Appraisal of re-irradiation for the recurrent glioblastoma in the era of MGMT promotor methylation

Despite recent innovation in treatment techniques and subsequently improved outcomes, the majority of glioblastoma (GBL) have relapses, especially in locoregional areas. Local re-irradiation (re-RT) has been established as a feasible option for recurrent GBL of all ages with safety, tolerability, and effectiveness both in survival and quality of life regardless of fractionation schedule. To keep adverse effects under acceptable range, cumulative dose limit in equivalent dose at 2 Gy fractions by the linear-quadratic model at α/β = 2 for normal brain tissue (EQD2) with narrow margin should be observed and single/hypofractionated re-RT should be undertaken very carefully to recurrent tumor with large volume or adjacent to the brainstem. Promising outcome of re-operation (re-Op) plus re-RT (re-Op/RT) need to be validated and result from re-RT with temozolomide/bevacizumab (TMZ/BV) or new strategy is expected. Development of new-concept prognostic scoring or risk group is required to select patients properly and make use of predictive biomarkers such as O(6)-methylguanine-DNA methyltransferase (MGMT) promotor methylation that influence outcomes of re-RT, re-Op/RT, or re-RT with TMZ/BV.

High-Dose Thoracic Re-irradiation of Lung Cancer Using Highly Conformal Radiotherapy Is Effective with Acceptable Toxicity / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Thoracic re-irradiation (re-RT) of lung cancer has been challenged by the tolerance doses of normal tissues. We retrospectively analyzed local control, overall survival (OS) and toxicity after thoracic re-RT using highly conformal radiotherapy, such as intensity modulated radiotherapy and stereotactic body radiotherapy. MATERIALS AND METHODS: Thirty-one patients who received high-dose thoracic re-RT were analyzed. Doses were recalculated to determine biologically equivalent doses. The median interval to re-RT was 15.1 months (range, 4.4 to 56.3 months), the median initial dose was 79.2 Gy₁₀ (range, 51.75 to 150 Gy₁₀), and the median re-RT dose was 68.8 Gy₁₀ (range, 43.2 to 132 Gy₁₀). RESULTS: Eighteen (58.1%) and eleven (35.5%) patients showed loco-regional recurrence and distant metastasis, respectively, after 17.4 months of median follow-up. The 1-year and 2-year local control rates were 60.2% and 43.7%, respectively. The median loco-regional recurrence-free-survival (LRFS) was 15.4 months, and the median OS was 20.4 months. The cumulative and re-RT biologically equivalent dose for α/β=10 (BED₁₀) doses were the most significant prognostic factors. Cumulative BED₁₀ ≥145 Gy₁₀ and re-RT BED₁₀≥68.7 Gy₁₀ were significantly associated with longer OS (p=0.029 and p=0.012, respectively) and LRFS (p=0.003 and p=0.000, respectively). The most frequent acute toxicity was grade 1-2 pulmonary toxicity (41.9%). No acute grade 3 or higher toxicities occurred. CONCLUSION: Our results show that high-dose thoracic re-RT of lung cancer can be safely delivered using highly conformal radiotherapy with favorable survival and acceptable toxicity. An optimal strategy to select patients who would benefit from re-RT is crucial in extending the indications and improving the efficacy with a sufficiently high dose.

Hypofractionated Re-irradiation after Maximal Surgical Resection for Recurrent Glioblastoma: Therapeutic Adequacy and Its Prognosticators of Survival

