Cycles Of CT Research Articles

Phase II trial of erlotinib maintenance therapy after platinun-based chemotherapy in advanced non-small cell lung cancer (NSCLC)

e19013 Background: phase II trial-efficacy & toxicity of sequential erlotinib in advanced NSCLC after platinum-based CT Methods: Pts with adv NSCLC, PS 0/1, adequate renal, hepatic and bone marrow function, no PD after CT. Treatment: erlotinib 150 mg/day starting 3–4 weeks after CT until progression. Safety was evaluated monthly and tumor evaluation bimonthly. Results: 47 pts enrrolled:42(89%)stageIV & 5(11%)wet IIIB, all valid for response & toxicity. Median age 62 y(r:39 -77): 39(83%) males and 8(17%) females. Histology: adenocarcinoma 8(61.7%), bronquioloalveolar 3(6.4%), large cell 3(6.4%), squamous12(25.5%). PS 0: 23(49%), PS 1:24(51%). 38(81.9%) completed 6 cycles of CT. Response: CR: 1(2.1%), PR: 2(51.1%), EE: 22 (46%). Sequential erlotinib improved RR in 6 (12.8%), 23 (48.9) prolonged stabilization, 18 (38.3%) had progression. Median TTP and OS were 9.4 m (95% CI, 4.96–13–84), and 19.23 m (95% CI, 8.82–29.64). No significant differences in TTP according to age, sex, PS, histology or previous response to CT, but yes depending on RR to erlotinib: PR: 31.5 m (95% CI 15.37–47.63), EE: 12.8 m (95% CI, 10.58–15.03), PD: 6.3 m (95% CI, 5.36–7.3), p < 0.001; and moreover depending on smoking status: Never: 21.67 m(95% CI, 5.39–37.94), previous smoker > 5 years: 14.03 m(95% CI, 10.77–17.30), previous smoker 1 year: 7.77 m(95% CI, 7.62–7.91), current smoker: 5.9 m(95% CI, 5.12–6.34), p <0.001. In Cox-regression model, smoking status ( p< 0.001), and response to erlotinib (p=0.002) were associated with a significant difference in TTP. Similar results in OS, although in Cox-regression model only never smoker or > 5 years previous smoker pts had a significant better survival. Toxicity: The most frequent was skin rash, grade (g) 1 in 11(23.4%), g 2: 16(34%) and g 3: 3(6.4%). Only 1 p had diarrea g 3, and no other side effects were observed. We found a significant benefit in p with g 2–3 skin toxicity respect g 0–1, in both TTP( p= 0.0003) and OS (p= 0.0014). Conclusions: Erlotinib-maintenance therapy after platinum-based CT had promising results. Pts with the best benefit were those with response to erlotinib, in never or past (> 5 years) smokers and with g 2–3 skin toxicity. No significant financial relationships to disclose.

Adding the specific COX-2 inhibitor celecoxib to docetaxel plus carboplatin in first line for stage IC-IV epithelial ovarian cancer: A randomized phase II study

5545 Background: Inhibition of COX-2 reduces the growth rate of tumors in vitro and COX-2 is over-expressed in ovarian cancer, so a COX-2 inhibitor might be beneficial. Methods: After debulking surgery patients (pts) with advanced epithelial ovarian cancer (FIGO IC-IV) received docetaxel 75 mg/m2 and carboplatin AUC=5 (CT) for 6–9 cycles q 3-wks and were randomized to celecoxib 400 mg BID (COX) for max three years or to control (CTR), stratified for residual tumor present in 58% vs 54%. Response rates and progression-free survival were based on CA-125 levels according to Rustin. Primary endpoints were biochemical CR (bCR)and safety, secondary progression free- (PFS) and overall survival (OS). Results: 183 of 201 pts enrolled were analyzed and baseline characteristics were well balanced between COX (n = 91) and control (CTR) arms (n = 93). Safety: Docetaxel and carboplatin was given full dose in 89% vs 84% pts and creatinine clearance remained stable vs baseline in both arms (96% vs 97% at Cycle 6). Toxicity grade 3–4 (COX vs CTR) was neutropenia in 26 vs 32, febrile neutropenia 12 vs 12, N/V 6 vs 5, allergy 7 vs 0 pts. Neurosensory grade 2–3 was less in COX (4 vs 13 pts, p< 0.05). Efficacy: Median duration of COX treatment was 6 months and 60% completed the combination with six or more cycles of CT. At a median follow-up of 20 months, CA-125 normalized (bCR) in COX 55/74 (74%) and CTR 49/74 (66%) pts with elevated baseline levels (n.s.). Median PFS was 17.4 vs 14.5 months (n.s.) and median survival 34.2 vs 34.7 months (n.s.). Conclusions: Celecoxib added to docetaxel/carboplatin in epithelial ovarian cancer had no effect on creatinine clearance, CA-125 response, PFS or OS. Celecoxib during CT was associated with allergic skin reactions but less neurotoxicity. No significant financial relationships to disclose.

