OPTIMA: a phase II dose and volume de-escalation trial for human papillomavirus-positive oropharyngeal cancer.

BACKGROUND: Patients with HPV+ oropharyngeal squamous cell carcinoma were assigned to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy (CRT) based on response to induction chemotherapy in an effort to limit treatment-related toxicity while preserving efficacy. PATIENTS AND METHODS: Patients were classified as low-risk (≤T3, ≤N2B, ≤10 pack-year history) or high-risk (T4 or ≥N2C or >10 PYH). After three cycles of carboplatin/nab-paclitaxel, response was assessed using Response Evaluation Criteria in Solid Tumors 1.1. Low-risk patients with ≥50% response received 50 Gray (Gy) RT (RT50) while low-risk patients with 30%-50% response or high-risk patients with ≥50% response received 45 Gy CRT (CRT45). Patients with lesser response received standard-of-care 75 Gy CRT (CRT75). RT/CRT was limited to the first echelon of uninvolved nodes. The primary end point was 2-year progression-free survival compared with a historic control of 85%. Secondary end points included overall survival and toxicity. RESULTS: Sixty-two patients (28 low risk/34 high risk) were enrolled. Of low-risk patients, 71% received RT50 while 21% received CRT45. Of high-risk patients, 71% received CRT45. With a median follow-up of 29 months, 2-year PFS and OS were 95% and 100% for low-risk patients and 94% and 97% for high-risk patients, respectively. The overall 2-year PFS was 94.5% and within the 11% noninferiority margin for the historic control. Grade 3+ mucositis occurred in 30%, 63%, and 91% of the RT50, CRT45, and CRT75 groups, respectively (P = 0.004). Rates of any PEG-tube use were 0%, 31%, and 82% for RT50, CRT45, and CRT75 groups, respectively (P < 0.0001). CONCLUSIONS: Induction chemotherapy with response and risk-stratified dose and volume de-escalated RT/CRT for HPV+ OPSCC is associated with favorable oncologic outcomes and reduced acute and chronic toxicity. Further evaluation of induction-based de-escalation in large multicenter studies is justified. CLINICAL TRIAL REGISTRATION: Clinical trials.gov identifier: NCT02258659.

Response-adapted volume de-escalation (RAVD) in locally advanced head and neck cancer.

BACKGROUND: Efforts to reduce the late toxicity associated with chemoradiation (CRT) for locally advanced head and neck squamous cell cancer (LA-HNSCC) have focused on radiotherapy (RT) dose de-escalation. In this phase I/II protocol investigating the addition of everolimus to induction chemotherapy (IC), we incorporated a novel response-adapted volume de-escalation (RAVD) approach using IC response to guide the extent of RT volume reduction. PATIENTS AND METHODS: Patients with measurable LA-HNSCC received two cycles of IC (cisplatin, paclitaxel, cetuximab ± everolimus). Patients with ≥50% reduction in the sum of tumor diameters [good response (GR)] received TFHX (paclitaxel, fluorouracil, hydroxyurea, and 1.5 Gy twice daily RT every other week) to a dose of 75 Gy with the single planning target volume (PTV1) encompassing exclusively gross disease. Patients with <50% response [non-response (NR)] were treated with TFHX encompassing PTV1 and the next nodal station at risk (PTV2) to a dose of 45 Gy followed by a sequential boost to PTV1 to a dose of 75 Gy. RESULTS: Ninety-four patients were enrolled. Randomization to everolimus was discontinued on interim analysis after 50 patients due to futility. IC response was evaluable in 89 patients. Thirty-seven patients (41.6%) had GR and 52 (58.4%) had NR. There was a trend for improved progression-free (P = 0.086) but not overall survival (P = 0.94) for GR versus NR. The 2-year PFS and OS were 86.0% and 83.5% for GR and 68.7% and 85.4% for NR, respectively. NR were significantly more likely to undergo G-tube placement during treatment (50.0% GR versus 73.5% NR, P = 0.040) and be G-tube dependent at 6-month follow-up (5.7% GR versus 32.6% NR, P = 0.005). CONCLUSIONS: The addition of everolimus to IC was not beneficial. The elimination of elective nodal coverage in patients with GR to IC did not appear to compromise outcomes and resulted in significantly decreased late toxicity. Further investigation of RAVD is warranted. CLINICALTRIALSGOV: NCT01133678.

