Concurrent Paclitaxel Research Articles

A Phase II Study of Radiotherapy and Concurrent Paclitaxel Chemotherapy in Breast-Conserving Treatment for Node-Positive Breast Cancer

Administering adjuvant chemotherapy before breast radiotherapy decreases the risk of systemic recurrence, but delays in radiotherapy could yield higher local failure. We assessed the feasibility and efficacy of placing radiotherapy earlier in the breast-conserving treatment course for lymph node-positive breast cancer. Between June 2000 and December 2004, 44 women with node-positive Stage II and III breast cancer were entered into this trial. Breast-conserving surgery and 4 cycles of doxorubicin (60 mg/m(2))/cyclophosphamide (600 mg/m(2)) were followed by 4 cycles of paclitaxel (175 mg/m(2)) delivered every 3 weeks. Radiotherapy was concurrent with the first 2 cycles of paclitaxel. The breast received 39.6 Gy in 22 fractions with a tumor bed boost of 14 Gy in 7 fractions. Regional lymphatics were included when indicated. Functional lung volume was assessed by use of the diffusing capacity for carbon monoxide as a proxy. Breast cosmesis was evaluated with the Harvard criteria. The 5-year actuarial rate of disease-free survival is 88%, and overall survival is 93%. There have been no local failures. Median follow-up is 75 months. No cases of radiation pneumonitis developed. There was no significant change in the diffusing capacity for carbon monoxide either immediately after radiotherapy (p = 0.51) or with extended follow-up (p = 0.63). Volume of irradiated breast tissue correlated with acute cosmesis, and acute Grade 3 skin toxicity developed in 2 patients. Late cosmesis was not adversely affected. Concurrent paclitaxel chemotherapy and radiotherapy after breast-conserving surgery shortened total treatment time, provided excellent local control, and was well tolerated.

Esophageal cancer: Is preoperative chemoradiation the new standard?

Most patients with esophageal cancer require multi-disciplinary management, with radiation therapy constituting a key component of therapy. In this issue, Jabbour et al. present an excellent review article on the role of radiation therapy in the postoperative management of esophageal cancer (1). The authors must be commended for this thorough, evidence-based review article. In addition to discussing postoperative radiotherapy for esophageal cancer, the authors also discuss the roles of definitive chemoradiation, preoperative chemoradiation, preoperative chemotherapy and postoperative chemotherapy. As Jabbour et al. have discussed, multiple randomized trials have evaluated whether preoperative chemoradiation improves outcomes compared to surgery alone for esophageal cancer (1). In the Cancer and Leukemia Group B (CALGB) 9781 trial, patients with T1-T3 esophageal squamous cell carcinoma or adenocarcinoma were randomized to receive either surgery alone, or surgery with preoperative chemoradiation, with a dose of 50.4 Gy in 1.8 Gy fractions, along with concurrent cisplatin and 5-fluorouracil (2). Patients in the preoperative chemoradiation arm had a median survival of 4.5 years and a 5-year survival of 39%, while patients in the surgery alone arm had a median survival of 1.8 years and a 5-year survival of 16% (P=0.002). However, it should be noted that this trial had a poor accrual of only 56 patients, out of a planned accrual of 475 patients. The case for preoperative chemoradiation has been recently bolstered by presentation of results from the CROSS trial from the Netherlands (3). In this phase III trial, 363 patients with T2-3 N0-1 esophageal carcinoma were randomized to receive either surgery alone, or surgery with preoperative chemoradiation, with a dose of 41.4 Gy in 1.8 Gy fractions, with concurrent paclitaxel (50 mg/m2) and carboplatin (AUC 2). Of the enrolled patients, 75% had adenocarcinoma, 24% had squamous cell carcinoma, and 1% had other histologies. Overall survival was significantly improved in the preoperative chemoradiation arm (P=0.01). Patients in the preoperative chemoradiation arm had a median survival of 49 months and a 3-year survival of 59%, whereas patients in the surgery alone arm had a median survival of 26 months and a 3-year survival of 48%. Formal publication of this trial is being eagerly awaited. Nevertheless, this trial has the potential of being regarded as a landmark study, which will pave the way for establishing preoperative chemoradiation as a standard of care for resectable esophageal cancer. Jabbour et al. have included a detailed discussion on the relative advantages and disadvantages of preoperative and postoperative therapy. An important advantage of preoperative chemoradiation is that smaller fields can be used in most cases. With postoperative chemoradiation, the field has to be expanded to include the anastomosis, which can potentially lead to higher rates of toxicity. While preoperative chemoradiation is likely to play an increasingly important role in the management of resectable esophageal cancer, postoperative chemoradiation will also continue to play a role. Since clinical staging is not always accurate, some patients deemed not to be candidates for preoperative chemoradiation based on clinical staging, may be found to have more advanced disease at surgery, and may then require postoperative chemoradiation. Moreover, in patients with gastroesophageal junction carcinomas, the role of post-operative chemoradiation is supported by the phase III Intergroup trial (4). In this trial, 556 patients with gastric (around 80%) or gastroesophageal junction (around 20%) adenocarcinoma were randomized to receive either surgery alone or surgery with post-operative chemoradiation. Patients in the post-operative chemoradiation arm had a median survival of 36 months and patients in the surgery alone arm had a median survival of 27 months (P=0.005). In summary, Jabbour et al. have presented a well-written, thorough, evidence-based review article on the role of postoperative chemoradiation and other approaches for the treatment of esophageal cancer. This review article will help increase our understanding of combined modality therapy for esophageal cancer.

