Early surgery for failure after chemoradiation in operable thoracic oesophageal cancer. Analysis of the non-randomised patients in FFCD 9102 phase III trial: Chemoradiation followed by surgery versus chemoradiation alone

BackgroundTwo randomised trials concerning thoracic oesophageal cancer concluded that for squamous cell carcinoma, chemoradiation alone leads to the same overall survival (OS) as chemoradiation followed by surgery. One of these trials, FFCD 9102, randomised only fit, compliant and operable responders to induction chemoradiation between continuation of chemoradiation and surgery. In the present analysis, the outcome in the patients not eligible for randomisation was calculated to determine if attempt of surgery should be recommended.MethodsEligible patients had operable T3-N0/N1-M0 thoracic oesophageal cancer. After initial chemoradiation, patients with no clinical response, or with contraindication to follow any attributed treatment, were not randomised. OS was studied first in the whole population of not randomised patients, and then specifically in clinical non-responders. The impact of surgery on OS was studied in these two populations.FindingsOf the 451 registered patients in the trial, 192 were not randomised. Among them, 111 were clinical non-responders. Median OS was significantly shorter for non-randomised patients (11.5 months) than for randomised patients (18.9 months; p = 0.0024). However, for the 112 non-randomised patients who underwent surgery, median OS was not different from that in randomised patients: 17.3 versus 18.9 months (p = 0.58).Concerning clinical non-responders, median OS was longer for those who underwent surgery compared to non-operated patients: 17.0 versus 5.5 months (hazard ratio (HR) = 0.39 [0.25–0.61]; p < 0.0001), and again was not different from that in responding, randomised patients (p = 0.40).InterpretationIn patients with locally advanced thoracic oesophageal cancer, overall survival did not differ between responders to induction chemoradiation and patients having surgery after clinical failure of chemoradiation. Surgery should therefore be considered in those patients who are still operable.     

Outcome of upfront combination chemotherapy followed by chemoradiation for locally advanced pancreatic adenocarcinoma

Purpose  The role and timing of chemotherapy and radiation for treating stage III pancreatic adenocarcinoma remains controversial. Methods  Treatment-naive patients with stage III non-resectable pancreatic adenocarcinoma were treated with PEFG/PEXG (cisplatin, epirubicin, 5-fluorouracil (F)/capecitabine (X), gemcitabine) or PDXG (docetaxel substituting epirubicin) regimen for 6 months followed by radiotherapy (50–60 Gy) with concurrent F or X or G. Results  Ninety-one patients were registered between April 1997 and December 2007. Forty-three patients (47%) had a partial remission and 38 (42%) had a stable disease. Thirteen patients (14%) were radically resected yielding one pathologic complete remission. Median survival (OS) was 16.2 months. Median progression-free survival was 9.9 months. Pattern of failure consisted of isolated local failure (N = 26, 35%); both local and systemic failure (N = 14, 19%); isolated systemic failure (N = 35, 47%). Conclusion  Combination chemotherapy with four-drug regimens followed by chemoradiation was a feasible strategy showing relevant results in stage III pancreatic adenocarcinoma.     

A phase II study of preoperative chemotherapy with S-1 plus cisplatin followed by D2/D3 gastrectomy for clinically serosa-positive gastric cancer (JACCRO GC-01 study)

Aims

Clinically serosa-positive (T3–4) gastric cancer has a poor prognosis. This phase II trial explored the feasibility and safety of preoperative chemotherapy followed by D2 or D3 gastrectomy in this type of gastric cancer.

Methods

Patients with T3–4 gastric cancer received one course of S-1 (80 mg/m² daily for 3 weeks) and cisplatin (60 mg/m² on day 8) chemotherapy and then underwent D2 or D3 gastrectomy with curative intent. Primary endpoint was toxicities.

Results

Of 50 patients enrolled, 49 were eligible and received the treatment protocol. Chemotherapy-related toxicities were mild; grade 3 neutropenia in 2 patients, anorexia in 3, and nausea in 2, and no grade 4 toxicities. Clinical response was achieved in 13 of 34 evaluable patients. Of the 49 patients, 39 underwent D2 or D3 dissection. There was no surgical mortality. Operative morbidity occurred in 5 of 49 patients, including pancreatic fistula in 1 and abdominal abscess in 2.

Conclusion

This multi-modality treatment seems to be feasible and safe for T3–4 gastric cancer.     