Comparison of outcomes of locoregionally advanced oropharyngeal and non-oropharyngeal squamous cell carcinoma over two decades.

BACKGROUND: Human papillomavirus (HPV) has emerged as a causative agent and positive prognostic factor for oropharyngeal (OP) head and neck squamous cell cancer (HNSCC). This prompts inquiry into whether therapy improvements or increasing incidence of HPV drives the apparent improvements in HNSCC outcomes observed in non-randomized clinical trials. PATIENTS AND METHODS: We reviewed all locoregionally advanced HNSCC patients treated with chemotherapy and radiation in prospective institutional trials at a single institution. Patients were divided into three groups (1, 2, 3) according to treatment time period (1993-1998, 1999-2003, 2004-2010, respectively). We reasoned that if a favorable trend was observed over time in OP but not non-OP patients, HPV status may be confounding treatment effects, whereas this would be unlikely if both subgroups improved over time. RESULTS: Four hundred and twenty-two patients were identified with OP (55.7%) and non-OP (44.3%) HNSCC. Five-year OP overall survival (OS) improved from 42.3% (group 1) to 72.5% (group 2), and 78.4% (group 3), adjusted P = 0.0084. Non-OP 5-year OS was 51.0% (group 1), 58.8% (group 2), and 66.3% (group 3), adjusted P = 0.51. Five-year recurrence-free survival (RFS) improved for OP groups from 42.3% to 68.4% to 75.8% (adjusted P = 0.017). Non-OP 5-year RFS was 42.9%, 53.6%, and 61.7% for sequential groups (adjusted P = 0.30). Five-year OP distant failure-free survival (DFFS) improved from 42.3% to 71.1% to 77.8% (adjusted P = 0.011). Five-year non-OP DFFS was 46.9%, 57.1%, and 66.0% for sequential groups (adjusted P = 0.38). CONCLUSIONS: Over the past two decades, OP HNSCC outcomes improved significantly, while non-OP outcomes only trended toward improvement. Although our patients are not stratified by HPV status, improving OP outcomes are likely at least partly due to the increasing HPV incidence. These data further justify trial stratification by HPV status, investigations of novel approaches for carcinogen-related HNSCC, and current de-intensification for HPV-related HNSCC.

Outcomes of induction chemotherapy followed by concurrent chemoradiation for nasopharyngeal carcinoma.

PURPOSE: Current standard therapy for nasopharyngeal carcinoma (NPC) is concurrent chemoradiation based on randomized data. However, limited randomized data exist to support the addition of induction chemotherapy (ICT). METHODS: 58 Patients with NPC were treated from 1990 to 2010. All patients received platinum-based ICT. All 58 patients were treated with chemoradiation, 57 in a week-on/week-off (WOWO) fashion. Concurrent chemotherapy included hydroxyurea/5-fluorouracil for all patients. Median radiation dose was 70 Gy. No patient received adjuvant chemotherapy. RESULTS: AJCC 2009 stage was II=13, III=21, IVa=13, and IVb=11. Median follow-up for surviving patients was 66 months. Response to ICT was complete response (CR) 17% and partial response (PR) 64%. The CR rate after chemoradiation was 96%. Five-year actuarial freedom from local failure (FFLF), freedom from distant failure (FFDF), cause-specific survival (CSS), and overall survival (OS) was 98%, 90%, 90%, and 76%, respectively. Analysis of pediatric patients (n=9) demonstrated 5-year actuarial FFLF, FFDF, CSS, and OS of 100%, 88%, 80%, and 80%, respectively. CONCLUSIONS: ICT followed by concurrent chemoradiation demonstrates excellent FFLF, FFDF, CSS, and OS with tolerable toxicity. Induction chemotherapy followed by concurrent chemoradiation for patients with NPC should be explored further in a randomized setting.

Pathologic response rates following definitive dose image-guided chemoradiotherapy and resection for locally advanced non-small cell lung cancer.