Five-year results of preoperative concurrent paclitaxel with radiation in locally advanced breast cancer (LABC).

567 Background: Prospective trials of preoperative concurrent paclitaxel (P) and radiation (RT) for LABC were conducted at three academic institutions. Rates of pathologic response, DFS and OS are reported. Methods: 105 LABC patients were treated between March 1997 and August 2009; 33 at University of Southern California, 36 at New York University and 36 at Vanderbilt University. P was given at 30 mg/m2 intravenously twice a week for 10-12 weeks. RT was delivered daily at 1.8 Gy to the breast, axillary and supraclavicular lymph nodes (LN) during weeks 2-7, to a total dose of 45 Gy followed by a tumor boost of 14 Gy at 2 Gy/fraction. Weekly trastuzumab (2 mg/kg) was added for 8 recent patients whose tumor over-expressed Her-2/neu. At one institution three cycles of P (175 mg/m2 q 3 weeks) were given prior to chemo-radiation. Pathologic response was defined as absence of invasive cancer in breast and LN (pCR) or less than 10 microscopic foci of invasive cancer in breast or LN (pPR). After surgery additional systemic therapy was left to the discretion of the treating physician. Results: Pathologic response (pCR and pPR) after concurrent P-RT was achieved in 34% (36/105) of patients. At a median follow-up of 60 months, the median survival has not been reached. The estimated 5-year DFS is 82.3% (95% CI: 71.6-89.3%), the 5-year OS is 71.6% (95% CI: 60.5-80.1%). The 5-year estimated OS for patients achieving a pathological response was 87.9% compared with 61.6% for nonresponders (Log-Rank = 8.61, p-value = 0.003). Local recurrence was only observed in 4/105 patients (3.8%): in 3 of 4 patients synchronously with or following systemic recurrence. Patients with a pathologic response had a lower risk of recurrence or death compared to patients who did not have a pathologic response (hazard ratio = 0.35, 95% CI: 0.15-0.80, logrank p-value = 0.009); similarly, responders were 0.23 times less likely to die over the time period than non-responders (95% CI: 0.08, 0.68). Conclusions: This series of 105 LABC patients treated with concurrent paclitaxel and radiation demonstrated a 71.6% 5-year OS and 96% local control. Pathologic response to concurrent paclitaxel and radiation was associated with a significantly better 5-year survival. No significant financial relationships to disclose.

Predictors of pathologic response and correlation with long-term outcomes in a trial of neoadjuvant concurrent paclitaxel radiation in locally advanced breast cancer (LABC).

589 Background: The association of hormone receptor (HR) status of the original tumor with pathologic response and correlation with DFS and OS from a multi-institutional trial of concurrent paclitaxel (P) and radiation (RT) are reported. Methods: 105 LABC patients were treated with neoadjuvant concurrent P and RT (P: 30 mg/m2 2x/week for 10-12 weeks; RT: 1.8 Gy daily to breast, axillary and supraclavicular LN weeks 2-7 to total of 45 Gy followed by a tumor boost of 14 Gy at 2 Gy/fraction). Pathologic response was defined as absence of invasive cancer in breast and LN (pCR) or persistence of less than 10 microscopic foci of invasive cancer in breast or LN (pPR). Logistic regression methods were used to predict response status, logrank tests and Cox proportional hazards methods to evaluate DFS and OS in relation to HR status and pathologic response. Results: Pathologic response (pCR+pPR) for the entire cohort was achieved in 36/105 patients (34%, 95% CI: 25-44%). For all patients, lack of a pathologic response conveyed 4.4 times greater death rate than for pathologic responders (95% CI 1.5-12.7). Nonresponders have a median survival time of 84 months; median not reached for responders. A significantly greater rate of pathologic response occurred in patients with HR negative cancers compared with HR positive cancers (p < 0.001): 54% (95% CI 39-69%) compared to 18% (95% CI of 9-30%). HR status was the only predictor of pathologic response after concurrent P-RT. As expected, HR negative tumors had a worse prognosis than HR positive ones; this feature remained despite the achievement of a pathologic response. However, pathologic response and HR status jointly predicted DFS (likelihood ratio p < 0.001). The clinical benefit from achieving a pathologic response was most pronounced in patients with HR negative tumors with a reduction in recurrence or death rate of 75% as compared with HR negative nonresponders. Conclusions: Conclusions: HR status is highly predictive of response to neoadjuvant concurrent paclitaxel and radiation; more than half of the patients with HR negative tumors achieved a pathologic response, which translates into superior DFS and OS. No significant financial relationships to disclose.

