Three-dimensional conformal radiation therapy for non-small-cell lung cancer: a phase I/II dose escalation clinical trial

PURPOSE: A prospective Phase I/II dose escalation study was conducted to determine the maximum tolerated dose (MTD) in three-dimensional conformal radiation therapy (3D-CRT) for non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: MTD would be reached via a dose escalation study. After 42 Gy/21 fractions, 4.2 weeks by conventional fractionated irradiation through anteroposterior/posteroanterior fields, the 3D-CRT technique was used as boost. The planned total dose escalation depended on lung volume irradiated. According to the percentage of lung volume receiving >20 Gy, the patients were divided into three subgroups (i.e., <25%, 25%-37%, and >37%). The scheduled dose escalation began with 69 Gy and continued to 78 Gy. The boost doses were delivered at 3 Gy per fraction, once per day, five fractions per week. Each dose level includes 5 patients. Besides radiotherapy, all patients received neoadjuvant and adjuvant chemotherapy with MVP regimen (Mitomycin, Vindesine, cis-platium). The criterion for stopping further dose escalation was > or =20% of patients with > or =RTOG Grade 3 radiation pneumonitis. RESULTS: Between June 1999 and February 2001, 50 patients had been enrolled in this study, including 4 with Stage II disease, 31 with Stage IIIa disease, and 15 with Stage IIIb disease. The dose escalation plan has been completed. All subgroups reached the highest predetermined dose levels (i.e., 78 Gy for the <25% subgroup, 78 Gy for the 25-37% subgroup, and 75 Gy for the >37% subgroup). Although none of the subgroups developed more than 20% of >/=Grade 3 acute pneumonitis, dose escalation was terminated because long-term follow-up was needed to observe late complications. Median follow-up time (MFT) for the entire group was 18 months (6-37 months). The most common acute complication was esophagitis in 56% of patients with RTOG Grade 1-2, and in 4% with Grade 3. Acute radiation pneumonitis developed in 36% of patients with RTOG Grade 1-2. Only 1 patient had Grade 3 pneumonitis, which was in the 25-37% subgroup at 75 Gy. The hematopoietic toxicity appeared in 58% of patients with Grade 1-2, and 8% with Grade 3. As to late complications, only 30% of patients developed pulmonary fibrosis of RTOG Grade 1-2. The median survival time for the entire group was 18 months. Two-year overall survival, locoregional progression-free rate, and distant metastasis rate were 44%, 40%, and 41%, respectively. CONCLUSIONS: Although MFT was 18 months, it had not yet been declared because a longer follow-up was needed to observe the late complications. The 2-year overall survival of 44% was very encouraging and implied that 3D-CRT combined with chemotherapy would improve the outcome for locally advanced NSCLC.     

Cancer stem cell enrichment marker CD98: A prognostic factor for survival in patients with human papillomavirus-positive oropharyngeal cancer

PurposeSeveral hypotheses have been proposed to explain the relatively good prognosis of patients with a human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) and one of these is a higher sensitivity to (chemo)radiation. Previous studies have suggested that treatment failure in OPSCC patients is caused by resistance of cancer stem cells (CSCs). The purpose of this study was to evaluate the association between the number of CSCs and prognosis in HPV-positive OPSCC patients.Experimental designAll OPSCC patients (n = 711) treated between 2000 and 2006 in two Dutch university hospitals were included. Presence of HPV in a tumour tissue specimen was tested by p16-immunostaining followed by HPV DNA GP5+/6+polymerase chain reaction (PCR). The presence and intensity of tumour CSC markers CD44 and CD98 were determined by immunohistochemistry and semiquantitative scoring was performed. Overall survival (OS) and progression-free survival (PFS) rates were compared between patients with low and high CD44/CD98 expression in relation to HPV status.ResultsHPV-positive tumours showed a lower percentage of cells with CD44 and CD98 expression than HPV-negative tumours (p < 0.001, χ²-test). Within the group of patients with HPV-positive OPSCC, a high percentage of CD98-positive tumour cells was associated with a significantly worse 5-year OS and PFS (OS: 36.4% and PFS: 27.3%) compared to patients with a low percentage of CD98-positive cells (OS: 71.9% and PFS: 70.5%, respectively) (p < 0.001).ConclusionsHPV-positive OPSCCs harbour fewer cells expressing the CSC enrichment markers CD44 and CD98. Furthermore, OS and PFS were significantly worse for patients with HPV-positive OPSCC with a high percentage of CD98-positive cells.     

