does not return to original levels after 2 years. Without stimulation, at 24 months, the predicted saliva is 86% of pretreatment levels for 25 Gy and <31% for >40 Gy. We do not find evidence to support that the overproduction of stimulated saliva at 18 and 24 months after low dose in 1 parotid gland is the result of low saliva production from the other parotid gland. CONCLUSIONS: Saliva production is affected significantly by radiation, but with doses <25-30 Gy, recovery is substantial and returns to pretreatment levels 2 years after RT.     

Intensity-modulated radiation therapy: emerging cancer treatment technology

The use of intensity-modulated radiation therapy (IMRT) is rapidly advancing in the field of radiation oncology. Intensity-modulated radiation therapy allows for improved dose conformality, thereby affording the potential to decrease the spectrum of normal tissue toxicities associated with IMRT. Preliminary results with IMRT are quite promising; however, the clinical data is relatively immature and overall patient numbers remain small. High-quality IMRT requires intensive physics support and detailed knowledge of three-dimensional anatomy and patterns of tumour spread. This review focuses on basic principles, and highlights the clinical implementation of IMRT in head and neck and prostate cancer.     

Randomized trial of conventional versus high fractional dose radiation therapy in the treatment of advanced head and neck cancer

A prospectively randomized clinical trial was undertaken to compare conventionally fractionated radiation therapy and high fractional dose irradiation in the treatment of advanced, surgically unresectable head and neck squamous cell carcinoma. Sixty-four patients were entered into the study between 1973 and 1979 and were randomized to receive either 200 rad daily to total tumor doses of 6000-7000 rad in 6-7 weeks, or 400 rad daily to a total of approximately 4400 rad in 2-3 weeks. The distribution of patients between the two fractionation schedules was comparable regarding site of the primary tumor, extent of disease, degree of histologic differentiation and performance status. Twenty-nine of 31 (94%) patients in the 200 rad group and 29 of 33 (88%) in the 400 rad group has Stage IV disease. Twenty-six in the former group and 30 in the latter completed radiation therapy as planned. Acute skin and mucosal reactions occurred earlier in patients treated with 400 rad daily, but were of equivalent intensity and well within acceptable levels in both groups. No increase in late adverse effects was seen with high daily doses. Palliation of tumor-related symptoms and extent of tumor control were comparable in the two groups. Actuarial five year disease-free survival rates were approximately 10% in both treatment groups with a mean follow-up period of 5 1/2 years. We conclude that high fractional dose irradiation is equivalent to conventionally fractionated radiation therapy in the treatment of advanced head and neck cancer.     

The function of the parotid gland following radiation therapy for head and neck cancer

The parotid gland was selected for study of its salivary output before and after radiation therapy for head and neck cancer. Before radiation therapy, a sialogram of the parotid gland was performed with the patient's head positioned for radiation therapy; a lateral radiographic view of the parotid gland was used to compare with the radiation treatment portal to determine the portion of the parotid gland to he irradiated. Samples of stimulated saliva were collected from the parotid gland before and at 1 and 6 months post-radiation. Eighteen patients with head and neck cancer who received radiation therapy were studied. The data showed that in the irradiation of nasopharyageal, advanced oropbaryngeal and Waldeyer's ring lesions, 100% of the parotid gland was irradiated; for the early oropharyageal and hypopbaryugeal lesions, from 30 to 90% of the parotid gland was irradiated and for the supragiottic and oral cavity lesions, 25–30% of the parotid gland was irradiated. When 100% of the parotid gland was irradiated, no saliva was produced at 1 month post-radiation; this remained the same when re-tested at 4–8 months, however, when any portion of the parotid gland was not irradiated, there was residual salivary function.     

Intensity-modulated radiation therapy (IMRT) for nasopharynx cancer: update of the Memorial Sloan-Kettering experience

