A phase II study of weekly neoadjuvant chemotherapy followed by radical chemoradiation for locally advanced cervical cancer

Background:

We investigated the feasibility of dose-dense neoadjuvant chemotherapy (NACT) with paclitaxel and carboplatin before radical chemoradiation (CRT) and assessed the response rate to such a regimen.

Methods:

CxII is a single-arm phase II trial of 46 patients, with locally advanced cervical cancer (stage Ib2-IVa). Patients received dose-dense carboplatin (AUC2) and paclitaxel (80 mg m⁻²) weekly for six cycles followed by CRT (40 mg m⁻² of weekly cisplatin, 50.4 Gy, 28 fractions plus brachytherapy). The primary end point was response rate 12 weeks post-CRT.

Results:

Baseline characteristics were: median age at diagnosis 43 years; 72% squamous, 22% adenocarcinoma and 7% adenosquamous histologies; FIGO stage IB2 (11%), II (50%), III (33%), IV (7%). Complete or partial response rate was 70% (95% CI: 54–82) post-NACT and 85% (95% CI: 71–94) post-CRT. The median follow-up was 39.1 months. Overall and progression-free survivals at 3 years were 67% (95% CI: 51–79) and 68% (95% CI: 51–79), respectively. Grade 3/4 toxicities were 20% during NACT (11% haematological, 9% non-haematological) and 52% during CRT (haematological: 41%, non-haematological: 22%).

Conclusion:

A good response rate is achieved by dose-dense weekly NACT with carboplatin and paclitaxel followed by radical CRT. This treatment regimen is feasible as evidenced by the acceptable toxicity of NACT and by the high compliance to radiotherapy (98%).     

Prospective phase II study of neoadjuvant doxorubicin followed by cisplatin/docetaxel in locally advanced breast cancer

The objective of this study is to evaluate the efficacy and safety profile of the doxorubicin followed by cisplatin/docetaxel as primary chemotherapy for patients with locally advanced breast cancer (LABC). For this evaluation, 59 patients with LABC (T2–T4, N0–N2, M0) received three cycles of doxorubicin, followed by three cycles of cisplatin/docetaxel and followed by definitive surgery and locoregional radiotherapy with or without tamoxifen. The primary end point was pathologic complete response (pCR) in breast and axilla. Fifty-nine patients were evaluable for analysis: median age: 41 years, premenopausal: 68%, median tumor size: 6.0 cm (4–10), Stage IIB: 32% and IIIA/IIIB: 68%, both ER/PR positive: 53%, Her2/neu (3+) by IHC staining: 29%. Clinical complete response was seen in 44%, and clinical partial response was seen in 56%. Breast conserving surgery was performed in 44%, and MRM in 56%. pCR in the breast was 30.5%, in axilla was 37%, and pCR in both breast and axilla was 24%. Overall at follow-up of 60 months, the disease-free (DFS) and overall survival (OS) were 70 and 82%, respectively. The DFS and OS of patients who achieved complete pathologic response in breast and axilla were 78 and 100%, respectively, while 14 patients relapsed of which 46% were Her2 positive. Sequential combination of doxorubicin followed by docetaxel/cisplatin is a safe, feasible, and active combination, which offers the possibility of conservative surgery and is associated with high clinical and pathologic response rates, with promising and encouraging survival outcomes.     

A phase II trial of neoadjuvant docetaxel and capecitabine for locally advanced breast cancer.