Preoperative paclitaxel/carboplatin radiochemotherapy for stage III/IV resectable oral and oropharyngeal cancer: seven-year follow-up of a phase II trial

Numerous treatment concepts for advanced but resectable oral and oropharyngeal squamous cell carcinoma exist. In this study, we present the 7-year results of a promising treatment with preoperative simultaneous chemoradiation using paclitaxel and carboplatin within a prospective phase II trial comprising 56 patients. After determination of the local tumor extension, chemoradiation was applied for 4 weeks and up to 40 Gy. Following a recovery period of 3-4 weeks, tumor resection was performed within the initially tattooed resection margins, together with a functional modified neck dissection. The median follow-up time was 44.9 +/- 19.6 months (range 0.76-87.9). After 7 years, 35 (63.3%) patients were alive and 20 (36.4%) had died. In 2 patients (3.6%), the cause of death was related to treatment. After 7 years, the overall survival rate declined to 63.6%, whereas the local recurrence-free probability was still 84.2%. These results confirm the excellent local control and high survival rates of preoperative radiochemotherapy with the combination of paclitaxel/carboplatin.     

Gemcitabine in advanced pancreatic cancer: a phase II trial

The 5-year survival for pancreatic cancer is usually less than 5%, and no treatment has demonstrated consistent effect on patient survival and disease-related symptoms. Early studies with gemcitabine suggested a modest antitumor activity with significant improvement in disease-related symptoms. This phase II study reports the activity of gemcitabine on 33 consecutive patients with unresectable pancreatic carcinoma. Twenty-three patients had metastatic and 10 locally advanced unresectable disease. Twenty-six patients had not received any previous treatment and seven had received first-line chemotherapy with 5-fluorouracil. Gemcitabine 1,000 mg/m2 was administered intravenously in 30 minutes in the first cycle once weekly for up to 7 weeks followed by 1 week rest; then in subsequent cycles, once weekly for 3 of every 4-week cycle. Four patients obtained partial response (12%). Fifteen patients (45%) had stable disease with a median duration of 32 weeks (range: 16-75 weeks), and 14 patients experienced progressive disease. Median duration of response was 34.5 weeks (range: 19-50 weeks). Median survival was 33 weeks (range: 2-91 weeks). All 4 responding patients and 14 of 15 (93%) patients with stable disease had improvement in performance status and decrease in daily analgesic requirement. Toxicity was mild and mainly consisted of moderate and rapidly reversible myelosuppression. We conclude that gemcitabine chemotherapy was very well tolerated and determined a significant clinical improvement with modest antitumoral activity in patients with advanced pancreatic cancer.     

Recombinant human interleukin 6 in metastatic renal cell cancer: a phase II trial.

A phase II trial investigating the anti-tumour effects of recombinant human interleukin 6 (rhIL-6) in patients with metastatic renal cell cancer was carried out. RhIL-6 (150 microgram) was administered as a daily subcutaneous injection for 42 consecutive days on an outpatient basis. Forty-nine patients were studied, 12 with and 37 without previous immunotherapy. Forty patients were evaluable for response. A partial remission was noted in two patients, stable disease in 17 and progressive disease in 21. Toxicity was moderate and reversible and consisted mainly of fever, flu-like symptoms, nausea, weight loss and hepatotoxicity. Anaemia, leucocytosis and thrombocytosis and induction of acute phase protein synthesis were noted in most patients. In 15% of the patients anti-IL-6 antibodies developed, and were neutralising in only one patient. Baseline plasma IL-6 concentrations did not correlate with tumour behaviour before or after rhIL-6 treatment. In conclusion, rhIL-6 can be safely administered on an outpatient basis for prolonged period of time and has moderate, reversible toxicity. Its administration induces IL-6-antibody production in only a minority of patients. Antitmour effects of rhIL-6 in metastatic renal cancer are limited.     

Verapamil with mitoxantrone for advanced ovarian cancer: a negative phase II trial

Fourteen patients with advanced epithelial ovarian cancer were treated with oral verapamil 240 to 480 mg daily for 3 days and intravenous mitoxantrone 12 to 14 mg/m2 on the second days of verapamil administration. Courses were repeated at 21 day intervals to a maximum of 4 courses. Most patients had cancers refractory to prior cisplatin or carboplatin, or had cancers which recurred quickly after such treatments. This poor prognostic profile of patients probably accounted for the lack of objective responses to verapamil plus mitoxantrone. Despite maximally tolerated daily oral verapamil doses (480 mg daily) our inability to achieve in vivo levels of verapamil that in vitro have an optimum cytotoxic potentiating effect mitigate against further clinical exploration of verapamil as a sole enhancing agent.     

