Locoregionally Advanced Research Articles

Gemcitabine and Carboplatin in Inoperable, Loco-Regionally Advanced and Metastatic Gallbladder Cancer- A Study from Northern Indian Cancer Institute

Gemcitabine and Carboplatin in Inoperable, Loco-Regionally Advanced and Metastatic Gallbladder Cancer- A Study from Northern Indian Cancer Institute

Acute Toxicity and Outcomes of Radiation Alone Versus Concurrent Chemoradiation for Locoregional Advanced Stage Cervical Cancer

Objective: To evaluate and determine the toxicity and outcomes in patient receiving radiation (RT) alone versus concurrent chemoradiation (CRT) using cisplatin for locoregional advanced cervical cancer in Dr. Cipto Mangunkusumo Hospital (RSCM).
 
 Methods: Simple randomized single-blind clinical study, done during the period of November 2010-April 2011, in 32 patients with locoregional advanced cervical cancer (16 were treated RT alone and the rest is treated with CRT). Teletherapy was administrated using 60Co Gamma Rays 1.3 MV and photon beam linear accelerator 4-10 MV. The radiation was administered as much as 2.0 Gy per fraction
 daily for 5 days/week, for the total of 25 fractions. Brachytherapy was performed using HDR after-loading method, with Microselectron plane radiation source 129I, as much as 3x7 Gy doses to point A. CRT using cisplatin 30 mg/m2 were given for 5 series during the radiotherapy
 course. The toxicity assessments were carried out each
 week, up until 3 months after the therapy was deemed completed based on the RTOG and ECOG criteria.
 
 Results: We acquired 100% complete response in both the CRT and RT groups. In the CRT group, we found acute gastrointestinal toxicity grade 3 (18.75%) and grade 2 (43.75%); acute genitourinary toxicity grade 3 (25%), grade 2 (31.25%); and acute hematological toxicity
 grade 3 (12.50%) and grade 2 (25%). It is contrasted with the RT group, in which we did not found any cases of acute gastrointestinal toxicity, genitourinary or acute hematologic toxicity. The overall time treatment (OTT) of 56-58 days in CRT and RT group were 25% vs. 81.25% respectively, and the OTT of 59-70 days in CRT and RT
 group were 75% vs. 18.75%, respectively.
 
 Conclusion:The response to CRT and RT for locoregional advanced cervical cancer was not different in 3 month evaluation. Acute gastrointestinal, genitourinary, and hematologic toxicities found in CRT were higher than in RT (p=0.000; p=0.000; p=0.002).
 [Indones J Obstet Gynecol 2012; 36-1:37-42]
 
 Keywords: acute toxicity, concurrent chemoradiation, locoregional advanced stage cervical cancer, response therapy

Outcomes of Induction Chemotherapy Plus Intensity-Modulated Radiotherapy (IMRT) Versus IMRT Plus Concurrent Chemotherapy for Locoregionally Advanced Nasopharyngeal Carcinoma: A Propensity Matched Study

PURPOSE: It deserves investigation whether induction chemotherapy (IC) followed by intensity-modulated radiotherapy (IMRT) is inferior to the current standard of IMRT plus concurrent chemotherapy (CC) in locoregionally advanced nasopharyngeal carcinoma. METHODS: Patients who received IC (94 patients) or CC (302 patients) plus IMRT at our center between March 2003 and November 2012 were retrospectively analyzed. Propensity-score matching method was used to match patients in both arms at equal ratio. Failure-free survival (FFS), overall survival (OS), distant metastasis–free survival (DMFS), and locoregional relapse–free survival (LRFS) were assessed with Kaplan-Meier method, log-rank test, and Cox regression. RESULTS: In the original cohort of 396 patients, IC plus IMRT resulted in similar FFS (P = .565), OS (P = .334), DMFS (P = .854), and LRFS (P = .999) to IMRT plus CC. In the propensity-matched cohort of 188 patients, no significant survival differences were observed between the two treatment approaches (3-year FFS 80.3% vs 81.0%, P = .590; OS 93.4% vs 92.1%, P = .808; DMFS 85.9% vs 87.7%, P = .275; and LRFS 93.1% vs 92.0%, P = .763). Adjusting for the known prognostic factors in multivariate analysis, IC plus IMRT did not cause higher risk of treatment failure, death, distant metastasis, or locoregional relapse. CONCLUSIONS: IC plus IMRT appeared to achieve comparable survival to IMRT plus CC in locoregionally advanced nasopharyngeal carcinoma. Further investigations were warranted.

