Jiade J. Lu

RADIATION-INDUCED CRANIAL NERVE PALSY: A CROSS-SECTIONAL STUDY OF NASOPHARYNGEAL CANCER PATIENTS AFTER DEFINITIVE RADIOTHERAPY

PURPOSE To address the characteristics and the causative factors of radiation-induced cranial nerve palsy (CNP) in nasopharyngeal carcinoma (NPC) patients with an extensive period of followed-up. PATIENTS AND METHODS A total of 317 consecutive and nonselected patients treated with definitive external-beam radiotherapy between November 1962 and February 1995 participated in this study. The median doses to the nasopharynx and upper neck were 71 Gy (range, 55-86 Gy) and 61 Gy (range, 34-72 Gy), respectively. Conventional fractionation was used in 287 patients (90.5%). Forty-five patients (14.2%) received chemotherapy. RESULTS The median follow-up was 11.4 years (range, 5.1-38.0 years). Ninety-eight patients (30.9%) developed CNP, with a median latent period of 7.6 years (range, 0.3-34 years). Patients had a higher rate of CNP (81 cases, 25.5%) in lower-group cranial nerves compared with upper group (44 cases, 13.9%) (χ(2) = 34.444, p < 0.001). Fifty-nine cases experienced CNP in more than one cranial nerve. Twenty-two of 27 cases (68.8%) of intragroup CNP and 11 of 32 cases (40.7%) of intergroup CNP occurred synchronously (χ(2) = 4.661, p = 0.031). The cumulative incidences of CNP were 10.4%, 22.4%, 35.5%, and 44.5% at 5, 10, 15, and 20 years, respectively. Multivariate analyses revealed that CNP at diagnosis, chemotherapy, total radiation dose to the nasopharynx, and upper neck fibrosis were independent risk factors for developing radiation-induced CNP. CONCLUSION Radiation-induced fibrosis may play an important role in radiation-induced CNP. The incidence of CNP after definitive radiotherapy for NPC remains high after long-term follow-up and is dose and fractionation dependent.

Intraoperative Radiotherapy Combined With Adjuvant Chemoradiotherapy for Locally Advanced Gastric Adenocarcinoma

PURPOSE To evaluate the efficacy of intraoperative radiotherapy (IORT) followed by concurrent chemotherapy and external beam RT (EBRT) in the treatment of locally advanced gastric adenocarcinoma. METHODS AND MATERIALS A total of 97 consecutive and nonselected patients with newly diagnosed Stage T3, T4, or N+ adenocarcinoma of the stomach underwent gastrectomy with D2 lymph node dissection between March 2003 and October 2005. Of the 97 patients, 51 received adjuvant concurrent chemotherapy (5-fluorouracil, leucovorin, docetaxel, and cisplatin) and EBRT (EBRT group) and 46 received IORT (dose range, 12-15 Gy) immediately after gastrectomy and lymph node dissection before concurrent chemoradiotherapy (EBRT+IORT group). RESULTS After a median follow-up of 24 months, the 3-year locoregional control rate was 77% and 63% in the two groups with or without IORT, respectively (p = 0.05). The 3-year overall survival and disease-free survival rate was 47% and 36% in the EBRT group and 56% and 44% in the EBRT+IORT group, respectively (p > 0.05). Multivariate analyses revealed that the use of IORT, presence of residual disease after surgery, and pN category were independent prognostic factors for locoregional control and that IORT, pN, and pT categories were independent prognostic factors for overall survival (p < 0.05). Four patients experienced Grade 3 or 4 late complications, but no significant difference was observed between the two groups. CONCLUSIONS Radical gastrectomy with D2 lymph node dissection and IORT followed by adjuvant chemoradiotherapy appeared to be feasible and well-tolerated in the treatment of locally advanced gastric cancer. The addition of IORT to the trimodality treatment significantly improved the 3-year locoregional control rate.

Adjuvant intraoperative electron radiotherapy and external beam radiotherapy for locally advanced transitional cell carcinoma of the ureter