Definitive concurrent chemoradiation (CRT) with weekly paclitaxel and carboplatin for patients (pts) with irresectable esophageal cancer: A phase II study.

e14508 Background: This multicenter phase II study investigated the efficacy and feasibility of a non-cisplatin based definitive CRT regimen consisting of carboplatin and paclitaxel and concurrent radiotherapy for pts with irresectable esophageal carcinoma. Methods: Patients with locally irresectable (T4N0-1M0) carcinoma of the esophagus received CRT consisting of RT (50.4 Gy in 28 fractions, 5 days/week) and concurrent paclitaxel 50 mg/m2 and carboplatin AUC = 2 on days 1, 8, 15, 22, 29 and 35. Results: From December 2003 to November 2007 52 patients: male/female 34/18, median age 63 (42-76), squamous/adeno/undifferentiated carcinoma 36/14/2, lymph node involvement yes/no 44/8 were enrolled. Forty-two pts completed CRT without delay or dose-reduction, 6 pts received less than 6 courses chemotherapy but completed radiotherapy, and 4 pts received less than 46 Gy radiotherapy and less than 6 courses of chemotherapy. Major toxicities (grade ≥ 3): neutropenia 16%, thrombocytopenia 4%, esophagitis 12%, fatigue 8%, pulmonary 2% and 2 pts died because of a fatal bleeding. Five pts needed to be hospitalized during CRT for bleeding (2 pts), pneumonia (2 pts), or esophagitis and non-neutropenic fever (1 pt). During CRT dysphagia improved in 23 pts and worsened in 7 pts. Five pts underwent surgery after CRT, 2 pts showed complete pathological response. The median overall survival was 17 months (1-49+). One-, two- and three-year overall survival was 64%, 32%, and 16%, respectively. The median disease-free survival was 9 months (8 pts local recurrence, 9 pts distant metastases, 13 pts both). The median time to local progression was 14 months. Conclusions: Radiotherapy with concurrent weekly paclitaxel and carboplatin as definitive treatment for irresectable esophageal carcinoma is a tolerable regimen, which can be given on an outpatient basis and leads to durable locoregional control and palliation in about half of the patients. No significant financial relationships to disclose.

A Phase I/II Radiation Dose Escalation Study With Concurrent Chemotherapy for Patients With Inoperable Stages I to III Non-Small-Cell Lung Cancer: Phase I Results of RTOG 0117

In preparation for a Phase III comparison of high-dose versus standard-dose radiation therapy, this Phase I/II study was initiated to establish the maximum tolerated dose of radiation therapy in the setting of concurrent chemotherapy, using three-dimensional conformal radiation therapy for non-small-cell lung cancer. Eligibility included patients with histologically proven, unresectable Stages I to III non-small-cell lung cancer. Concurrent chemotherapy consisted of paclitaxel, 50 mg/m(2), and carboplatin, AUC of 2, given weekly. The radiation dose was to be sequentially intensified by increasing the daily fraction size, starting from 75.25 Gy/35 fractions. The Phase I portion of this study accrued 17 patients from 10 institutions and was closed in January 2004. After the initial 8 patients were accrued to cohort 1, the trial closed temporarily on September 26, 2002, due to reported toxicity. Two acute treatment-related dose-limiting toxicities (DLTs) were reported at the time: a case of grade 5 and grade 3 radiation pneumonitis. The protocol, therefore, was revised to de-escalate the radiation therapy dose (74 Gy/37 fractions). Patients in cohort 1 continued to develop toxicity, with 6/8 (75%) patients eventually developing grade >or=3 events. Cohort 2 accrued 9 patients. There was one DLT, a grade 3 esophagitis, in cohort 2 in the first 5 patients (1/5 patients) and no DLTs for the next 2 patients (0/2 patients). The maximum tolerated dose was determined to be 74 Gy/37 fractions (2.0 Gy per fraction) using three-dimensional conformal radiation therapy with concurrent paclitaxel and carboplatin therapy. This dose level in the Phase II portion has been well tolerated, with low rates of acute and late lung toxicities.

Abstract 5639: Preoperative concurrent paclitaxel and radiation in locally advanced breast cancer (LABC): Five-year outcomes on 105 patients