Afatinib in squamous cell carcinoma of the head and neck

ABSTRACTIntroduction: Recently new data on the efficacy of afatinib in head and neck squamous cell carcinoma (HNSCC) have been published.Areas covered: We searched the literature for published and ongoing studies with afatinib in HNSCC.Phase I data and results of phase II and III studies of afatinib in HNSCC are discussed. The maximum tolerated dose (MTD) of afatinib monotherapy with continuous administration was determined at 40 or 50 mg/day, rash and diarrhea being the principal dose-limiting toxicities. The MTD was lower when combined with chemotherapy. Studies with afatinib have been conducted or are ongoing both in the recurrent or metastatic (R/M) and in the locoregionally advanced (LA) HNSCC disease setting.Expert opinion: Comparable disease control and tumor shrinkage rates were observed with cetuximab and afatinib in HNSCC progressing after platinum-containing chemotherapy. In patients with R/M- Squamous cell carcinoma of the head and neck (SCCHN) who had progressed on/after first-line platinum-based therapy, afatinib induced significantly higher disease control rate, longer progression-free survival and improved patient-reported outcome compared to methotrexate. Randomized phase III trials studying the role of adjuvant afatinib after definitive or postoperative chemoradiation in LA-HNSCC are ongoing.

Asian expert recommendation on management of skin and mucosal effects of radiation, with or without the addition of cetuximab or chemotherapy, in treatment of head and neck squamous cell carcinoma.

With increasing numbers of patients with unresectable locoregionally advanced (LA) head and neck squamous cell carcinoma (HNSCC) receiving cetuximab/radiotherapy (RT), several guidelines on the early detection and management of skin-related toxicities have been developed. Considering the existing management guidelines for these treatment-induced conditions, clinical applicability and standardization of grading methods has remained a cause of concern globally, particularly in Asian countries. In this study, we attempted to collate the literature and clinical experience across Asian countries to compile a practical and implementable set of recommendations for Asian oncologists to manage skin- and mucosa-related toxicities arising from different types of radiation, with or without the addition of cetuximab or chemotherapy. In December 2013, an international panel of experts in the field of head and neck cancer management assembled for an Asia–Pacific head and neck cancer expert panel meeting in China. The compilation of discussion outcomes of this meeting and literature data ultimately led to the development of a set of recommendations for physicians with regards to the approach and management of dermatological conditions arising from RT, chemotherapy/RT and cetuximab/RT, and similarly for the approach and management of mucositis resulting from RT, with or without the addition of chemotherapy or cetuximab. These recommendations helped to adapt guidelines published in the literature or text books into bedside practice, and may also serve as a starting point for developing individual institutional side-effect management protocols with adequate training and education.

Gemcitabine-Based Chemoradiation in the Treatment of Locally Advanced Head and Neck Cancer: Systematic Review of Literature and Meta-Analysis.

Platinum-based concurrent chemoradiation (CCRT) improves locoregional control and overall survival of locoregionally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN) when compared to radiotherapy alone, but this approach is hampered by significant toxicity. Therefore, alternative ways to enhance the radiation effects are worth investigating. Gemcitabine (2',2'-difluorodeoxycytidine), in addition to its activity against a variety of solid tumors, including SCCHN, is one of the most potent radiosensitizers, and it has an overall favorable safety profile. In this paper, the clinical experience with gemcitabine-based chemoradiation in the treatment of patients with LA-SCCHN is reviewed. We conducted a review of the literature on the clinical experience with radiotherapy combined with either single-agent gemcitabine or gemcitabine/cisplatin-based polychemotherapy for the treatment of patients with LA-SCCHN. We also searched abstracts in databases of major international oncology meetings from the last 20 years. A meta-analysis was performed to calculate pooled proportions with 95% confidence intervals (CIs) for complete response rate and grade 3-4 acute mucositis rate. A total of 13 papers were eligible for the literature review. For schedules using a gemcitabine dose intensity (DI) below 50 mg/m(2) per week, the complete response rate was 86% (95% CI, 74%-93%) with grade 3-4 acute mucositis rate of 38% (95% CI, 27%-50%) and acceptable late toxicity. In one of the studies employing such low DIs, survival data were provided showing a 3-year overall survival of 50%. Compared with DI ≥50 mg/m(2) per week, there was no difference in the complete response rate (71%; 95% CI, 55%-83%; p = .087) but a significantly higher (p < .001) grade 3-4 acute mucositis rate of 74% (95% CI, 62%-83%), often leading to treatment interruptions (survival data provided in 8 studies; 3-year overall survival, 27%-63%). Late toxicity comprising mainly dysphagia was generally underreported, whereas information about xerostomia and skin fibrosis was scarce. This review highlights the radiosensitizing potential of gemcitabine and suggests that even very low dosages (less than 50 mg/m(2) per week) provide a sufficient therapeutic ratio and therefore should be further investigated. Refinements in radiation schemes, including intensity-modulated radiation therapy, in combination with low-dose gemcitabine and targeted agents, such as cetuximab, are currently being investigated. Cisplatin-based concurrent chemoradiation (CCRT) has become the standard treatment of locally advanced head and neck cancer (LAHNC). This approach is hampered by significant toxicity. This paper reviews the studies using gemcitabine as an alternative radio-sensitizer for CCRT in patients with LAHNC. In this capacity, despite its mild intrinsic toxicity, gemcitabine comes with high rates of severe mucositis when used in dosages exceeding 50 mg/m(2) per week. CCRT with low-dose gemcitabine provides a sufficient therapeutic ratio, combining clinical activity, similar to the higher-dose regimens, with lower toxicity. Further investigation is warranted.