OBJECTIVE Surgery is the mainstay treatment for transitional cell carcinoma (TCC) of the ureter; however, local recurrence remains a common cause of treatment failure for locally advanced disease after surgery, and the benefit of adjuvant radiotherapy has not been completely determined. The objective of this analysis was to evaluate the outcome of postsurgical high dose radiotherapy consisting of intraoperative electron beam radiotherapy (IOERT) and external beam radiotherapy (EBRT) in locally advanced transitional cell carcinoma of the ureter. METHODS Seventeen patients with pathologically diagnosed TCC of ureter were treated with nephroureterectomy and adjuvant radiation consisted of IOERT and EBRT according to an institutional research protocol. The dose of IOERT ranged between 10 to 20 Gy (median 14 Gy). Conventional EBRT given with the total dose ranged between 36 and 45 Gy (median 42 Gy). Chemotherapy was utilized in 10 of the 17 patients at the discretion of their primary oncologist. RESULTS The median follow-up for all patients was 48 months (range, 10-91 months). The overall survivals of the entire group of patients at 1, 3, and 5 years were 82%, 65%, and 46%, respectively. The estimated locoregional control rates at 1, 3, and 5 year were 82%, 64%, and 51%, respectively. Depth of invasion (pT), histological grade, and presence of residual disease were significant prognostic factors in univariate analysis. Multivariate analysis revealed that independent prognostic factors for survival included histological grade (grade 1 + 2 vs. grade 3 + 4; P = 0.03) and presence of residual disease after surgery (R0 vs. R1 or R2 resection; P = 0.053). Acute and long-term adverse effects rated grade 3 or higher were seen in 4 and 2 patients, respectively. No grade 5 toxicity occurred. CONCLUSION IOERT and EBRT following surgery produced a 51% local control and 46% overall survival rate for locally advanced TCC of ureter at 5 years of follow-up, with acceptable rates of acute and late toxicity. Adjuvant IOERT appears to permit dose escalation safely in patients who received conventional adjuvant EBRT and chemotherapy. This strategy deserves to be optimized and then tested in a prospective trial to learn if it can further improve outcome.

Salvage Intensity-Modulated Radiation Therapy (IMRT) for Locally Recurrent Nasopharyngeal Cancer after Definitive IMRT: A Novel Scenario of the Modern Era.

Locally recurrent nasopharyngeal carcinoma (rNPC) after definitive IMRT occurs in 10% of all cases and represents a distinct clinical entity that has been selectively enriched by radio-resistant cancer cells. Therefore, we report of the outcomes of 77 patients who had repeat salvage-IMRT for rNPC after only a definitive course of IMRT. Various clinical outcomes were measured. Log-rank tests were used to detect differences in the survival outcomes between factor-defined subgroups. Multivariable analysis was performed using the Cox proportional hazard model. The median follow-up time was 25.7 months (range 3.0–75.7 months), measured from the time of recurrence. The median OS time and PFS time of the entire cohort was 37.0 and 20.5 months, respectively. Thirty-four patients (44.2%) died. Approximately 35% of these patients died from disease progression, but 53% were from treatment-induced severe adverse effects (SAEs) without evidence of disease progression. Higher T-classification of the recurrent tumor and the development of SAEs were found to be the only independent and significant adverse prognostic factors on multivariable analysis. These outcomes underscore the particularly virulent characteristics of rNPC after definitive IMRT. Concerning is the impact of re-irradiation toxicity on patient mortality.

Effects of induction docetaxel, platinum, and fluorouracil chemotherapy in patients with stage III or IVA/B nasopharyngeal cancer treated with concurrent chemoradiation therapy: Final results of 2 parallel phase 2 clinical trials

The effects of docetaxel, platinum, and fluorouracil (TPF) induction chemotherapy plus concurrent chemoradiotherapy (CCRT) on locoregionally advanced nasopharyngeal cancer (NPC) are unclear. This study examined the long‐term outcomes of the addition of this regimen to CCRT for stage III and IVA/B NPC.

The relative biological effectiveness of proton and carbon ion beams in photon-sensitive and resistant nasopharyngeal cancer cells

Background: Approximately 10–15% of all nasopharyngeal carcinoma (NPC) cases will develop local recurrence (LR) after definitive radiation therapy. Clinical data has demonstrated a decreased treatment-related toxicities and a potential improved local control rate with carbon ion radiotherapy (CIRT) as compared to photon-based intensity-modulated radiotherapy (IMRT) for LR-NPC. However, the relative biological effectiveness (RBE) for NPC cells, especially the photon-radioresistant nasopharyngeal carcinoma (prNPC) cells within recurrent tumors, have not been determined. Methods: An established prNPC cell line (CNE-2R), which represents a cell model for extremely photon resistant NPC, and its parental cell line, CNE-2 were irradiated by photons or protons (energy, 74.55– 95.8 MeV; LET, ~3.125 keV/μm) with doses of 2, 4, 6, 8 and 10 Gy or by carbon ion pencil beam (energy, 148.3–180.3 MeV/u; LET, ~315.7 keV/μm) with physical doses of 2, 4, 6 and 8 Gy. Clonogenic survival was studied by analyzing the macrocolony formation and RBE values were at 10% (D 10 ) and 37% (D 37 ) survival. Results: For photon response, the α/β ratio for CNE-2 cells is higher compared to CNE-2R cells. The proton-treated cell survival curves demonstrated similar profiles to those of X-rays for CNE-2 and CNE-2R cell lines. The RBE of proton beam at 10% survival (D 10 ) was 0.95 for CNE-2 cells as compared with 0.98 for CNE-2R cells. The surviving fraction (SF) at 2 Gy, after exposure to photons, ~3.125 keV/μm protons and 315.7 keV/μm carbon ions, were 0.547, 0.566 and 0.166 for CNE-2 and 0.686, 0.750 and 0.310 for CNE-2R cells, respectively. The CNE-2R cells were less sensitive to carbon ions than CNE-2 cells. The RBE for carbon at 10% and 37% survival levels were 2.46 and 2.90 for CNE-2 cells compared with 1.95 and 2.53 for CNE-2R cells, respectively. Therefore, the RBEs in the photon-resistant CNE-2R cells were relatively lower than those in photon-sensitive CNE-2 cells following X-ray or carbon ion irradiation at 315.7 keV/μm. Conclusions: Compared with photons and protons, carbon ion shows better cell inactivation capability in both CNE-2 cells and photon resistant CNE-2R cells. The RBE values of NPC cells can help in making strategic decisions on the design of clinical trials using carbon ion therapy.