A multicenter phase II study of induction CT with FOLFOX-4 and cetuximab followed by RT and cetuximab in locally advanced esophageal cancer (LAEC)

4546 Background: Preoperative CRT improves the survival of pts with EC when compared with surgery alone. Epidermal growth factor receptor (EGFR) is overexpressed in 30–90% of EC and is associated with poor prognosis, providing the rationale for using the anti-EGFR monoclonal antibody cetuximab (C). The purpose of the study was to investigate the efficacy, toxicity and feasibility of C with FOLFOX- 4 regimen as induction CT followed by C and RT in pts with LAEC in a multicenter setting. Methods: Eligibility criteria: resectable, locally advanced (uT3 or uN1, T4 if deemed resectable) squamous cell carcinoma (SCC) or adenocarcinoma (AC) of the esophagus; staged by EUS, CT and PET scan; age 18–70y; PS <2; normal organ functions.All pts received induction treatment with C at a starting dose of 400 mg/m2 and further weekly infusion at a maintenance dose of 250 mg/m2 and 4 cycles of FOLFOX-4 every two weeks. Post-induction EUS and CT scans were performed, while a PET scan was repeated early before second cycle of CT: pts without PD were given daily RT (180cGy fractions to 5040cGy) with concurrent weekly C. Post RT, EUS plus biopsies, CT scan and PET were performed. At wk 18, pts without PD had esophagectomy. Simons two stage design was used. Primary endpoint was histopathological response rate. Results: Up to December 2008, 40 pts, 30 men, were enrolled from 4 institutions; median age 59 y (35–70y); AC 12; SCC 28; stage II 15, stage III 25 pts. At this time 32/40 pts were evaluable. The most frequent grade 3/4 toxicity of chemoradiotherapy were skin (32%),neutropenia (29%) and esophagitis (9%); 10 pts had no resection (9 progressive disease,1 patient's refusal). Of 22 operated pts, 17 pts (77%) had RO-resection, 5 pts had palliative surgery.2 pts died due to complications after surgery (1 after > 30 days). The pathological response rate was 68 %, with a complete histopathological remission recorded in 6 pts (27%);17 pts (53%) are still alive without residual or recurrent disease. Conclusions: The current findings suggest the feasibility of incorporating cetuximab into a preoperative regimen for LAEC pts and an encouraging antineoplastic activity with 68% histopathological responders. No significant financial relationships to disclose.

Maintenance sunitinib postchemotherapy (CT) in patients (pts) with advanced urothelial carcinoma (UC): A randomized placebo controlled phase II trial

5073 Background: Although response to CT is common in pts with advanced UC it is rarely durable. Sunitinib is an oral small molecule inhibitor of receptor tyrosine kinases regulating angiogenesis including VEGFR-1, -2, -3, and PDGFR-α, -β with demonstrated antitumor activity in a variety of solid tumors. Inhibition of angiogenesis following CT may delay disease progression. Therefore, we are evaluating maintenance sunitinib in a phase II study. Methods: Pts with advanced UC, > stable disease (SD) after 4–6 cycles of CT, a performance status (PS) 0–2, adequate organ function and < 42 days from last CT dose were randomized to sunitinib 50 mg or placebo; 4 weeks (wks) on 2 off in 6 wk cycles. Pts were stratified by response to CT. Disease was assessed every 12 wks. Pts were unblinded for progression or unacceptable adverse events (AEs), with placebo pts offered open label sunitinib. The primary end point is 6 month progression rate using a modified version of the randomized selection design (Simon 1985). 42 pts/arm are to be accrued to allow selection of the superior arm with 90% probability. Other endpoints include safety, response rate (RR), time to progression, median survival, RR to open label sunitinib and correlation of changes in serum VEGF and sVEGFR-2 levels with outcome. Results: To date, 28 pts have been registered and 26 have completed > 12 wks of therapy. Median age is 69 years (48–81) and PS is 1 (37% PS 0, 52% PS 1). 12% had a complete response (CR) to prior CT, 46% a partial response (PR) and 42% SD. 14 pts have progressed after a median of 2 cycles (range 1–12). 7 pts received open label sunitinib at progression, 1/7 remains on treatment. Median duration on open label therapy is 2.2 months (11 days-15 months). Best response to open label therapy to date is progressive disease (2 pts), SD (2 pts) for 24 wks, PR in 1 pt through 60 weeks and 2 pts have not reached first assessment. Grade 3 AEs on open label sunitinib included: bladder hemorrhage, increased creatinine, fatigue, thrombocytopenia and hand-and-foot syndrome. No grade 4 or 5 AEs were observed. Conclusions: Preliminary results indicate that maintenance sunitinib post CT is feasible in advanced UC pts and is associated with clinical activity. Supported by Pfizer. [Table: see text]

Advanced epithelial ovarian cancer (EOC): Is there a place for maintenance therapy in patients with sub-optimal debulking?

e14580 Background: Survival of patients with advanced epithelial ovarian cancer (EOC) with initial suboptimal debulking surgery (residual disease (>1 cm) and those with recurrent EOC is poor. We used EGFR inhibitor gefitinib for maintenance and analyzed data on safety and toxicity. Methods: Between Nov. 2004 and Dec. 2008, Patients who achieved complete response (CR) following six cycles of paclitaxel and carboplatin received gefitinib as (Group I). Similarly, patients with recurrent EOC who achieved CR following six cycles of salvage CT received gefitinib (Group II). Both groups received gefitinib 250 mg once daily till evidence of relapse. Patients were examined every month and toxicity (CTC version II) was recorded. Serum CA-125 was done once in 2 months and CAT scan of abdomen & pelvis every 6 month. The study was approved by Institute Ethics Committee and informed written consent was obtained from each patient. Results: A total of 48 patients (median age 47 years, range 23 to 63) have been recruited. Group I: 17 subjects and Group II 31 patients (1st relapse- 13, 2nd- 9, 3rd -6 & 4th relapse in 3 patients). The mean duration of gefitinib treatment is 8.77 months (Gp-I: 14.4 months, Gp-II: 5.68 months). Toxicity was mainly in the form of skin rash & diarrhea. Skin rash: 16 patients (33.3%); Group I - 8 (grade I-2, II-4, III-3,) & Group II - 8 patients (grade I-3,II-4,III-1). Diarrhea: 12 patients (25%); Group I-3, group II- 9) all grade I. Two patients had both skin rashes and diarrhea. No pulmonary or hematological toxicity was observed. Currently, 13 patients are on gefitinib (mean duration of treatment 12.6 months); in 34 patients gefitinib has been discontinued due to relapse and in 1 patient due to grade III skin rashes over face. Among 18 patients with skin toxicity, 8 continue to be disease-free compared to 6 of 30 without skin toxicity (p=0.07). Conclusions: Gefitinib was tolerated well with mild toxicities limited to skin and GIT. Correlations between EGFR expressions vs. response may help to identify patients likely to benefit from gefitinib therapy. No significant financial relationships to disclose.