PURPOSE: This study evaluated the toxicity and efficacy of docetaxel/capecitabine as neoadjuvant treatment for stage 2/3 breast cancer. EXPERIMENTAL DESIGN: Subjects with newly diagnosed invasive stage 2 and 3 breast cancer were eligible. The first cohort of patients was treated at dose A with neoadjuvant docetaxel (75 mg/m(2) i.v. day 1) and capecitabine (1000 mg/m(2) orally twice daily days 2-15) for four cycles. A second cohort of subjects was treated with a reduced dose, dose B, of docetaxel (60 mg/m(2) i.v. day 1) and capecitabine (937.5 mg/m(2) orally twice daily days 2-15). RESULTS: Thirty patients were enrolled. Eight of 10 patients treated at dose A required dose reductions of either docetaxel or capecitabine secondary to grade 3 or 4 toxicities: mucositis (1), hand-foot syndrome (3), diarrhea (2), perirectal abscess (1), and neutropenia (2). Because of a high rate of dose reductions, the next 20 patients were treated at dose B. The mean cumulative administered dose of docetaxel was 285 and 231 mg/m(2) at dose A and dose B, respectively. For capecitabine, the mean cumulative dose at dose A and B were similar at 1585 and 1627 mg/m(2)/day, respectively. The overall clinical response rate was 90% with 31% of patients having a complete response and 59% having a partial response. A pathological complete response in the breast was achieved in 10% of patients after four cycles of docetaxel/capecitabine. CONCLUSIONS: Docetaxel/capecitabine is a highly active regimen in the neoadjuvant setting. Neoadjuvant therapy with 75 mg/m(2) docetaxel and 1600 mg/m(2)/day days 2-15 is recommended.     

A phase II trial of induction chemotherapy followed by continuous hyperfractionated accelerated radiotherapy in locally advanced non-small-cell lung cancer

Background and purpose

We conducted a phase II study combining induction chemotherapy with continuous hyperfractionated accelerated radiotherapy (CHART) in locally advanced non-small-cell lung cancer (NSCLC).

Materials and methods

A total of 40 patients with stage III NSCLC were enrolled. All patients received 3 cycles of chemotherapy followed by CHART (56 Gy in 36 fractions over 12 days). The primary outcome measure was radiation toxicity. Secondary endpoints were response rate, overall survival, disease-free survival and loco-regional progression-free survival.

Results

Acute radiation toxicity was minimal and there were no significant late toxicities. The response rate after completion of chemoradiation was 65%. The median and 2-year overall survival, progression-free survival and loco-regional progression-free survivals were 15.7 months, 28%; 12.1 months, 23%; and 26.4 months, 51%, respectively.

Conclusions

Induction chemotherapy can be safely combined with CHART. The survival results are consistent with previous studies of chemotherapy followed by accelerated radiotherapy. This approach should be compared with synchronous chemoradiation to determine if it represents a less toxic alternative.     

Phase II trial of paclitaxel and cisplatin as neoadjuvant chemotherapy for locally advanced gastric cancer

Purpose

Paclitaxel–cisplatin (TC) combination is effective and well tolerated in patients with unresectable gastric cancer. We investigated the efficacy and safety of TC for locally advanced gastric cancers in a neoadjuvant setting.

Methods

Patients received 2–4 courses of paclitaxel (80 mg/m²) and cisplatin (25 mg/m²) on days 1, 8, and 15 in a 4-weekly schedule, followed by radical gastrectomy. Primary endpoint was the pathological response rate: percentage of tumors in which one-third or more parts were affected.

Results

All 52 patients enrolled were eligible. Thirty-six (69.7 %) patients completed two or more courses of chemotherapy. Forty-three patients (82.7 %) underwent surgery, 33 (63.5 %) had R0 resection, and there was no treatment-related death. The pathological response was 34.6 % (95 % CI 22.0–49.1) for all registered patients; the null hypothesis of tumor response ≤10 % was rejected (p < 0.0001). The 3-year overall survival was 41.5 % (95 % CI 27.4–55.0).

Conclusions

The neoadjuvant chemotherapy with TC was safe and effective for patients with locally advanced gastric cancer, and further study is needed to confirm the effectiveness of this regimen.     

Phase II trial of neoadjuvant docetaxel and gefitinib followed by radical prostatectomy in patients with high‐risk,locally advanced prostate cancer

BACKGROUND:

Prostate cancer trials investigating neoadjuvant hormonal therapy, followed by surgery, have demonstrated that elimination of all tumor cells from the primary site is rare. The authors report a phase 2 trial assessing the efficacy and toxicity of docetaxel and gefitinib in patients with high‐risk localized prostate cancer as neoadjuvant therapy before radical prostatectomy (RP).