PURPOSE: We previously demonstrated that intensity-modulated radiation therapy (IMRT) significantly improves radiation dose distribution over three-dimensional planning for nasopharynx cancer and reported positive early clinical results. We now evaluate whether IMRT has resulted in improved outcomes for a larger cohort of patients with longer follow-up. METHODS AND MATERIALS: Since 1998, all 74 patients with newly diagnosed, nonmetastatic nasopharynx cancer were treated with IMRT using accelerated fractionation to 70 Gy; 59 received a hyperfractionated concomitant boost, and more recently 15 received once-daily treatment with dose painting. With the exception of Stage I disease (n = 5) and patient preference (n = 1), 69 patients received concurrent and adjuvant platinum-based chemotherapy similar to that in the Intergroup 0099 trial. RESULTS: Patient characteristics: median age 45; 32% Asian; 72% male; 65% World Health Organization III; 6% Stage I, 16% Stage II, 30% Stage III, 47% Stage IV. Median follow-up is 35 months. The 3-year actuarial rate of local control is 91%, and regional control is 93%; freedom from distant metastases, progression-free survival, and overall survival at 3 years are 78%, 67%, and 83%, respectively. There was 100% local control for Stage T1/T2 disease, compared to 83% for T3/T4 disease (p = 0.01). Six patients failed at the primary site, with median time to local tumor progression 16 months; 5 were exclusively within the 70 Gy volume, and 1 was both within and outside the target volume. There is a trend for improved local control with IMRT when compared to local control of 79% for 35 patients treated before 1998 with three-dimensional planning and chemotherapy (p = 0.11). Six months posttherapy, 21%, 13%, 15%, and 0% of patients with follow-up audiograms (n = 24 patients) had Grade 1, 2, 3, and 4 sensorineural hearing loss, respectively. For patients with >1 year follow-up (n = 59), rates of long-term xerostomia were as follows: 26% none, 42% Grade 1, 32% Grade 2, and zero Grade 3. CONCLUSIONS: The pattern of primary site failure within the target volume suggests locally advanced T stage disease may require a higher biologic dose to gross tumor. Rates of severe (Grade 3-4) ototoxicity and xerostomia are low with IMRT as a result of normal-tissue protection. Distant metastases are now the dominant form of failure, emphasizing the need for improved systemic therapy.     

Intensity-modulated radiotherapy for head and neck cancer of unknown primary: toxicity and preliminary efficacy

PURPOSE: Unknown primary head and neck cancers often require comprehensive mucosal and bilateral neck irradiation. With conventional techniques, significant toxicity can develop. Intensity-modulated radiotherapy (IMRT) has the potential to minimize the toxicity. METHODS AND MATERIALS: Between 2000 and 2005, 21 patients underwent IMRT for unknown primary head and neck cancer at our center. Of the 21 patients, 5 received IMRT with definitive intent and 16 as postoperative therapy; 14 received concurrent chemotherapy and 7 IMRT alone. The target volumes included the bilateral neck and mucosal surface. The median dose was 66 Gy. Acute and chronic toxicities, esophageal strictures, and percutaneous endoscopic gastrostomy tube dependence were evaluated. Progression-free survival, regional progression-free survival, distant metastasis-free survival, and overall survival were estimated with Kaplan-Meier curves. RESULTS: With a median follow-up of 24 months, the 2-year regional progression-free survival, distant metastasis-free survival, and overall survival rate was 90%, 90%, and 85%, respectively. Acute grade 1 and 2 xerostomia was seen in 57% and 43% of patients, respectively. Salivary function improved with time. Percutaneous endoscopic gastrostomy tube placement was required in 72% with combined modality treatment and 43% with IMRT alone. Only 1 patient required percutaneous endoscopic gastrostomy support at the last follow-up visit. Two patients treated with combined modality and one treated with IMRT alone developed esophageal strictures, but all had improvement or resolution with dilation. CONCLUSION: The preliminary analysis of IMRT for unknown primary head and neck cancer has shown acceptable toxicity and encouraging efficacy. The analysis of the dosimetric variables showed excellent tumor coverage and acceptable doses to critical normal structures. Esophageal strictures developed but were effectively treated with dilation. Techniques to limit the esophageal dose could help further minimize this complication.     

MR加速器在头颈部肿瘤自适应放疗中的临床应用北大核心CSCD

自适应放疗(ART)通过在放疗中适应肿瘤和正常组织轮廓变化从而提高了头颈部肿瘤治疗比。基于MR加速器的MR引导放疗(MRgRT)是目前创新性的头颈部肿瘤ART模式。MR加速器基于MR能实现每日ART, 同时也能在治疗中进行实时MR成像。通过每日ART能明显提高头颈部肿瘤治疗靶区准确性, 更好地避开周围重要危及器官。虽然目前发表的关于MRgRT在头颈部肿瘤ART的临床应用和实施技术的研究逐渐增加, 但总体上这个新型的放疗模式还处于初步发展阶段。本文将对基于MR加速器的MRgRT在头颈部肿瘤ART中的基本原理、临床应用及前景进行综述。     

Patterns of failure and toxicity after intensity-modulated radiotherapy for head and neck cancer

