The Effect of Hospital Case Volume on Clinical Outcomes in Patients with Nasopharyngeal Carcinoma: A Multi-institutional Retrospective Analysis (KROG-1106)

PURPOSE: The purpose of this study was to investigate the effect of hospital case volume on clinical outcomes in patients with nasopharyngeal carcinoma (NPC). Materials and Methods: Data on 1,073 patients with cT1-4N0-3M0 NPC were collected from a multi-institutional retrospective database (KROG 11-06). All patients received definitive radiotherapy (RT) either with three-dimensional-conformal RT (3D-CRT) (n=576) or intensity-modulated RT (IMRT) (n=497). The patients were divided into two groups treated at high volume institution (HVI) (n=750) and low volume institution (LVI) (n=323), defined as patient volume ≥ 10 (median, 13; range, 10 to 18) and < 10 patients per year (median, 3; range, 2 to 6), respectively. Endpoints were overall survival (OS) and loco-regional progression-free survival (LRPFS). RESULTS: At a median follow-up of 56.7 months, the outcomes were significantly better in those treated at HVI than at LVI. For the 614 patients of propensity score-matched cohort, 5-year OS and LRPFS were consistently higher in the HVI group than in the LVI group (OS: 78.4% vs. 62.7%, p < 0.001; LRPFS: 86.2% vs. 65.8%, p < 0.001, respectively). According to RT modality, significant difference in 5-year OS was observed in patients receiving 3D-CRT (78.7% for HVI vs. 58.9% for LVI, p < 0.001) and not in those receiving IMRT (77.3% for HVI vs. 75.5% for LVI, p=0.170). CONCLUSION: A significant relationship was observed between HVI and LVI for the clinical outcomes of patients with NPC. However, the difference in outcome becomes insignificant in the IMRT era, probably due to the standardization of practice by education.ope

Anti-Vascular Endothelial Growth Factor Treatment Augments Tumor Radiation Response under Normoxic or Hypoxic Conditions.

Recent studies in experimental animals have shown that combining antiangiogenic therapy with radiation can enhance tumor response. Whether this enhancement is mainly attributable to angiogenesis inhibition, endothelial cell radiosensitivity, tumor cell apoptosis, or a decrease in the number of hypoxic cells (improved oxygenation) is not known. We designed this study to discern the role of tumor oxygenation. We chose an anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibody (mAb) which has a known target, human VEGF. We also measured interstitial fluid pressure (IFP) to test the hypothesis that the decreased vascular permeability induced by the anti-VEGF mAb can lower IFP. The effect of anti-VEGF mAb on vascular density, partial oxygen tension (pO2), and apoptosis was also measured. Athymic NCr/Sed nu/nu mice bearing 6-mm xenograft of the human glioblastoma multiforme (U87), or colon adenocarcinoma (LS174T) were treated with anti-VEGF mAb injected i.p. on alternate days for a total of six injections at a dosage of 100 microg/injection/mouse. For combined anti-VEGF and radiation, single radiation doses were given under normal blood flow (20 and 30 Gy) or clamped hypoxic conditions (30 and 40 Gy) 24 h after the sixth injection of mAb. The inhibition of the growth of U87 and LS174T tumors by the anti-VEGF mAb was associated with a significant reduction in tumor vascular density and a relatively small increase in the number of apoptotic cells. Compared with size-matched controls, IFP decreased by 74% in LS174T, and 73% in U87 in mice treated with anti-VEGF mAb. After antibody treatment PO2 increased significantly in U87, but did not change in LS174T tumors. Combined treatment induced in U87 tumors a tumor-growth delay (TGD) which was greater than additive; in LS174T except for the 40-Gy hypoxic group, the effect was only additive. In both U87 and LS174T the TGD induced by the antibody was independent of oxygen levels in the tumor at the time of radiation. The fact that the increase in TGD occurred under both normoxic and hypoxic conditions suggests that anti-VEGF mAb treatment can compensate for the resistance to radiation induced by hypoxia.ope

The Socioeconomic Impact of Terminal Cancer on Patients´ Families and Its Associated Factors

