Accelerated superfractionated radiotherapy with concomitant boost for locally advanced head-and-neck squamous cell carcinomas

PURPOSE: A growing body of evidence supports the efficacy of accelerated superfractionated radiotherapy with concomitant boost for advanced head-and-neck carcinomas. This study represents a single-institution experience, performed to identify the factors influencing tumor control, survival, and toxicity. MATERIALS AND METHODS: Between 1988 and 1999, 133 patients with primary squamous cell head-and-neck carcinoma underwent accelerated superfractionated radiotherapy using a concomitant boost. The concomitant boost in this regimen was delivered using reduced fields delivered 3 times weekly in a twice-daily schedule during the final phase. The total radiation dose ranged from 64.8 Gy to 76.5 Gy (mean 71.1). Patients were evaluated in follow-up for local control and late toxicity. Multivariate analysis of treatment and patient parameters was performed to evaluate their influence on toxicity, local control, and overall survival. RESULTS: With a mean follow-up of 37 months, the actuarial overall survival rate for the entire group at 5 years was 24% and the local control rate was 57%. The tumor volume was the most significant predictor of local control, such that each 1-cm(3) increase in volume was associated with a 1% decrease in local control. For patients with tumor volumes 30 cm(3), the 5-year disease-specific survival rate was 52% and 27% (p = 0.004) and locoregional control rate was 76% and 26% (p <0.001), respectively. Seventy-six patients with a minimum of 12 months and median of 39 months toxicity follow-up were studied for late effects. None of these patients experienced Grade 4 or 5 toxicity. The actuarial rate of significant toxicity (Grade III or greater) was 32% at 5 years. Of the toxicities observed, xerostomia (19%) was the most common. Multivariate analysis revealed N stage and dose as independent predictors of Grade 3 effects. CONCLUSION: The locoregional control and survival for patients in this institutional experience compare favorably to other published reports. Tumors of the larynx had the best prognosis. Larger volume tumors were associated with significantly lower local control and survival. Significant late effects were related to dose and nodal status.     

Gemcitabine and cisplatin in a concomitant alternating chemoradiotherapy program for locally advanced head-and-neck cancer: a pharmacology-guided schedule

PURPOSE: Administration of gemcitabine together with cisplatin at cytotoxic doses in a chemoradiotherapy regimen is hampered by a high degree of local toxicity. Using the pharmacologic properties of the drug we designed a modified schedule aimed at reducing toxicity while preserving activity. METHODS AND MATERIALS: Patients with squamous cell carcinomas of the oral cavity, pharynx and larynx, bulky T4, and/or N2 to N3 were eligible. Gemcitabine was administered at a dose of 800 mg/m2 on Days 1 and 12 and cisplatin at a dose of 20 mg/m2 on Days 2 to 5, every 21 days for 3 courses. Radiotherapy, delivered with standard fractionation, was given on Days 8 to 12 and 15 to 19 and was repeated 3 times up to a total dose of > or = 60 Gy. RESULTS: A total of 28 patients were selected. Grade 3 to 4 stomatitis was recorded in 25 patients (89%). Thirteen patients (46%) experienced Grade 3 to 4 neutropenia. Febrile neutropenia occurred in 8 patients (29%) and in 2 was complicated by infection and death. The overall complete response rate was 79%. At a median follow up of 71 months, 11 patients had a locoregional relapse (3-year locoregional control, 64%); 6 patients had distant metastases, among whom only 2 were without locoregional recurrence. The 3-year progression-free survival is 39% and 3-year overall survival has been 43%. CONCLUSION: The schedule modification did not attenuate local toxicity. Moreover, infections and especially pneumonia, were a major problem. The high activity of gemcitabine when combined with radiotherapy would most likely be better exploited in the context of modified radiation schemes.     