Abstract Purpose: A prospective trial of preoperative concurrent paclitaxel and radiation for patients with LABC was conducted at three academic institutions. Five-year local and systemic control rates are reported. Patients and Methods: 105 patients with LABC were treated with concurrent neoadjuvant paclitaxel and radiation. Paclitaxel was administered at 30 mg/m2 intravenously twice a week for 10-12 weeks. Daily radiotherapy was delivered to the breast, axillary and supraclavicular lymph nodes during weeks 2-7, at 1.8 Gy per fraction to a total dose of 45 Gy followed by a boost of 14 Gy at 2 Gy per fraction to the originally palpable tumor. Weekly trastuzumab (2mg/kg) was added for 8 more recent patients whose tumor over-expressed Her-2/neu. At one of the three institutions preoperative paclitaxel (3 cycles of 175 mg/m2 q 3 weeks) was also administered prior to chemo-radiation to 36 patients. Pathologic response was defined as complete response (pCR) in the absence of invasive cancer in breast or lymph nodes; partial response (pPR) as the persistence of &amp;lt; 10 microscopic foci of invasive carcinoma in breast or lymph nodes. After surgery additional systemic therapy was left to the discretion of the treating physician. Results: Pathological response (pCR and pPR) after neoadjuvant chemo-radiation was achieved in 36/105 patients (34.3%, 95% confidence interval: 25.3% - 44.2%). 30/105 patients underwent breast-conserving surgery after neoadjuvant chemo-radiation (28.6%), while 74 underwent mastectomy. One patient progressed during therapy and did not undergo surgery. With a median follow up of 60 months and a maximum of 137 months, the median survival has not been reached. The estimated 5-year overall cumulative survival (OS) is 71.6% (95% confidence interval: 60.5% - 80.1%). Local recurrence occurred in 4/105 patients (3.8%): in 3/4 synchronously with or following systemic recurrence. Five patients (4.8%) developed contra-lateral breast cancer. Patients without a pathologic response had a higher risk of recurrence or death than patients who had a pathologic response (hazard ratio = 2.86, logrank p-value=0.009); similarly, survival was shorter (hazard ratio = 4.28, logrank p-value=0.003). The 5-year estimated OS for non-responders was 61.6% compared with 87.9% for responders. A separate analysis of patients who received additional preoperative paclitaxel before chemo-radiation showed a pathologic response rate of 41.7% (15/36 patients, 95% confidence interval: 25.5% to 59.2%); with an estimated 5-year OS of 63.9% (95% confidence interval: 46.1% - 77.2%). Conclusion: This series of 105 patients with LABC treated with concurrent paclitaxel and radiation demonstrated a 71.6% 5-year OS and 96% local control rate. Pathological response to concurrent paclitaxel and radiation was associated with a significantly better 5-year survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5639.

First-line therapy for ovarian cancer with carboplatin followed by paclitaxel–gemcitabine (SCOTROC5): A feasibility study and comparative analysis of the SCOTROC series

Background We have conducted a series of four feasibility studies in stage Ic–IV ovarian cancer exploring six sequential first-line schedules with the same entry criteria in a total of 339 patients. Here we present the results of the sixth study, and an analysis of the overall series. Methods In this trial patients received 4 cycles of carboplatin AUC 7 every 3 weeks, followed by 4 cycles of concurrent paclitaxel 175 mg/m 2 (day 1) and gemcitabine 1000 mg/m 2 (days 1 and 8) every 3 weeks. The primary end-point of the trial was feasibility of administering all cycles of planned chemotherapy to >60% of patients. Results Fifty-four patients were recruited to the trial between June 05 and June 06. A total of 40 (74.1%) patients received all 8 cycles of treatment. Reasons for early discontinuation included toxicity ( n = 8) and disease progression ( n = 4). The overall response rate was 73.7%, and the median progression free survival (PFS) was 14.2 months with a median follow-up of 24 months. A comparative analysis of all six regimens from the SCOTROC series suggests that the sequential schedule in which paclitaxel was given weekly (median PFS 19.5 m) is most effective. 1 Conclusion The sequential schedule explored in this trial is feasible, but comparative efficacy analysis suggests that trials involving weekly paclitaxel should be prioritised for further study.

Concomitant Cisplatin, Paclitaxel, and Hyperfractionated Radiotherapy in Locally Advanced Head and Neck Cancer

To determine feasibility and efficacy of concurrent paclitaxel and cisplatin with definitive hyperfractionated radiotherapy (HFRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC). Forty-two patients stages III to IV head-and-neck squamous cell carcinoma were enrolled in 2 consecutive prospective trials from August 1998 to January 2006. In study 1, 16 patients received HFRT in 2 courses of 39.6 Gy each with a split of 2 weeks with concurrent paclitaxel (175 mg/m) and cisplatin (100 mg/m) on days 1, 21, 36, and 57. In study 2, 26 patients received a continuous course of 74.4 Gy of HFRT with concurrent weekly paclitaxel (50 mg/m) and cisplatin (30 mg/m). Tumor locations included oropharynx 48%, hypopharynx 24%, larynx 12%, paranasal sinuses 7%, salivary gland 2%, oral cavity 2% and unknown primary 5%. In study 1, all patients received 3 to 4 cycles of chemotherapy and completed the programmed radiotherapy course. In study 2, 69% received 5 to 6 cycles of chemotherapy and 92% completed the irradiation. Overall, 93% of objective responses were observed (complete 76%, partial 17%). Median follow-up was 50 months (range: 12-97). Pattern of recurrence was local 8%, distant 13%, and combined 3%. Acute toxicity grades 3 to 4 in studies 1 and 2 was 75% and 88%, respectively (P = ns). Globally, 5-year overall survival were 68%, with a median of 71 months (range: 50-91). On multivariate analysis, male gender (P = 0.04) and complete response (P = 0.01) were predictive of improved survival. HFRT combined with cisplatin and paclitaxel is very active but at the expense of severe toxicity. Efficacy and toxicity in studies.1 and 2 were not different despite completely different treatment strategies (chemotherapy dose intensity vs. radiotherapy dose intensity).