Background : We conducted this study to investigate the financial burden of terminal cancer patients' family and to identify factors influencing their economic burden. Methods : We approached 187 family members supporting their famly member with terminal cancer who was enrolled in four hospice and palliative care program. We constructed a questionnaire examining the impact of illness on their family. With multiple logistic analysis, we examined the patients' and family members' demographic and the patients' clinical factors associated with the burden caused by terminal cancer. Results : The majority of families reported the loss of savings (54%), the need to make major life changes in order to care for the patient (50%), the loss of incomes (34%), the inability to function normally because of the stress of the illness (27%). Many families had to move to a less expensive home (18%), delay medical care for other family members (12%), or change educational plans for other family members (13%). Families that cared for patients who wanted to be cared for at institution (odds ratio: 2.72, 95% confidence interval: 1.19∼6.19), patients with liver cancer (3.61, 1.53∼8.57), and families who were poor caregivers (2.97, 1.24∼7.10), or primary caregiver was a spouse (3.57, 1.47∼8.68) were more likely to lose savings. Families that were in 'new couple' in family life cycle stages (3.91, 1.04∼14.63), 'birth of the first child' (8.34, 2.74∼25.32), and 'the adolescent family or the launching family' (10.56, 4.07∼27.33), were more likely to lose savings than 'the empty family or the aging family'.ope

Comparison of the Clinical Outcomes of Patients with Squamous Cell Carcinoma of the Tonsil Receiving Postoperative Ipsilateral Versus Bilateral Neck Radiotherapy: A Propensity Score Matching Analysis (KROG 11-07)

Purpose: The impact of postoperative ipsilateral neck radiotherapy (INRT) versus bilateral neck radiotherapy (BNRT) on the clinical outcomes of patients with tonsillar squamous cell carcinoma was analyzed retrospectively. Materials and methods: Between October 2001 and June 2012, 241 patients with T1-2 and N0-N2b tonsillar carcinoma from 16 institutes underwent postoperative INRT (n=84) or BNRT (n=157) following a tonsillectomy. Seventy patients were identified from each group by propensity score matching and compared in terms of the overall survival (OS), disease-free survival (DFS), locoregional relapse-free survival (LRRFS), and distant metastasis-free survival (DMFS) rates calculated using the Kaplan-Meier method with a log-rank test. Results: The median follow-up was 55 months (range, 3 to 133 months). The survival outcomes in the INRT and BNRT groups were similar: 5-year OS (92.8% vs. 94.0%, p=0.985), DFS (80.5% vs. 94.2%. p=0.085), LRRFS (88.1% vs. 97.1%, p=0.083), and DMFS (92.7% vs. 97.0%, p=0.370). Subgroup analysis revealed no contralateral neck recurrence in 61 patients with T1-2N0-2a regardless of the treatment groups. For 79 patients with N2b, contralateral neck recurrence was more common in the INRT group than in the BNRT group (7.9% vs. 0.0%), but the difference was not significant (p=0.107). The overall grade ≥ 2 toxicities were lower in the INRT group: acute (45.7% vs. 74.3%, p=0.001) and late (4.3% vs. 31.4%, p < 0.001), respectively. Conclusion: INRT is an attractive strategy for patients with T1-2N0-2a tonsillar carcinoma compared to BNRT. For patients with N2b, there was a small risk of contralateral neck recurrence when treated with INRT, but its impact on the OS was limited with successful salvage treatment.ope

Toxicity of tomotherapy-based simultaneous integrated boost in whole-pelvis radiation for prostate cancer

PURPOSE: The validity of tomotherapy-based simultaneous integrated boost (TOMOSIB) was assessed in terms of acute intestinal/urinary toxicity by comparing with 3-dimensional conformal radiotherapy (3DCRT) in cases of whole-pelvis radiation therapy (WPRT) for prostate cancer. MATERIALS AND METHODS: Thirty-eight consecutive patients who underwent curative WPRT were retrospectively reviewed. Twenty six (68.4%) received 3DCRT and the others (31.6%) were treated with TOMOSIB. A local boost to the prostate circumferential area was added to WPRT sequentially for 3DCRT and concomitantly for TOMOSIB. The total median prostate or prostatic bed dose was 64.8 Gy including median 45.0 Gy of WPRT. Acute toxicities were assessed according to RTOG criteria. RESULTS: Overall intestinal toxicity was lower in TOMOSIB group than 3DCRT group (p=0.008). When it was divided into rectum and non-rectum intestine (NRI), TOMOSIB showed borderline superiority only in NRI toxicity (p=0.047). For the urinary toxicity, there was no significant difference between two groups (p=0.796). On dosimetric analysis for the rectum and bladder, dose delivered to 80% (p<0.001) and volume receiving 25-40 Gy (p<0.001) were remarkably higher in 3DCRT. For the NRI, only maximum dose showed significant results between two groups (p<0.001). CONCLUSION: Intestinal toxicity should be verified with more detailed anatomic categorization such as rectum and NRI. TOMOSIB could not reduce urinary toxicity because of inevitably high dose exposure to the prostatic urethra. Current dosimetry system did not properly reflect intestinal/urinary toxicity, and suitable dosimetric guidelines are needed in TOMOSIB.ope

