Alfred W. Rademaker

Weekly Carboplatin and Paclitaxel Followed by Concomitant Paclitaxel, Fluorouracil, and Hydroxyurea Chemoradiotherapy: Curative and Organ-Preserving Therapy for Advanced Head and Neck Cancer

PURPOSEnThe paclitaxel, fluorouracil, and hydroxyurea regimen of paclitaxel, infusional fluorouracil, hydroxyurea, and twice-daily radiation therapy (TFHX) administered every other week has resulted in 3-year survival rates of 60% of stage IV patients. Locoregional and distant failure rates were 13% and 23%, respectively. To reduce distant failure rates, we added a brief course of induction chemotherapy to TFHX.nnnPATIENTS AND METHODSnSixty-nine patients received six weekly doses of carboplatin (AUC2) and paclitaxel (135 mg/m2) followed by five cycles of TFHX.nnnRESULTSnNinety-six percent had stage IV disease. Response to induction chemotherapy was partial response 52% and complete response (CR) 35%. Symptomatically, there was a significant reduction in mouth and throat pain. The most common grade 3 or 4 toxicity was neutropenia (36%). Best response following completion of TFHX was CR in 83%. Toxicities of TFHX consisted of grade 3 or 4 mucositis (74% and 2%) and dermatitis (47% and 14%). At a median follow-up of 28 months, locoregional or systemic disease progression were each noted in five patients. The overall 3-year progression-free survival was 80% (95% confidence interval [CI], 71% to 90%), and the 2- and 3-year overall survival rates were 77% (95% CI, 66% to 87%) and 70% (95% CI, 59% to 82%), respectively. At 12 months, five patients were completely feeding-tube dependent.nnnCONCLUSIONnAdministration of carboplatin and paclitaxel before TFHX chemoradiotherapy results in high response activity and may decrease distant failure rates. Overall survival, progression, and organ preservation/functional outcome data support definitive evaluation of this approach.

Concomitant Infusional Paclitaxel and Fluorouracil, Oral Hydroxyurea, and Hyperfractionated Radiation for Locally Advanced Squamous Head and Neck Cancer

PURPOSEnTo 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.nnnPATIENTS AND METHODSnSixty-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.nnnRESULTSnThe 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.nnnCONCLUSIONnT-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.

Radiation therapy with concomitant hydroxyurea and fluorouracil in stage II and III head and neck cancer

PURPOSEnIn 1986, a multi-institutional phase II trial was begun to study the use of chemotherapy with concomitant radiation in patients with stage II and III head and neck cancer. End points were overall survival, progression-free survival, local/regional control, and toxicity in the setting of organ preservation with concomitant treatment.nnnMETHODSnEligible patients with stage II or III disease received chemotherapy and radiation on a 2-week cycle. Chemotherapy consisted of continuous infusion fluorouracil (5-FU) at 800 mg/m2/d for 5 consecutive days (days 1 to 5) and hydroxyurea (HU) at 1 g orally every 12 hours for 13 doses starting the evening before the start of irradiation. Radiation therapy was given as single 1.8- to 2.0-Gy fractions for 5 consecutive days (days 1 to 5) with chemotherapy. Each 5 days of treatment was followed by a 9-day break (days 6 to 14), during which no additional treatment was given. Treatment cycles were repeated until the completion of the planned radiation dose (six to eight cycles).nnnRESULTSnBetween 1989 and 1996, 60 patients were enrolled. All patients were eligible for analysis, with a median follow-up of 52 months for surviving patients and 42 months for all patients. Grade 3 to 4 mucositis occurred in 57% of patients. The 5 year-actuarial overall survival, progression-free survival, and local/regional control were 65%, 82%, and 86%, respectively. Eight patients developed local and/or regional recurrence after treatment. Surgical salvage was possible in three of these patients. Thus, the ultimate 5-year local/ regional control was 91%.nnnCONCLUSIONnConcomitant radiation and chemotherapy with 5-FU and HU is an effective regimen in patients with stage II and III head and neck cancer. Progression-free survival and local/regional control appear to be superior to expected rates in patients treated with surgery and radiation. Further testing of this regimen in a phase III setting is indicated.

Prospective evaluation of internal adenopathy in a cohort of 43 patients with hairy cell leukemia.

PURPOSEnTo determine the role of computed tomography (CT) in patients with hairy cell leukemia (HCL), we report a series of 43 patients prospectively evaluated for internal adenopathy by CT before and after treatment with 2-chlorodeoxyadenosine (2-CdA).nnnPATIENTS AND METHODSnCT was performed on 43 consecutive patients with HCL before and 3 months after a single cycle of 2-CdA. Twenty-four patients were previously diagnosed and 19 were newly diagnosed. Adenopathy was considered bulky if the greatest dimension of any confluent mass was between 5 and 10 cm and massive if greater than 10 cm.nnnRESULTSnInternal adenopathy was present in six of 43 patients (14%). Three of the six patients had massive abdominal adenopathy and one had bulky abdominal adenopathy. All six patients with adenopathy were previously diagnosed, while none of the 19 newly diagnosed patients had internal adenopathy. In those patients previously diagnosed, the six with adenopathy had a median disease duration of 68 months, while the 18 patients without adenopathy had a median disease duration of 24 months (P = .01). Adenopathy was more common in splenectomized patients. In previously diagnosed patients, adenopathy occurred in five of 10 (50%) splenectomized patients and one of 14 (7%) nonsplenectomized patients (P = .05). However, the 10 splenectomized patients had a median disease duration of 56 months, while the 14 nonsplenectomized patients had a median disease duration of 16 months (P = .004). All six patients had significant reduction in adenopathy 3 months after 2-CdA and were without residual HCL in the bone marrow.nnnCONCLUSIONnSignificant internal adenopathy in patients with HCL is more frequent than previously recognized. Adenopathy is rare at diagnosis and appears to be related to disease duration. As patients treated with 2-CdA have long disease-free survival durations, detection of significant adenopathy by CT scan may be important; however, routine CT scans are not recommended at the time of diagnosis.