A multi-center phase II study of oxaliplatin, irinotecan, and capecitabine in advanced gastric/gastroesophageal junction carcinoma

Background  There is no standard first-line therapy for advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma and the prognosis remains poor. Our institution conducted a phase I study of oxaliplatin, irinotecan, and capecitabine given in a novel, weekly schedule. The regimen was tolerated; pharmacodynamic studies revealed no drug interactions, and there was one confirmed response in a gastric cancer patient. We performed a phase II trial in advanced gastric and GEJ adenocarcinoma to determine response rate and response duration. Methods  This was a multi-center single treatment arm study involving six sites. Only prior adjuvant therapy was allowed. Patients had ECOG performance status of 0–2, adequate organ function, and were able to tolerate oral medications. All patients received oxaliplatin 60 mg/m² intravenously (IV) and irinotecan 50 mg/m² IV weekly times 4 weeks with a 2-week rest period. Capecitabine 450 mg bid orally was received on days 1 through 5 every week for 4 weeks, followed by a 2-week rest. Patients were assessed for response after the first two cycles; response duration, overall survival, and adverse events were also recorded. We estimated an improvement in historical response rate by 30% would have clinical meaning. Results  A total of 39 patients were accrued and all were assessed for toxicity; 30 patients were evaluable for response. The median age was 57.8 years (31–79 years) and 74% were male. Two patients had a complete response, with nine patients achieving a partial response. The total response rate was 28%, with nine patients not evaluable for response. The median response duration was noted at 5.97 months and median overall survival was 8.98 months. There were no grade 5 treatment related events, with all deaths secondary to disease progression. Only five grade 4 events occurred (neutropenia, hyperkalemia, hypokalemia (2), thrombosis/embolism) without grade 4 diarrhea or sensory neuropathy. Conclusions  Oxaliplatin, irinotecan, and capecitabine given in a novel, weekly schedule does induce responses in advanced gastric and GEJ adenocarcinoma. However, the total response rate is modest and not an improvement over other regimens.     

Neoadjuvant concurrent chemoradiation with weekly paclitaxel and carboplatin for patients with oesophageal cancer: a phase II study

This study was performed to assess the efficacy and safety of preoperative chemoradiation consisting of carboplatin and paclitaxel and concurrent radiotherapy for patients with resectable (T2-3N0-1M0) oesophageal cancer. Treatment consisted of paclitaxel 50 mg m(-2) and carboplatin AUC=2 on days 1, 8, 15, 22 and 29 and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by oesophagectomy. All 54 entered patients completed the chemoradiation without delay or dose-reduction. Grade 3-4 toxicities were: neutropaenia 15%, thrombocytopaenia 2%, and oesophagitis 7.5%. After completion of the chemoradiotherapy 63% had a major endoscopical response. Fifty-two patients (96%) underwent a resection. The postoperative mortality rate was 7.7%. All patients had an R0-resection. The pathological complete response rate was 25%, and an additional 36.5% had less than 10% vital residual tumour cells. At a median follow-up of 23.2 months, the median survival time has not yet been reached. The probability of disease-free survival after 30 months was 60%. In conclusion, weekly neoadjuvant paclitaxel and carboplatin with concurrent radiotherapy is a very tolerable regimen and can be given on an outpatient basis. It achieves considerable down staging and a subsequent 100% radical resection rate in this series. A phase III trial with this regimen is now ongoing.     

A multicenter phase II study of biweekly paclitaxel and S-1 combination chemotherapy for unresectable or recurrent gastric cancer

Purpose  This Phase II study assessed the activity and safety of biweekly paclitaxel and oral S-1 as treatment for unresectable and recurrent gastric cancer. The maximum tolerated dose for this regimen had been established previously in a Phase I study performed in Japanese patients. Patients and methods  Chemotherapy was performed using two anticancer agents, S-1 and paclitaxel. Oral S-1 (80 mg/m²) was administered twice a day after meals for two consecutive weeks from Day 1 to 14, followed by a 2 week recovery period; paclitaxel (120 mg/m²) was administered intravenously, biweekly, on Days 1 and 15. The patient received cycles of this regimen every 4 weeks (q 28-day cycles). The primary end point was the response rate according to the Response Evaluation Criteria in Solid Tumors. Results  A total of 39 patients (median age, 65 years) were enrolled; 13 other patients were screened, but found to be ineligible. All patients had unresectable and recurrent gastric cancer. The most common treatment-related Grade 3/4 adverse events were neutropenia (37.5%), appetite loss, diarrhea, decreased sodium (each 5%), and anemia, increased alanine aminotransferase, general fatigue, and dizziness (each 2.5%). Almost all the patients experienced alopecia. Intent-to-treat analysis showed a response rate of 43.6%. With a median follow-up of 14 months (range 8–21 months), median survival was 256 days and the median time to progression was 4 months. Conclusion  A combination regimen of biweekly paclitaxel and oral S-1 was well tolerated and showed promising activity against unresectable and recurrent gastric cancer.     