Hyperfractionated radiotherapy and paclitaxel for locally advanced/unresectable pancreatic cancer

PURPOSE: To determine prospectively the maximal tolerated dose and potential antitumor activity of weekly paclitaxel with concurrent hyperfractionated radiotherapy in patients with locally advanced and/or unresectable pancreatic cancer. METHODS AND MATERIALS: We embarked on Phase I-II study of hyperfractionated radiotherapy using a concomitant in-field boost to a total dose of 63.80 Gy in 6 weeks at 1.1 Gy/fraction. Paclitaxel was administered weekly on Days 1, 8, 15, 22, 29, and 36 as a 3-h infusion. Paclitaxel doses were escalated from 20 mg/m(2)/wk to 70 mg/m(2)/wk. Twenty patients were studied, 14 women and 6 men (mean age 64 years). Some patients presented with one or more symptoms. Obstructive jaundice was the main presenting symptom in 10 patients and epigastric pain in 14. All patients had unresectable histologically proven adenocarcinoma of the pancreas (15 head, 4 body, and 1 tail). Reasons for unresectability were involvement of the portal vein, and/or superior mesenteric artery (n = 14), paraaortic nodes (n = 8), and medically inoperable (n = 1). Fourteen patients underwent a biliary bypass procedure before treatment (four endoscopic stenting, five choledochojejunostomy, and five cholecystojejunostomy). The follow-up period ranged from 14 to 66 months (median 44). RESULTS: The dose-limiting toxicity was observed at 70 mg/m(2)/wk. Grade IV Radiation Therapy Oncology Group late GI toxicity was seen in 1 patient in the form of duodenal stricture and hemorrhage. Grade II gastrointestinal adverse effects occurred in 13 patients and Grade 3 in 1 patient. No neurologic morbidity was encountered. Eight patients required cytokine support for Grade 2 and 3 neutropenia. The treatment course was delivered within the planned time in 80% of the patients. Complete relief of pain occurred in 10 of 14 patients. The CA 19-9 level was either stable or decreasing in 12 of 15 patients. Of 17 assessable patients, stable disease was seen in 10, regression in 2, a partial response in 3, and a complete response in 2. CONCLUSION: The use of hyperfractionated radiotherapy to a dose of 63.80 Gy with concomitant weekly paclitaxel is tolerated. The maximal tolerated dose of paclitaxel for this study was 60 mg/m(2)/wk. The preliminary objective responses denote activity of the regimen. We recommend testing this regimen in larger scale studies.     

Current role of radiotherapy in the treatment of locally advanced laryngeal carcinomas

BACKGROUND AND OBJECTIVES: During the past few years, radiotherapy (RT) has been increasingly used in combination with surgery in the treatment of locally advanced laryngeal carcinomas to improve survival rates in patients with more extensive tumors. METHODS: This is a retrospective study of a large series of stage III and IV laryngeal carcinomas, and postoperative RT was indicated for some of these cases. We retrospectively reviewed the medical records of 380 patients with stage III and IV tumors, of which 163 (43%) underwent surgery only and 217 (57%) received surgery and postoperative RT. RESULTS: The survival rates of patients who underwent surgery and RT were comparable to those of patients who underwent surgery only, but the former group was composed of subjects suffering from negative prognostic factors. CONCLUSIONS: The indications for combined treatment should be correlated with the prognostic factors to increase the survival rate of patients with stage III and IV laryngeal carcinoma.     

Combined surgery and postoperative radiation therapy for advanced laryngeal and hypopharyngeal carcinomas

The survival, pattern of failure and complications in 47 patients with Stage III and IV cancers of the glottis, supraglottis and hypopharynx treated with surgery and postoperative radiotherapy using a new treatment technique referred to as "mini-mantle" were analyzed. The absolute survival probability of the entire group was 53 and 31% at 3 and 5 years. The local control probability at 3 and 5 years was 63 and 58%, and was higher for the supraglottic/hypopharyngeal than for glottic carcinomas. Advanced lesions, lymph node metastases and positive resection margins were significantly related to a worse local control. Five patients developed complications requiring surgical correction, but none experienced mortality. Moderate complications were treated conservatively without lasting sequelae. This technique is a reasonably safe and efficient procedure and can be effectively employed for the management of advanced laryngeal and hypopharyngeal carcinomas after definitive surgery.     