PURPOSE: To determine the outcome of patients treated with intensity-modulated radiotherapy (IMRT) for head and neck cancer. METHODS AND MATERIALS: We reviewed the charts of 100 consecutive patients treated with IMRT for squamous cell carcinoma of the oropharynx (64%), nasopharynx (16%), hypopharynx (14%), and larynx (6%). Most patients were treated with a concomitant boost schedule to 72 Gy. Of the 100 patients, 54 (54%) received adjuvant chemotherapy, mostly concurrent cisplatin. The dosimetry plans for patients with either locoregional failure or Grade 4-5 complications were reviewed and fused over the computed tomography images corresponding with the location of the event. Marginal failures were defined as those that occurred at a region of high-dose falloff, where conventional fields would have provided better coverage. RESULTS: The median follow-up of living patients was 3.1 years (range, 1-5.2 years). The 3-year rate of local control, locoregional control, freedom from relapse, cause-specific survival, and overall survival for all patients was 89%, 87%, 72%, 78%, and 71%, respectively. The 3-year rate of freedom from relapse, cause-specific survival, and overall survival for the 64 oropharynx patients was 86%, 92%, and 84%, respectively. Of the 10 local failures, 2 occurred at the margin of the high-dose planning target volume. Both regional failures occurred within the planning target volume. No locoregional failures occurred outside the planning target volume. Of the 100 patients, 8 and 5 had Grade 4 and 5 complications from treatment, respectively. All patients with Grade 5 complications had received adjuvant chemotherapy. No attempt was made to discriminate between the complications from IMRT and other aspects of the patients' treatment. CONCLUSION: Intensity-modulated radiotherapy did not compromise the outcome compared with what we have achieved with conventional techniques. The 2 cases of recurrence in the high-dose gradient region highlight the potential hazard of approaches that involve highly conformal dose distributions.     

光动力治疗消化道和头颈部肿瘤的临床观察

目的　探讨光动力疗法治疗消化道和头颈部肿瘤的疗效和安全性。方法　选取消化道肿瘤９例、头颈部复发转移癌７例行光动力治疗,其中早期４例,晚期１２例。具体治疗：静脉输注血卟啉３～５ｍｇ／ｋｇ,４８～７２ｈ在肿瘤表面或瘤体内行激光照射（输出波长６３０ｎｍ,输出功率６００～８００ｍＷ,能量密度为２００～３００Ｊ／ｃｍ２）。根据治疗后肉眼及内镜观察、Ｂ超和ＣＴ检查肿瘤缩小及症状缓解情况评价疗效。结果　所有患者治疗后随访１０～３９个月。４例早期患者均获ＣＲ,随访期间无复发;１２例晚期患者,获ＳＲ７例,ＭＲ４例,ＮＲ１例。全组患者的总有效率为９３.７％。主要毒副反应为暴露部位皮肤肤色加深,无严重并发症。结论　光动力疗法对于早期病灶局限的恶性肿瘤可达到局部根治的作用,对于晚期病例也能缓解症状并改善生存质量。     

The management of head and neck tumors with high technology radiation therapy

Squamous cell carcinoma is responsible for 90% of the head and neck cancers affecting over 600,000 people worldwide. Radiation therapy, surgery and chemotherapy are the most important treatment modalities in head and neck squamous cell carcinoma. The aim of this review is to summarize the recent innovations in head and neck radiation therapy, which intends to appreciate the cutting-edge intensity-modulated radiation therapy strategies to mitigate long-term toxicities and evaluate promising technologies in the field as adaptive treatment, dose painting and proton therapy.     

Intensity-modulated radiotherapy with concurrent chemotherapy for previously irradiated, recurrent head and neck cancer

PURPOSE: Primary treatment fails in >70% of locally advanced head and neck cancer patients. Salvage therapy has a 30-40% response rate, but few long-term survivors. Intensity-modulated radiotherapy (IMRT) has recently emerged as a new modality for salvage therapy. This retrospective study evaluated our experience using every-other-week IMRT with concurrent chemotherapy. METHODS AND MATERIALS: Between 2001 and 2006, 41 patients underwent IMRT as repeat RT with concurrent chemotherapy. All but 6 patients received 60 Gy at 2 Gy/fraction. RT was delivered on an alternating week schedule. RESULTS: With a median follow-up time of 14 months, the overall response rate was 75.6%, with a complete response and partial response rate of 58.5% and 17.1%, respectively. The Kaplan-Meier estimate of overall survival, disease-free survival, and progression-free survival at 24 months was 48.7%, 48.1%, and 38%, respectively. Patients who underwent surgery as a part of their salvage therapy had a mean estimated survival of 30.9 months compared with 22.8 months for patients who received only chemoradiotherapy (p = 0.126). Grade 3 or 4 acute toxicities occurred in 31.7% of patients, but all had resolved within 2 months of therapy completion. No deaths occurred during treatment, except for 1 patient, who died shortly after discontinuing treatment early because of previously undiagnosed metastatic disease; 6 patients had long-term complications. CONCLUSIONS: Concurrent chemotherapy with repeat radiotherapy with IMRT given every other week appears to be both well tolerated and feasible in patients treated with previous radiotherapy for recurrent head and neck cancer. IMRT represents a reasonable modality for reducing treatment-related toxicities in a repeat RT setting.     