METHODS:

Thirty‐one patients with high‐risk prostate cancer were treated with docetaxel and gefitinib for 2 months before RP. All patients met the criteria of clinical stage T2b‐3 or serum prostate‐specific antigen (PSA) level >20 ng/mL, or Gleason score of 8 to 10. The primary endpoint was pathologic complete response. Secondary objectives included clinical response. When available, endorectal coil magnetic resonance imaging (eMRI) was performed as part of clinical response evaluation. Immunohistochemical staining of epidermal growth factor receptor and HER‐2/neu was performed on prechemotherapy and postchemotherapy prostate tissue.

RESULTS:

The median age of the patients was 60 years, the median pretreatment PSA level was 7.43 ng/mL, and the median Gleason score was 8. Clinical staging prior to treatment consisted of: T1 in 4 patients, T2 in 17 patients, and T3 in 10 patients. One patient with enlarged pelvic adenopathy and T4 disease did not undergo RP. Thirty patients received all scheduled therapies including RP. Grade 3 toxicities included asymptomatic liver function test elevation in 4 (13%) patients, diarrhea in 1 (3%) patient, and fatigue in 1 (3%) patient. One patient experienced grade 4 toxicity with elevated alanine aminotransferase. RP specimen pathology demonstrated residual carcinoma in all cases. Twenty‐nine (94%) patients achieved a clinical partial response, including 35% of patients who demonstrated radiographic improvement on eMRI.

CONCLUSIONS:

No pathologic complete response was noted in 31 patients treated with docetaxel and gefitinib. This combination was well tolerated, and did not result in increased surgical morbidity. Cancer 2009. © 2009 American Cancer Society.     

局部晚期胃癌全新辅助治疗Ⅱ期临床研究中期分析

目的 探讨“新辅助同步放化疗+巩固化疗+手术”的全新辅助治疗模式在局部晚期胃癌治疗中的安全性和疗效。方法 2018—2020年间前瞻性纳入局部晚期胃腺癌或Siewert Ⅱ/Ⅲ型胃食管结合部腺癌患者 28例,首先接受同步放化疗(CCRT),放疗剂量为45Gy,1.8 Gy/次,同步口服替吉奥 40~60mg,2 次/d。CCRT后3周接受 4~6周期SOX方案巩固化疗(CNCT)。CNCT结束后 4~6周完成胃 癌D2根治术。结果 28例患者均完成新辅助治疗,治疗中≥3级不良反应在CCRT期间出现 3例(11%),分别为血小板下降、白细胞下降、食欲下降;在CNCT期间出现白细胞下降 2例(7%)、血小板下降 3例(11%)。共 20例(71%)完成手术,达病理完全缓解者占50%。3例手术并发症分别为吻合口瘘、吻合口狭窄、感染,对症处理后好转。结论 中期分析结果示局部晚期胃癌接受全新辅助治疗可获得显著的降期,治疗不良反应及手术并发症可耐受。     

A phase I/II trial of docetaxel and oxaliplatin in patients with advanced gastric cancer

Purpose  We designed this phase I/II study of docetaxel–oxaliplatin combination chemotherapy to determine the dose-limiting toxicity (DLT), maximum tolerated dose and efficacy as a first-line treatment in patients with advanced gastric cancer. Methods  Patients with histologically proven, chemo-naive gastric adenocarcinoma were eligible. For the phase I part, three dose levels of oxaliplatin and docetaxel every 3 weeks were tested in a cohort of three patients for each level (respectively, 100 and 60 mg/m², 100 and 75 mg/m², 130 and 75 mg/m²). Patients were treated up to a maximum of nine cycles of oxaliplatin and docetaxel unless there was documented disease progression, an unacceptable adverse event, or withdrawal of consent. Results  No DLT was observed at any of the three levels tested in the phase I portion. Therefore, oxaliplatin 130 mg/m² and docetaxel 75 mg/m² were recommended for the phase II study. All 47 patients were evaluable for toxicity and treatment response. The overall response rate was 55.3% (95% CI, 40.6–70.1%) and median duration of response was 4.2 months (range 0.9–9.5 months). After a median follow-up duration of 13.3 months, median overall survival was 12.7 months (95% CI: 10.4–14.9). The median time to progression was 5.0 months (95% CI, 3.4–6.5 months). The main toxicities (grade 3 or 4) were febrile neutropenia (14.9%), neutropenia (23.4%), diarrhea (10.6%) and neurotoxicity (8.5%). Conclusion  The combination of docetaxel and oxaliplatin was feasible with favorable toxicity profile and showed a promising anti-tumor activity in unresectable, metastatic gastric cancer patients.     