339TiP Phase III study of afatinib vs placebo as adjuvant therapy after chemo-radiotherapy (CRT) in primary unresected patients with locoregionally advanced (LA) head and neck squamous cell carcinoma (HNSCC) in Asia: LUX-Head & Neck 4 (LUX-H&N4)

339TiP Phase III study of afatinib vs placebo as adjuvant therapy after chemo-radiotherapy (CRT) in primary unresected patients with locoregionally advanced (LA) head and neck squamous cell carcinoma (HNSCC) in Asia: LUX-Head & Neck 4 (LUX-H&N4)

Treatment Compliance and Outcomes for Women With Locoregionally Advanced Cervical Cancer Treated in a Safety Net Health System.

This study aims to assess treatment compliance among women undergoing definitive chemoradiation with weekly cisplatin for cervical cancer within a safety net health system and to quantify the impact of chemotherapy compliance on outcomes. All women who were treated for International Federation of Gynecology and Obstetrics stage IB2 to stage IVA cervical cancer between April 2008 and May 2014 were identified. Treatment delays were attributed to toxicity, comorbid conditions, or system issues, or categorized as patient-initiated. Disease-free survival and overall survival of women who received fewer than 6 versus 6 or more doses of weekly cisplatin 40 mg/m were compared using Kaplan-Meier analyses. One hundred nineteen women (mean [SD] age, 48.5 [11.8] years) were identified. Most women (n = 112; 94.1%) completed definitive radiotherapy, requiring a mean (SD) of 56.5 (20.1) days. Sixty-four women (57.1%) completed definitive radiotherapy in 56 days or less. Only 44 women (36.4%) received 6 or more cycles of cisplatin. Of 122 delayed cycles, reasons for delay were as follows: grade 2 or higher toxicity (n = 70; 57.4%), medical comorbidity (n = 12; 9.8%), system issues (n = 9; 7.4%), and patient-initiated (n = 14; 11.5%). Multiple issues complicated treatment for 3 doses (2.5%). Reasons for delay were not documented in 14 doses (11.5%). Among patients who received 6 or more cycles, disease-free survival improved by 17.4 months (mean [SD], 61.1 [3.7] vs 43.7 [4.3] months, P = 0.002) and overall survival improved by 8.6 months (mean [SD], 68.7 [2.3] vs 60.1 [3.7] months, P = 0.011). Higher rates of toxicity and psychosocial barriers to chemotherapy compliance adversely impact survival among women who seek care in low-resource settings. In our population, administration of all 6 cycles of cisplatin was necessary for optimal survival benefit. Future efforts to improve cervical cancer outcomes should address preventable reasons for treatment delays among underinsured or uninsured individuals.

The relationship between pathologic nodal disease and residual tumor viability after induction chemotherapy in patients with locally advanced esophageal adenocarcinoma receiving a tri-modality regimen.