Patterns of local-regional recurrence following parotid-sparing conformal and segmental intensity-modulated radiotherapy for head and neck cancer

Purpose: To analyze the patterns of local-regional recurrence in patients with head and neck cancer treated with parotid-sparing conformal and segmental intensity-modulated radiotherapy (IMRT).

Methods and Materials: Fifty-eight patients with head and neck cancer were treated with bilateral neck radiation (RT) using conformal or segmental IMRT techniques, while sparing a substantial portion of one parotid gland. The targets for CT-based RT planning included the gross tumor volume (GTV) (primary tumor and lymph node metastases) and the clinical target volume (CTV) (postoperative tumor bed, expansions of the GTVs and lymph node groups at risk of subclinical disease). Lymph node targets at risk of subclinical disease included the bilateral jugulodigastric and lower jugular lymph nodes, bilateral retropharyngeal lymph nodes at risk, and high jugular nodes at the base of skull in the side of the neck at highest risk (containing clinical neck metastases and/or ipsilateral to the primary tumor). The CTVs were expanded by 5 mm to yield planning target volumes (PTVs). Planning goals included coverage of all PTVs (with a minimum of 95% of the prescribed dose) and sparing of a substantial portion of the parotid gland in the side of the neck at less risk. The median RT doses to the gross tumor, the operative bed, and the subclinical disease PTVs were 70.4 Gy, 61.2 Gy, and 50.4 Gy respectively. All recurrences were defined on CT scans obtained at the time of recurrence, transferred to the pretreatment CT dataset used for RT planning, and analyzed using dose–volume histograms. The recurrences were classified as 1) “in-field,” in which 95% or more of the recurrence volume (V_recur) was within the 95% isodose; 2) “marginal,” in which 20% to 95% of V_recur was within the 95% isodose; or 3) “outside,” in which less than 20% of V_recur was within the 95% isodose.

Results: With a median follow-up of 27 months (range 6 to 60 months), 10 regional recurrences, 5 local recurrences (including one noninvasive recurrence) and 1 stomal recurrence were seen in 12 patients, for a 2-year actuarial local-regional control rate of 79% (95% confidence interval 68–90%). Ten patients (80%) relapsed in-field (in areas of previous gross tumor in nine patients), and two patients developed marginal recurrences in the side of the neck at highest risk (one in the high retropharyngeal nodes/base of skull and one in the submandibular nodes). Four regional recurrences extended superior to the jugulodigastric node, in the high jugular and retropharyngeal nodes near the base of skull of the side of the neck at highest risk. Three of these were in-field, in areas that had received the dose intended for subclinical disease. No recurrences were seen in the nodes superior to the jugulodigastric nodes in the side of the neck at less risk, where RT was partially spared.

Conclusions: The majority of local-regional recurrences after conformal and segmental IMRT were “in-field,” in areas judged to be at high risk at the time of RT planning, including the GTV, the operative bed, and the first echelon nodes. These findings motivate studies of dose escalation to the highest risk regions.     

Evidence-based review: Quality of life following head and neck intensity-modulated radiotherapy

Inverse planned Intensity modulated radiotherapy (IMRT) can minimize the dose to normal structures and therefore can reduce long-term radiotherapy-related morbidity and may improve patients’ long-term quality of life. Despite overwhelming evidence that IMRT can reduce late functional deficits in patients with head and neck cancer, treated with radiotherapy, a review of the published literature produced conflicting results with regard to quality of life outcomes. Following a critical appraisal of the literature, reasons for the discrepant outcomes are proposed.     