INTRODUCTION: Treatment of technically operable, medically fit locoregionally advanced non-small cell lung cancer (NSCLC) patients is a controversial therapeutic challenge. Our group routinely uses a trimodality approach. Recent advances in radiotherapy allow for improved tumor targeting and daily patient positioning. We hypothesized that these technologies would improve pathologic response rates. We analyzed consecutively treated stage IIIA/IIIB NSCLC patients undergoing chemoradiotherapy before major lung resection, with particular attention paid to the impact of advanced technologies. METHODS: Locoregionally advanced NSCLC patients (N2) staged in a multidisciplinary forum with mediastinoscopy were planned to receive platinum-based chemotherapy and 60Gy and major lung resection. Four-dimensional CT (4DCT) and image-guided radiotherapy (IGRT) were used as available. Survival endpoints were estimated using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using Cox proportional hazards models. RESULTS: We identified 53 patients from 2/1999 to 2/2010. Median RT dose was 59Gy. 68% underwent lobectomy. Forty-three patients were downstaged pathologically (81%), 38 experienced mediastinal sterilization (72%), and 21 (40%) had complete pathologic response (pCR). 1 and 2 year OS were 85.5% and 61.6%. Superior OS and DFS were associated with nodal downstaging and mediastinal sterilization (pN0). Treatment with IGRT/4DCT in 10 patients resulted in high rates of nodal downstaging (100% vs 77%, p=0.0452), mediastinal sterilization (90% vs 67%, p=0.0769), and pCR (60% vs 35%, p=0.0728). CONCLUSIONS: In selected patients, definitive dose CRT followed by major lung resection results in promising DFS and OS. The use of advanced radiotherapy techniques (4DCT and IGRT) appears to result in promising pathologic response rates.

A randomized phase II study of 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy compared with bevacizumab plus 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy for intermediate-stage and T4N0-1 head and neck cancers.

INTRODUCTION: We conducted a randomized phase II study to evaluate the impact of adding bevacizumab (B) to 5-fluorouracil (5-FU), hydroxyurea (HU), and radiotherapy (FHX) for intermediate-stage and select T4 head and neck squamous cell cancers (HNSCC). PATIENTS AND METHODS: Eligible patients had newly diagnosed HNSCC. Randomization was 2:1 in favor of BFHX. All patients received 500 mg HU p.o. b.i.d., 600 mg/m(2)/day continuous infusion 5-FU, and b.i.d. radiotherapy with or without bevacizumab 10 mg/kg administered on day 1 of each 14-day cycle. Patients received five cycles consisting of chemoradiotherapy for 5 days followed by 9 days without therapy. RESULTS: Twenty-six patients were enrolled (19 BFHX and 7 FHX). The study was halted following unexpected locoregional progression. Two-year survival was 68%; 89% treated with FHX and 58% (95% confidence interval 33% to 78%) treated with BFHX. Two-year locoregional control was 80% after chemoradiotherapy and 85% after surgical salvage. All locoregional progression occurred in T4 tumors randomized to BFHX. Two patients receiving BFHX died during therapy, and one died shortly after therapy. No catastrophic bleeding events were seen. CONCLUSIONS: Locoregional progression seen in T4N0-1 tumors treated with BFHX was unexpected and led to study termination. The addition of bevacuzimab to chemoradiotherapy for HNSCC should be limited clinical trials.

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

BACKGROUND: We 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 METHODS: Stages 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. RESULTS: A 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). CONCLUSIONS: IndCT 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.

Functional organ preservation with definitive chemoradiotherapy for T4 laryngeal squamous cell carcinoma.