A complete pathologic response to induction chemo-radiotherapy (CRT) has been identified as a favorable prognostic factor for patients with loco-regionally advanced (LRA) adenocarcinoma (ACA) of the esophagus and gastro-esophageal junction (E/GEJ). Nodal involvement at the time of surgery has been found to be prognostically unfavorable. Less is known, however, about the prognostic import of less than complete pathologic regression and its relationship to residual nodal disease after induction chemotherapy. Between February 2008 and January 2012, 60 evaluable patients with ACA of the E/GEJ enrolled in a phase II trial of induction chemotherapy, surgery, and post-operative CRT. Eligibility required a clinical stage of T3-T4 or N1 or M1a (AJCC 6(th)). Induction chemotherapy with epirubicin 50 mg/m(2) d1, oxaliplatin 130 mg/m(2) d1, and fluorouracil 200 mg/m(2)/day continuous infusion for 3 weeks, was given every 21 days for three courses and was followed by surgical resection. Adjuvant CRT consisted of 50-55 Gy at 1.8-2.0 Gy/d and two courses of cisplatin (20 mg/m(2)/d) and fluorouracil (1,000 mg/m(2)/d) over 4 days during weeks 1 and 4 of radiotherapy. Residual viability (RV) was defined as the amount of remaining tumor in relation to acellular mucin pools and scarring. Of the 60 evaluable patients, 54 completed induction therapy and underwent curative intent surgery. The Kaplan-Meier projected 3-year overall survival (OS) for patients with pathologic N0 (n=20), N1 (n=12), N2 (n=13), and N3 (n=9) disease is 73%, 57%, 35%, and 0% respectively (P<0.001). The Kaplan-Meier projected 3-year OS of patients with low (0-25%, n=19), intermediate (26-75%, n=26), and high (>75%, n=9) residual tumor viability was 67%, 42%, and 17% respectively (P=0.004). On multivariable analysis (MVA), both the pN descriptor and RV were independently prognostic for OS. In patients with less nodal dissemination (N0/N1), RV was prognostic for OS [3-year OS 85% (0-25% viable) vs. 51% (>25% viable), P=0.028]. Outcomes were poor, however, for patients with advanced nodal disease (N2/N3) regardless of RV [3-year OS 20% (0-25% viable) vs. 21% (>25% viable), P=0.55]. RV and the pN descriptor after induction chemotherapy are independent pathologic prognostic factors for OS in patients with LRA ACA of the E/GEJ. Patients with extensive nodal disease, however, have poor outcomes irrespective of residual tumor viability.

The relationship between pathologic nodal disease and residual tumor viability (RV) in patients with loco-regionally advanced (LRA) adenocarcinoma (ACA) of the esophagus and gastro-esophageal junction (E/GEJ) receiving induction chemotherapy, surgery, and post-operative chemo-radiotherapy (CRT).

The relationship between pathologic nodal disease and residual tumor viability (RV) in patients with loco-regionally advanced (LRA) adenocarcinoma (ACA) of the esophagus and gastro-esophageal junction (E/GEJ) receiving induction chemotherapy, surgery, and post-operative chemo-radiotherapy (CRT).

The impact of persistent dysphagia (PD) after induction chemotherapy in patients with loco-regionally advanced (LRA) adenocarcinoma (ACA) of the esophagus and gastro-esophageal junction (E/GEJ) receiving a tri-modality treatment regimen.

The impact of persistent dysphagia (PD) after induction chemotherapy in patients with loco-regionally advanced (LRA) adenocarcinoma (ACA) of the esophagus and gastro-esophageal junction (E/GEJ) receiving a tri-modality treatment regimen.

The impact of persistent dysphagia (PD) after induction chemotherapy in patients with locoregionally advanced (LRA) adenocarcinoma (ACA) of the esophagus and gastroesophageal junction (E/GEJ) receiving a trimodality treatment regimen.