Phase II Study of Concurrent Chemoradiation in Combination With Erlotinib for Locally Advanced Esophageal Carcinoma

To investigate the feasibility and efficacy of concurrent chemoradiation in combination with erlotinib for locally advanced esophageal carcinoma. Twenty-four patients with locally advanced esophageal carcinoma were treated with concurrent chemoradiotherapy. A daily fraction of 2.0 Gy was prescribed to a total dose of 60 Gy over 6 weeks. Concurrent paclitaxel (135 mg/m(2), d(1)) and cisplatin (20 mg/m(2), d(1-3)) were administered on Day 1 and Day 29 of the radiotherapy. Erlotinib, an oral epidermal growth factor receptor-tyrosine kinase inhibitor, was taken by every patient at the dose of 150 mg daily during the chemoradiotherapy. The median follow-up of the 24 patients was 18.6 months (range, 7.1-29.6 months). The 2-year overall survival, local-regional control, and relapse-free survival were 70.1% (95% CI, 50.4-90%), 87.5% (95% CI, 73.5-100%), and 57.4% (95% CI, 36.3-78.7%), respectively. During the chemoradiotherapy, the incidences of acute toxicities of Grade 3 or greater, such as leucopenia and thrombocytopenia, were 16.7 % (4/24) and 8.3% (2/24). Application of concurrent chemoradiotherapy in combination with erlotinib for locally advanced esophageal carcinoma yielded satisfactory 2-year overall survival and local-regional control. The toxicities were well tolerated.

An Evaluation of the Safety and Efficacy of Lapatinib Plus Trastuzumab Plus Paclitaxel in First-Line HER2+ Metastatic Breast Cancer.

Abstract Background: Trastuzumab given concomitantly with paclitaxel is an established first-line metastatic breast cancer (MBC) treatment; however, approximately 30% to 40% of patients show no response as defined by RECIST to this combination. Lapatinib is an oral dual tyrosine kinase inhibitor of EGFR and HER2 and approved, in combination with capecitabine, after trastuzumab-based therapy for HER2+ MBC. The differing mechanisms of action may allow synergy between lapatinib and trastuzumab when given concurrently with paclitaxel for MBC.Methods: This is an open-label phase I safety study. The primary objective of the study was to assess the safety and tolerability of lapatinib when administered with concurrent paclitaxel and trastuzumab. Patients were enrolled into 1 of 3 cohorts. Cohort 1 received lapatinib (1000 mg/d), paclitaxel (80 mg/m2 weekly for 3 weeks of a 4-week cycle), and the standard weekly dose of trastuzumab. Cohort 2 received lapatinib (1000 mg/d), paclitaxel (70 mg/m2), and trastuzumab. Cohort 3 received lapatinib (750 mg/d), paclitaxel (80 mg/m2), and trastuzumab. Patients: were 3+ by IHC or FISH amplified for HER2; had not received prior treatment in the metastatic setting; and had an ECOG performance status of 0 or 1. Safety was assessed weekly and tumor response per RECIST every 8 weeks. Treatment continued until disease progression or toxicity. All patients received prophylactic loperamide per protocol amendment.Results: Open-label safety enrollment is complete and preliminary safety data are available for all 63 patients. The most frequently reported AEs for all cohorts were diarrhea (81%), fatigue (71%), rash (68%), nausea (59%), alopecia (56%), and vomiting (37%). Dehydration was the most frequently reported serious AE (SAE) (n=6; 10%) and most were in cohort 1 (5 patients). Diarrhea of any grade was reported for 97% of patients in cohort 1, 93% of patients in cohort 2, and 50% of patients in cohort 3. No grade 4 or 5 diarrhea events were reported. The proportion of patients with a maximum toxicity of grade 3 diarrhea was 62% in cohort 1, 43% in cohort 2, and 20% in cohort 3. Two patients (both in cohort 1) reported diarrhea as a serious AE and a total of 4 patients (6%) had lapatinib withdrawn due to diarrhea (none in cohort 3).Conclusions: Preliminary safety results show a high incidence of grade 3 diarrhea when lapatinib was given at a dose of 1000 mg/d concurrently with paclitaxel and trastuzumab. This incidence was significantly reduced with a lapatinib dose of 750 mg/d in combination with paclitaxel and trastuzumab when given with loperamide. Final safety and efficacy data, including overall response and progression-free survival, from this open-label safety study will be presented. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5085.

Phase II Trial of Neoadjuvant Pegylated Liposomal Doxorubicin with Paclitaxel and Trastuzumab in Patients with Operable Her2-Positive Breast Cancer.