BACKGROUND: Randomized trials established chemoradiotherapy as standard treatment for advanced laryngeal cancer. Patients with large-volume T4 disease (LVT4) were excluded from these trials. The purpose of this study was to report T4 laryngeal cancer patient outcome, including those with LVT4 disease, treated with chemoradiotherapy. PATIENTS AND METHODS: This study is a retrospective subset analysis of 32 patients with T4 laryngeal carcinoma including LVT4 tumors treated on three consecutive protocols investigating paclitaxel (Taxol), 5-fluorouracil, hydroxyurea, and 1.5-Gy twice daily (BID) radiotherapy (TFHX). RESULTS: Median follow-up is 43 months. Four-year locoregional control (LRC), disease-free survival (DFS), overall survival (OS), and laryngectomy-free survival (LFS) was 71%, 67%, 53%, and 86%, respectively. Four patients required laryngectomy for recurrent or persistent disease. Of disease-free patients with >or=1 year follow-up, 90% demonstrated normal or understandable speech. None required laryngectomy for complications. Among LVT4 patients, 4-year LRC, DFS, OS, and LFS was 71%, 65%, 56%, and 81%, respectively. Induction chemotherapy improved 4-year LRC (90% versus 46%, P = 0.03) and DFS (84% versus 42%, P = 0.03). CONCLUSIONS: Promising control and functional outcomes are achieved with TFHX for T4 laryngeal patients. LVT4 disease had outcomes similar to patients with less advanced disease treated on Radiation Therapy Oncology Group 91-11. Induction chemotherapy improved outcomes, warranting further investigation.

Patterns of failure, prognostic factors and survival in locoregionally advanced head and neck cancer treated with concomitant chemoradiotherapy: a 9-year, 337-patient, multi-institutional experience.

BACKGROUND: Locoregionally advanced, stage IV head and neck cancer has traditionally carried a poor prognosis. We sought to assess changes in patterns of failure, prognostic factors for recurrence, and overall outcome, using two different strategies of chemoradiotherapy conducted in prospective, multi-institutional phase II trials. PATIENTS AND METHODS: Three hundred and thirty-seven stage IV patients were treated from 1989 to 1998. We compared locoregional and distant recurrence rates, overall survival and progression-free survival from two different treatment strategies: intensive induction chemotherapy followed by split-course chemoradiotherapy (type 1, n=127), or intensified, split-course, hyperfractionated multiagent chemoradiotherapy alone (type 2, n=210). Univariate and multivariate analyses of 12 chosen covariates were assessed separately for the two study types. RESULTS: The pattern of failure varied greatly between study types 1 and 2 (5-year locoregional failure of 31% and 17% for study types 1 and 2, respectively, P=0.01; 5-year distant failure rate of 13% and 22% for study types 1 and 2, P=0.03). Combined 5-year overall survival was 47% [95% confidence interval (CI) 41% to 53%) and progression-free survival was 60% (95% CI 55% to 66%). Both treatment strategies yielded similar survival rates. Poor overall survival and distant recurrence were best predicted by advanced nodal stage. Locoregional recurrence was extremely rare for patients with T0-T3 tumor stage, regardless of lymph-node stage. CONCLUSIONS: This analysis suggests that pattern of failure in primary head and neck cancer may be dependent upon treatment strategy. Randomized clinical trials of induction chemotherapy are warranted as a means to determine if a decrease in distant metastases can lead to an increase in survival rates in the setting of effective chemoradiotherapy for locoregional control. Additionally, this analysis provides impetus for randomized clinical trials of organ preservation chemoradiotherapy in sites outside the larynx and hypopharynx.

Concurrent chemoradiotherapy for N2 or N3 squamous cell carcinoma of the head and neck from an occult primary.

BACKGROUND: Our aim was to explore the use of concurrent chemoradiotherapy in the management of patients with squamous cell carcinoma of the head and neck from an occult primary (HNCOP). PATIENTS AND METHODS: From 1991 to 2000, 25 patients with T0N2M0 or T0N3M0 HNCOP were entered into five sequential phase II clinical trials. Chemoradiotherapy consisted of a split course of radiotherapy with concurrent 5-fluorouracil and hydroxyurea either alone or with cisplatin, or paclitaxel. Two of the five protocols incorporated induction chemotherapy. RESULTS: Nodal stage was N2a in five patients (20%), N2b in 13 (52%), N2c in one (4%) and N3 in six (24%). Twenty-two patients (88%) underwent neck dissection; 14 of 22 patients underwent neck dissection before initiating protocol therapy. Total radiation doses of 55-75 Gy (median 60 Gy) were delivered; radiation fields included the potential sites of mucosal primaries and the neck bilaterally. Selected patients received a radiation boost to the involved neck. With a median follow-up of 3.9 years, three patients have progressed (one local, two distant) and seven patients have died. Deaths were due to disease progression (three) or unrelated causes (four). No metachronous primaries developed. The 5-year progression-free and overall survival was 87% and 75%, respectively. CONCLUSION: Combined-modality treatment with intensive chemoradiotherapy results in excellent disease control and long-term survival for patients with N2-N3 HNCOP and compares favorably with traditional therapy.

Induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of locoregionally advanced nasopharyngeal cancer.

BACKGROUND: Since 1990, we have treated patients with advanced nasopharyngeal cancer with induction chemotherapy and concomitant chemoradiotherapy. We herein report the results of our experience. PATIENTS AND METHODS: From 1990 to 1999, 27 patients with locoregionally advanced nasopharyngeal cancer were treated with induction chemotherapy followed by concomitant chemoradiotherapy. Using the American Joint Committee on Cancer's 1992 stage classification, all patients were stage III (11%) or IV (89%). By histology, 63% were poorly differentiated carcinoma and 37% squamous cell carcinoma. The median age was 42 years. Three cycles of induction chemotherapy consisting of cisplatin, 5-fluorouracil, leucovorin and interferon-alpha2b were administered, followed by concomitant chemoradiotherapy consisting of seven cycles of 5-fluorouracil, hydroxyurea and once-daily radiotherapy (FHX) on a week-on week-off schedule. The median radiotherapy dose was 70 Gy. RESULTS: Clinical response to induction chemotherapy was 100%, 54.2% complete response (CR) and 45.8% partial response. Clinical and/or pathological (37% of all patients had post-treatment biopsy with or without neck dissection) CR after FHX was 100%. At a median follow-up of 52 months, three failures were observed. Two patients have died of disease, one of local failure and one of distant metastases. One patient is alive with an isolated rib metastasis. At 5 years, actuarial locoregional control is 93% and actuarial distant control 92%. The overall survival at 3 and 5 years is 88% and 77%, respectively. Four patients died of unrelated illnesses and had no evidence of disease with respect to their nasopharyngeal cancer. The progression-free survival at 3 and 5 years is 92% and 86%, respectively. Thirty-three per cent of patients required a reduction in the chemotherapy dose due to acute toxicity. Chronic toxicity was not observed, with all patients able to eat orally without dietary restrictions. CONCLUSIONS: Treatment of locoregionally advanced nasopharyngeal cancer with induction chemotherapy followed by concomitant chemoradiotherapy resulted in excellent overall survival with acceptable toxicity. These results are encouraging and warrant further investigation of intensified approaches.

A phase I trial of the oral platinum analogue JM216 with concomitant radiotherapy in advanced malignancies of the chest.

JM216 is an orally administered platinum analogue. We undertook this study to determine the maximally tolerated dose (MTD) of JM216 when administered with concomitant radiotherapy to the chest (200 cGy daily, 5 x/week) in patients with locoregionally advanced non-small cell lung (NSCLC) or esophageal cancer. Patients were excluded for inadequate bone marrow reserve, prior radiotherapy to the primary tumor or previous treatment with platinum drugs. A dose-limiting toxicity (DLT) was defined using the National Cancer Institute (NCI) Common Toxicity Criteria (CTC) and consisted of grade > or = 2 renal, hepatic, cardiac, or pulmonary toxicity or grade > or = 3 hematologic, neurological, or gastrointestinal toxicity. A total of 23 patients were registered; two never received treatment and are excluded from analyses. Six patients were treated at a dose of 30 mg/m2/day for 5 days with two grade 2 DLT's: cough (1 pt) and elevated trans-aminases (1 pt). Seven evaluable patients were treated at 60 mg/m2/day and seven experienced grade 3 or 4 toxicity, five related to myelosuppression. The dose was then reduced to 45 mg/m2/d. Eight patients were evaluable for toxicity, of which 5 experienced DLT: myelosuppression (3 pts), esophagitis (2 pts), dyspnea (1 pt), and elevated creatinine (1 pt). Fourteen patients were evaluable for efficacy, of which 6 had an objective response, including one complete response. The recommended phase II dose of JM216 with concurrent radiation therapy is 30 mg/m2/d for 5 days. The major DLT is myelosuppression with only limited increased toxicity within the field of radiation. This conceivably may limit the use of JM216 as a radiation sensitizer.