PURPOSE: To evaluate the adequacy of retreatment, including hypofractionated re-irradiation (HFReRT), after surgery for recurrent glioblastoma (GBM) and related prognosticators of outcomes. MATERIALS AND METHODS: From 2011 to 2014, 25 consecutive patients with recurrent (n=17) or secondary (n=7) disease underwent maximal surgery and subsequent HFReRT after meeting the following conditions: 1) confirmation of recurrent or secondary GBM after salvage surgery; 2) Karnofsky performance score (KPS) ≥60; and 3) interval of ≥12 months between initial radiotherapy and HFReRT. HFReRT was delivered using a simultaneous integrated boost technique, with total dose of 45 Gy in 15 fractions to the gross tumor volume (GTV) and 37.5 Gy in 15 fractions to the clinical target volume. RESULTS: During a median follow-up of 13 months, the median progression-free and overall survival (OS) were 13 and 16 months, respectively. A better KPS (p=0.026), no involvement of the eloquent area at recurrence (p=0.030), and a smaller GTV (p=0.005) were associated with better OS. Additionally, OS differed significantly between risk groups stratified by the National Institutes of Health Recurrent GBM Scale (low-risk vs. high-risk, p=0.025). Radiologically suspected radiation necrosis (RN) was observed in 16 patients (64%) at a median of 9 months after HFReRT, and 8 patients developed grade 3 RN requiring hospitalization. CONCLUSION: HFReRT after maximal surgery prolonged survival in selected patients with recurrent GBM, especially those with small-sized recurrences in non-eloquent areas and good performance.

The study of re-irradiation for head and neck cancer / 中华放射肿瘤学杂志

Nearly 50% patients with head and neck cancer after radiotherapy will recurrence in the previous radiation fields.Salvage surgery is the first choice of treatment.Clinical studies have shown that a small number of patients with recurrent head and neck cancer can benefit from salvage surgery plus postoperative re-irradiation or re-irradiation with or without chemotherapy or targeted therapy,and these patients can achieved tumor control and long-term survival.However, the overall efficacy is not satisfactory, and often accompanied by severe acute and late, and even fatal treatment-related toxicity.Therefore, it is necessary to give full consideration to the condition of recurrent tumor, the first radiotherapy related factors and the patient′s related status before implementation of re-irradiation.The development of radiotherapy technology and comprehensive treatment, including the clinical application of proton and heavy ion and immune therapy, provides the possibility of improving the prognosis and reducing treatment-related toxicity for these patients.

Reirradiation of head and neck cancer in the era of intensity-modulated radiotherapy: patient selection, practical aspects, and current evidence

Locoregional failure is the most frequent pattern of failure in locally advanced head and neck cancer patients and it leads to death in most of the patients. Second primary tumors occurring in the other head and neck region reach up to almost 40% of long-term survivors. Recommended and preferred retreatment option in operable patients is salvage surgical resection, reporting a 5-year overall survival of up to 40%. However, because of tumor location, extent, and underlying comorbidities, salvage surgery is often limited and compromised by incomplete resection. Reirradiation with or without combined chemotherapy is an appropriate option for unresectable recurrence. Reirradiation is carefully considered with a case-by-case basis. Reirradiation protocol enrollment is highly encouraged prior to committing patient to an aggressive therapy. Radiation doses greater than 60 Gy are usually recommended for successful salvage. Despite recent technical improvement in intensity-modulated radiotherapy (IMRT), the use of concurrent chemotherapy, and the emergence of molecularly targeted agents, careful patient selection remain as the most paramount factor in reirradiation. Tumors that recur or persist despite aggressive prior chemoradiation therapy imply the presence of chemoradio-resistant clonogens. Treatment protocols that combine novel targeted radiosensitizing agents with conformal high precision radiation are required to overcome the resistance while minimizing toxicity. Recent large number of data showed that IMRT may provide better locoregional control with acceptable acute or chronic morbidities. However, additional prospective studies are required before a definitive conclusion can be drawn on safety and effectiveness of IMRT.

Re-Irradiation for Recurrent Gliomas: Treatment Outcomes and Prognostic Factors

PURPOSE: The aim of this study was to evaluate the efficacy of re-irradiation in patients with recurrent gliomas and to identify subgroups for whom re-irradiation for recurrent gliomas is most beneficial. MATERIALS AND METHODS: We retrospectively reviewed 36 patients with recurrent or progressive gliomas who received re-irradiation between January 1996 and December 2011. Re-irradiation was offered to recurrent glioma patients with good performance or at least 6 months had passed after initial radiotherapy (RT), with few exceptions. RESULTS: Median doses of re-irradiation and initial RT were 45.0 Gy and 59.4 Gy, respectively. The median time interval between initial RT and re-irradiation was 30.5 months. Median overall survival (OS) and the 12-month OS rate were 11 months and 41.7%, respectively. In univariate analysis, Karnofsky performance status (KPS) ≥70 (p<0.001), re-irradiation dose ≥45 Gy (p=0.040), and longer time interval between initial RT and re-irradiation (p=0.040) were associated with improved OS. In multivariate analysis, KPS (p=0.030) and length of time interval between initial RT and re-irradiation (p=0.048) were important predictors of OS. A radiographically suspected mixture of radiation necrosis and progression after re-irradiation was seen in 5 patients. CONCLUSION: Re-irradiation in conjunction with surgery could be a salvage treatment for selected recurrent glioma patients with good performance status and recurrence over a long time.