160 Background: For patients with LRA ACA of the E/GEJ who receive pre-operative therapy, advanced pathologic stage at surgery is strongly associated with recurrence and death. Identification of such patients prior to resection, however, is problematic. Given the morbidity of esophageal resection, alternative treatment strategies may be desirable in this patient population. Methods: Between 2/08 and 1/12, 60 evaluable patients with LRA ACA of the E/GEJ enrolled in single arm phase II trial of induction chemotherapy, surgery, and post-operative chemoradiotherapy. A clinical stage of T3, N1 or M1a (AJCC 6th) was required for eligibility. Induction chemotherapy with epirubicin 50mg/m2 d1, oxaliplatin 130mg/m2 d1, and fluorouracil 200mg/m2/day continuous infusion for 3 weeks, was given every 21 days for 3 courses and was followed by surgical resection. Adjuvant CRT consisted of 50-55Gy @ 1.8-2.0 Gy/d and 2 courses of cisplatin (20mg/m2/d) and fluorouracil (1000mg/m2/d) given as 96 hour infusions during weeks 1 and 4 of radiotherapy. Dysphagia was assessed at baseline and after induction chemotherapy. Updated results as of March 2014 are presented. Results: Of the 60 evaluable patients enrolled, 54 completed induction therapy and underwent surgery. Of these 54 patients, 44 patients experienced complete resolution of dysphagia, while 10 patients had persistent symptoms. PD was associated with worse distant metastatic control [HR 3.48 (1.43 – 8.43), p=0.006], recurrence free survival [HR 3.04 (1.34 – 6.92), p=0.008], and overall survival [HR 3.31 (1.43 – 7.66), p=0.005]. PD was associated with more advanced pathologic T-descriptor (pT) (p=0.048) and N-descriptor (pN) (p=0.002), a greater median number of involved lymph nodes (3 v 1, p=0.003), and greater residual tumor viability (p=0.05). No patients with PD had pT0-T2 or pN0 disease. Of the 9 patients with pN3 disease, 5 (56%) had PD. Conclusions: PD after induction chemotherapy is associated with more advanced pathologic stage and inferior outcomes. These patients may require alternative treatment strategies. Clinical trial information: NCT00601705.

The relationship between pathologic nodal disease and residual tumor viability (RV) in patients with locoregionally advanced (LRA) adenocarcinoma (ACA) of the esophagus and gastroesophageal junction (E/GEJ) receiving induction chemotherapy, surgery, and postoperative chemoradiotherapy (CRT).

165 Background: A complete pathologic response to induction CRT has been identified as a favorable prognostic factor for patients with LRA ACA of the E/GEJ. Less is known, however, about the impact of pathologic regression after induction chemotherapy. Methods: Between 2/08 and 1/12, 60 evaluable patients with ACA of the E/GEJ enrolled in a phase II trial of induction chemotherapy, surgery, and post-operative CRT. Eligibility required a clinical stage of T3 or N1 or M1a (AJCC 6th). Induction chemotherapy with epirubicin 50mg/m2 d1, oxaliplatin 130mg/m2 d1, and fluorouracil 200mg/m2/day continuous infusion for 3 weeks, was given every 21 days for 3 courses and was followed by surgical resection. Adjuvant CRT consisted of 50-55Gy @ 1.8-2.0 Gy/d and 2 courses of cisplatin (20mg/m2/d) and fluorouracil (1000mg/m2/d) over 4 days during weeks 1 and 4 of radiotherapy. RV was defined as the amount of remaining tumor in relation to acellular mucin pools and scarring. Results: Of the 60 evaluable patients, 54 completed induction therapy and underwent curative intent surgery. The Kaplan-Meier (KM) projected 3 year OS for patients with pathologic N0 (n=20), N1 (n=12), N2 (n=13), and N3 (n=9) disease is 73%, 57%, 35%, and 0% respectively (p&lt;0.001). The KM projected 3 year OS of patients with low (0-25%, n=19), intermediate (26-75%, n=26), and high (&gt;75%, n=9) RV was 67%, 42%, and 17% respectively (p=0.004). On multivariable analysis, both the pN descriptor and RV were independently prognostic for OS. In patients with less nodal dissemination (N0/N1), RV was prognostic for OS [3yr OS 85% (0-25% viable) v 51% (&gt;25% viable), p=0.028]. Outcomes were poor, however, for patients with advanced nodal disease (N2/N3) regardless of RV [3yr OS 20% (0-25% viable) v 21% (&gt;25% viable), p=0.55]. Conclusions: RV and the pN descriptor after induction chemotherapy are independent pathologic prognostic factors for OS in patients with LRA ACA of the E/GEJ. Patients with extensive nodal disease, however, have poor outcomes irrespective of viability. Clinical trial information: NCT00601705.

The impact of 5-fluorouracil (5FU) dose intensity (DI) on survival outcomes in patients (pts) receiving multimodality therapy for locoregionally advanced (LRA) adenocarcinoma (ACA) of the esophagus (E) and gastroesophageal junction (GEJ).

e15031 Background: Perioperative chemotherapy improves outcomes for pts with LRA ACA of the E/GEJ compared to surgery alone. Combination chemotherapy regimens are frequently employed, and toxicity ...

A phase II trial of induction epirubicin, oxaliplatin, and flourouracil, surgery and post-operative concurrent cisplatin and fluorouracil chemoradiotherapy (CRT) in patients (pts) with loco-regionally advanced (LRA) adenocarcinoma (ACA) of the esophagus (E) and gastroesophageal junction (GEJ).