Biomarker potential of EGFR gene copy number by FISH in the phase III EXTREME study: Platinum-based CT plus cetuximab in first-line R/M SCCHN

6005 Background: Platinum-based CT + cetuximab is the first systemic therapy in ∼30 years to show a survival benefit vs platinum-based CT in first-line R/M SCCHN (Vermorken JB, et al. N Engl J Med 2008;359:1116–1127). A retrospective analysis has evaluated the influence of EGFR gene copy number, determined by FISH, on clinical outcome in the EXTREME study. Methods: Pts were randomized to 3-weekly cycles of platinum-based CT (cisplatin 100 mg/m2 or carboplatin AUC 5, day 1; 5-fluorouracil 1000 mg/m2/day continuous infusion, days 1–4) with or without cetuximab (initial dose 400 mg/m2, then 250 mg/m2 weekly). The proportion of FISH+ cells per pt (FISH score) was determined using 5 different enrichment models. Tumors were also classified as FISH+ or FISH- using the Colorado scoring system. Results: In the overall population (n=442), addition of cetuximab significantly improved median OS (10.1 vs 7.4 months; p=0.04). No association between FISH score and OS, PFS, or best overall response was determined for any enrichment model. Pts with Colorado FISH+ tumors were evenly distributed between the CT + cetuximab (50/158) and CT-alone (51/154) arms of the FISH- evaluable population (71% of ITT population). Colorado FISH status had no influence on OS in either treatment arm, on PFS in the CT-alone arm, or on RR in the CT + cetuximab arm (see table ). In the CT + cetuximab arm, pts with FISH+ tumors had a lower risk of progression than pts with FISH- tumors. Higher RRs among pts with FISH- tumors in the CT-alone arm may have been due to twice as many nonevaluable response observations in the FISH+ vs the FISH- population (percentage of pts with SD or PD was comparable). Conclusions: EGFR gene copy number, as determined by FISH, is not a predictive biomarker for cetuximab efficacy in R/M SCCHN. [Table: see text] [Table: see text]

Organ preservation in locally advanced head and neck cancer of the larynx using induction chemotherapy followed by improved radiation schemes

The present prospective study seeks to evaluate overall and disease free survival, response and organ preservation rate, and toxicity of an intensive chemotherapy regimen (CT) followed by unconventional radiotherapy (RT) in patients with locally advanced operable head and neck cancer. Between January 1998 and December 2006 (June 2005), 115 patients with locally advanced, operable head and neck cancer were evaluated. A total of 333 cycles of neoadjuvant CT (cisplatin-5FU, days 1, 14, 28) followed by hyperfractionated/accelerated radiotherapy were given to 108 patients. A total of 108 patients were evaluable and received the planned CT-RT treatment. Two months after the end of RT, 97.2% of patients had a clinical complete remission of the primary and 67.5% of the neck node site. The overall survival was 55% and cause-specific survival was 73% at 5 years. Of the 33 relapsed patients, 12 recurred only at the primary site and 10 patients had distant metastases. The overall organ preservation rate was 73.5%. The chemotherapy regimen reported an overall cardiotoxicity from 5FU in 14% of patients, with severe toxicity in 3%. The radiotherapy schedule developed 84% of Grade 3-4 mucositis in the observed patients. The accelerated CT-RT regimen is able to achieve a high rate of larynx preservation, a good tolerability, and a satisfactory cause-specific overall survival.

Induction primary CT with Folfox-4 and cetuximab followed by RT and cetuximab in locally advanced esophageal cancer (LAEC): Analysis of preliminary data from B152 Trial

15524 Background: Primary CRT improves the survival of pts with EC when compared with surgery alone.However, the survival benefit conferred by CRT is modest and further improvements in the management of LAEC are required. In EC, increased EGFR expression correlates with a worse prognosis in terms of shorter DFS and OS suggesting the possibility of treatment with anti- EGFR mAb Cetuximab (C). Methods: Based on this background, we initiated a phase II trial to investigate the feasibility of C with FOLFOX- 4 regimen as induction CT followed by C and RT in pts with LAEC. Pts underwent staging with EUS plus biopsies, PET and CT scans. Eligibility: untreated EC; EUS stage II-III; ECOG PS 0–2; adequate organs function; informed consent. All pts received induction treatment with C at a starting dose of 400 mg/m2 and further weekly infusion at a maintenance dose of 250 mg/m2 and 4 cycles of FOLFOX-4 every two weeks. Post-induction EUS and CT scans were performed, while a PET scan was repeated early before second cycle of CT: pts without PD were given daily RT (180cGy fractions to 5040cGy) with concurrent weekly C. Post RT, EUS plus biopsies, CT scan and PET were performed. At wk 18, pts without PD had esophagectomy. The primary end-point was the pathologic complete responses (pCR) rate. According on a two step Simon design, 31 pts have to be enrolled at the first step of the study. In case of 4 or more pCR, the study will be continued and 24 additional pts will be treated. Results: Up to December 2007, 27 pts have been enrolled: 21 men, 6 women, squamous cell carcinoma 18, adenocarcinoma 9, stage II 3 pts, stage III 24 pts. After induction treatment, the following grade 3–4 toxicities were recorded: neutropenia 7%, thrombocytopenia 4%, skin 4%. Between the 16 pts who completed RT and C, the main grade 3–4 toxicities were: esophagitis 6%, skin 12 %. After CRT 3 pts had PD; of the remaining pts, 10 underwent esophagectomy and 3 pts await surgery. All 10 pts had R0 resections:9 pts were downstaged and 1 pt had no change; a pCR was recorded in 4 pts (40%). Conclusions: The integration of CRT with C is well tolerated; the preliminary activity, indicate that this regimen is efficacy suggesting the continuation of the study until the final sample of 55 pts. No significant financial relationships to disclose.