Re-Irradiation of Hepatocellular Carcinoma: Clinical Applicability of Deformable Image Registration

PURPOSE: This study aimed to evaluate whether the deformable image registration (DIR) method is clinically applicable to the safe delivery of re-irradiation in hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between August 2010 and March 2012, 12 eligible HCC patients received re-irradiation using helical tomotherapy. The median total prescribed radiation doses at first irradiation and re-irradiation were 50 Gy (range, 36-60 Gy) and 50 Gy (range, 36-58.42 Gy), respectively. Most re-irradiation therapies (11 of 12) were administered to previously irradiated or marginal areas. Dose summation results were reproduced using DIR by rigid and deformable registration methods, and doses of organs-at-risk (OARs) were evaluated. Treatment outcomes were also assessed. RESULTS: Thirty-six dose summation indices were obtained for three OARs (bowel, duodenum, and stomach doses in each patient). There was no statistical difference between the two different types of DIR methods (rigid and deformable) in terms of calculated summation operatorD (0.1 cc, 1 cc, 2 cc, and max) in each OAR. The median total mean remaining liver doses (M(RLD)) in rigid- and deformable-type registration were not statistically different for all cohorts (p=0.248), although a large difference in M(RLD) was observed when there was a significant difference in spatial liver volume change between radiation intervals. One duodenal ulcer perforation developed 20 months after re-irradiation. CONCLUSION: Although current dose summation algorithms and uncertainties do not warrant accurate dosimetric results, OARs-based DIR dose summation can be usefully utilized in the re-irradiation of HCC. Appropriate cohort selection, watchful interpretation, and selective use of DIR methods are crucial to enhance the radio-therapeutic ratio.

Treatment outcome of hepatic re-irradiation in patients with hepatocellular carcinoma

PURPOSE: We evaluated the efficacy and toxicity of repeated high dose 3-dimensional conformal radiation therapy (3D-CRT) for patients with unresectable hepatocellular carcinoma. MATERIALS AND METHODS: Between 1998 and 2011, 45 patients received hepatic re-irradiation with high dose 3D-CRT in Samsung Medical Center. After excluding two ineligible patients, 43 patients were retrospectively reviewed. RT was delivered with palliative or salvage intent, and equivalent dose of 2 Gy fractions for alpha/beta = 10 Gy ranged from 31.25 Gy10 to 93.75 Gy10 (median, 44 Gy10). Tumor response and toxicity were evaluated based on the modified Response Evaluation Criteria in Solid Tumors criteria and the Common Terminology Criteria for Adverse Events (CTCAE) ver. 4.0. RESULTS: The median follow-up duration was 11.2 months (range, 4.1 to 58.3 months). An objective tumor response rate was 62.8%. The tumor response rates were 81.0% and 45.5% in patients receiving > or =45 Gy10 and or =50 Gy10. CONCLUSION: Hepatic re-irradiation may be an effective and tolerable treatment for patients who are not eligible for further local treatment modalities, especially in patients with Child-Pugh A and T1-3.

Progresses on reirradiation for locally recurrence of non-small-cell lung cancer patients after radio-therapy and chemotherapy / 实用肿瘤学杂志

The recurrence rate of non -small cell lung cancer ( NSCLC) patients after radiotherapy and chemotherapy have been increasing .The therapy scheme consists of reirradiation、chemotherapy、and chemoradio-therapy,with the purpose of improving the local control and prolonging the survival time .Reirradiation is feasible for locally recurrence of non -small-cell lung cancer patients , treatment is security and could better improve quality of life in patients .The majority of patients are tolerable and have better short -term efficacy , No severe short term radiation induced injury is observed .But the long term radiation induced injury and long term efficacy need further investigation .In the present paper ,we review the roles of reirradiation for locally recurrence of non -small-cell lung cancer patients after radiotherapy and chemotherapy and the progress in clinical research .