Pancreatic radiation effect in apoptosis-related rectal radiation toxicity

Pancreatic radiation effect (PRE) can be a component of gastrointestinal tract (GIT) radiotoxicity. This inter-organ correlation between the GIT and the pancreas was assessed through a rat model. Separate local irradiation to the abdomen and the pelvis was applied concurrently for 8-week-old male Sprague Dawley rats. Abdominal irradiation was categorized into pancreatic shield (PS) and non-pancreatic shield (NPS) irradiation. After 5 Gy and 15 Gy irradiation, the rectal mucosa was analyzed at the first week (early phase, Ep) and the 14th week (late phase, Lp). A slow gain in body weight was observed initially, particularly in the NPS group receiving a 15 Gy dose (P < 0.001). The large number of apoptotic bodies after 15 Gy at Ep decreased at Lp. At Ep for the 5-Gy group, the NPS group revealed more fibrotic change than the PS group (P = 0.002). Cleaved caspase-3 (CCP3) expression was greater at Lp, and the Ep-Lp increase was prominent in the NPS-15-Gy group (P = 0.010). At Lp, for 15 Gy irradiation, CCP3 was expressed more in the NPS group than in the PS group (P = 0.032). Despite no direct toxicity difference between the PS and NPS groups, small changes in parameters such as fibrosis or CCP3 expression suggest that pancreatic shielding does have an effect on the radiation response in the rectal mucosa, which suggests a need for a multi-organ effect-based approach in GIT radiotoxicity assessment.ope

High Precision Radiotherapy

The technical advances that have been achieved over the last decade in the area of 3-dimensional radiotherapy treatment planning capabilities and new and more flexible hardware capabilities, such as computer-controlled treatments, multileaf collimators, and real-time portal imaging devices, have brought about 3-dimensional conformal radiation therapy. For the purpose of highly conformal radiation therapy, a variety of radiation treatment techniques and treatment machines such as stereotactic radiosurgery(SRS) using gamma-knife, stereotactic radiotherapy(SRT) using linear accelerator, and stereotactic whole body radiotherapy have been invented. Intensity-modulated radiation therapy(IMRT) is a new and evolving technological advance in high-precision radiation therapy. It is an extension of 3-dimensional conformal radiotherapy(3-DCRT) that allows the delivery of highly complex isodose profiles to the target, while minimizing radiation exposure to surrounding normal tissues. Image-guided adaptive radiotherapy(IGRT) combines scanning and radiation equipment, to provide images of the patient's organs in the treatment position, at the time of the treatment, optimizing the accuracy and precision of the radiotherapy. Respiratory-gated radiotherapy was developed to overcome the motion of organs. Most high precision radiation therapy approaches increase the time and efforts required by physicians and physicists, because optimization systems are not yet robust enough to provide automated solutions for all disease sites, and routine QA testing is still quite time-consuming. Preliminary clinical experiences of high precision radiation therapy have been encouraging by high rates of local control and decrease of toxicity. This article provides an overview of high precision radiotherapy such as 3-DCRT, SRS, SRT, Cyberknife, IMRT, and IGRT.ope

Patterns of care for patients with nasopharyngeal carcinoma (KROG 11-06) in South Korea