Abstract Background: Doxorubicin, paclitaxel and trastuzumab are among the most active agents used in the treatment of Her2-positive invasive breast cancer. However, trastuzumab is associated with cardiotoxicity that is significantly amplified in the presence of doxorubicin. Pegylated liposomal doxorubicin (PLD) has been reported to have greatly reduced cardiotoxicity when compared to native doxorubicin. This pilot study was designed to assess safety and efficacy of concurrent PLD, paclitaxel (TAX), and trastuzumab in the preoperative setting.Methods: Eligible patients included women with T1c-T4, N0-1, M0, Her2-positive invasive breast cancer who had received no prior treatment. The treatment regimen consisted of concomitant PLD 24 mg/m2 or 20 mg/m2 (14pts/10pts) q 3 weeks, TAX 80 mg/m2 weekly, and trastuzumab 2mg/m2 weekly after an initial 4 mg/m2 loading dose, for a total of 18 weeks. MUGA scans were obtained at baseline, after 9 weeks, and after 18 weeks prior to surgery. The primary endpoint was pathologic complete response (pCR).Results: Twenty-four patients were entered on study. The median age was 55 (range 30-72). One subject had AJCC Stage I disease, 14 subjects had Stage II disease, 9 subjects had Stage III disease, and the median pre-treatment tumor size was 4.5 cm (1.2 cm-10.0 cm). Twelve subjects required dose reductions of PLD, 9 required dose reduction of TAX, and 5 discontinued therapy early. One subject withdrew during the 1st cycle, and 1 patient died due to an event unrelated to the investigational treatment. Thirteen of the 22 evaluable subjects had pCR (59%), 9 subjects had PR (41%). The principal treatment-related toxicity was Grade II or III skin toxicity in 18 of 24 subjects (75%). No overt cardiotoxicity was noted, with the mean change between pre-treatment and pre-surgical MUGA of -.25% (range -12-7%).Discussion: The combination of PLD, TAX, and trastuzumab given every 3 weeks, appears to be a highly effective regimen, without evidence of increased cardiotoxicity. However skin toxicity is prominent and may be exacerbated by a previously reported effect of TAX on PLD pharmacokinetics. Further investigation of this highly effective regimen should focus on reducing skin toxicity, while maintaining efficacy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1098.

Early Postoperative Paclitaxel Followed by Concurrent Paclitaxel and Cisplatin With Radiation Therapy for Patients With Resected High-Risk Head and Neck Squamous Cell Carcinoma: Report of the Phase II Trial RTOG 0024

We sought to improve outcomes for patients with high-risk head and neck squamous cell cancer (HNSCC) after surgical resection by testing the feasibility and safety of early postoperative chemotherapy followed by concurrent chemoradiotherapy. Eligible patients had resected, stages III to IV HNSCC with positive margins, extracapsular nodal extension, or multiple positive nodes. Paclitaxel (80 mg/m(2)) was given once weekly during postoperative weeks 2, 3, and 4 and was given before radiation therapy (RT). Paclitaxel (30 mg/m(2)) and cisplatin (20 mg/m(2)) were given once weekly during the last 3 weeks of RT (60 Gy over 6 weeks, beginning 4 to 5 weeks after surgery). The primary end points were treatment safety and tolerability compared with concurrent cisplatin (100 mg/m(2) every 3 weeks) and RT, as tested in Radiation Therapy Oncology Group trial RTOG 9501. The median follow-up time for the 70 patients enrolled was 3.3 years (range, 0.6 to 4.4 years) for surviving patients. Tolerability of all treatment components was comparable to that of RTOG 9501 treatment, which is the current standard of care (compliance rate, 75%; 95% CI, 63% to 85%). One patient died, and seven patients experienced grade 4 nonhematologic toxicities. Rates of locoregional control, disease-free survival, and overall survival exceeded those of RTOG 9501 after adjustment for important prognostic variables (ie, positive margins, extracapsular extension, primary site, and performance status). Chemotherapy soon after surgery followed by concurrent chemoradiotherapy therapy was feasible; tolerance was in line with standard postoperative chemoradiotherapy; and this regimen led to excellent rates of locoregional control and disease-free survival.

Correlation of body mass index with toxicity and survival in locoregionally advanced head and neck cancer patients treated with induction chemotherapy and concurrent chemoradiotherapy

6074 Background: Concurrent chemoradiotherapy (CRT) offers high functional organ preservation rates for locoregionally advanced head and neck cancer (LRAHNC) patients, but is associated with significant acute and chronic speech and swallowing toxicity. Recently, body mass index (BMI) has been suggested as a predictor of head and neck cancer patient outcome. In this analysis we sought to determine the impact of BMI on survival and toxicity outcomes in LRAHNC patients treated with CRT. Methods: 220 LRAHNC patients were treated on a multiinstitutional protocol consisting of induction carboplatin and paclitaxel followed by CRT. CRT was delivered for 4–5 cycles; each 14-day cycle consisted of 5 days concurrent paclitaxel, continuous infusion 5-FU, hydroxyurea, and 1.5 Gy twice daily radiation followed by 9 days without any treatment. Each patient's pre-treatment BMI was classified as overweight (BMI &gt;= 25) or non-overweight (BMI &lt; 25). As an independent variable, BMI was analyzed as a predictor of IndCT or CRT toxicity, locoregional control, and overall survival. BMI was analyzed as categorical variable, and also a continuous variable in a multivariate proportional hazards model. Results: There was no association between BMI and IndCT toxicity. During CRT overweight patients had significantly lower rates (24/103 vs 42/112) of grade 3 or higher neutropenia (p = 0.027), mucositis (p = 0.05), dermatitis (p = 0.028) and higher rates of anorexia (p = 0.05). Overweight patients had 12% long term PEG tube rate, compared to 34% of non-overweight patients (p &lt; 0.001). On pooled survival analysis, patients with BMI &gt; 25 had significantly better overall survival outcomes (mean 81.2 months, 95% CI 75.1–87.3 months) than patients with BMI &lt; 25 (median 58.2 months; mean 56.5 months, 95% CI 49.6–63.3 months) (log-rank p &lt; 0.001). Conclusions: Our data suggest patients with pre-treatment BMI &gt; 25 experience lower rates of toxicity commonly associated with chemoradiation, and have a significantly better prognosis than patients with BMI &lt; 25. Although the mechanism of BMI as an independent predictor of outcomes is unclear, we are continuing to explore mechanisms underlying this association. No significant financial relationships to disclose.