Salvage treatment using carbon ion radiation in patients with locoregionally recurrent nasopharyngeal carcinoma: Initial results

Reirradiation for locoregionally recurrent nasopharyngeal carcinoma (NPC) after a definitive dose of radiotherapy (RT) is challenging and usually associated with severe toxicities. Intensity‐modulated carbon ion RT (IMCT) offers physical/biologic advantages over photon‐based intensity‐modulated RT. Herein, the authors report their initial experience of IMCT in previously irradiated patients with locoregionally recurrent NPC.

Effects of induction taxotere, platinum, and fluorouracil (TPF) chemotherapy in patients with stage III and IVA/B nasopharyngeal cancer treated with concurrent chemoradiation therapy: final results of two parallel phase 2 clinical trials

BACKGROUND Concurrent chemoradiotherapy (CCRT) is the standard treatment for locally advanced nasopharyngeal cancer. The effect of induction chemotherapy plus CCRT in patients with this stage of disease is unclear. We therefore examined the long-term outcomes of the addition of induction chemotherapy (consisting of docetaxel, cisplatin, and fluorouracil [TPF]) to CCRT in patients with stage III and IVA/B nasopharyngeal cancer. METHODS Between January, 2007, and July, 2011, we synchronously undertook two parallel phase 2 single-arm trials to evaluate the efficacy and toxicity of TPF-based induction chemotherapy. One trial was for patients with stage III nasopharyngeal cancer, and the other was for patients with stage IVA/B disease. Treatment regimens used in both trials were identical. The induction chemotherapy consisted of three cycles of docetaxel 75 mg/m2 (day 1), cisplatin 75 mg/m2 (day 1), and a continuous fluorouracil infusion at 500 mg/m2 per day (days 1-5) every 4 weeks. Radiotherapy was given mainly with intensity-modulated technique (IMRT) at 2·0 Gy per fraction with five daily fractions per week to a total dose of 70 Gy to the primary tumour and neck adenopathy, and 54-60 Gy to the uninvolved neck region. The concurrent chemotherapy consisted of weekly cisplatin at 40 mg/m2. Our primary endpoint for both trials was 5-year overall survival, based on intention-to-treat analysis. Both studies were designed to detect a 20% improvement in 5-year overall survival from historical controls. Comparison of results between the two trials was planned. The protocol was conducted with approval from the institutional review board of the Shanghai Proton and Heavy Ion Center. The trials are registered with ClinicalTrials.gov, numbers NCT00816855 and NCT00816816. FINDINGS 52 eligible patients with stage III nasopharyngeal cancer and 64 eligible patients with non-metastatic stage IV disease were accrued to the two trials. With a median follow-up of 66·8 months (range 15·9-105·4), 5-year overall survival was 91·6% (95% CI 83·6-99·6) for stage III patients and 83·1% (72·9-93·3) for stage IVA/B patients (p=0·059), which approximated to a 20% improvement compared with historical controls. 5-year progression-free survival was 80·1% (95% CI 69·1-91·1) versus 66·8% (54·1-79·5; p=0·072), distant metastasis free survival was 93·0% (85·4-100·0) versus 93·1% (86·6-99·6; p=0·387), and local progression-free survival was 92·0% (84·6-99·4) versus 87·2% (77·6-96·8; p=0·276), for patients with stage III versus stage IVA/IVB nasopharyngeal cancer. Multivariate analyses indicated that T-classification (T1/2 vs T3/4) and N-classification (N3 vs N0-2) were the only two significant prognosticators for overall survival (hazard ratio [HR] 2·52, 95% CI 1·178-5·394, p=0·017; HR 1·808, 95% CI 1·002-3·264, p=0·045, respectively), whereas age, gender, number of induction chemotherapy cycles (two vs three), number of concurrent chemotherapy cycles (four or more vs five or less), RT technique, and the presence of residual primary or neck disease were not significant in predicting overall survival. INTERPRETATION TPF-based induction chemotherapy significantly improved overall and progression-free survival when given before CCRT in locoregionally advanced nasopharyngeal cancer. T-classification and N-classification were the only two significant prognostic factors in predicting overall survival. A phase 3 trial is ongoing to confirm such benefit. FUNDING None.