Topotecan in colorectal cancer: A phase II study of the EORTC early clinical trials group

Background: This phase II study with the topoisomerase I inhibitortopotecan was performed to determine its clinical activity andtoxicity in patients with metastatic or locally unresectablecolorectal cancer Patients and methods: Topotecan 1.5 mg/m² was administered intravenouslyby 30-minute infusion for 5 days. Fifty-nine patients enteredthe study, 2 were considered ineligible and 57 were evaluablefor response and toxicity Results: Partial response was obtained in 4 of 57 evaluablepatients (7%). The median duration of the response was 11 months(range 9.3 to 12.2). This topotecan regimen was very well tolerated.A total of 290 courses were given, with a median of 4 coursesper patient (range, 1 to 18). The major toxic effects were leuko-and neutropenia (91%), grade 3–4 in 48% and 79% of courses,respectively, but with only 2 infectious complications. Otherside effects were grade 1 alopecia (77%) in 46%, nausea (35%),vomiting (10%), and maculo-papular rash (6%) Conclusions: Topotecan administered as a daily-times-five regimenhas only minor activity as a single-agent therapy in colorectalcancer phase II, topotecan, colorectal cancer     

N-(Phosphonacetyl)-l-aspartate (PALA) in advanced breast cancer: a phase II trial of the EORTC breast cancer cooperative group

Twenty-nine evaluable patients with extensively pretreated breast cancer received PALA, a new pyrimidine antimetabolite. The drug was given by intravenous infusion over 60 min, at a daily dose of 2.5 g/m² for 2 consecutive days. Courses were repeated at 2-week intervals and doses were escalated to toxicity. Two objective partial remissions were observed, lasting for 3 and 4.5 months respectively. Toxic effects were dose-related and consisted mainly of mucocutaneous manifestations, i.e., skin rashes, stomatitis, diarrhea, conjunctivitis and corneal ulcerations. Evidence of antitumor potential in far-advanced disease and lack of myelosuppression point to the need for additional trials of PALA in a more favorable selection of patients with breast cancer.     

Treatment of advanced gastric cancer with the combination fluorouracil,leucovorin, etoposide,and cisplatin: a phase II study of the ONCOPAZ cooperative group

A phase II study was performed to assess the efficacy and toxicity of the combination of 5-fluorouracil (5-FU), leucovorin (LV), etoposide, and cisplatin (FLEP) in patients with advanced gastric carcinoma. A total of 46 consecutive, previously untreated patients with unresectable, measurable gastric carcinoma were treated with 300 mg/m² LV, 100 mg/m² etoposide, 500 mg/m² 5-FU, and 30 mg/m² cisplatin on days 1–3 every 28 days. All courses were given on an outpatient basis. A total of 169 courses of treatment were given. In all, 18 of the 46 patients (39%) had an objective response [95% confidence interval (CI), 25%–54%] and 2 (4%) patients experienced a clinical complete response. The median duration of response was 5 months. The main side effects were hematological and gastrointestinal. Grade 3–4 toxicity was encountered as follows: leukopenia, in 9.5% of the courses; anemia, in 3%; thrombocytopenia, in 3%; nausea/vomiting, in 4%; and diarrhea, in 5%. Hospitalization due to fever and granulocytopenia was required in 5 patients, 3 of whom died of sepsis. In conclusion, FLEP shows moderate activity in patients with advanced gastric carcinoma, albeit at the cost of a high degree of toxicity. For this reason we do not recommend its use.     

Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer

To grow and metastasize, solid tumours must develop their own blood supply by neo-angiogenesis. Thalidomide inhibits the processing of mRNA encoding peptide molecules including tumour necrosis factor-alpha (TNF-alpha) and the angiogenic factor vascular endothelial growth factor (VEGF). This study investigated the use of continuous low dose Thalidomide in patients with a variety of advanced malignancies. Sixty-six patients (37 women and 29 men; median age, 48 years; range 33-62 years) with advanced measurable cancer (19 ovarian, 18 renal, 17 melanoma, 12 breast cancer) received Thalidomide 100 mg orally every night until disease progression or unacceptable toxicity was encountered. Three of 18 patients with renal cancer showed partial responses and a further three patients experienced stabilization of their disease for up to 6 months. Although no objective responses were seen in the other tumour types, there were significant improvements in patients' sleeping (P < 0.05) and maintained appetite (P < 0.05). Serum and urine concentrations of basic fibroblast growth factor (bFGF), TNF-alpha and VEGF were measured during treatment and higher levels were associated with progressive disease. Thalidomide was well tolerated: Two patients developed WHO Grade 2 peripheral neuropathy and eight patients developed WHO grade 2 lethargy. No patients developed WHO grade 3 or 4 toxicity. Further studies evaluating the use of Thalidomide at higher doses as a single agent for advanced renal cancer and in combination with biochemotherapy regimens are warranted.     

Phase II trial of CPT-11 in patients with advanced pancreatic cancer, an EORTC early clinical trials group study

BACKGROUND: CPT-11 (irinotecan) is a semi-synthetic derivative of camptothecinand exerts its activity by inhibiting DNA topoisomerase I. Aphase II study of this drug was performed in patients with pancreaticcancer. PATIENTS AND METHODS: Eligibility criteria included advanced non-chemotherapy-pretreatedpancreatic cancer. CPT-11 was administered as a 30-minute i.v.infusion at a dose of 350 mg/m² diluted in 250 ml normal salineevery 3 weeks. RESULTS: Thirty-four eligible patients were enrolled in the study, thirty-twoof them were evaluated, and three achieved partial responses(9%; 95% C.I. = 3%–25%). The duration of response was7.2, 7.5 and 7.8 months, respectively. Thirteen patients hadno change, fourteen patients had progressive disease and twohad early progressive disease. The median duration of survivalfor all patients treated was 5.2 months. The main toxicities(CTC grade>3) were diarrhea, leuko-cytopenia, asthenia, nauseaand vomiting in, respectively, 7%, 16%, 8%, 6%, 4% of the courses.Thse toxicities were reversible and manageable with anti-emeticsand prophylactic or curative antidiarrheal agents. CONCLUSION: CPT-11 is an interesting moderately effective drug in pancreaticcancer. CPT-11, irinotecan, pancreatic cancer     

Paclitaxel and gemcitabine in advanced non-nasopharyngeal head and neck cancer: A phase II study conducted by the Hellenic Cooperative Oncology Group

Background: Paclitaxel as monotherapy or in combination with other drugs has demonstrated significant activity in patients with squamous cell carcinoma of the head and neck region (SCCHN). Preclinical studies have shown gemcitabine to be highly active in SCCHN cell lines.Purpose of the study: To evaluate the activity and toxicity of the combination of paclitaxel by three-hour infusion and gemcitabine as first-line chemotherapy in patients with recurrent and/or metastatic head and neck cancer (HNC).Patients and methods: From September 1996 until May 1998, 44 patients with non-nasopharyngeal recurrent and/or metastatic HNC entered the study. There were 37 men and seven women with a median age of 61 years (range 35–79) and a median performance status of 1 (range 0–2). The location of the primary tumor in the majority of them was either the larynx or the oral cavity. Treatment consisted of six cycles of gemcitabine 1100 mg/m2 over 30 min on days 1 and 8 immediately followed on day 1 by paclitaxel 200 mg/m2 by three-hour infusion. The treatment was repeated every three weeks.Results: Twenty-four (55%) patients completed all six cycles of treatment. A total of 205 cycles were administered, 165 (81%) of them at full dose. The median relative dose intensity (DI) of gemcitabine was 0.93 and of paclitaxel 0.95. Except for alopecia, which was universal, grade 3–4 toxicities included neutropenia (21%), thrombocytopenia (5%), anemia (5%), infection (5%), flu-like syndrome (5%) and peripheral neuropathy (2%). Five (11%) patients achieved complete and 13 (30%) partial responses, for an overall response rate of 41%. After a median follow-up of 13 months, the median time to progression was four months and median survival nine months.Conclusions: The combination of paclitaxel and gemcitabine is active and well tolerated in patients with recurrent and/or metastatic HNC – randomized studies comparing this combination with other regimens are warranted.     