Sequential induction chemotherapy and concomitant chemoradiotherapy in the management of locoregionally advanced laryngeal cancer.

PURPOSE: To determine overall survival, progression-free survival, rate of voice preservation, and patterns of failure in locoregionally advanced laryngeal cancer treated with induction chemotherapy with or without surgery followed by concomitant chemoradiation. BACKGROUND: Locoregionally advanced laryngeal cancer has been conventionally treated with either surgery and adjuvant radiotherapy or radiotherapy alone, and clinical and functional outcomes have been poor. Chemoradiotherapy has been demonstrated to improve functional outcome and disease control over conventional treatment in recent randomized head and neck trials. PATIENTS AND METHODS: Advanced head and neck cancer patients were enrolled onto two consecutive phase II studies. Induction treatment consisted of three cycles of cisplatin, 5-fluorouracil (5-FU), leucovorin, and interferon-alpha 2b (PFL-IFN) followed by surgery for residual disease. Surgical intent was to spare the larynx when possible. All patients then proceeded to concomitant chemoradiation consisting of seven or eight cycles of 5-FU, hydroxyurea, and a planned total radiotherapy dose of 7000 cGy (FHX). RESULTS: A subset of thirty-two laryngeal cancer patients with predominantly stage IV disease comprises the study group for this report. Clinical CR was observed in 59% of patients following induction therapy. The median follow-up was 63.0 months for surviving patients and 44.5 months for all patients. At five years, overall survival is 47%, progression-free survival is 78%, and locoregional control is 78%. No distant failures were observed. Voice preservation with disease control was 75% at five years. Only two total laryngectomies were performed during the course of treatment and follow-up. Treatment-related toxicity accounted for two deaths. CONCLUSIONS: The addition of concomitant chemoradiotherapy to induction chemotherapy for locoregionally advanced laryngeal cancer appears to increase locoregional control and survival rates. PFL-IFN-FHX resulted in high rates of disease cure and voice preservation in a group of patients that has traditionally fared poorly in both clinical and functional outcome.

Induction chemotherapy followed by concomitant chemoradiotherapy in the treatment of locoregionally advanced oropharyngeal cancer.

PURPOSE: Locoregionally advanced oropharyngeal cancer has been conventionally treated with either surgery and adjuvant radiotherapy or radiotherapy alone, and clinical and functional outcomes have been poor. Chemoradiotherapy has been demonstrated to improve functional outcome and disease control over conventional treatment in recent randomized head and neck trials. Herein, we report overall survival, progression-free survival, and patterns of failure in locoregionally advanced oropharyngeal cancer treated with induction chemotherapy with or without conservative surgery followed by concomitant chemoradiation. MATERIALS AND METHODS: Three cycles of induction chemotherapy consisting of cisplatin, 5-fluorouracil, leucovorin, and interferon alpha-2b (PFL-IFN) were followed by conservative, organ-sparing surgery for residual disease. All patients then proceeded to concomitant chemoradiation consisting of seven or eight cycles of 5-fluorouracil, hydroxyurea, and a total radiotherapy dose of roughly 7,000 cGy. RESULTS: Sixty-one patients with predominantly stage IV disease were treated. Clinical complete response was observed in 65% of patients after induction therapy. The median follow-up was 68.0 months for survivors and 39.0 months for all patients. At 5 years, overall survival is 51%, progression-free survival is 64%, locoregional control is 70%, and distant control is 89%. Locoregional recurrence accounted for 80% of all initial failures. Only five radical surgeries (none were total glossectomy) were performed for initial disease control. Treatment-related toxicity accounted for four deaths. CONCLUSION: PFL-IFN given with 5-fluorouracil, hydroxyurea, and radiotherapy produces a high rate of cures with organ preservation in a disease group that has traditionally fared poorly. Local and distant disease control and survival rates exceed those observed with more standard treatment approaches involving surgery and radiotherapy. Further investigation into chemoradiotherapy as a curative modality for this disease is warranted.