Phase II trial of neoadjuvant docetaxel and cisplatin followed by intensity-modulated radiotherapy with concurrent cisplatin in locally advanced nasopharyngeal carcinoma

Purpose

To evaluate the feasibility and efficacy of neoadjuvant chemotherapy involving docetaxel and cisplatin followed by intensity-modulated radiotherapy (IMRT) with concurrent cisplatin in patients with newly diagnosed stage III to IVB nasopharyngeal carcinoma (NPC).

Methods

Docetaxel (75 mg/m² on day 1) and cisplatin (75 mg/m² on day 1) were administered on a 3-week cycle for 2 courses, followed by radical IMRT (72 Gy/33F/6.5–7 W) with concurrent cisplatin (75 mg/m², on day 1) every 3 weeks for 2 cycles.

Results

From June 2008 to October 2010, forty-six patients were recruited in this trial. Forty-five patients completed neoadjuvant setting, and all patients completed planned concurrent chemoradiotherapy (CCRT). The complete and partial response rates were 28.3 and 56.5 % after neoadjuvant chemotherapy, and 91.3, 8.7 % after CCRT, respectively. After median follow-up of 26 months (range 12–39 months), one patient experienced local recurrence and 4 patients developed distant metastasis. The 3-year overall survival and progression-free survival rate were 94.1 and 72.7 %, respectively. Neutropenia (37.0 %) and vomiting (28.3 %) were the most common Grade 3–4 adverse effects during neoadjuvant course, while mucositis (30.4 %), xerostomia (30.4 %) and radiodermatitis (21.7 %) were the most common Grades 3 acute toxicities during CCRT. Xerostomia (73.9 %), dysphagia (56.5 %), hear loss (30.4 %) and skin reaction (21.7 %) were the common Grade 1–2 late effects. There were no Grades 3–4 late toxicities.

Conclusions

The protocol of neoadjuvant docetaxel and cisplatin followed by IMRT with concurrent cisplatin was well tolerated, with outstanding compliance and efficacy in locally advanced NPC, which deserved further follow-up.     

Phase II trial of preoperative S-1 plus cisplatin followed by surgery for initially unresectable locally advanced gastric cancer

Background

The aim of this study was to evaluate the efficacy and feasibility of preoperative chemotherapy with S-1 plus cisplatin in patients with initially unresectable locally advanced gastric cancer.

Methods

We enrolled patients with initially unresectable locally advanced gastric cancer because of severe lymph node metastases or invasion of adjacent structures. Preoperative chemotherapy consisted of S-1 at 80 mg/m² divided in two daily doses for 21 days and cisplatin at 60 mg/m² intravenously on day 8, repeated every 35 days. If a tumor decreased in size, patients received 1 or 2 more courses. Surgery involved radical resection with D2 lymphadenectomy.

Results

Between December 2000 and December 2007, 27 patients were enrolled on the study. No CR was obtained, but PR was seen in 17 cases, and the response rate was 63.0%. Thirteen patients (48.1%) had R0 resections. There were no treatment related deaths. The median overall survival time (MST) and the 3-year overall survival (OS) of all patients were 31.4 months and 31.0%, respectively. Among the 13 patients who underwent curative resection, the median disease-free survival (DFS) and the 3-year DFS were 17.4 months and 23.1%, respectively. The MST and the 3-year OS were 50.1 months and 53.8%, respectively. The most common site of initial recurrence after the R0 resection was the para-aortic lymph nodes.

Conclusions

Preoperative S-1 plus cisplatin can be safely delivered to patients undergoing radical gastrectomy. This regimen is promising as neoadjuvant chemotherapy for resectable gastric cancer. For initially unresectable locally advanced gastric cancer, new trials using more effective regimens along with extended lymph node dissection are necessary.     