Cisplatin-based chemoradiation plus cetuximab in locally advanced head and neck cancer: a phase II clinical study

BackgroundIntensification of chemoradiation for advanced head and neck squamous cell carcinoma (HNSCC) is unlikely due to toxicity. Cetuximab combined either with radiotherapy or with chemotherapy showed favourable toxic profile with positive results in both combinations. Therefore, cetuximab could intensify chemoradiation without worsening toxicity. We conducted a phase II study of chemoradiation and cetuximab.Patients and methodsEligible patients had stage III–IV M0 HNSCC. Treatment consisted of three cycles of cisplatin (20 mg/m²/day × 5 days) and fluorouracil (200 mg/m²/day × 5 days) rapidly alternated to three split courses of radiotherapy up to 70 Gy and concurrent weekly cetuximab. The primary end point of the study was complete response (CR) rate. Secondary end points were toxicity, progression-free survival (PFS) and overall survival (OS).ResultsFourty-five patients were enrolled: median age was 56 years, 38 had stage IV disease and 40 nodal involvement. CR occurred in 32 patients (71%). PFS and OS was 21+ months and 32.6+, respectively. Acute grade 3–4 toxic effects were in the expected range, but grade 3 radiodermatitis occurred in 33 patients.ConclusionsThe combination of cetuximab, cisplatin, fluorouracil and radiotherapy leads to a very high proportion of CR and it is feasible with toxic effects similar to those expected by radiochemotherapy. The only unexpected toxicity was skin toxicity: grade 3 radiodermatitis occurred in 73% of the patients.     

Zeniplatin in advanced malignant melanoma and renal cancer: phase II studies with unexpected nephrotoxicity

The antitumor activity of zeniplatin, a third-generation, water-soluble platinum compound that has shown broad preclinical antitumor activity and no significant nephrotoxicity in phase I trials, was tested in patients with advanced malignant melanoma and advanced renal cancer. Patients who had not previously been treated, except with local limb perfusion and immunotherapy, were given zeniplatin as bolus injections at 125 mg/m² every 3 weeks. The main hematological toxicity was leukopenia (7/30 patients, WHO grade ≥ 3) and the main nonhematological toxicity was nausea and vomiting (21/30 patients, WHO grade ≥ 2). Serious nephrotoxicity was observed early in the renal cancer study and, later, also in the melanoma study. Hyperhydration did not prevent the nephrotoxicity, and the studies were stopped after 6 renal cancer patients and 24 malignant melanoma patients had been included. Zeniplatin gave objective responses in 3 of the 21 evaluable malignant melanoma patients [2 complete responses (CRs) in patients with lymph-node metastases lasted 5 and 14 months, respectively; 1 partial response (PR) in a patient with lymph-node and liver metastases lasted 6 months]. In the renal cancer study, only four patients were evaluable for response and none responded. The results show that zeniplatin has some activity (14%) in patients with advanced malignant melanoma, but no conclusion can be drawn regarding the activity of zeniplatin in renal cancer as the number of patients was too low. The main toxicities were leukopenia and nausea and vomiting. Unexpected and serious nephrotoxicity was observed, and for this reason the studies were terminated before the planned number of patients had been included. A possible explanation for the nephrotoxicity may be drug interactions, but no firm conclusion can yet be drawn. Received: 16 March 1996 / Accepted: 25 March 1997     

A late phase II clinical study of RP56976 (docetaxel) in patients with advanced or recurrent gastric cancer: a cooperative study group trial (group B)