Time for global efforts with clinical trials for advanced cervical cancer patients

Time for global efforts with clinical trials for advanced cervical cancer patients

Long-Term Outcomes and Toxicity of Concurrent Paclitaxel and Radiotherapy for Locally Advanced Head-and-Neck Cancer

To report the long-term outcomes and toxicity of a regimen of infusion paclitaxel delivered concurrently with radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck. Between 1995 and 1999, 35 patients with nonmetastatic, Stage III or IV squamous cell carcinoma of the head and neck were treated with three cycles of paclitaxel as a 120-h continuous infusion beginning on Days 1, 21, and 42, concurrent with radiotherapy. The initial 16 patients received 105 mg/m(2)/cycle, and the subsequent 19 patients received 120 mg/m(2)/cycle. External beam radiotherapy was delivered to a dose of 70.2-72 Gy at five fractions weekly. Patients were followed to evaluate the disease outcomes and late toxicity of this regimen. The median follow-up for all patients was 56.5 months. The median survival was 56.5 months, and the median time to local recurrence was not reached. Of the 35 patients, 15 (43%) developed hypothyroidism. Of the 33 patients who underwent percutaneous endoscopic gastrostomy tube placement, 11 were percutaneous endoscopic gastrostomy tube dependent until death or their last follow-up visit. Also, 5 patients (14%) required a tracheostomy until death, and 3 (9%) developed a severe esophageal stricture. All evaluated long-term survivors exhibited salivary hypofunction. Fibrosis in the radiation field occurred in 24 patients (69%). The results of our study have shown that concurrent chemoradiotherapy with a 120-h infusion of paclitaxel provides long-term local control and survival in patients with squamous cell carcinoma of the head and neck. Xerostomia, hypothyroidism, esophageal and pharyngeal complications, and subcutaneous fibrosis were common long-term toxicities; however, the vast majority of toxicities were grade 1 or 2.

Feasibility and Outcomes of Concurrent Paclitaxel Chemotherapy and Radiotherapy for Node-positive Stage II-III Breast Cancer

Feasibility and Outcomes of Concurrent Paclitaxel Chemotherapy and Radiotherapy for Node-positive Stage II-III Breast Cancer

Phase I/II Study of Biweekly Paclitaxel and Radiation in Androgen-Ablated Locally Advanced Prostate Cancer

To determine the maximum-tolerated dose (MTD) of concurrent paclitaxel and radiation therapy (RT) in patients with locally advanced prostate cancer. Eligible patients had T2-4 tumors with Gleason scores greater than 7 and/or PSA levels greater than 10 ng/mL and/or had tumors with pathologic stage TxN1. Hormonal ablation was initiated 3 months before RT and was given for 9 months. RT was delivered daily (1.8 Gy) with concurrent twice-weekly paclitaxel (30 mg/m(2)). The whole pelvis was irradiated to 39.6 Gy. The radiation dose was escalated as follows: 63 Gy, 66.6 Gy, 70.2 Gy, and 73.8 Gy. The last RT dose level was fixed at 73.8 Gy. Between January 2000 and October 2006, 22 patients were enrolled. The median age was 59 years (range, 48 to 72 years); the median PSA level was 22.4 ng/mL (range, 2.8 to 113 ng/mL). The number of patients per stage was as follows: three with T1, eight with T2, 11 with T3, and five with pN1 = 5. No grade 3 toxicities occurred at 63 Gy. Grade 3 diarrhea occurred in three patients at 66.6 Gy. The protocol then was amended to treat the prostate volume first followed by the whole pelvis. No grade 3 toxicities were observed at 70.2 Gy. One patient experienced grade 3 diarrhea at 73.8 Gy. Five additional patients were treated to 73.8 Gy without grade 3 toxicity, which established the MTD for combined paclitaxel and RT at 73.8 Gy. At 38 months median follow-up (range, 9 to 87 months), 21 (95%) of 22 patients are alive. Six (27%) of 22 experienced recurrence. Concurrent biweekly paclitaxel with RT is feasible, with an MTD of 73.8 Gy. Recovery of gonadal function occurs in the majority of patients. These results encourage testing in a phase III setting.