Maintenance sunitinib or observation in metastatic pancreatic adenocarcinoma: A phase II randomised trial

BackgroundNew strategies to prolong disease control warrant investigation in patients with metastatic pancreatic adenocarcinoma. This open-label, randomised, multi-centre phase II trial explored the role of maintenance sunitinib after first-line chemotherapy in this setting.MethodsPatients with pathologic diagnosis of metastatic pancreatic adenocarcinoma, performance status >50%, no progression after 6 months of chemotherapy were centrally randomised by an independent contract research organisation, which was also responsible for data collection and monitoring, to observation (arm A) or sunitinib at 37.5 mg daily until progression or a maximum of 6 months (arm B). The primary outcome measure was the probability of being progression-free at 6 months (PFS-6) from randomisation. Assuming P0 = 10%; P1 = 30%, α .10; β .10, the target accrual was 26 patients per arm.Results28 per arm were randomised. One arm B patient had kidney cancer and was excluded. Sunitinib was given for a median of 91 days (7–186). Main grade 3–4 toxicity was thrombocytopenia, neutropenia and hand–foot syndrome (12%), diarrhoea 8%. In arm A versus B, PFS-6 was 3.6% (95% confidence interval (CI): 0–10.6%) and 22.2% (95% CI: 6.2–38.2%; P < 0.01); 2y overall survival was 7.1% (95% CI: 0–16.8%) and 22.9% (95% CI: 5.8–40.0%; P = 0.11), stable disease 21.4% and 51.9% (P = 0.02).ConclusionThis is the first randomised trial on maintenance therapy in metastatic pancreatic adenocarcinoma. The primary end-point was fulfilled and 2y overall survival was remarkably high, suggesting that maintenance sunitinib is promising and should be further explored in this patient population.     

Neo-adjuvant platinum-based chemotherapy followed by chemoradiation and radical surgery in locally advanced cervical cancer (Lacc) patients: A phase II study

Purpose

The aim of this Phase II, non-randomized study was to assess activity and safety of neoadjuvant chemotherapy (NACT) before chemoradiation (CT/RT) followed by radical surgery (RS) in locally advanced cervical cancer (LACC) patients.

Phase II study of dose-intense chemotherapy with sequential topoisomerase-targeting regimens with irinotecan/oxaliplatin followed by etoposide/carboplatin in chemotherapy naive patients with extensive small cell lung cancer

Introduction

Topoisomerase inhibitors are active agents in small cell lung cancer (SCLC), and preclinical models indicate that sequential administration of a topoisomerase I inhibitor followed by a topoisomerase II inhibitor can result in enhanced cytotoxicity.

Patients and methods

In this phase II study, patients with extensive SCLC were treated with two sequential topoisomerase-based regimens: irinotecan (150 mg/m²)/oxaliplatin (85 mg/m²) [regimen A] on day 1 followed by etoposide (100 mg/m² × 3)/carboplatin (AUC 6) [regimen B] on day 15. Regimen A was repeated 3 weeks later. The primary objective was objective response rate. Secondary endpoints included progression-free survival (PFS), overall survival (OS), toxicity, and exploratory correlative analysis of the tumor expression of the excision repair cross complementing (ERCC1) and topoisomerase II-α. Patients received a maximum of 5 cycles of sequential therapy of regimen A → B.

Results

The overall response rate was 96%, the 6-month PFS was 76.9%, the median PFS was 8.95 months, and OS was 12.9 months in 26 evaluable patients. Grade 4 neutropenia (23%) and thrombocytopenia (58%) were observed with regimen B; and grade 2/3 nausea-vomiting (54%) and diarrhea (46%) with regimen A. Seven patients required dose reductions in regimen A and 19 patients in regimen B. The dose intensity, delivered during the first three cycles was 89%. No significant correlations were observed between the tumor expression of the ERCC1 and topoisomerase II-α and clinical outcomes (PFS or OS).