4087 Background: In pts with LRA ACA of the E/GEJ, CRT and surgery results in excellent locoregional control. Distant failure remains common, however, suggesting potential benefit from additional chemotherapy. This single arm phase II study investigated the addition of induction chemotherapy to surgery and post-operative CRT. Methods: Pts with an ultrasound-based clinical stage of T3, N1 or M1a (AJCC 6th) ACA of the E/GEJ were eligible. Induction chemotherapy with epirubicin 50mg/m2 d1, oxaliplatin 130mg/m2 d1, and flourouracil 200mg/m2/day continuous infusion for 3 weeks, was given every 21 days for 3 courses and was followed by surgical resection. Adjuvant CRT consisted of 50-55Gy at 1.8-2.0 Gy/d and 2 courses of cisplatin (20mg/m2/d) and flourouracil (1000mg/m2/d) given as 96 hour infusions during weeks 1 and 4 of radiotherapy. Results: Between 2/08 and 1/12, 60 evaluable pts enrolled; 95% male, 97% white and 78% with GEJ tumors. Resection was accomplished in 54 pts (90%) and adjuvant CRT in 48 (80%). Toxicity included 1 death during induction (2%), and 2 post-operative deaths (4%). Unplanned hospitalization was required in 18% of pts during induction and 19% during adjuvant CRT. Induction chemotherapy produced a symptomatic response in 79% of pts, a clinical (ultrasound) response in 48% and a pathologic response in 41% (5% complete). With a median follow-up of 31 months, the Kaplan-Meier 3-year projected locoregional control (LRC) is 84%, distant metastatic control (DMC) 44%, relapse-free survival (RFS) 39%, and overall survival (OS) 42%. Symptomatic response to induction and the percentage of remaining viable tumor at surgery proved the strongest predictors of DMC, RFS, and OS. Conclusions: Induction chemotherapy, surgery and adjuvant CRT is feasible and produces outcomes similar to other multimodality treatment schedules in LRA E/GEJ ACA. Despite excellent LRC, projected DMC and OS remain poor. A symptomatic response to induction and less residual viable tumor at surgery are associated with improved outcomes. Clinical trial information: NCT00601705.

Role of Repeat Staging Laparoscopy in Locoregionally Advanced Gastric or Gastroesophageal Cancer after Neoadjuvant Therapy

Staging laparoscopy (SL) can identify occult, subradiographic metastatic (M1) disease in patients with gastric or gastroesophageal (G/GEJ) cancer who are unlikely to benefit from gastrectomy. The purpose of this study is to determine the yield of repeat SL following neoadjuvant therapy for G/GEJ adenocarcinoma after initial negative pretreatment SL. Retrospective review of a prospective database identified patients with locoregionally advanced (T3-4Nany or TanyN+) G/GEJ adenocarcinoma who underwent pretreatment SL. The yield of repeat SL following neoadjuvant therapy was determined. From 1994 to 2010, 276 patients with locoregionally advanced G/GEJ adenocarcinoma were identified, of whom 244 proceeded to operation after neoadjuvant therapy, at a median time of 105 days. One hundred sixty-four patients (67 %) underwent repeat SL, and 80 patients (33 %) proceeded directly to laparotomy. Occult M1 disease was identified in 12 (7.3 %) and 6 (7.5 %) patients, respectively. In the repeat SL cohort, M1 disease was identified at laparoscopy in nine patients (5.5 %). M1 disease not identified by laparoscopy was discovered at laparotomy in three patients (1.8 %). The median follow-up for the study population was 31 months. For patients with M1 disease, median overall survival was 15 months, versus 41 months for patients resected without M1 disease (p < 0.0001). Occult, subradiographic M1 disease develops in approximately 7 % of patients following neoadjuvant therapy for locoregionally advanced G/GEJ adenocarcinoma. These patients have poor prognosis, and repeat SL can be a valuable tool in selecting patients with locoregionally advanced G/GEJ tumors for potentially curative resection after neoadjuvant therapy.