A phase II study of an adapted CT with oxaliplatin (Oxa) and bolus 5FU in I-line treatment of metastatic CRC in elderly patients not eligible to FOLFOX

15124 Background: FOLFOX and FOLFIRI have been established to be an effective I-line CT for mCRC. Not all over 70-yrs old pts can receive infusional 5-FU because of cardiac comorbidity, refuse of infusional CT or vulnerability state at the comprehensive geriatric assessment (CGA). Till now no alternative schedules containing Oxa have been assessed in elderly pts. The aim of the present study was to evaluate the feasibility and activity of biweekly Oxa plus bolus 5FU and low dose LV as I-line CT. Methods: pts ≥70 yrs with measurable, chemonaive mCRC, ECOG PS ≤2, not eligible to infusional 5FU, fit or vulnerable at CGA (Balducci et al) received Oxa 85 mg/m2 on d 1 and 15, LV 20 mg/m2 plus bolus 5FU 500 mg/m2 on d 1, 8 and 15 every 28d. Study design was 1 stage, estimated sample size 34. Toxicity was the primary endpoint. Response was evaluated by CT-scan every 2 cy. Results: 35 pts, median age 74 (range 70–84) entered the study. Ten pts (28.6%) had cardiological comorbidities. Median number of comorbidities was 1.3 among 20 vulnerable pts, 0 among 15 fit pts. Toxicity according to CTC v 3.0 (see table), was not related to age or CGA. 46.7% of fit pts and 70% of vulnerable pts received < 6 cycles of CT because of toxicity (7 pts), PD (6 pts) or refuse (8 pts). Out of 28 valuable pts 10 PR were observed for an RR of 35.7% (95% CI 17.9–53.4%). Eleven pts had SD (39.3%) while 7 progressed during treatment (25%). After a median follow up of 29.3 mo 32 pts progressed or died, with a median PFS of 9.4 mo. Totally 24 out of 35 pts died, for a median OS of 16.3 mo. A clinical difference in terms of OS among 15 pts receiving II line CT and the other 20 receiving only best supportive care (13.9 vs 11.4, p=0.19 n.s.) was reported. Conclusions: Biweekly Oxa with bolus 5-FU is a safe and effective alternative in elderly pts not susceptible to FOLFOX because of refuse by pts or vulnerability at CGA. Toxicity Toxicities Grade 2 Grade 3 Grade 4 Number % Number % Number % Anemia 4 11.4 1 2.8 0 0 Neutropenia 3 8.6 3 8.6 1 2.8 Trombocytopenia 3 8.6 0 0 0 0 Diarrhea 2 5.7 5 14.3 1 2.8 Mucositis 2 5.7 0 0 1 2.8 Vomiting 2 5.7 1 2.8 0 0 Neurotoxicity 6 17.1 3 8.6 1 2.8 Fatigue 3 8.6 1 2.8 0 0 No significant financial relationships to disclose.

Cases of extranodal lymphoma in the head and neck region

18544 Background: Primary extranodal lymphomas of the head and neck region constitute 10–20% of all NHLs. Since they are frequently encountered as localised disease, radiotherapy accounts for the important part in the treatment although other modalities are also available. Cases with the diagnosis of primary extranodal lymphomas of the head and neck region, who administered to our clinic were evaluated retrospectively and presented here. Materials and Methods: Total 13 patients who administered to the Radiation Oncology Clinic of Kartal Education and Research Hospital between years 2000 and 2005, with the diagnosis of primary extranodal lymphoma of the head and neck region were enrolled into the study. All information was gathered from the patients‘ files and evaluated in the electronic environment. Results: Median age was 61 (36–80). Nine patients (69%) were female, and 4 patients (41%) were male. Primary site was found to be tonsil in 8 cases (61%), nasopharynx in 4 cases (30%), and thyroid in one case (7%). Of the 13 cases, 5 (38%) had stage 1, 4 (30%) stage II, 3 (23%) stage III, and 1 (9%) stage IV diseases. Histological type was diffuse large B-cell lymphoma in 8 patients (7 originating from tonsil, 1 from thyroid), T-cell lymphoma in 2 patients (originating from nasopharynx), poorly differentiated histiocytic lymphoma in 1 patient (originating from nasopharynx), and diffuse mixed large B-cell and small B-cell lymphoma in 1 patient. Therapeutic approach was CT+RT in 7 cases, CT+RT+surgery in 3 cases, CT+ surgery in 1 case, RT+ surgery in 1 case, and CT alone in 1 case. Total 44 Gy RT was performed in 22 fractions to involved fields and regional lymph nodes by using cobalt 60 machine. Median 4 cycles of CT that consisted of CHOP were performed to the patients. Of the 13 patients 10 are still under control with no medical problem. One patient with stage 4 disease was lost under treatment after 3 cycles of CT. One case with nasopharyngeal lymphoma was referred due to progression after 2 series of CT, and died 1 month after palliative RT. One case with stage IB tonsil lymphoma received 2 cycles of CT+ RT+ 2 cycles of CT, and died of other medical reason during her 12th month follow up period. Conclusion: Primary extranodal lymphomas of the head and neck region constitute a heterogeneous group of patients, and RT represents an important part of the treatment. No significant financial relationships to disclose.