Reirradiation of recurrent cervical cancer / 国际肿瘤学杂志

Pelvic exenteration,first line salvage therapy for selected recurrent cervical cancer patients,is accompanied by a high operative mortality and loss of structure and function of pelvic organs.Advances in radiation therapy,especially 3-dimensional brachytherapy and stereotactic body radiotherapy,provide the opportunity to achieve similar efficacy of pelvic exenteration with acceptable complications and protect the structure and function of pelvic organs.

Re-irradiation of recurrent esophageal cancer after primary definitive radiotherapy

PURPOSE: For recurrent esophageal cancer after primary definitive radiotherapy, no general treatment guidelines are available. We evaluated the toxicities and clinical outcomes of re-irradiation (re-RT) for recurrent esophageal cancer. MATERIALS AND METHODS: We analyzed 10 patients with recurrent esophageal cancer treated with re-RT after primary definitive radiotherapy. The median time interval between primary radiotherapy and re-RT was 15.6 months (range, 4.8 to 36.4 months). The total dose of primary radiotherapy was a median of 50.4 Gy (range, 50.4 to 63.0 Gy). The total dose of re-RT was a median of 46.5 Gy (range, 44.0 to 50.4 Gy). RESULTS: The median follow-up period was 4.9 months (range, 2.6 to 11.4 months). The tumor response at 3 months after the end of re-RT was complete response (n = 2), partial response (n = 1), stable disease (n = 2), and progressive disease (n = 5). Grade 5 tracheoesophageal fistula developed in three patients. The time interval between primary radiotherapy and re-RT was less than 12 months in two of these three patients. Late toxicities included grade 1 dysphagia (n = 1). CONCLUSION: Re-RT of recurrent esophageal cancer after primary radiotherapy can cause severe toxicity.

Preliminary study of nimotuzumab combined with reirradiation in patients with recurrent high-grade glioma / 肿瘤

Objective: To prospectively evaluate the side-effect and outcomes of nimotuzumab combined with reirradiation in patients with recurrent high-grade glioma. Methods: Ten patients with recurrent high-grade glioma recruited between October 2008 and March 2011 were reirradiated with conventional fractionation. The interval between initial radiation therapy and reirradiation was 7-42 months (the median time was 20 months). The irradiation dose was 40-51 Gy (18-27 fx) for 26-40 d [the median dose was 48 Gy (24 fx ) for 35d]. Intravenous injection of nimotuzumab was used weekly during radiation therapy for 3-6 weeks. The toxicities and short responses were recorded. The overall survival and the progression-free survival were calculated. Results: The acute adverse reactions were gradesI-II headache, digestive system side effects, and aggravation of the neurologic dysfunction, but they were all relieved after symptomatic treatment. The toxicity of more than grade III was not observed. The radiation-induced brain necrosis was found in three patients. Of the 10 patients, 3 had partial response, 6 had stable disease, and 1 had progressive disease. The Karnofsky performance status score was increased, unchanged and decreased in 4, 4 and 2 patients, respectively. The median time to progression was 6.5 months. The 6-month and 1-year progression-free survival rates were 60% and 20%, respectively. The median overall survival was 11.5 months. The 6-month and 1-year overall survival rates were 80% and 50%, respectively. Conclusion: The preliminary results demonstrate that nimotuzumab combined with reirradiation for recurrent high-grade glioma appears to be effective and safe. The further follow-up is required to determine the long-term outcomes. Copyright © 2012 by TUMOR.