A late phase II clinical study of RP56976 (docetaxel) in patients with advanced or recurrent gastric cancer was performed to evaluate the anti-tumor activity and clinical toxicity as a multicenter cooperative trial. Docetaxel was administered intravenously at a dose of 60 mg/m2 every 3-4 weeks. Of 72 patients enrolled, 63 patients were eligible and 59 patients were evaluable for response. The anti-tumor effects obtained complete response (CR) in one patient partial response (PR) in 13, minor response (MR) in 3, no change (NC) in 20, and progressing disease (PD) in 22 patients. The overall response rate in 59 patients was 23.7% (14/59). For 14 CR or PR cases, a response appeared 10 to 107 days (median 33.5 days) and 1 to 8 (median 2) times of dosing after the initial administration. The response rate was 9.5% in the primary tumor, 31.3% livers, 50.0% abdominal tumor, and 24.1% lymph nodes, respectively. The major adverse reactions were gastrointestinal symptoms including nausea/vomiting, anorexia, fatigue, alopecia and fever. Leukocytopenia and neutrocytopenia were also observed with a high incidence, but they recovered after 8 days from the nadir. The results show that docetaxel is an effective anti-tumor agent for advanced or recurrent gastric cancer. It is necessary to conduct another clinical trial by concomitant administration with other anti-tumor agents.     

Teniposide (VM-26) in patients with advanced refractory ovarian cancer: a phase II study of the Netherlands joint study group for ovarian cancer

In 23 evaluable patients with advanced ovarian epithelial cancer refractory to combination therapy with cisplatin and an alkylating agent, teniposide (VM-26) was administered as a short-term i.v. infusion at a dose of 100 mg/m² on days 1 and 2, every 3 weeks. Toxocity was moderate and comparable to the pattern known from other studies. No objective response has been observed, showing that teniposide is not active as second-line therapy in this disease.     

Multi institutional phase II study of concomitant stereotactic reirradiation and cetuximab for recurrent head and neck cancer

Purpose

Recurrent head and neck cancer is associated to a poor survival prognosis. A high toxicity rate is demonstrated when surgery and/or radiotherapy and/or chemotherapy are combined. Furthermore, the duration of treatment is often not ethically compatible with the expected survival (median survival < 1 year). Normal tissues tolerance limits the use of reirradiation and stereotactic body radiotherapy (SBRT) could offer precise irradiation while sparing healthy tissues. After completion of a feasibility study, results of a multicentric study (Lille, Nancy & Nice) using SBRT with cetuximab are reported. The aim of the study was to deliver non toxic short course SBRT (2 weeks) in order to get the same local control as the one demonstrated with longer protocols.

Methods and materials

Patients with inoperable recurrent, or new primary tumor in a previously irradiated area, were included (WHO < 3). Reirradiation (RT) dose was 36 Gy in six fractions of 6 Gy to the 85% isodose line covering 95% of the PTV with 5 injections of concomitant cetuximab (CT). All patients had previous radiotherapy, 85% had previous surgery and 48% previous chemotherapy.

Results

Between 11/2007 and 08/2010, 60 were included (46 men and 14 women), 56 received CT + RT, 3 were not treated and 1 received only CT. Median age was 60 (42–87)) and all 56 patients had squamous carcinoma and received concomitant cetuximab. Mean time between previous radiotherapy and the start of SBRT was 38 months. Cutaneous toxicity was observed for 41 patients. There was one toxic death from hemorrhage and denutrition. Median follow-up was 11.4 months. At 3 months, response rate was 58.4% (95% CI: 43.2–72.4%) and disease control rate was 91.7% (95% CI: 80.0–97.7%). The one-year OS rate was 47.5% (95% CI: 30.8–62.4).

Conclusion

These results suggest that short SBRT with cetuximab is an effective salvage treatment with good response rate in this poor prognosis population with previously irradiated HNC. Treatment is feasible and, with appropriate care to limiting critical structure, acute toxicities are acceptable. This combination may be the reference treatment is this population.     