Relationship between treatment duration and outcomes in patients receiving concurrent chemoradiotherapy (CCRT) and surgery for locoregionally advanced (LRA) esophageal and gastroesophageal junction (E/GEJ) adenocarcinoma (ACA).

e14665 Background: Retrospective studies in breast, colon, and head and neck cancer have suggested that delays in administration of adjuvant chemotherapy result in inferior outcomes. We explore this question in patients with LRA E/GEJ ACA. Methods: From 11/99 to 7/06, 152 patients with cT3, N1, or M1a disease were enrolled on one of two clinical trials at the Cleveland Clinic. Two courses of CCRT consisting of 30Gy radiation (@1.5Gy BID) with continuous infusion cisplatin (20mg/m2/day x 4 days) and 5Fu (1000mg/m2/d x 4 days) were given both before and after surgical resection. In the second trial, 75 patients also received gefitinib during the 4 week induction and for a total of two years postoperatively. Using recursive partitioning analysis (RPA), we retrospectively explored the relationship between treatment duration and loco-regional control (LRC), distant metastatic control (DMC), freedom from recurrence (FFR), and overall survival (OS) in the 115 patients (76%) who completed all treatment. Outcomes were estimated using the Kaplan-Meier method and compared among groups using the log-rank test. Results: RPA analysis identified three groups of patients: 19 patients in whom resection occurred ≤45 days from the start of CCRT to resection (short treatment), 63 patients who underwent resection &gt;45 days from the start of CCRT and required &lt;50 days to complete treatment after surgery (intermediate treatment), and 33 patients who underwent resection &gt;45 days from the start of CCRT but required ≥50 days to complete treatment after surgery (prolonged treatment). With a median follow-up of 90 (range 57-126) months, we found that patients with shorter treatment times had better 5 year DMC [64% (short) v 26% (intermediate) v 16% (prolonged); p=0.004], FFR [57% (short) v 23% (intermediate) v 16% (prolonged); p=0.015)], and OS [42% (short) v 30% (intermediate) v 12% (prolonged); p=0.08]. LRC was not different between the groups. Conclusions: Treatment delays in patients receiving multimodality therapy for LRA E/GEJ ACA may result in a greater risk of recurrence and decreased survival.

An open-labeled, multicentric clinical study of cetuximab combined with intensity-modulated radiotherapy (IMRT) plus concurrent chemotherapy in locoregionally advanced (LA) nasopharyngeal carcinoma (NPC): A 2-year follow-up report.

5535 Background: To evaluate the safety and efficacy outcomes of concurrent cetuximab plus IMRT and cisplatin in Chinese patients with LA NPC. Methods: Patients with primary stage III-IVb (UICC/AJCC 2002 staging system) and non-keratinizing NPC were enrolled in this prospective, multicentric, phase II study. Cisplatin (80mg/m2,q3week) and cetuximab (400mg/m2 one w before radiation, and then 250mg/m2/w) were given concurrently. The prescription dose of IMRT to GTVnx (primary tumor in nasopharynx) was 66 Gy - 75.9 Gy, GTVnd (positive cervical lymph nodes) was 60 Gy - 70Gy, The response rate was evaluated according to RECIST 1.0 criteria, and adverse events (AEs) were graded according to NCI CTCAE V3.0 criteria. Results: From July 2008 to April 2009, 100 patients were enrolled (74 male), with median age of 43 years. The proportion of stage III, IVa and IVb patients were 71%, 22% and 7% respectively. 99% of enrolled patients completed the planned treatment. AEs were within the expected range and manageable. No toxic death occurred during the treatment. Acneiform skin eruptions, mucositis, in-field dermatitis, xerostomia and neucopenia were the most common seen AEs, with 64% grade 2/3 acneiform eruptions, 26% grade 2/3 in-field dermatitis, 90% ≥ grade 2 mucositis (2 cases of grade 4 mucositis with spontaneous bleeding), 40% ≥ grade 2 xerostomia and 8% grade 2/3 neucopenia. With a median follow-up time of 23.5 months, the 2 year overall survival (OS), disease-free survival (DFS), local recurrence-free survival, regional (cervical lymph node) recurrence free survival and distant metastasis-free survival rates for the ITT population were 91%, 89%, 90%, 90% and 89%, respectively Multivariate analysis showed that N stage was the only prognostic factor for OS (p=0.0392, HR=2.946) and DFS (p=0.0062, HR=4.246) in these patients. Conclusions: Cetuximab combined with IMRT plus concurrent cisplatin in patients with LA NPC shows satisfactory 2-year locoregional control rate and 2-year overall survival. The combination seems to be well tolerated with a manageable side-effect profile.