Paclitaxel/carboplatin (PC) followed by twice daily chemoradiation (hfRT/PC) versus hfRT/PC followed by PC as induction to surgery in stage III non-small cell lung cancer (NSCLC): A randomized phase III trial of the Lung Cancer Study Group Mitteldeutschland

7541 Background: In multimodal neoadjuvant therapy of stage III NSCLC, the potential impact of the sequencing of the different induction modalities on survival has not been evaluated. Methods: Patients (pts) with biopsy-proven stage III (PET obligatory) NSCLC were stratified (center/technical operability) and then randomized to (arm 1) 2–3 cycles paclitaxel 225 mg/m2 d 1 / carboplatin AUC 6 d 1, followed by hfRT at 1.5 Gy 2x/d (total 45 Gy) with concurrent paclitaxel 50 mg/m2 / carboplatin AUC 2 d 1, 8, 15 vs (arm 2) hfRT/PC followed by PC at identical dosages to arm 1, then restaging incl. PET and surgery. The primary (secondary) endpoint was median overall survival (mOS), the secondary endpoint was median progression-free survival (mPFS). Assuming a median survival advantage of 6 months (mo) for arm 2, 104 pts per arm would detect a difference with type I (type II) error ≤ 5% (20%). Results: 210 pts were randomized between 01/01 and 06/05, 207 were evaluable. Median follow-up was 35 mo. The pts were well balanced between treatment arms 1/2: 106/104 pts; stage IIIA 34%/39%; stage IIIB 64%/60%; primary technical operability 24%/23%; PS 0 19%/18%; PS 1 29%/29%. mOS was 543 vs 550 days (p=073). mPFS was 326 vs 343 days (p=0.86). mOS of Stage IIIA was 489 vs 775 days (p=0.14), of stage IIIB 594 vs 546 days (ns). Grade 3 and 4 nonhematologic toxicities were not significantly different between treatment arms, leukopenias were more frequent in arm 2 (8 vs 28 pts). Conclusions: The sequence of chemotherapy and chemoradiation as multimodal induction therapy before surgery has no impact on mOS or mPFS in Stage III NSCLC. In Stage IIIA there is, however, a trend favoring arm 2. Grade 3 and 4 leukopenias are more frequent in arm 2. No significant financial relationships to disclose.

Induction Chemotherapy Followed by Concurrent Chemoradiotherapy in the Treatment of Locally Advanced Base of Tongue Cancer

To report our experience with the treatment of base of tongue (BOT) cancer using induction chemotherapy followed by concurrent chemoradiotherapy. From 11/1998–6/2002, 42 patients with locally advanced Stage III (n = 5) or stage IV (n = 37) BOT cancer were treated with 2 cycles of induction carboplatin (area under the curve 2) and paclitaxel (135 mg/m2) followed by concurrent paclitaxel, continuous infusion 5-fluorouracil, hydroxyurea, and 1.5 Gy BID radiation for 5 consecutive days of treatment followed by a 9-day break during which no additional treatment was given. Four patients who started, but did not complete treatment, were excluded from the analysis. The median dose to gross tumor was 72.5 Gy (R 59 Gy-75.5 Gy). Only two patients received less then 70 Gy. All patients underwent CT based planning. Neck dissections were planned on all patients with N2a–N3 disease. The median follow-up for all patients was 58 months (R 13–87 months) and for living patients 62 months (R 13–73 months). The breakdown by stage was as follows: T stage (10 T1, 9 T2, 8 T3, 15 T4) and N stage (5 N0, 6 N1, 5 N2a, 12 N2b, 10 N2c, 4 N3). Following therapy, 98% of patients (41/42) demonstrated a clinical complete response; neck dissections were positive for metastatic disease in 48% (11/23) and directed biopsies of the primary tumor were positive in 0% (0/31). There were three local failures, one regional failure, and four distant failures. The 2 and 5 year overall survival was 83.3% (95% CI: 68.2–91.7) and 70.4% (95% CI: 53.6–82.0), respectively. The 2 and 5 year disease-free survival was 85.3% (95% CI: 70.2–93.1) and 82.7% (95% CI: 67.0–91.4), respectively. The crude local failure rate was 7% (3/42). Loco-regional progression free survival at 5 years was 90.5% (95% CI: 75.8–96.2). Grade 3 or higher toxicity occurred in 36% of patients, while 12% experienced chemotherapy-related peripheral neuropathy. Feeding tubes were placed in 69% of treated patients, the majority of which were placed prior to starting radiotherapy. Pre-treatment swallowing function evaluation was performed on 38 patients and 84% had mild to severe dysphagia. At 6 months following treatment completion, the number of patients still requiring feeding tube and tracheostomy were 8 (19%) and 7 (17%), respectively. Six patients developed new primary cancers during follow-up, one of which was attributed to treatment-induced carcinogenesis. Our results demonstrate the effectiveness of induction chemotherapy and concurrent chemoradiotherapy delivered on a 14-day schedule for locally advanced base of tongue cancer.