A phase II trial of gemcitabine and erlotinib followed by ChemoProton therapy plus capecitabine and oxaliplatin for locally advanced pancreatic cancer

BackgroundEpidermal growth factor receptor (EGFR) is overexpressed in pancreatic cancer. EGFR expression plays a potentially important role in modulation of tumor sensitivity to either chemotherapy or radiotherapy. Erlotinib is a receptor tyrosine kinase inhibitor with specificity for EGFR/HER1. A phase II trial was conducted to explore the efficacy of a regimen utilizing erlotinib and proton therapy.MethodsPatients with unresectable or borderline resectable non-metastatic adenocarcinoma of the pancreas were included. Patients received 8-week systemic treatment with gemcitabine 1,000 mg/m² and erlotinib 100 mg (GE). If there was no evidence of metastatic disease after GE, then patients preceded with proton therapy to 50.4 Gy in 28 fractions with concurrent capecitabine 825 mg/m² (CPT). This was followed with oxaliplatin 130 mg/m² and capecitabine 1,000 mg/m² (CapOx) for 4 cycles. The primary study objective was 1-year overall survival (OS). The benchmark was 43% 1-year survival as demonstrated in RTOG/NRG 98-12. The Kaplan-Meier method was used to estimate the one-year OS and the median OS and progression-free survival (PFS).ResultsThe study enrolled 9 patients ages 47–81 years old (median 62) between January 2013 and March 2016, when the trial was closed due to low patient accrual. The 1-year OS rate was 55.6% (95% CI: 31% to 99%). The median OS was 14.1 months (95% CI: 11.4–NE) and the median PFS was 10.8 months (95% CI: 7.44–NE). A majority of patients completed CPT and GE, but only 33.3% completed the four cycles of CapOx. A third of patients experienced grade 3 toxicities, which were all hepatic along with one patient who also had grade 3 diarrhea. There were no grade 4 or 5 toxicities. Four patients were enrolled with borderline resectable disease, three of which were eligible for pancreaticoduodenectomy after GE and CPT treatment. One of two patients who underwent resection had a negative margin.ConclusionsThis regimen for locally advanced pancreatic cancer (LAPC) exceeded the pre-specified benchmark and was safe and well tolerated. Additional investigations utilizing more current systemic treatment regimens with proton therapy are warranted.Trial RegistrationClinicalTrials.gov identifier (NCTNCT01683422).     

Preoperative twice-weekly paclitaxel with concurrent radiation therapy followed by surgery and postoperative doxorubicin-based chemotherapy in locally advanced breast cancer: a phase I/II trial.

PURPOSE: Preoperative chemotherapy is the conventional primary treatment in locally advanced breast cancer (LABC). We investigated the safety and efficacy of primary twice-weekly paclitaxel and concurrent radiation (RT) before modified radical mastectomy followed by adjuvant doxorubicin-based chemotherapy. PATIENTS AND METHODS: Stage IIB (T3N0) to III LABC patients were eligible. Primary chemoradiation consisted of paclitaxel, 30 mg/m(2) delivered intravenously for 1 hour twice weekly for a total of 8 to 10 weeks, and concurrent RT (45 Gy at 1.8 Gy/fraction). Modified radical mastectomy was performed at least 2 weeks after completion of chemoradiation or on recovery of skin toxicity. Postoperatively, patients who responded to paclitaxel and RT received four cycles of doxorubicin/paclitaxel, whereas patients who did not respond received doxorubicin/cytoxan. RESULTS: Forty-four patients were accrued. Toxicity from paclitaxel/RT included grade 3 skin desquamation (7%), hypersensitivity (2%), and stomatitis (2%). Postsurgery complications occurred in six patients (14%). The only grade 4 toxicity of postmastectomy chemotherapy was hematologic (10%). Grade 3 toxicities were leukopenia (24%), infection (22%), peripheral neuropathy (17%), arthralgia and pain (17%), stomatitis (12%), fatigue (10%), esophagitis (5%), and nausea (2%). Overall clinical response rate to preoperative paclitaxel and RT was 91%. Thirty-four percent of patients achieved a pathologic response in the mastectomy specimen: 16% pathologic complete responses (clearance of invasive cancer in the breast and axillary contents) and 18% pathologic partial responses (< 10 residual microscopic foci of invasive breast cancer). CONCLUSION: Twice-weekly paclitaxel with concurrent RT is a feasible and effective primary treatment for LABC. Future studies should compare primary chemoradiation to chemotherapy in LABC.     