Whole-Field Sequential Intensity-Modulated Radiotherapy for Local-Regional Advanced Head-and-Neck Squamous Cell Carcinoma.

Purpose:There is little published data on the technique and results of whole-field (WF) sequential intensity–modulated radiotherapy (S-IMRT) for patients with head-and-neck squamous cell carcinoma (HNSCC). We report the treatment outcomes, adverse events (AEs), and dosimetric parameters in local-regional advanced (LRA) HNSCC patients treated with the WF S-IMRT technique. Methods:The IRB approved this retrospective study. Patients received WF S-IMRT with or without concomitant chemotherapy. Three separate IMRT plans corresponding to 3 planning target volumes were generated. This study reports patient and tumor characteristics, treatment-induced acute AEs based on CTCAE version 3.0, chronic AEs according to RTOG scale and treatment outcomes, local-regional control (LRC), distant metastases (DM), relapse-free survival (RFS), and overall survival (OS). Results:Between January 2003 and December 2010, 103 patients with LRA HNSCC were treated either definitively or postoperatively with WF S-IMRT, with (99 patients) or without (4 patients) concurrent chemotherapy. The median age was 55 years (range, 30 to 89 y). The median cumulative target dose was 70 Gy (range, 60 to 75 Gy). At a median follow-up of 40 months (range, 4 to 95 mo), the 2- and 5-year rates of OS were 94% and 77%, RFS were 90% and 84%, LRC were 97% and 93%, and DM were 9% and 11%, respectively. Grade 3 acute AEs included mucositis (68%), dysphagia (35%), weight loss (19.6%), and xerostomia (7.8%). Chronic worst grade 3 AEs included xerostomia (21.9%), weight loss (12.8%), and dysphagia (12.5%). Chronic grade 3 AEs at last follow-up included weight loss (6.25%), dysphagia (6.2%), and xerostomia (6.2%). No patient had an acute or chronic grade 4 AE, brachial plexopathy, or spinal cord injury. Conclusions:WF S-IMRT results in excellent tumor control and an acceptable toxicity profile in LRA HNSCC patients treated with this technique.

THE USEFULNESS OF TOUCH PREPARATION CYTOLOGICAL EVALUATION AND PROSTATIC CAPSULE INVOLVEMENT IN PREDICTION OF PROSTATE CANCER RECURRENCE

PURPOSEnTouch preparation cytology has been used in oncology as a technique to assist in predicting local tumor recurrence. We prospectively investigated the relationship between this cytological evaluation and the standard histological method of assessing specimens, measuring the distance from the tumor to the various anatomical boundaries and disease recurrence in radical retropubic prostatectomy patients.nnnMATERIALS AND METHODSnIn a prospective study of 91 consecutive clinical stages T1c and T2 cancer cases radical retropubic prostatectomy touch preparation cytology was performed intraoperatively in an anatomical fashion (apex, posterior, lateral right and left, and base). A single blinded cytopathologist reviewed all prostate touch preparation specimens and categorized them as malignant, benign or atypical cells. Benign or atypical cells were classified as negative cytology. Detailed histological margin analysis of the surgical specimens was also done in which distances between the tumor front, and prostate capsule (inner and outer edge) and surgical margins (apex, posterior, right and left lateral, and base) were measured. All specimens were re-staged by the same pathologist. Median followup was 38 months. Disease recurrence was determined biochemically (prostate specific antigen), and with bone scans, prostatic fossa biopsies and digital rectal examinations.nnnRESULTSnOf the 91 specimens 25 were excluded from study because distance measurements could not be made for technical reasons. Multivariate analysis was performed on the remaining 66 patients based on the variables of stage, age, cytology status, distance from tumor to the inner prostatic capsule, distance from tumor to the surgical margin and postoperative Gleason sum. The only variable with independent prognostic value was postoperative Gleason sum (p = 0.04). Cytology status was not statistically significant (p = 0.07) nor were distance data to the inner capsule (p >0.05) and surgical margin (p >0.05).nnnCONCLUSIONSnAlthough touch preparation cytology does not enhance prognostic information already provided by Gleason sum, it does correlate highly with postoperative Gleason sum. Other gross macroscopic variables, that is pathological stage, margin status and distance measurements, although lacking in independent predictive value, correlated with postoperative Gleason sum. The constancy of Gleason sum leads us to believe that the key to predicting prostatic cancer behavior lies not on the macroscopic but on the molecular or cellular level. Of the various factors analyzed in this study postoperative Gleason sum remains the most powerful predictor of recurrence risk.