Concomitant infusional paclitaxel and fluorouracil, oral hydroxyurea, and hyperfractionated radiation for locally advanced squamous head and neck cancer.

PURPOSE: To improve local disease control and survival with organ preservation, we conducted a phase II multi-institutional trial with a concomitant taxane-based chemotherapy and hyperfractionated radiation regimen. PATIENTS AND METHODS: Sixty-four patients with locally advanced squamous cancers (stage IV, 98%; N2/3, 81%) were treated on an intensive regimen consisting of 5-day (120-hour) infusions of paclitaxel (20 mg/m(2)/d) and fluorouracil (600 mg/m(2)/d), oral hydroxyurea 500 mg every 12 hours for 11 doses, and radiation 1.5 Gy bid (T-FH2X). Chemoradiation was administered concomitantly on days 1 to 5 of each 14-day cycle. A full treatment course consisted of five cycles during a 10-week period to a total radiation dose of 72 to 75 Gy. RESULTS: The median follow-up for the group is 34 months. At 3 years, progression-free survival is 63%, locoregional control is 86%, and systemic control is 79%; overall survival is 60%. Seventeen patients died of recurrent cancer, two died of second primary cancers, and four died of other causes. Side effects observed include anemia (22% required transfusion), leucopenia (34%, grade 3 to 4), and mucositis (84%, grade 3 to 4). Organ preservation principles were maintained. At 1 year posttreatment, 61% of patients had severe xerostomia and 47% had compromised swallowing. There was little disturbance of speech quality in 97% of patients at the same follow-up point. CONCLUSION: T-FH2X is a highly active and tolerable concomitant chemotherapy and hyperfractionated radiation regimen that induces sustained local tumor control and holds promise for improved survival with organ preservation in high-risk patients. Identification of less toxic therapy and improved distant disease control are needed. T-FH2X should be tested in a randomized trial and compared with a less intensive concomitant regimen that uses once-daily radiation fractionation.

A phase I-II study of concomitant chemoradiotherapy with paclitaxel (one-hour infusion), 5-fluorouracil and hydroxyurea with granulocyte colony stimulating factor support for patients with poor prognosis head and neck cancer.

BACKGROUND: Concomitant chemoradiotherapy is an effective treatment modality for advanced head and neck cancer, but improved regimens are needed. We sought to define the toxicities, recommended phase II dose, and outcome of a combination chemotherapy regimen with concomitant hyperfractionated radiotherapy in patients with poor prognosis cancers of the head and neck, including those having received prior curative intent radiotherapy. PATIENTS AND METHODS: From 1995 until 1997, 54 patients were treated, 25 of whom had received a prior full course of radiotherapy to the head and neck. Patients were treated with 5-fluorouracil (5-FU) 600 mg/m2/day continuous infusion x 5 days (days 1-5), hydroxyurea, 500 mg p.o. bid x 11 doses (days 1-6) and paclitaxel (60-150 mg/m2) by one-hour infusion on day 2 using a dose escalation strategy. Radiotherapy was given concomitantly on days 2-6, 150 cGy bid. Each of 4-5 cycles was delivered every other week. RESULTS: The MTD of paclitaxel was 100 mg/m2. The regimen was feasible; radiotherapy was delivered at a median of 7300 cGy and 83% of patients received > or = 80% planned dose intensity. Hematological toxicity, with granulocyte colony stimulating factor, was very mild. Dose limiting toxicities were mucositis and dermatitis. Despite poor prognosis, two-year survival was 45%. CONCLUSIONS: The recommended phase II dose of this regimen is 5-FU 600 mg/m2/day x 120 hours (days 1-5), hydroxyurea 500 mg p.o. b.i.d. x 11 doses (days 1-6), paclitaxel 100 mg/m2 over one hour on day 2, and radiotherapy 150 cGy b.i.d. days 2-6. Concomitant chemotherapy and re-irradiation was feasible on this protocol and resulted in long-term survival in patients without other curative intent options.