Late phase II clinical study of KW-2307 in advanced/recurrent breast cancer patients (II)

A late phase II clinical study (II) of a novel vinca alkaloid derivative KW-2307 (vinorelbine ditartrate) in advanced/recurrent breast cancer patients was performed at 22 institutions throughout Japan. An intravenous dose of KW-2307, 20 mg/m2, was administered once a week. Of the 60 patients enrolled in the study, 58 were eligible and 56 were evaluable. The response rate was 33.9% (19/56; 95% confidence interval: 21.8 to 47.8%) with one CR and 18 PRs. The response rate was as high as 37.0% (17/46; 95% confidence interval: 23.2 to 52.5%) when KW-2307 was used as a first-line chemotherapy for advanced/recurrent disease. The most common adverse event was myelosuppression including leukopenia in 96.4% (54/56) and neutropenia in 94.3% (50/53). Other events observed were increased GOT in 51.8% (29/56), increased GPT in 55.4% (31/56), LDH increased in 50.0% (27/54), serum total protein decrease in 39.3% (22/56), anorexia in 41.1% (23/56), nausea and vomiting in 66.1% (37/56), constipation in 30.4% (17/56), alopecia in 33.9% (19/56) and general fatigue in 46.4% (26/56). None of them were serious. This study demonstrated that KW-2307 was an effective and safe treatment for advanced/recurrent breast cancer patients.     

Pemetrexed and cisplatin in patients with advanced gastric cancer: a Korean cancer study group multicenter phase II study

BACKGROUND: Pemetrexed is a multitargeted antifolate enzyme inhibitor, which has activity against a variety of tumors, including advanced gastric cancer (AGC). The aim of this study was to assess efficacy and safety of pemetrexed plus cisplatin (PemCis) combination in the treatment of AGC in Korean patients. PATIENTS AND METHODS: This was a multicenter, single arm, open label study. Patients with no prior palliative chemotherapy received pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) day 1, every 3 weeks plus folic acid and vitamin B(12) supplementation. Response rate was assessed according to response evaluation criteria in solid tumors (RECIST) criteria. RESULTS: Of the 50 patients evaluable for efficacy, 13 had partial response for an overall response rate of 26% (95% CI, 14.6-40.3%) and 15 (30%) had stable disease. Median time to progression was 2.8 months (95%CI, 2.2-4.4 months), and median overall survival was 6.6 months (95% CI, 4.8-10.4 months). Of the 51 patients evaluable for safety, the most frequent NCI-CTC grade 3/4 toxicities were neutropenia in 49% of patients (25% of cycles) and anorexia in 10% of patients (4% of cycles). CONCLUSION: PemCis has a modest activity and acceptable toxicity profile in patients with AGC. Clinical trials with different combinations and dose regimens are, therefore, warranted.     

Phase II trial of anaxirone (1,2,4-triglycidylurazol,TGU) in patients with advanced ovarian carcinoma: an EORTC gynecological cancer cooperative group study

Sixteen patients with advanced ovarian carcinoma were treated with anaxirone (1,2,4-trigycidyl urazol, TGU), 600 mg/m² every 4 weeks. Anaxirone was the second or later line of therapy. All patients had evaluable tumors and evidence of failure of prior therapy. None of the patients responded. Two had stabilization of the disease for 4 months. In one patient WHO grade 4 leukopenia and grade 4 thrombocytopenia were observed after the second TGU cycle starting on day 41 and persisted until the patient died due to tumor progression (day 50). No patient experienced thrombophlebitis.     

Multicentric parallel phase II trial of the polo-like kinase 1 inhibitor BI 2536 in patients with advanced head and neck cancer,breast cancer,ovarian cancer,soft tissue sarcoma and melanoma. The first protocol of the European Organization for Research and Treatment of Cancer (EORTC) Network Of Core Institutes (NOCI)