Global and health-related quality of life after intensity-modulated radiation therapy for head and neck cancer

This study aims to evaluate the current literature regarding the effects of conventional radiation therapy (CRT) versus intensity-modulated radiation therapy (IMRT) on global quality of life (QoL) among patients treated for head and neck cancer. A PubMed literature review was performed. Only articles comparing global QoL scores in head and neck cancer patients treated with CRT versus IMRT were included. Studies were scrutinized for methodology, level of evidence and limitations. Outcomes were evaluated for external validity, level of evidence and applicability. Between 2005 and 2012, 14 eligible studies (six prospective, two randomized controlled trials) were identified. Although all presented data comment on the advantages of IMRT, differences in study design made comparisons difficult. The vast majority of these were also limited by relatively small sample sizes and heterogeneity with respect to patient and treatment-related characteristics. Although more robust evidence is needed in the future, the published data reasonably support the benefits of IMRT as compared with CRT (either 2D or 3D) in improving QoL, beginning at approximately 3–6 months post-treatment, and possibly potentiating with time up to 2 and 3 years.     

Choosing an intensity-modulated radiation therapy technique in the treatment of head-and-neck cancer

PURPOSE: With the emerging use of intensity-modulated radiation therapy (IMRT) in the treatment of head-and-neck cancer, selection of technique becomes a critical issue. The purpose of this article is to establish IMRT guidelines for head-and-neck cancer at a given institution. METHODS AND MATERIALS: Six common head-and-neck cancer cases were chosen to illustrate the points that must be considered when choosing between split-field (SF) IMRT, in which the low anterior neck (LAN) is treated with an anterior field, and the extended whole-field (EWF) IMRT in which the LAN is included with the IMRT fields. For each case, the gross tumor, clinical target, and planning target volumes and the surrounding critical normal tissues were delineated. Subsequently, the SF and EWF IMRT plans were compared using dosimetric parameters from dose-volume histograms. RESULTS: Target coverage and doses delivered to the critical normal structures were similar between the two different techniques. Cancer involving the nasopharynx and oropharynx are best treated with the SF IMRT technique to minimize the glottic larynx dose. The EWF IMRT technique is preferred in situations in which the glottic larynx is considered as a target, i.e., cancer of the larynx, hypopharynx, and unknown head-and-neck primary. When the gross disease extends inferiorly and close to the glottic larynx, EWF IMRT technique is also preferred. CONCLUSION: Depending on the clinical scenario, different IMRT techniques and guidelines are suggested to determine a preferred IMRT technique. We found that having this treatment guideline when treating these tumors ensures a smoother flow for the busy clinic.     

A nomogram to predict loco-regional control after re-irradiation for head and neck cancer

Background and purpose

Loco-regionally recurrent head and neck cancer (HNC) in the setting of prior radiotherapy carries significant morbidity and mortality. The role of re-irradiation (re-RT) remains unclear due to toxicity. We determined prognostic factors for loco-regional control (LRC) and formulated a nomogram to help clinicians select re-RT candidates.

Material and methods

From July 1996 to April 2011, 257 patients with recurrent HNC underwent fractionated re-RT. Median prior dose was 65 Gy and median time between RT was 32.4 months. One hundred fifteen patients (44%) had salvage surgery and 172 (67%) received concurrent chemotherapy. Median re-RT dose was 59.4 Gy and 201 (78%) patients received IMRT. Multivariate Cox proportional hazards were used to identify independent predictors of LRC and a nomogram for 2-year LRC was constructed.

Results

Median follow-up was 32.6 months. Two-year LRC and overall survival (OS) were 47% and 43%, respectively. Recurrent stage (P = 0.005), non-oral cavity subsite (P < 0.001), absent organ dysfunction (P < 0.001), salvage surgery (P < 0.001), and dose >50 Gy (P = 0.006) were independently associated with improved LRC. We generated a nomogram with concordance index of 0.68.

Conclusion

Re-RT can be curative, and our nomogram can help determine a priori which patients may benefit.     

Current status of intensity-modulated radiation therapy (IMRT)

External-beam radiation therapy has been one of the treatment options for prostate cancer. The dose response has been observed for a dose range of 64.8–81 Gy. The problem of external-beam RT for prostate cancer is that as the dose increases, adverse effects also increase. Three-dimensional conformal radiation therapy (3D-CRT) has enabled us to treat patients with up to 72–76 Gy to the prostate, with a relatively acceptable risk of late rectal bleeding. Recently, intensity-modulated radiation therapy (IMRT) has been shown to deliver a higher dose to the target with acceptable low rates of rectal and bladder complications. The most important things to keep in mind when using an IMRT technique are that there is a significant trade-off between coverage of the target, avoidance of adjacent critical structures, and the inhomogeneity of the dose within the target. Lastly, even with IMRT, it should be kept in mind that a “perfect” plan that creates completely homogeneous coverage of the target volume and zero or small dose to the adjacent organs at risk is not always obtained. Participating in many treatment planning sessions and arranging the beams and beam weights create the best approach to the best IMRT plan.