The role of cervical lymphadenectomy after aggressive concomitant chemoradiotherapy: the feasibility of selective neck dissection.

OBJECTIVES: To evaluate the necessity, technical feasibility, and complication rate of neck dissection performed on patients with head and neck cancer after 5 cycles of concomitant chemoradiotherapy (CRT) and to justify a selective neck dissection (SND) approach and define the optimal timing of post-CRT neck dissection. DESIGN AND SETTING: Retrospective analysis in an academic university medical center. PATIENTS: Sixty-nine eligible patients with advanced (stage III and IV) head and neck cancer who have undergone 1 of 4 CRT protocols. Patients ranged in age from 36 to 75 years, and surgical procedures were performed over a 4-year period. Follow-up ranged from 6 to 64 months. INTERVENTION: Neck dissection (most commonly unilateral SND) performed within 5 to 17 weeks after CRT completion. MAIN OUTCOME MEASURES: Complication rate and incidence of positive pathology (viable cancer) in pathologic neck dissection specimens. RESULTS: Seven (10%) of 69 patients developed wound healing complications, 4 (6%) of whom required surgical intervention for ultimate closure. There were no wound infections. Other complications occurred in 11 (16%) of 69 patients and included need for tracheotomy, nerve transection and paresis, and permanent hypocalcemia. Twenty-four (35%) of 69 patients revealed microscopic residual disease. Ten (50%) of 20 patients with N3 neck disease had positive pathology, whereas 14 (36%) of 39 patients with N2 disease had viable carcinoma in the dissection specimen (P =.09 by chi(2) analysis). There was no significant relation between radiologic complete response or partial response and residual microscopic cancer. In 1 patient, disease recurred in the neck after dissection. Mean follow-up time was 30.3 months. CONCLUSIONS: (1) Neck dissection for patients with N2 or greater neck disease after CRT is necessary to eradicate residual disease. (2) The complication rate of SND after CRT with hyperfractionated radiotherapy is low. (3) SNDs are technically feasible when performed within the "window" between the acute and chronic CRT injury (4-12 weeks). (4) SNDs, rather than more radical procedures, appear to be therapeutically appropriate in this group of patients because of the low incidence of disease recurrence in the neck.

The use of concurrent chemotherapy and radiotherapy for locoregionally advanced head and neck cancer.

The long-term prognosis of patients with advanced head and neck cancer has been poor. Combined modality approaches, such as induction chemotherapy, adjuvant chemotherapy, and concomitant chemoradiotherapy, have been studied in an effort to control local tumor and reduce systemic tumor dissemination. Randomized clinical trials and meta-analyses have both demonstrated a survival benefit with concomitant chemoradiotherapy, despite the omission of surgery. Because of both direct and indirect toxicities of concomitant chemoradiotherapy, less-toxic and equally effective strategies are being investigated. Concurrent chemoradiotherapy should be considered a possible standard therapy option for head and neck cancer patients and should be administered at treatment centers with experienced health care providers who have access to clinical trials.

Concomitant chemoradiotherapy as primary therapy for locoregionally advanced head and neck cancer.

PURPOSE: To achieve locoregional control of head and neck cancer, survival, and organ preservation using intensive concomitant chemoradiotherapy. PATIENTS AND METHODS: This study was a phase II trial of chemoradiotherapy with cisplatin 100 mg/m(2) every 28 days, infusional fluorouracil 800 mg/m(2)/d for 5 days, hydroxyurea 1 g orally every 12 hours for 11 doses, and radiotherapy twice daily at 1.5 Gy/fraction on days 1 through 5 (total dose, 15 Gy). Five days of treatment were followed by 9 days of rest, during which time patients received granulocyte colony-stimulating factor. Five cycles (three with cisplatin) were administered over 10 weeks (total radiotherapy dose, locoregional). Surgery after concomitant chemoradiotherapy is feasible. Compliance with adjuvant chemoprevention is poor. Identification of less toxic regimens and improved distant disease control emerge as important future research goals.