AimsBI 2536 is a selective and potent small-molecule inhibitor of polo-like kinase 1. We performed a multi-centre, multi-tumour phase II trial to investigate the efficacy, safety and pharmacokinetics of BI 2536 in five solid tumour types.Patients and methodsPatients with advanced head and neck, breast and ovarian cancer, soft tissue sarcoma and melanoma were selected according to protocol-defined general and tumour-specific criteria. They were ?18 years old, had a good performance status, adequate bone marrow, renal and liver function, measurable progressive disease and had completed other relevant systemic treatments >4 weeks ago. BI 2536 200–250 mg was given intravenously on day 1 every 3 weeks until intolerance, progression or refusal. The study was based on a Simon two-stage design, with 12 patients entering in stage 1 and additional 25 patients to be entered in case of at least one response in the first stage. The rate of objective responses (RECIST criteria) was chosen as primary end-point.ResultsSeventy six patients were included, 71 started treatment and received a median number of two cycles (four in ovarian cancer). Frequent grade 3–4 adverse events were neutropaenia (81.6%), thrombocytopaenia (19.7%), febrile neutropaenia (19.7%), anaemia (15.5%) and pain (9.9%). We did not observe confirmed objective responses. All cohorts were closed after the entry of 14–15 eligible non-responding patients. Pharmacokinetic analyses revealed multi-compartmental behaviour and a rapid distribution of BI 2536.ConclusionsBI 2536 showed limited antitumour activity according to the design of this trial in five different tumour types. Derivatives of BI 2536 with a more favourable pharmacological profile are currently explored further in prospective studies.     

Combination chemotherapy with carboplatin and bleomycin for advanced and recurrent head and neck cancer: a phase II study

Carboplatin is a platinum analogue with activity reported in head and neck cancer. We conducted a phase II trial with 14 patients who had recurrent head and neck cancer. They were treated with carboplatin 300 mg/m2 intravenously (I.V.) and bleomycin 30 units I.V. every 4 weeks. No responses were observed in this group of patients. Dose intensity of carboplatin administration may be an important determinant of response.     

An early phase II clinical study of YM 294 (rhlL-11) in patients with solid tumors and malignant lymphoma

An early phase II study was conducted to examine the efficacy and safety of YM 294 on chemotherapy-induced thrombocytopenia in patients with solid tumors and malignant lymphoma. The response rates which were judged as having good or excellent efficacy by the investigators were 66.7% in all groups with 25 microg/kg or more, and the increase in nadir platelet counts and decrease in platelet transfusions were observed. Adverse reactions were fever, edema, abnormal electrocardiogram and weight gain. All adverse reactions as well as abnormal changes in laboratory values for which the casual relationship with the study drug could not be excluded were resolved and proved to be not serious. The results of this study suggest the efficacy of YM 294 at 25 microg/kg or more for chemotherapy-induced thrombocytopenia in patients with solid tumors and malignant lymphoma. It was considered that a study should be performed to assess the efficacy and safety of YM 294 using a dose of 25 microg/kg or more in the future.     

Ifosfamide and vinorelbine in advanced pretreated ovarian cancer: a phase II study

Purpose: The response rate to salvage chemotherapy in advanced ovarian cancer (AOC) has been disappointing in patients who do not respond or relapse after platinum-containing regimens. Ifosfamide (IFO) showed an overall response rate of 20% and vinorelbine (VNR) 15.6%. Trials of the association of these two drugs for AOC have not yet been published. Patients and methods: Between April 1996 and August 1997, 17 patients with AOC were treated with intravenous IFO 2000 mg/m² per day, days 1 to 3, with mesna uroprotection, and VNR 25 mg/m² per day, days 1 and 8, every 3 weeks. All patients but one had been heavily pretreated. All patients had been treated with platinum compounds and 16/17 with taxanes. Results: All 17 patients were evaluable for toxicity, and 16 for response (one lost to follow-up). One patient showed a partial response, 12 progressive disease and three stable disease. No complete responses were observed. The main toxicity was neutropenia (grade 3-4 in 82% of patients) with neutropenic fever in 17.6% of patients. In 70.5% of patients (19/59 of courses) VNR was not administered on day 8. In four patients (10/59 courses) the dose was reduced by 25% for persistent leukopenia grade 2-3. Other toxicities were not significant. Conclusions: This combination showed no activity in this set of patients. The poor outcome, as compared with the significant activity reported with the agents used singly, could be ascribed to the patients' characteristics, the low dose intensity of VNR administered and possible cross-resistance between the study drugs and previously used agents. Received: 1 December 1999 / Accepted: 25 January 2000     