Induction chemotherapy and concurrent chemoradiotherapy for locoregionally advanced head and neck cancer: a multi-institutional phase II trial investigating three radiotherapy dose levels

BackgroundWe hypothesized induction chemotherapy (IndCT) would improve distant control (DC) without compromising locoregional control (LRC) for locoregionally advanced head and neck cancer patients. Additionally, we systematically lowered radiotherapy (RT) doses attempting to maintain LRC while decreasing toxicity.Patients and methodsStages III–IV (M0) locoregionally advanced head and neck cancer patients received carboplatin/paclitaxel (Taxol) IndCT followed by four or five cycles consisting of 5 days of paclitaxel, fluorouracil, hydroxyurea, and BID RT followed by a nine day break. RT dose to gross disease (high risk), intermediate, and low-risk volumes were reduced from cohort A (n = 68): 75, 60, and 45 Gy; to cohort B (n = 64): 75, 54, and 39 Gy; then cohort C (n = 90): 72, 51, and 36 Gy.ResultsA total of 222 patients accrued from November 1998 to September 2002. Median follow-up is 56 months. In all, 93/96/76% achieved a complete response to concurrent chemoradiotherapy (CRT) in cohort A/B/C. Three- and 5-year overall survivals (OSs) are 68% and 62%, respectively. Five-year LRC and DC are 91% and 87%, respectively. Response to IndCT predicted for OS, LRC, and time to progression (TTP). Cohort C patients had similar OS (P = 0.95), LRC, and DC, but worse (TTP) (P = 0.027).ConclusionsIndCT before CRT reduces distant progression while maintaining high LRC. The cohort B schedule provides the best therapeutic ratio. A randomized trial investigating IndCT before CRT has been initiated.     

Treatment of metastatic breast cancer with AZQ: a phase II trial

Seventeen patients with metastatic breast cancer who had failed prior chemotherapy were treated with intravenous AZQ at a dose of 15-20 mg/m2 weekly for four consecutive weeks followed by a two-week rest period. No responses were observed. Myelosuppression was the dose-limiting toxicity. One patient experienced massive liver infarction possibly related to AZQ. Our data suggest that this agent at the schedule and dosage used is of no benefit in pretreated breast cancer patients.     

Maximum tolerated dose in a phase I trial on adaptive dose painting by numbers for head and neck cancer

Purpose

To determine the maximum tolerated dose (MTD) in a phase I trial on adaptive dose-painting-by-numbers (DPBN) for non-metastatic head and neck cancer.

Materials and methods

Adaptive intensity-modulated radiotherapy was based on voxel intensity of pre-treatment and per-treatment [¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (¹⁸F-FDG-PET) scans. Dose was escalated to a median total dose of 80.9 Gy in the high-dose clinical target volume (dose level I) and 85.9 Gy in the gross tumor volume (dose level II). The MTD would be reached, if ?33% of patients developed any grade ?4 toxicity (DLT) up to 3 months follow-up.

Results

Between February 2007 and August 2009, seven patients at dose level I and 14 at dose level II were treated. All patients completed treatment without interruption. At a median follow-up for surviving patients of 38 (dose level I) and 22 months (dose level II) there was no grade ?4 toxicity during treatment and follow-up but six cases of mucosal ulcers at latency of 4-10 months, of which five (36%) were observed at dose level II. Mucosal ulcers healed spontaneously in four patients.

Conclusions

Considering late mucosal ulcers as DLT, the MTD of a median dose of 80.9 Gy has been reached in our trial.     

Radical radiation therapy for oligometastatic breast cancer: Results of a prospective phase II trial

Background and purpose

We conducted a prospective phase II multicentric trial to determine if radical radiation therapy to all metastatic sites might improve the progression-free survival (PFS) in oligometastatic breast cancer patients. Secondary endpoints were local control (LC), overall survival (OS) and toxicity.

Management of human papillomavirus-positive and human papillomavirus-negative head and neck cancer

A subset of squamous cell carcinomas of the head and neck is now known to be caused by oncogenic human papillomavirus (HPV) infection. Viral-associated malignancies arise predominantly from the oropharynx and are generally more responsive to treatment compared with non-HPV squamous cell head and neck carcinomas. Although many patients with HPV-positive disease lack the traditional risk factors of tobacco and alcohol use, retrospective recursive partitioning analysis indicates that patients with a >10 pack-year smoking history and HPV-positive disease may be at intermediate risk for survival. This warrants further study in a prospective clinical trial. Thus, current clinical trials that are being designed to study curative treatment regimens, such as transoral surgery or combinations of radiation with systemic therapy, are being developed separately for HPV-positive and HPV-negative disease with attention to tobacco history. This review will discuss some of the ongoing research efforts for HPV-positive and HPV-negative head and neck carcinomas.     