Conclusions

Although cross-study comparisons are difficult to make, our data suggests that sequential topoisomerase-targeting regimens may enhance the efficacy of chemotherapy in newly diagnosed SCLC patients (Clinical Trial Registration Number, 9 NCT00240097; Clinical Trials.gov number, NCT00240097).     

The combination of axitinib followed by paclitaxel/carboplatin yields extended survival in advanced BRAF wild-type melanoma: results of a clinical/correlative prospective phase II clinical trial

Background:

Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity.

Methods:

We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0–1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1–14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m⁻²) was administered on day 1 starting with cycle 2. 3′-Deoxy-3′-¹⁸F-fluorothymidine (¹⁸F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma.

Results:

The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing ¹⁸F-FLT-PET scans showed increases (23–92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAF^V600E/K patients had significantly worse PFS than patients without these mutations.

Conclusions:

Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3′-Deoxy-3′-¹⁸F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal.     

Salvage treatment with paclitaxel and gemcitabine for patients with non-small-cell lung cancer after cisplatin- or docetaxel-based chemotherapy: A multicenter phase II study

Background: To evaluate the tolerance and efficacy of the combination of paclitaxel and gemcitabine as salvage treatment in patients with advanced non-small-cell lung cancer (NSCLC).Patients and methods: Forty-nine patients with measurable NSCLC (PS 0–1: 80%; stage IV: 84%) who progressed or failed first-line chemotherapy were enrolled. Prior chemotherapy was cisplatin-based with (n = 20) or without (n = 22) docetaxel and docetaxel–vinorelbine (n = 7). Patients received gemcitabine (900 mg/m2 i.v.; days 1 and 8) and paclitaxel (175 mg/m2; day 8) every three weeks; G-CSF (150 µg/m2/day s.c.; days 9–15) was given prophylactically to all patients.Results: One (2%) complete and eight (16%) partial responses were achieved (overall response 18%; 95% CI: 4%–24%); 14 patients (29%) had stable disease and 26 (53%) progressive disease. Six responses were observed in 17 patients who responded to first-line chemotherapy. The median duration of response was seven months, the median TTP eight months and the median survival 11 months. The one-year survival rate was 37%. Grade 3–4 neutropenia occured in six (12%) patients, grade 2–3 neurotoxicity in 16 (32%) and grade 2–3 asthenia in 25 (51%). Other toxicities were mild.Conclusions: The paclitaxel-gemcitabine combination is a well-tolerated and relatively active salvage regimen in patients with NSCLC and it merits further investigation.     

Gemcitabine and oxaliplatin for metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II study.

BACKGROUND: This study was performed to determine the efficacy of gemcitabine and oxaliplatin in patients with advanced or metastatic pancreatic adenocarcinoma (ACA). PATIENTS AND METHODS: Pancreatic ACA patients with previously untreated advanced or metastatic disease were enrolled in a phase II study of gemcitabine and oxaliplatin. Oxaliplatin was given i.v. on day 1 and gemcitabine i.v. on days 1 and 8 of a 3-week cycle. The primary end point of the trial was 6-month survival. Secondary end points included response rate, overall survival, median time to progression and toxicity. RESULTS: A total of 47 patients were enrolled, 46 of whom were evaluable. Of those patients assessed for the primary end point 50% lived for > or =6 months. The median time to progression was 4.53 months. Five confirmed responses were seen with a median duration of response of 2.7 months. Overall, the treatment was well tolerated. However, one patient died as a result of treatment-related hemolytic uremic syndrome. CONCLUSIONS: Gemcitabine and oxaliplatin, at doses of 1000 mg/m(2) and 100 mg/m(2), respectively, showed moderate activity in patients with pancreatic ACA. Based on the results of this study further evaluation of this combination is warranted.     

A phase II study of a paclitaxel and oxaliplatin combination in platinum-sensitive recurrent advanced ovarian cancer patients.