Phase II trial of neoadjuvant chemotherapy with XELOX plus bevacizumab for locally advanced rectal cancer

In Western countries, the standard treatment for locally advanced rectal cancer is preoperative chemoradiotherapy followed by total mesorectal excision. On the other hand, in Japan, treatment results without radiotherapy are by no means inferior; therefore, extrapolation of results of preoperative treatment in Western countries to Japan is controversial. We consider that survival may be improved by preoperative treatment with new anticancer agents as they are expected not only to decrease the local recurrence rate but also to prevent distant metastases. We are conducting a multicentre Phase II study to evaluate the safety and efficacy of neoadjuvant chemotherapy using XELOX plus bevacizumab without radiotherapy in patients with locally advanced rectal cancer. The primary endpoint of the study is treatment compliance. Secondary endpoints are overall survival, disease-free survival, local recurrence-free survival, objective response rate, R0 resection rate and adverse events. Thirty patients are required for this study.     

A phase II study of cetuximab,capecitabine and radiotherapy in neoadjuvant treatment of patients with locally advanced resectable rectal cancer

Background

Neoadjuvant chemoradiotherapy (CRT) reduces local tumor recurrence in locally advanced rectal cancer (LARC). This phase II study assessed neoadjuvant cetuximab with capecitabine-based CRT in LARC.

Methods

Patients with stage II/III LARC received capecitabine 1250 mg/m² twice daily for 2 weeks followed by intravenous cetuximab 400 mg/m² at week 3, then weekly intravenous 250 mg/m² cetuximab plus CRT including capecitabine 825 mg/m² twice daily (including weekends during radiotherapy) with radiotherapy of 45 Gy (25 × 1.8 Gy), 5 days a week for 5 weeks. Total mesorectal excision was scheduled 4–6 weeks following completion of CRT. The primary endpoint was pathological complete response (pCR).

Results

Thirty-seven patients were eligible for safety and efficacy. TMN staging at baseline was: T4N2, 11%; T3N2, 40%; T2N2, 3%; T3N1, 35%; T2N1, 3% and T3N0 8%. The most common adverse events included, grade 1/2 acneiform skin rash (86%), and grade 3 radiodermatitis, (16%), diarrhea (11%) and hypersensitivity (5%). pCR was achieved in 3 patients (8%). Overall-, T- and N-downstaging rates were 73%, 57% and 81% respectively. Total sphincter preservation rate was 76%, and 53% in 17 patients whose tumors were located within 5 cm from the anal verge. Non-fatal perioperative complications occurred in 13 patients (35%) with delayed wound healing occurring in 6 patients (16%). One death was recorded due to sepsis following colonic necrosis.

Conclusion

Neoadjuvant cetuximab with capecitabine-based CRT is tolerable in patients with resectable LARC. Whilst the pCR rate was similar to recent reports, a high pathological downstaging rate was achieved.     

局部晚期胃癌术后同步放化疗临床研究

目的观察局部晚期胃癌术后辅助同步放化疗的临床疗效。方法将79例胃癌患者随机分为A组和B组。A组39例,第1次ECF化疗结束3周后开始同步放化疗。放疗采用常规四野照射6、0Co和6/15MV直线加速器、三维适型放疗,35天为1周期。放疗第1天及放疗结束前3天均分别行CF＋5-FU方案化疗1周,后继续ECF方案化疗3周期。B组40例,术后单纯ECF方案化疗6周期。结果 A组1、2、5年复发率分别为12.8%、17.9%、23.1%,B组1、2、5年复发率分别为20.0%、32.5%、45.0%,两组比较差异有统计学意义（P〈0.05）;A组1、2、5年生存率分别为89.7%、71.8%、48.7%,B组为80.0%、50.0%、30.0%,差异有统计学意义（P〈0.05）。结论同步放化疗是局部晚期胃癌相对理想的辅助治疗手段。