Second Line Palliative Endobronchial Radiotherapy with HDR Ir 192 in Recurrent Lung Carcinoma

PURPOSE: To observe the efficiency of reirradiation with high dose rate intraluminal brachytherapy in symptomatic palliation of recurrent endobronchial tumors. MATERIALS and METHODS: Between January 1994 and June 1998, 21 patients diagnosed with recurrent endobronchial tumors following external beam radiotherapy were treated palliatively with high dose rate intraluminal irradiation at Hacettepe University Oncology Institute. A single fraction of 10Gy was prescribed to the specified area in 9 patients and 15Gy to 12. RESULTS: Endobronchial treatment improved the performance and reduced symptomatology in 17 (81%) patients. Ten dyspneic patients (10/14, 71%) recovered clinically with an accompanying radiological downstaging. The median symptomatic palliation was 45 days (range, 0-9 months), and the overall median survival was 5.5 months (range, 4-12 months). The palliative intrabronchial brachytherapy was well tolerated, with the exception of in one patient with a fatal hemorrhage, and another with medically salvaged bronchospasm and intrabronchial edema. CONCLUSION: Recurrent patients with a history of previous thoracic external beam irradiation can be effectively palliated with high dose rate endobronchial reirradiation if the symptoms are directly related to the endobronchial tumor.

Advance in the clinical research on local recurrent nasopharyngeal carcinoma / 中国癌症杂志

Local recurrent nasopharyngeal carcinoma(NPC) presents a troublesome challenge to radiation oncologist. Reirradiation is the primary modality nowadays. However, clinical data on reirradiation are still relatively scarce. This article summarized the treatment advances and the clinical characteristics associated with relapse of NPC, and reviewed the outcomes of different radiation techniques in the management of recurrence of NPC, i.e. conventionalradiotherapy, stereotactic radiotherapy, brachytherapy, three-dimensional conformal radiotherapy and intensity modulate radiotherapy, or some combination of above in recent years.

High Dose 3-Dimensional Re-Irradiation for Locally Recurrent Nasopharyngeal Cancer

This is to report the results of 3-dimensional (3D) high dose re-irradiation (re-RT) for patients with locally recurrent nasopharyngeal cancer. Between May 1995 and Dec. 2000, 21 patients with locally recurrent cancer of the nasopharynx received high dose 3D re-RT at Samsung Medical Center. The median 55 (45 - 70) Gy was applied by daily fractions of 2.5 Gy or 3.0 Gy. The median survival period, the rates of local control, overall survival and disease-free survival at 5 years, of all patients, were 21 months, 71.8%, 32.3%, and 21.2% respectively. The number of patients who experienced treatment failures at any site was 14 (67.0%) : eight patients (38.1%) experienced distant hematogenous metastases; five patients (23.8%) experienced recurrences within the current re-RT treatment volume; and seven patients (33.0%) had recurrences outside this volume. Five patients (23.8%) experienced severe late radiation-induced complications of RTOG grade IV or V, and these were brainstem necrosis (2), temporal lobe necrosis (1), mucosal necrosis (1), and massive epistaxis (1). For locally recurrent nasopharyngeal cancer patients, high dose 3D re-RT could lead to improved results when compared with the historic data by conventional re-RT techniques. Further treatment refinements, that would be necessary, may include optimization in patient selection, improvement in target localization and patient immobilization, and the addition of systemic agents, either as a radiation sensitizer or a radiation protector.

Reirradiation in Rcurrent Cervical Cancer Following Definite Radiation Therapy / 대한방사선종양학회지