PURPOSE: A multicentric, phase II study to evaluate the efficacy and safety of the combination paclitaxel and oxaliplatin in patients with platinum-sensitive recurrent ovarian cancer. PATIENTS AND METHODS: Patients received 175 mg/m(2) paclitaxel (over 3 h) followed by 130 mg/m(2) oxaliplatin (over 2 h) every 21 days for up to nine cycles without hydration or primary granulocyte colony-stimulating factor prophylaxis. Patients had to have an Eastern Cooperative Oncology Group performance status of 0-2 and to have received no more than one prior cisplatin- and/or carboplatin-containing chemotherapy regimen with a platinum-progression-free interval > or =6 months. RESULTS: Of the 105 patients enrolled and treated, 98 were eligible. An overall response rate of 81% (79 of 98 patients) (95% confidence interval 71% to 88%) was observed according to RECIST criteria (third party reviewed), and 88% (86 of 98) when this was complemented with CA-125 response. With a median follow up of 43.6 months (range 30.2-64.2) the median progression-free survival was 10.2 months (range 0.3-21.4) and the overall survival 32.4 months. Seven hundred and eight cycles were administered (median seven per patient; range one to nine). A total of 67% of patients experienced National Cancer Institute Common Toxicity Criteria grade 3-4 neutropenia, including 8% with concomitant febrile episode, without treatment-related deaths. Ninety-three per cent of patients experienced neuropathy of grade 1 or more, including 25% with cumulative reversible peripheral neuropathy of grade 3-4. Oxaliplatin doses were reduced in 30 patients due to neurotoxicity. CONCLUSIONS: The oxaliplatin/paclitaxel combination can be administered in an outpatient setting every 3 weeks without specific measures. The high level of activity and its duration observed warrants further evaluation of this combination in pretreated platinum-sensitive advanced ovarian cancer patients.     

Randomised phase II study of docetaxel plus vandetanib versus docetaxel followed by vandetanib in patients with persistent or recurrent epithelial ovarian,fallopian tube or primary peritoneal carcinoma: SWOG S0904

BackgroundVandetanib is an oral tyrosine kinase inhibitor of VEGFR-2/3, EGFR and RET, which has demonstrated clinical activity as a single agent and in combination with taxanes. We explored the efficacy, safety and toxicity of docetaxel and vandetanib in women with recurrent ovarian cancer (OC).MethodsWomen with refractory or progressive OC were randomised 1:1 to docetaxel (75 mg/m², IV) + vandetanib (100 mg daily, PO, D + V) or docetaxel (75 mg/m², D). Up to three additional cytotoxic regimens for recurrence and prior anti-angiogenic agents (as primary therapy) were allowed. The primary end-point was progression free survival (PFS). The study had 84% power to detect a PFS hazard ratio of 0.65, using a one-sided P of 0.1. This corresponds to an increase in median PFS from 3.6 months to 5.6 months. Patients progressing on D were allowed to receive single agent vandetanib (D → V).Results131 Patients were enrolled; two were excluded. 16% had received prior anti-angiogenic therapy. The median PFS estimates were 3.0 mos (D + V) versus 3.5 (D); HR: 0.99 (80% CI: 0.79–1.26). 61 Patients on D + V were assessable for toxicity; 20(33%) had treatment-related Grade (G) 4 events, primarily haematologic. Similarly, 17 (27%) of 64 patients receiving D had G4 events, primarily haematologic. 27 Evaluable patients crossed-over to V. 1/27(4%) experienced a G4 event. G3 diarrhoea was observed in 4% D → V patients. Median OS was 14 mos (D + V) versus 18 mos (D → V); HR(OS): 1.25 (80% CI: 0.93–1.68). Crossover vandetanib response was 4% (1/27 evaluable patients). High plasma IL-8 levels were associated with response to D + V.ConclusionsCombination docetaxel + vandetanib did not prolong PFS relative to docetaxel alone in OC patients. No unexpected safety issues were identified.     