PURPOSE: To investigate the patterns of care for patients with nasopharyngeal carcinoma (NPC) in South Korea. MATERIALS AND METHODS: A multi-institutional retrospective study was performed (Korean Radiation Oncology Group [KROG] 11-06) on a total of 1,445 patients from 15 institutions. RESULTS: Of the 1,445 patients, more than half were stages III (39.9%) and IV (35.8%). In addition to patterns of care, we also investigated trends over time with the periods 1988-1993, 1994-2002, and 2003-2011. The frequencies of magnetic resonance imaging and positron emission tomography-computed tomography were markedly increased in the third period compared to previous 2 periods. Concurrent chemoradiation (CCRT) was performed on 894 patients (61.9%), neoadjuvant chemotherapy on 468 patients (32.4%), and adjuvant chemotherapy on 366 patients (25.3%). Of stage II-IV patients, CCRT performed on 78.8% in 2003-2011 compared to 15.0% in 1988-1993. For patients treated with CCRT, cisplatin was the most commonly used agent in 81.3% of patients. Over the periods of time, commonly used radiotherapy (RT) techniques were changed from 2-dimensional RT (1988-1993, 92.5%) to 3-dimensional RT (2003-2011, 35.5%) or intensity-modulated RT (IMRT; 2003-2011, 56.5%). Median RT doses given to primary tumors, high-risk lymphatics, and low-risk lymphatics were 70.0 Gy, 58.1 Gy, and 48.0 Gy, respectively. Adoption of IMRT increased the dose per fraction and escalated total radiation dose. CONCLUSION: Assessment of the patterns of care for NPC patients in South Korea demonstrated that management for NPC including diagnostic imaging, treatment regimen, RT techniques and dose schedule, advanced in accordance with the international guidelines.ope

Intensity-Modulated Radiotherapy-Based Reirradiation for Head and Neck Cancer: A Multi-institutional Study by Korean Radiation Oncology Group (KROG 1707)

Purpose: The benefits of reirradiation for head and neck cancer (HNC) have not been determined. This study evaluated the efficacy of reirradiation using intensity-modulated radiotherapy (IMRT) for recurrent or second primary HNC (RSPHNC) and identified subgroups for whom reirradiation for RSPHNC is beneficial. Materials and methods: A total of 118 patients from seven Korean institutions with RSPHNC who underwent IMRT-based reirradiation between 2006 and 2015 were evaluated through retrospective review of medical records. We assessed overall survival (OS) and local control (LC) within the radiotherapy (RT) field following IMRT-based reirradiation. Additionally, the OS curve according to the recursive partitioning analysis (RPA) suggested by the Multi-Institution Reirradiation (MIRI) Collaborative was determined. Results: At a median follow-up period of 18.5 months, OS at 2 years was 43.1%. In multivariate analysis, primary subsite, recurrent tumor size, interval between RT courses, and salvage surgery were associated with OS. With regard to the MIRI RPA model, the class I subgroup had a significantly higher OS than class II or III subgroups. LC at 2 years was 53.5%. Multivariate analyses revealed that both intervals between RT courses and salvage surgery were prognostic factors affecting LC. Grade 3 or more toxicity and grade 5 toxicity rates were 8.5% and 0.8%, respectively. Conclusion: IMRT-based reirradiation was an effective therapeutic option for patients with RSPHNC, especially those with resectable tumors and a long interval between RT courses. Further, our patients' population validated the MIRI RPA classification by showing the difference of OS according to MIRI RPA class.ope

Physician’s Attitude toward Treating Breakthrough Cancer Pain in Korea

Purpose : Adequate control of breakthrough pain is essential for patients with cancer. Managing breakthrough pain mainly depends on understanding the concept of breakthrough pain and the proper usage of rescue medication by physicians. This study aims to assess the attitudes and practice patterns of palliative physicians in managing breakthrough pain for patients in Korea. Methods : This study was based on data from the 2014 breakthrough cancer pain survey conducted by the Korean Society for Hospice and Palliative Care. One hundred physicians participated in the online survey. Among total 33 self-reported questionnaires, twelve items were selected in this analysis. Results : Rapid onset of action is the main influencing factor in selecting rescue opioids. Oral oxycodone (65%) and parenteral morphine (27%) are commonly used. A few physicians (3%) prefer to use transmucosal fentanyl. The percentage of physicians prescribing oral oxycodone due to its rapid onset of action is just 21.5%, whereas the percentage of physicians using parenteral morphine is 81.5%. Two thirds of respondents (66%) answered that breakthrough pain is not well controlled with rescue medications. Conclusion : There is a gap between the needs of physicians in terms of the perceived difficulties of managing breakthrough cancer pain and their practice patterns selecting rescue medications.ope