An early phase II clinical study of cis-diammine glycolato platinum, 254-S, for head and neck cancers]

An early phase II clinical study of 254-S, a new anticancer platinum complex, for head and neck cancer was conducted by the 254-S Head and Neck Cancer Study Group consisting of 10 institutions. Based on the results obtained in the phase I study, 254-S was administered at 100 mg/m2 by 60 min intravenous drip infusion after being dissolved in 300 ml of 5% xylitol. In principle, the 254-S administration was repeated at least 2 times at 4 week intervals. Hydration was performed, if needed. All 24 cases registered were regarded as complete cases evaluable for tumor response. Complete response (CR) was observed in 4 patients (16.7%), partial response (PR) in 5 (20.8%), no change (NC) in 11 and progressive disease (PD) in 4, for a 37.5% response rate. Three CR and 3 PR (40.0%) were obtained in 15 patients with prior chemotherapy, including 1 CR and 2 PR (33.3%) in 9 patients previously treated with cisplatin. Side effects were observed in 19 patients (79.2%). Major toxic effects were hematotoxicity, including thrombocytopenia (58.3%), leukopenia (58.3%) and anemia (33.3%), and gastrointestinal toxicity, including nausea and vomiting (45.8%) and anorexia (37.5%). Abnormal parameter changes on renal function were found in 2 patients (8.3%). Based on these results, it was concluded that 254-S is potentially a useful anticancer agent for the treatment of head and neck cancer, and should be further investigated in a late phase II clinical study.     

Preoperative hyperfractionated accelerated radiotherapy and radical surgery in advanced head and neck cancer: a prospective phase II study.

BACKGROUND AND PURPOSE: To evaluate whether preoperative hyperfractionated accelerated radiotherapy (RT) combined with major radical surgery is feasible and successful in the treatment of advanced primary head and neck cancer. PATIENTS AND METHODS: Ninety four patients with histologically confirmed head and neck squamous cell cancer (HNSCC) in the oral cavity (41/96; 43%), supraglottis (14/96; 15%), glottis (5/96; 5%), oropharynx (16/96; 17%), nasal cavity/paranasal sinuses (8/96; 8%), nasopharynx (3/96; 3%), hypopharynx (7/96; 7%) and two (2%) with unknown primary tumour and large cervical lymph nodes entered into the study. 21/96 patients (22%) had stage II, 17/96 (18%) stage III and 58/96 patients (60%) stage IV disease. The patients received preoperative hyperfractionated RT 1.6 Gy twice a day, 5 days a week to a median tumour dose of 63 Gy with a planned break for 11 days (median) after the median dose of 37 Gy. Then, after a median of 27 days the patients underwent major radical surgery of the primary tumour and metastatic lymph nodes including reconstructions with pedicled or microvascular free flaps when indicated as a part of the scheduled therapy. 12/96 patients had only ipsilateral or bilateral neck dissections. RESULTS: After a median follow-up time of 37.2 mos 77/96 (80.2%) patients had complete locoregional control. All but 2 patients had complete histological remission after surgery. 40/96 pts were alive without disease, two of them after salvage surgery. 32/96 patients had relapsed; 15 had locoregional and 13 distant relapses, 4 patients relapsed both locoregionally and distantly. Fifty patients have died; 29 with locoregional and/or distant relapse, eight patients died of second malignancy, and 19 had intercurrent diseases. Disease-specific and overall survival at 3 years was 67.7 and 51%, respectively. Acute grade three mucosal reactions were common, but transient and tolerable. Late grade 3-4 adverse effects were few. CONCLUSIONS: Preoperative hyperfractionated accelerated RT can be successfully combined with major radical surgery in the treatment of HNSCC. The amount of serious late adverse effects was not increased.