Palliative radiotherapy versus palliative chemoradiotherapy in treatment of NSCLC stage IIIA and IIIB: Phase II randomized trial

18128 Background: The optimal treatment for stage IIIA/IIIB NSCLC patients who do not qualify for radical treatment has not been identified. Different palliative radiotherapy regimens and chemotherapy are used but have not been compared. We decided to combine short chemotherapy and radiotherapy (CT-RT) in order to improve therapeutic index of radiotherapy (RT). Methods: Eligibility criteria: Locally advanced, inoperable patients (pts) in IIIA (N2 positive) -IIIB clinical stage with tumor larger than 8 cm in longest diameter or/and FEV1 smaller than 40%, PS: 0–2 (ECOG), non-eligible for radical CT-RT. Treatment: RT arm - 3-D radiotherapy, 30 Gy/3 Gy, 2 weeks. CT-RT arm - two cycles of CT (cisplatin: 80 mg/m2; d 1, 22; vinorelbine: 25 mg/m2 iv; d 1,8,22,29) followed by RT as in Arm 1 with concurrent third cycle of CT (cisplatin 80 mg/m2, d 43; vinorelbine 25 mg/m2 iv., d 43, 50). Study design: Phase II, two-center, randomized study, stratification IIIA vs. IIIB, PS 0–1 vs. 2, treating center (Warsaw vs. Olsztyn). Two-stage design, a and β errors = 0,1; p1 minus p0 = 0,20. Planned sample size - 46 pts/arm. Primary endpoint: response rate (RECIST). Secondary end-points: overall survival (OS), toxicity, progression free survival (PFS). Results: During 2 years 104 pts randomized, 98 eligible for toxicity and survival/progression analysis, 82 for response assessment. Demographics: median age - 65 (45–78), IIIA/IIIB: 27/71 pts. PS 0–1/2: 72/26. Well balanced between arms. Response rate: RT arm- 26%, CT-RT arm- 46%, median OS for RT arm - 195 days, CT-RT arm 2 - 385 days, log-rank test p=0,047, median PFS for RT arm - 140 days, CT-RT arm - 172 days, log-rank test p=0,16. Toxicity: deaths - 2 in RT arm, 2 in CT-RT arm; hematological G3–4 - 0 in RT arm, Arm CT- RT: anemia - 2, thrombocytopenia - 6, neutropenia - 11, esophagitis - 2. Other G3–4: RT arm -3, CT-RT arm -1. Conclusions: Palliative radiotherapy (30Gy) with chemotherapy postponed to progression is a suboptimal treatment for patients with locally advanced NSCLC. 2 cycles of cisplatin/vinorelbine plus RT concomitantly with 3 cycle increases clinical response rate and significantly prolongs survival at the cost of acceptable toxicity in palliative setting. No significant financial relationships to disclose.

Network analyses to define chemotherapy toxicity clusters in patients with colorectal cancer (CRC)

9045 Background: CRC patients undergoing CT are likely to experience multiple concurrent toxicities. Rather than appearing singularly, the hypothesis that certain toxicities occur in clusters may suggest a common pathobiology. We used Markov networks (MN), a probabilistic graphical born at the confluence of statistics and artificial intelligence describing the dependency among set of variables, to identify clusters of CT-induced toxicities, to examine how clusters are connected to each other, and how single toxicities are related to a specific cluster. Methods: Using a standardized data collection tool, we retrospectively reviewed electronic medical charts of 300 consecutive CRC pts receiving FOLFOX, FOLFIRI or 5-FU to record baseline demographic and clinical information. Toxicities were recorded using NCI-CTC criteria during the first cycle of CT. Following the standard Bayesian approach, the MN clustering the CT-induced toxicities was learned from the data as the network with the highest posterior probability given the data. Results: The network, in which associations between toxicities are represented as links, identified five strongly-related symptom clusters: a constitutional cluster involving fatigue, anorexia, and weight loss; a gastrointestinal cluster where dehydration was the connector between diarrhea, constipation and bloating on a side and taste nausea and vomiting, taste alteration, fever and chills on the flipside; a dermatological cluster composed by dry skin, HFS, rash and itching and connected with hemorrhage/bleeding and wound complication toxicity. Furthermore, we noticed strong connections between cough, dyspnea and infection, with palpitation and pain and we detected another cluster where depression and anxiety where connected with cystitis. Conclusions: The application of network analyses to define CT-induced toxicity clusters is new. The technique was effective in defining the relationships between individual toxicities associated with cycle 1 therapy. The lack of randomness between the relationships defined by the network provides a strong suggestion that each cluster shares a common pathobiological basis, which may provide an opportunity for intervention. [Table: see text]

Neoadjuvant and combined chemoradiotherapy followed by surgery in locally advanced esophageal cancer: A single-centre experience