PURPOSE: To evaluate treatment results in terms of local control, complications and survival after reirraidiation in recurrent cervical cancer following definite radiation therapy. MATERIAL AND METHODS: From November 1987 through March 1998, eighteen patients with recurrent cervical cancer following definite radiation therapy were subsequently treated with reirradiation at Keimyung University Dongsan Medical Center. In regard to the initial FIGO stage, one patient was stage Ia, five were stage IIa, three were IIb, two were IIb and two were IVa. The age range was 37 to 79 years old with median age of 57. The time interval from initial definite radiation therapy to recurrence ranged from 6 to 122 months with a median of 58 months. The recurrent sites were the uterine cervix in seven patients, vagina in ten and pelvic lymph node in one. Reirradiation was performed with external radiation and intracavitary radiation in twelve patients, external radiation and implantation in four and external radiation alone in two. The range of external radiation dose was 2,100~5,400 cGy and the range of the total radiation dose was 3,780~8,550 cGy. The follow-up periods ranged from 8 to 20 months with median of 25 following reirradiation. RESULTS: Fourteen of eighteen patients (78%) had local control just after reirradiation. The two year disease free survival (2YDFS) rate was 53.6%. There were statistically significant differences in the 2YDFS according to both recurrent site (2YDFS 28.5% in uterine cervix, 71.4% in vagina, ( p=0.03)) and the total dose (2YDFS 71.8% in >6,000 cGy , 25% in < OR = 6,000 cGy, p=0.007). Seven of ten patients who were followed for more than 20 months remain alive and disease free (7/18, 39%). Patients treated with external radiation and intracavitary radiation had a higher rate of 2YDFS. Seven patients including 4 patients with no local control experienced local failure in the uterus or vagina and two patients died with distant metastasis. Complications included rectal bleeding in 3 patients, bowel obstruction treated with surgery in two, hematuria in one, radiation cystitis in two, soft tissue swelling in two and vaginal necrosis spontaneously healed in one. There was no statistical difference in complications according to the total dose or the time to recurrence from initial radiation. CONCLUSION: In patients with recurrence following definite radiation therapy in the uterine cervical cancer, reirradiation may be effective but requires an effort to reduce radiation induced severe complications.

Hyperfractionated re-irradiation using a 3-dimensional conformal technique for locally recurrent carcinoma of the nasopharynx; preliminary results

To evaluate the efficacy of hyperfractionated re-irradiation using a three-dimensional conformal radiotherapy (3-D CRT) technique in patients with locally recurrent carcinoma of the nasopharynx. Four patients with locally recurrent nasopharyngeal cancer were retreated with a hyperfractionated schedule using a 3-D CRT technique. Re-irradiation was delivered in 1.1-1.2 Gy fractions twice per day (BID), with interfraction intervals of more than 6 hours. The total dose ranged from 59.4 to 69.2 Gy. A 3-D CRT technique with 5- or 6-field coplanar and/or non-coplanar beams were employed during the entire treatment procedure. All four patients achieved complete remission of locally recurrent lesions, with marked improvement of subjective symptoms, immediately after re-irradiation. All are alive and well without evidence of disease after limited follow-up periods, which range from 7 to 20 months. So far, there have been no radiation-induced neurologic complications. Four patients with locally recurrent carcinoma of the nasopharynx were successfully treated by hyperfractionated re-irradiation using a 3-D CRT technique. A relatively high re-irradiation dose of more than 60 Gy may be safely delivered with no serious acute or late radiation-induced complications in patients with local recurrences and who were initially treated with doses greater than 70 Gy.

Excellent Local Tumor Response after Fractionated Stereotactic Radiation Therapy for Locally Recurrent Nasopharynx Cancer / 대한치료방사선과학회지

PURPOSE: This study is to report experience with Fractionated Stereotactic Radiation Therapy (FSRT) for locally recurrent nasopharynx cancer after curative conventional radiation therapy. MATERIALS AND METHODS: Three patients with locally recurrent and symptomatic nasopharynx cancer were given FSRT as reirradiation method between the period of September of 1995 and August of 1996. For two patients, application of FSRT is their third radiation therapy directed to the nasopharynx. Two patients were given low dose chemotherapy as radiation sensitizer concurrently with FSRT. Authors used 3-dimensional coordinate system by individually made, relocatable Gill-Thomas-Cosman (GTC) stereotactic frame and multiple non-coplanar arc therapy dose planning was done using XKnife-3. Total of 45 Gy/18 fractions or 50 Gy/20 fractions were given. RESULTS: Authors observed satisfactory symptomatic improvement and remarkable objective tumor size decrease by follow-up MR images taken 1 month post-FSRT in all three patients, while no neurologic side effect attributable to reirradiation was noticed. Two died at 7 and 9 months with loco-regional and distant seeding outside FSRT field, while one patient is living for 4 month. CONCLUSION: Authors experienced satisfactory therapeutic effectiveness and safety of FSRT as reirradiation method for locally recurrent nasopharynx cancer. Development of more effective systemic chemotherapeutic regimen is desired for distant metastasis.