Tegafur and uracil plus leucovorin in advanced colorectal cancer: a phase II trial

The objective of this study was to evaluate the activity and toxicity of tegafur and uracil (UFT; 1:4 molar ratio) plus leucovorin (LV) in patients with advanced colorectal cancer. One hundred forty-one patients were entered into the study. The treatment schedule consisted of UFT 300 mg/m2/day (in three divided doses) plus oral LV 150 mg/day (50 mg t.i.d.) over 28 days. The treatment cycle was repeated every 5 weeks until progression or unacceptable toxicity was observed. The treatment was interrupted if grade 3/4 toxicity appeared and was resumed at the same dosage on recovery. One hundred thirty-six patients were evaluable for response and 141 were evaluable for toxicity. The response rate was 19.9% (95% confidence interval: 12%-28%). The total number of patients without progression (objective response + stable disease) was 76 (55.9%). The median time to progression was 5.6 months, and the overall survival was 11.6 months. The toxicity profile was low, with 11% of patients experiencing grade 3/4 nausea and vomiting, while 17% had grade 3/4 diarrhea. Oral administration of UFT modulated with LV is a comfortable regimen of chemotherapy for patients with advanced colorectal cancer.     

Preoperative radiochemotherapy in rectal cancer: long-term results of a phase II trial

PURPOSE: To assess toxicity and long-term results of preoperative chemoradiotherapy in rectal cancer. METHODS AND MATERIALS: Between 1989 and 1997, as a phase II study, 66 patients with T3 M0, rectal cancer received preoperatively a 45 Gy dose pelvic radiotherapy (XRT) combined with two 5-day chemotherapy courses (CT) of 5-Fluorouracil (5-FU) and Leucovorin (LV) delivered the first and fifth week of XRT. For each CT course, LV:20 mg/m2/d1-d5,. While the 5-FU dose was variable from 450 to 350 mg/m2/d first course and 370 to 350 mg/m2/d second course. Surgery was planned 3 weeks later. RESULTS: XRT-CT was stopped in 1 patient due to progressive disease. CT was stopped in 1 patient due to toxicity. Grades 2 and 3 diarrhea were observed in 8 and 3 patients, respectively. One patient died from acute diarrhea due to deviation from recommendations; 60 patients went to surgery. Among the 58 patients operated on for cure, 5 had an R1-resection. After a 4.5-year median follow-up, the 5-year pelvic disease-free survival was 92% for the whole group and 96% in the R0-resection group. CONCLUSION: Preoperative combined XRT-5-FU-LV is feasible if optimal XRT and patients are carefully managed. The recommended 5-FU daily dose is 350 mg/m2 for both CT courses. This approach is currently tested in a large EORTC phase III trial.     

Gemcitabine plus epirubicin in advanced pancreatic cancer: a phase II multicenter trial

The aim of this phase II multicenter trial was to evaluate the activity of a novel combination of gemcitabine (GEM) and epirubicin (EPI) in advanced pancreatic cancer patients. Clinical benefit and response rate were the main efficacy end-points. From December 1997 to October 1999, 30 consecutive patients with measurable advanced pancreatic cancer were enrolled. Gemcitabine was administered intravenously in 30 min at a dose of 800 mg/m2 on days 1, 8, 15 followed by i.v. injection of epirubicin 25 mg/m(2); treatment was repeated every 28 days. With regard to clinical benefit response, 8/21 patients (38%) experienced significant palliation of tumor-related symptoms; the median symptom control time was 25 weeks. No complete responses were recorded while 6 patients achieved a partial remission, for an overall response rate of 20%; 10 patients (30%) had a stable disease and 14 (46%) had progressive disease. The median time to progression was 14 weeks. Median survival was 26 weeks, with 6 patients (20%) having long-term survival at 46 weeks. In general, chemotherapy was well tolerated; 9 patients (30%) suffered from WHO grade 3-4 haematological toxicity and 5 patients (16.6%) suffered from grade 3 non-haematological toxicity. In conclusion, the GEM plus EPI regimen represent a feasible approach for improvement of clinical benefit in advanced pancreatic cancer patients, but confirmatory investigations are required.