15086 Background: Concomitant chemoradiotherapy (CT-RT) with CDDP-5FU CT is a standard treatment in locally advanced esophageal cancer (EC). Long-term results are poor. The role of neoadjuvant CT (nCT) and of radical surgery after CT-RT is unclear. Methods: Single-institution, prospective trial in pts with stage II-IVA EC (TNM). PS 0–1. Staging: CT scan, barium x-ray, esophagoscopy and endoscopic ultrasound. Treatment schema: 1 cycle of neoadjuvant CT (CDDP 100 mg/m2 d1 and 5-FU 1,000 mg/m2/24 h d1–5); after 21 days, 50 Gy of RT (1.8 cGy/day, M to F) and 2 cycles of reduced-dose CT (CDDP 15 mg/m2 d1–5 and 5-FU 800 mg/m2/24 h d1–5, q21 days). In pts deemed resectable, surgery was done after 4–6 weeks. In the remainder, a 10 Gy boost was given with 1 cycle of modified CT. Primary endpoint: clinical and pathological response rate (RR) after 1st phase. Secondary endpoints: OS and toxicity rates. Results: 71 pts accrued between 1998 and 2006. Median age 61 yrs (r 44–80). 96% males. 85% squamous cell carcinomas. Middle third: 51%; upper third: 27%; lower third 22%. Gastric involvement: 11%. cT3: 46%, cT4: 28%. cN positive: 48%. Grade 3–4 toxicity with nCT and CT-RT: mucositis (9 and 19.5%), emesis (9 and 9%) and infection (6 and 9%). Full dose CT-RT: 87%. Clinical RR after 1st phase: CR 50%, PR 25%, SD 9%, PD 7%. Confirmation (CT- biopsy): 69%. Surgery: 30%. Reasons for no surgery: comorbidity (11%) and age (10%). Pathologic RR: CR 39%, microscopic rest 39% and macroscopic rest 22%. Downstaging 50%. No pN positive. 3 pts had unresectable disease. 62% received 2nd phase RT boost, 31% with CT. Clinical RR: CR 69%, PR 6%, PD 25%. Median follow-up 50 m (r 6–129 m). Median OS 10.5 m (r 7.4–12.8 m). 4-year OS of 18%. 47% deaths due to progression, 5% treatment-related deaths and 10% in the postoperative period. Only a clinical CR after 1st phase was found to improve OS (13.5 vs 7 m, p 0.0141). Conclusions: This regimen is well tolerated and offers a high response rate. Clinical response evaluation overestimates the pathologic response rate. In our series, the possible survival benefit of surgery is offset by the postoperative death rate. No significant financial relationships to disclose.

A phase II study of gemcitabine (G), peghilated liposomal doxorubicin (PLD) and docetaxel (D) in locally advanced breast cancer (LABC): An interim analysis

10789 Background: On the basis of general and our own experience neoadjuvant therapy is justified in patients with locally advanced breast cancer to reduce cancer and to perform a conservative surgery. In this study we evaluated the efficacy of G plus D and PLD as first-line therapy in LABC. Methods: To date sixteen consecutive patients with LABC have been enrolled into the study. All patients before neoadjuvant treatment, underwent biopsy for hormonal receptors and c-erb-B2 assessment. Patients received G 1250 mg/m2 on day 1 and G 1000 mg/m2, T 75 mg/m2 and D 25–30 mg/m2 on day 8 (escalation dose was 25 mg/m2 at first cycle, 27.5 mg/m2 at second cycle and 30 mg/m2 at third cycle), every 21 days with G-CSF support on day 3, 10, 12 and 14. Tumor response was evaluated on the basis of surgeon consultation and breast MRI after 4 cycles. If tumor response was higher than 50% patients underwent 2 more cycles; if it was 50% ore less or because of unacceptable toxicity they underwent surgery after 4 cycles. Microscopic assessment of the extent and type of residual tumour was made. Results: 16 patients were enrolled comprehensive of 2 with no symptomatic bone metastases. Median age was 50 years-old, and 100% had a WHO performance status (PS) of 0 and EORTC QoL was submitted. Four patients were submitted to surgery after 4 cycles, one after 5 cycles of CT with 5 pPR more than 50%. Three patients had a pathological complete response, 2 partial response more than 50% and 1 stable disease after 6 cycles. (a total of 70% of pPR, 30% of pRC, 10% of pSD). Five patients are still on treatment. One patient died because of acute respiratory distress syndrome. Major toxicity was mucositis G3–4 in one patient. PPE was G3–4 in 3 patients, one discontinued chemotherapy with PLD and continued with Epirubicin. 2 patients received Epirubicin after the first cycle of PLG because of acute allergic reaction. Conclusions: This regimen of chemotherapy seems feasible and active in LABC. At the interim analysis results it has been noted that the best response to chemotherapy was among patients having worse prognostic factors (histology and staging). No significant financial relationships to disclose.

Phase II Study of Neoadjuvant Chemotherapy and Radiation Therapy in the Management of High-Risk, High-Grade, Soft Tissue Sarcomas of the Extremities and Body Wall: Radiation Therapy Oncology Group Trial 9514

On the basis of a positive reported single-institution pilot study, the Radiation Therapy Oncology Group initiated phase II trial 9514 to evaluate its neoadjuvant regimen in a multi-institutional Intergroup setting. Eligibility included a high-grade soft tissue sarcoma > or = 8 cm in diameter of the extremities and body wall. Patients received three cycles of neoadjuvant chemotherapy (CT; modified mesna, doxorubicin, ifosfamide, and dacarbazine [MAID]), interdigitated preoperative radiation therapy (RT; 44 Gy administered in split courses), and three cycles of postoperative CT (modified MAID). Sixty-six patients were enrolled, of whom 64 were analyzed. Seventy-nine percent of patients completed their preoperative CT and 59% completed all planned CT. Three patients (5%) experienced fatal grade 5 toxicities (myelodysplasias, two patients; infection, one patient). Another 53 patients (83%) experienced grade 4 toxicities; 78% experienced grade 4 hematologic toxicity and 19% experienced grade 4 nonhematologic toxicity. Sixty-one patients underwent surgery. Fifty-eight of these were R0 resections, of which five were amputations. There were three R1 resections. The estimated 3-year rate for local-regional failure is 17.6% if amputation is considered a failure and 10.1% if not. Estimated 3-year rates for disease-free, distant-disease-free, and overall survival are 56.6%, 64.5%, and 75.1%, respectively. This combined-modality treatment can be delivered successfully in a multi-institutional setting. Efficacy results are consistent with previous single-institution results.