Brostallicin versus doxorubicin as first-line chemotherapy in patients with advanced or metastatic soft tissue sarcoma: An European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group randomised phase II and pharmacogenetic study

AimBrostallicin is a DNA minor groove binder that has shown activity in patients with soft tissue sarcoma (STS) failing first-line therapy. The present study assessed the safety and efficacy of first-line brostallicin in patients with advanced or metastatic STS > 60 years or not fit enough to receive combination chemotherapy. A prospective explorative pharmacogenetic analysis was undertaken in parallel.MethodsPatients were randomised in a 2:1 ratio between IV brostallicin 10 mg/m² and doxorubicin 75 mg/m² once every 3 weeks for a maximum of six cycles. Disease stabilisation at 26 weeks (primary end-point) was considered a ‘success’. Further testing of brostallicin was warranted if ⩾35 ‘successes’ were observed in the first 72 eligible patients treated with brostallicin. In addition, patients were genotyped for glutathione S transferase (GST) polymorphisms.ResultsOne hundred and eighteen patients were included (79 brostallicin and 39 doxorubicin). Brostallicin was well tolerated in comparison to doxorubicin with less grade 3–4 neutropenia (67% versus 95%), grade 2–3 systolic dysfunction (0% versus 11%), alopecia (17% versus 61%) and grade 2–3 mucositis (0% versus 18%). For brostallicin versus doxorubicin, ‘successes’ were observed in 5/77 versus 10/36, progression free survival at 1 year was 6.5% versus 15.6%, objective response rate was 3.9% versus 22.2% and overall survival at 1 year was 50.5% versus 57.9%, respectively. Only GSTA1 genotype was significantly associated with success rate of doxorubicin treatment.ConclusionBrostallicin cannot be recommended at this dose and schedule in this patient population as first-line therapy. GSTA1 genotype may be predictive for doxorubicin efficacy but warrants further study.     

Feasibility of preoperative combined radiation therapy and chemotherapy with 5-fluorouracil and cisplatin in potentially resectable pancreatic adenocarcinoma: The French SFRO-FFCD 97-04 Phase II trial

PURPOSE: More than 80% of patients who undergo a potentially curative resection for pancreatic cancer develop local or distant recurrence. Neoadjuvant chemoradiotherapy might offer potential benefits regarding local and systemic control and survival. This multi-institutional Phase II trial explored the feasibility of preoperative chemoradiation in this situation. METHODS AND MATERIALS: Treatment consisted of concurrent radiotherapy (50 Gy within 5 weeks), and chemotherapy with 5-fluorouracil (300 mg/m(2)/day, 5 days/week, 5 consecutive weeks) and cisplatin (20 mg/m(2)/day, Days 1-5 and 29-33), followed by surgical resection of the pancreatic tumor in patients without progression. RESULTS: A total of 41 patients were enrolled. Of these, 38 (93%) received > or =47 Gy; 30 patients (73%) received > or =75% of the prescribed doses of chemotherapy. Surgical resection was performed in 26 patients (63%). Because of local or metastatic progression, 5 patients (12%) did not undergo surgery and 10 underwent surgery without resection of the pancreatic tumor. Operative mortality was 2.8%. Among 40 evaluable patients, 27 were successfully treated (67.5%; 95% CI, 50.9-81.4%). CONCLUSIONS: Pancreatic cancer is chemo-radiosensitive. The proposed pre-operative scheme is feasible, does not prevent successful surgery, and must be tested on a Phase III setting. Yet, the large proportion of tumor progression during and after chemoradiation justifies the use of more efficient drugs such as Gemcitabine, and optimized radiotherapy including new techniques such as intensity-modulated radiation therapy.     

A phase II study of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy followed by surgery and adjuvant S-1 chemotherapy in potentially resectable gastric or gastroesophageal junction adenocarcinoma

Purpose

Adjuvant chemotherapy trial of TS-1 for gastric cancer study demonstrated that postoperative S-1 chemotherapy for 1 year improved overall survival of locally advanced gastric cancer (LAGC) patients. The goals of this study were to evaluate the feasibility and efficacy of neoadjuvant docetaxel, oxaliplatin, and S-1 (DOS) chemotherapy followed by surgery and adjuvant S-1 chemotherapy.

Methods

In this single-center, open-label, phase II study, patients with potentially resectable adenocarcinoma of the stomach or gastroesophageal junction were eligible. For neoadjuvant chemotherapy, docetaxel 50 mg/m² on day (D) 1, oxaliplatin 100 mg/m² on D1, and S-1 40 mg/m² bid orally on D1–14 were administrated every 3 weeks for three cycles. After DOS chemotherapy, gastrectomy was performed, and then, adjuvant S-1 40 mg/m² bid was given on D1–28 every 6 weeks for 1 year. The primary endpoints were the proportion of patients who did not experience grade 3 or 4 toxicities (except grade 3 neutropenia) and R0 resection rates.