Correlation between toxicity and outcome after multimodality therapy of locoregionally advanced (LRA) adenocarcinoma (ACA) of the esophagus (E) and gastroesophageal junction (GEJ).

e14611 Background: Multiagent concurrent chemoradiation (CRT) and surgery is a standard curative-intent approach for patients (pts) with LRA ACA of the E/GEJ. This single institution retrospective analysis examined whether toxicities occurring during induction chemoradiation (ICRT) were independently prognostic for outcome. Methods: Between 11/99 and 7/06, 152 pts with T3, N1 or M1a ACA of the E/GEJ were entered onto one of two Cleveland Clinic trials. ICRT with 96 hour infusions of cisplatin (20mg/m2/d) and fluorouracil (1000mg/m2/d) beginning on day 1 of radiation (30Gy@1.5Gy bid), was followed by surgery and identical post-operative CRT. 75 pts also received 2 years of oral gefitinib. Multivariable Cox analysis was used to identify prognostic factors for overall survival (OS), freedom from recurrence (FFR), locoregional (LRC) and distant metastatic control (DMC). Both clinical features (including demographics, tumor characteristics, symptomatic and pathologic response), and ICRT- related toxicities (including nausea/vomiting, mucositis/dysphagia, neutropenia, thrombocytopenia, neutropenic fever and any unplanned hospitalization) were analyzed. Results: Of the 152 pts enrolled, resection proved possible in 138 (91%). With a median follow-up of 90 (range 57-126) months, the 5-year Kaplan-Meier projected OS is 22%, FFR 24%, DMC 27% and LRC 69%. As expected, in multivariable analysis, earlier clinical stage disease and a pathologic and symptomatic response to ICRT all proved favorable for treatment outcomes. In addition, the development of grade 3-4 (vs. grade 0-2) mucositis and/or dysphagia during ICRT was a significant risk factor for distant recurrence [HR 2.62 (1.34-5.12), p=0.005]; any recurrence [HR 2.08 (1.08-4.00), p=0.027] and death [HR 2.00 (1.07-3.74), p=0.031]. Neutropenic fever was also correlated with distant recurrence [HR 1.82 (1.03-3.22, p=0.039] and any recurrence [HR 2.19 (1.23-3.90) p=0.007]. Conclusions: Neutropenic fever and the development of grade 3-4 mucositis and/or dysphagia during ICRT are independently associated with worse outcomes after multimodality therapy for E/GEJ ACA.

Anti-epidermal growth factor receptor therapy for advanced head and neck squamous cell carcinoma: a meta-analysis

To assess the efficacy and safety of anti-epidermal growth factor receptor (EGFR) therapy versus non-anti-EGFR therapy for advanced head and neck squamous cell carcinoma (HNSCC). The Cochrane Central Register of Controlled Trials, Medline, and Embase databases were searched for relevant reports. Quantitative analysis was carried out to evaluate the overall response rate (ORR), overall survival (OS), progression free survival (PFS), and grade 3-4 adverse effects. Ten reports involving 2,396 patients were included. Primary meta-analysis indicated that anti-EGFR therapy could improve ORR [relative risk (RR) 1.36, 95% confidence interval (CI) 1.12-1.67] and PFS [hazard ratio (HR) 0.63, 95% CI 0.55-0.71), but failed to improve OS (HR 0.88, 95% CI 0.74-1.03). In subgroup analyses, we found that monoclonal antibodies (Mabs) could improve ORR, OS, and PFS for both locoregionally advanced (LA) (ORR: 1.21, 1.08-1.37; OS: 0.72, 0.59-0.89; PFS: 0.66, 0.53-0.83) and recurrent/metastatic (RM) HNSCC (ORR: 1.88, 1.40-2.54; OS: 0.79, 0.67-0.94; PFS: 0.61, 0.52-0.71), while tyrosine kinase inhibitors (TKIs) did not improve any of these in patients with either LA (ORR: 1.09, 0.91-1.32; OS: 0.7, 0.31-1.63; PFS: 0.71, 0.34-1.52) or RM (ORR: 1.65, 0.84-3.24; OS: 1.13, 0.97-1.31; PFS: not available) HNSCC. Analysis of adverse effects demonstrated that rash (RR 14.34, 95% CI 5.02-41.02), diarrhea (2.36, 1.15-4.87), and anorexia (2.49, 1.11-5.56) were significantly associated with anti-EGFR therapy. Anti-EGFR Mabs are effective for both LA and RM HNSCC. In contrast, TKIs were unsuitable for treatment of advanced HNSCC. During anti-EGFR therapy, rash and some gastrointestinal reactions, such as diarrhea and anorexia, should be carefully monitored.