The Impact of Relative Dose Intensity on Response and Survival in a Series of 180 Newly Diagnosed Patients with Hodgkin's Lymphoma.

To improve ABVD results we first developed a protocol which adds G-CSF to the standard ABVD treatment. From March 1997 to May 2004 69 patients with HL were treated with ABVD+G-CSF and 22 with a standard ABVD. Recently we designed a new dose-dense and dose-intensity ABVD scheme (escABVD-21) for advanced HL; in this new schedule the adriamycin was escalated from 25 to 35 mg/m2 (cycles 1,2,3,4) and the inter-cycle period was shortened from 28 to 21 days (for all 6 cycles); primary G-CSF was administered from d3 to d8 and drugs were delivered at d10 and d21 of every cycle. From June 2004, 19 patients were treated with this protocol.Relative dose-intensity (RDI) was calculated for any of these 110 newly diagnosed HL patients treated with ABVD. The results were also compared with a historical group of 70 patients who had undergone hybrid MOPP/ABVD.HL patients received from 4 to 8 cycles of CT +/− IF-RT. Patients were divided in 4 groups according to the RDI. The first group included 20 (11%) pts with RDI less than 0.80; the 2nd group, 64 (36%) pts with RDI values between 0.80 and 0.95, the 3rd group, 74 (42%) pts with RDI values between 0.96 and 1.10 and, finally, the 4th group included pts with RDI values of more than 1.10. In Tab 2 we report the CR, EFS and OS rates according to the 4 levels of RDI. Figures 1 shows EFS curve according to Kaplan-Meyer.Response and survival rates of groups 1,2,3 and 4 were: 50%vs91%vs97% vs 100%, for CR (p<0.0001); 20%vs78%vs92%vs100% for EFS (p< 0.0001); and 25%vs91%vs99%vs100% for OS (p< 0.0001).The best progression rates of CR, EFS and OS were seen in patients with RDI >1.10. In particular, the new dose-dense and dose-intensity escABVD-21 protocol seems very promising in terms of complete response and toxicity profile: 19/19 pts (100%) obtained an early CR; (PET negative at the end of the 2nd cycle), and, as on 8th August 2005, all these19 patients were disease-free. The dose-escalation of adriamycin and the dose-density of the schedule were well-tolerated; toxicity was mild. These results show that subptimal RDI may compromise outcomes proportionally to the level of RDI reduction. On the contrary, Primary G-CSF permits to deliver dose-dense and dose intense schedules such as escABVD-21 maintaining the same profile of toxicity of standard ABVD, higher RDI levels, and consequently, a significant impact on complete response and survival rates.tab1Presentation featuresn. of ptsmale sexage>45 yrsadvanced stageE sites>1bulkyB symptomsIPI score ≥ 3180924314823808356%51%24%82%13%44%46%31%tab.2Response and Survival according to 4 RDI levelsRDI level (range 0.5–1.5)N. of pts. (%)CR rateFisher's Exact test (2-sided)EFS ratelog-rank statistic0S ratelog-rank statisticoverall180(100%)90%80%88%<0.8020 (11%)50%20%25%0.80–0.9564 (36%)91%28.39178%74.9991%96.760.96–1.1076 (42%)97%92%99%>1.1020 (11%)100%100%100%significance<0.0001<0.0001<0.0001 [Display omitted]

Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN): Results of a phase II study

5502 Background: Pts with refractory SCCHN have a poor prognosis with few therapeutic options. Cetuximab (Erbitux), an IgG1 monoclonal antibody that binds selectively to EGFR, has shown activity in combination with cisplatin or carboplatin in pts with recurrent/metastatic SCCHN progressing on the same platinum-based regimen (Baselga #900, Kies #925; ASCO 2002). Methods: This multicenter phase II study was designed to investigate the efficacy of cetuximab as monotherapy in pts with platinum-refractory SCCHN. Main inclusion criteria were: stage III/IV recurrent and/or metastatic SCCHN not suitable for local therapy, with documented progression on or within 30 days after 2 to 6 cycles of a platinum-based CT. Cetuximab was given at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly until disease progression, with the option to switch to the combination of cetuximab with the same platinum that the pts had previously progressed on, after failure to cetuximab monotherapy. Results: 103 pts (84 M, 19 F) we...

Cetuximab monotherapy is active in patients (pts) with platinum-refractory recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN): Results of a phase II study