Results

A total of 41 patients were enrolled. All patients completed three planned cycles of neoadjuvant chemotherapy without disease progression. Eighteen patients (43.9 %) did not experience any grade 3–4 toxicity (except grade 3 neutropenia) during the neoadjuvant chemotherapy. All patients underwent surgery, and R0 resection was achieved in 40 patients (97.6 %).

Conclusion

Neoadjuvant DOS chemotherapy could be performed safely with a high R0 resection rate in LAGC patients. A phase III trial is currently underway.     

A phase II study of multimodality treatment for locally advanced cervical cancer: neoadjuvant carboplatin and paclitaxel followed by radical hysterectomy and adjuvant cisplatin chemoradiation.

BACKGROUND: Our aim was to evaluate the efficacy and safety of neoadjuvant chemotherapy followed by radical hysterectomy and adjuvant radiation concurrent with weekly cisplatin for locally advanced cervical carcinoma. PATIENTS AND METHODS: Forty-three patients staged as IB2-IIIB were treated with three 21-day courses of carboplatin (area under the time-concentration curve 6 mg.min/ml) and paclitaxel at 175 mg/m(2) by 3-h infusion both on day 1 followed by radical type III hysterectomy and adjuvant radiation concurrent with 6-weekly doses of cisplatin at 40 mg/m(2). Response rate, resectability, toxicity and survival were evaluated. RESULTS: From December 2000 to June 2001, 43 patients were recruited. All were evaluated for response and toxicity to neoadjuvant chemotherapy. A total of 129 courses were administered. Clinical responses were seen in 41 patients (95%) [95% confidence interval (CI) 89.2% to 100%] with four (9%) complete and 37 (86%) partial. Forty-one patients underwent surgery (resectability 95%); pathologically complete or near-complete responses were seen in seven (17%) and eight (20%), respectively, positive surgical margins in five (12%), and positive pelvic lymph nodes in eight (20%). Twenty-six patients were scheduled for adjuvant chemoradiation. External radiation was delivered for 42.8 days (range 33-61), with a mean dose of 49.3 Gy (range 46-56), and a median of five cisplatin courses (two to six). The mean dose of brachytherapy was 32 Gy (range 25.5-35.6). Neoadjuvant therapy was well-tolerated with neutropenia grade 3 and 4 in 12% and 3% of the courses, respectively. Toxicity to adjuvant chemoradiation was mainly hematological and gastrointestinal, mostly grades 1/2. A total of 39 patients completed all scheduled treatment. At a median follow-up of 21 months (range 3-26), the projected overall survival in the intention-to-treat analysis was 79% (95% CI 62% to 88%). CONCLUSIONS: The triple modality of neoadjuvant chemotherapy followed by radical hysterectomy and adjuvant radiation concurrent with cisplatin is a highly active treatment for locally advanced cervical carcinoma with acceptable toxicity.     

A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer

BackgroundThe contribution of induction chemotherapy (IC) before preoperative chemoradiation for esophageal cancer (EC) is not known. We hypothesized that IC would increase the rate of pathologic complete response (pathCR).MethodsTrimodality-eligibile patients were randomized to receive no IC (Arm A) or IC (oxaliplatin/FU; Arm B) before oxaliplatin/FU/radiation. Surgery was attempted ∼5–6 weeks after chemoradiation. The pathCR rate, post-surgery 30-day mortality, overall survival (OS), and toxic effects were assessed. Bayesian methods and Fisher's exact test were used.ResultsOne hundred twenty-six patients were randomized dynamically to balance the two arms for histology, baseline stage, gender, race, and age. Fifty-five patients in Arm A and 54 in Arm B underwent surgery. The median actuarial OS for all patients (54 deaths) was 45.62 months [95% confidence interval (CI), 27.63–NA], with median OS 45.62 months (95% CI 25.56–NA) in Arm A and 43.68 months (95% CI 27.63–NA) in Arm B (P = 0.69). The pathCR rate in Arm A was 13% (7 of 55) and 26% (14 of 54) in Arm B (two-sided Fisher's exact test, P = 0.094). Safety was similar in both arms.ConclusionsThese data suggest that IC produces non-significant increase in the pathCR rate and does not prolong OS. Further development of IC before chemoradiation may not be beneficial.Clinical trial no.: NCT 00525915 (www.clinicaltrials.gov).