5502 Background: Pts with refractory SCCHN have a poor prognosis with few therapeutic options. Cetuximab (Erbitux), an IgG1 monoclonal antibody that binds selectively to EGFR, has shown activity in combination with cisplatin or carboplatin in pts with recurrent/metastatic SCCHN progressing on the same platinum-based regimen (Baselga #900, Kies #925; ASCO 2002). Methods: This multicenter phase II study was designed to investigate the efficacy of cetuximab as monotherapy in pts with platinum-refractory SCCHN. Main inclusion criteria were: stage III/IV recurrent and/or metastatic SCCHN not suitable for local therapy, with documented progression on or within 30 days after 2 to 6 cycles of a platinum-based CT. Cetuximab was given at an initial dose of 400 mg/m2, followed by 250 mg/m2 weekly until disease progression, with the option to switch to the combination of cetuximab with the same platinum that the pts had previously progressed on, after failure to cetuximab monotherapy. Results: 103 pts (84 M, 19 F) were enrolled. Median age was 57 years (23–77), median baseline KPS was 80 (60–100) and median time from diagnosis to study entry was 20 months (3–283). Drug-related adverse events occurring in >10% of pts included: skin rash/acne 80% (1% grade 3), fatigue 24% (4% grade 3), fever/chills 19% (2% grade 3), nail changes 15% (all grade 1–2) and nausea 13% (1% grade 3). There was one treatment-related death due to hypersensitivity reaction in a patient not suitable to receive mechanical ventilation. Preliminary efficacy data (based on investigator assessment) were as follows: 5 CR, 12 PR, 38 SD, 47 PD, 1 not assessable, for an overall objective response rate of 16.5% (95% CI: 9.9%–25.1%). Disease control rate was 53.4% (95% CI: 43.3%–63.3%). Median TTP and median survival were 85 and 175 days, respectively. An independent review of all pre-treatment and on-study imaging assessments is ongoing and will be available at the meeting. Conclusions: Cetuximab as single agent can produce major objective responses in pts with platinum-refractory recurrent/metastatic SCCHN, with acceptable toxicity. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Merck

Correlation between complete response to anthracycline-based chemotherapy and topoisomerase II-α gene amplification and protein overexpression in locally advanced/metastatic breast cancer

Anthracycline-based regimens are among the most active but also with greater risk of both acute and long-term side effects, namely cardiotoxicity. Predictive markers of response to anthracyclines are therefore essential. Topoisomerase-IIalpha (topo-II) is the target of anthracyclines and preliminary data suggest its promising role as a predictive marker of sensitivity to these drugs. After screening a population of about 350 patients with locally advanced or metastatic breast cancer, two subgroups were selected for the present analysis: a study group (31 patients), composed of 14 complete responders (CR-a) and 17 true non-responders (PD-a) to anthracycline-based CT, and a control group (28 patients), composed of 7 CR (CR-t) and 21 true non-responders (PD-t) to taxane-based CT. True non-responders were defined as progressive disease (PD) within the first three cycles of CT. Archival tumor samples of these patients were collected, biological markers evaluated and their status correlated with response to therapy. HER-2 and topo-II gene status were evaluated by FISH (Vysis multi-color probe-positivity cut-off: >/=2 ratio for HER-2 and >/=1.5 for topo-II), topo-II protein was evaluated by IHC (positivity cut-off >10%). All cases in which HER-2 gene was non-amplified did not show topo-II gene aberrations. No association was found between HER-2 gene amplification and response to anthracyclines (5/14 (36%) CR and 5/17 (29%) PD to anthracycline-based CT were HER-2+). The topo-II gene was amplified in 3/14 (21%) CR but only in 1/17 (6%) PD to anthracyclines. Amplification of the topo-II gene was seen in 1/7 (14%) CR and in 3/21 (14%) PD to a taxane-based CT. Topo-II protein was overexpressed in 6/11 (55%) CR and in 2/17 (12%) PD to anthracyclines, while in the control group, overexpression was seen in 5/7 (71%) CR and 8/20 (40%) PD. i) HER-2 gene amplification did not seem to be correlated with response to anthracyclines. ii) Both topo-II gene amplification and protein overexpression seem to correlate with response to anthracyclines, although other factors, such as p53 and cell proliferation, are most likely to be involved. iii) The role of combined evaluation of several relevant markers and of potential 'molecular signatures' are currently being evaluated in prospective randomized clinical trials.

Paclitaxel and carboplatin in neo-adjuvant and concomitant chemoradiotherapy in locally advanced head and neck squamous cell carcinoma.

To evaluate feasibility of neoadjuvant chemotherapy (NA-CT) followed by CT + radiotherapy (RT) in locally advanced or unresectable head and neck squamous cell carcinoma (HNSCC). 22 HNSCC patients were enrolled (18 males, 4 females; median age, 59.5 years; median ECOG PS, 1). Sites of disease: oral cavity, 18.2%; oropharynx, 40.9%; hypopharynx, 18.2%; larynx, 4.6%, multiple sites, 18.2%. T (tumor) category: T2, 13.6%; T3, 31.8%; T4, 54.5%. N (nodes) category: NO, 9.1%; N1, 18.1%; N2, 40.9%; N3, 31.8%. Stage: III, 4.6%; IVA, 63.6%; IVB, 31.8%. Induction carboplatin (AUC = 6) and paclitaxel (200 mg/m2) x 3 cycles (q21 days) were given. Responders received definitive radiotherapy with concurrent carboplatin (35 mg/m2/day from days 1 to 5 in weeks 1, 3, 5 and 7) and paclitaxel (50 mg/m2 on days 10, 24 and 38). Patients with node involvement were suggested to undergo postradiotherapy neck dissection. NA-CT. 97% of planned chemotherapy cycles were administered. Prevalent toxicity was hematologic: 50% G4 neutropenia and 31.8% G3, one neutropenic fever. All patients had alopecia. Complete responses in T and N were 4 (18.2%) and 3 (15%), respectively. Partial responses were 13(59%) and 9 (45%). There was 1 progressive disease. CT + RT. 79.9% of planned cycles of CT were administered. In 19 patients (86.4%) more than 50% of planned cycles of CT were completed. Median dose of RT was 70.2 Gy on T/N+ and 54 Gy on NO. Limiting toxicity was mucositis in 77.3%, followed by neutropenia (59.1% G3-G4). Median weight loss was 4.9%.18.2% of patients required hospitalization. Complete responses in T and N were 15 (68.1%) and 8 (40%), respectively. Partial responses were 5 (22.7%) and 7 (35%). The preliminary results of this study are encouraging, despite the toxicity. Adequate follow-up is required to evaluate efficacy in terms of local-regional control and overall survival.