Simultaneous integrated boost intensity-modulated radiotherapy for locally advanced head-and-neck squamous cell carcinomas: II--clinical results

PURPOSE: To perform a Phase I radiation dose-escalation trial to determine the maximal tolerable dose (MTD) deliverable to the gross tumor volume (GTV) using an accelerated fractionation with simultaneous integrated boost intensity-modulated radiotherapy regimen with parotid gland sparing as the sole therapy in the treatment of locally advanced head-and-neck squamous cell carcinoma. The primary objective was the definition of the MTD using established criteria of quantifying acute dose-limiting toxicity (DLT). Secondary objectives included analysis of failure patterns, tumor control rates, and toxicity. METHODS AND MATERIALS: Between July 1999 and June 2002, eligible patients with bulky Stage II to Stage IVB head-and-neck squamous cell carcinoma, excluding laryngeal primaries, were enrolled. Intensity-modulated radiotherapy was delivered with 6-MV photons using a "sliding-window" technique. Enrollment of 6 patients for each dose level was planned; if DLTs were seen in >2 of 6 patients, the previous dose was to be expanded by an additional 6 patients to confirm that dose level as the MTD. All schedules administered a total of 30 fractions, but with escalating doses per fraction (2.27, 2.36, and 2.46 Gy) to achieve a total dose to the GTV of 68.1, 70.8, and 73.8 Gy, respectively. The remaining target tissues were constrained to receive the same dose in all patients regardless of the GTV dose level. The clinical target volume, defined as tissue within 1 cm around the GTV (at high risk of subclinical disease), received 60 Gy in 30 fractions of 2.0 Gy. The electively irradiated target volume, defined as the clinically uninvolved lymph node-bearing tissues, received 54 Gy in 30 fractions of 1.8 Gy. The parotid glands were spared to the degree possible without compromising target coverage. Acute toxicity was scored weekly using National Cancer Institute Common Toxicity Criteria. DLT was defined as any Grade 4 acute toxicity or any acute toxicity requiring either a dose reduction or a treatment break of >5 treatment days. RESULTS: Of 18 men and 2 women (average age, 57 years; range, 37-80 years), 17 presented with oropharyngeal primary tumors, and 1 each with squamous cell carcinoma of the oral cavity, nasopharynx, and hypopharynx. None of the 6 patients at dose level 1, and 2 of the 6 patients initially enrolled at dose level 2, developed DLT. Both patients treated at dose level 3 required a 3-day treatment break and dose reduction after rapid development of Grade 3 toxicity (by Day 15). Six additional confirmatory patients subsequently enrolled at dose level 2 completed treatment without DLT. At least 50% of the total parotid gland volume received <30 Gy in 14 patients (average, 54% of volume), with an average mean dose of 32 Gy. In contrast, >/=50% of the distal parotid gland volume received <25 Gy in 15 patients (average, 63% of volume), with an average mean dose of 24 Gy. With a median follow-up of 20 months from the date of enrollment and 28 months for surviving patients, the actuarial 2-year local control (primary site), regional control (nodal sites), and distant control rate was 76.3%, 66.7%, and 71.8%, respectively. CONCLUSION: Dose level 2, 70.8 Gy in 30 fractions of 2.36 Gy, was defined as the MTD deliverable to the GTV using this accelerated fractionation with simultaneous integrated boost intensity-modulated radiotherapy regimen with parotid gland sparing as the sole treatment for locally advanced head-and-neck squamous cell carcinoma. Adequate parotid sparing was achievable in most cases. Early toxicity, tumor control, and survival rates compared favorably with the outcomes after other accelerated regimens.     

Induction chemotherapy with paclitaxel and cisplatin, followed by concomitant cisplatin and radiotherapy for the treatment of locally advanced nasopharyngeal carcinoma

PURPOSE: To evaluate the efficacy and outcome of neoadjuvant paclitaxel and cisplatin chemotherapy followed by concurrent cisplatin and irradiation in patients with locally advanced nasopharyngeal (NP) squamous cell carcinoma. PATIENTS AND METHODS: The trial included 36 patients with locally advanced nasopharyngeal squamous carcinoma presented to Radiation Oncology and Otolaryngology departments-Ain Shams university hospitals, and Sohag Cancer Center between November 2002 and March 2006. Eligible patients were treated first with three cycles of induction chemotherapy (IC), paclitaxel (175 mg/m2 on day 1) and cisplatin (80 mg/m2 on day 1) followed by concomitant conventionally fractionated radiation (70 Gy in 2 Gy fractions) and cisplatin 20-mg/m2/day on days 1- 5, 22-26 and 43-47 of the radiation therapy. RESULTS: Twenty nine patients (80%) and 32 patients (89%) achieved objective response after IC and concomitant chemoradiation (CCRT) respectively. The actuarial 3 years survival was 68%, and the actuarial 3 year progression free survival (PFS) was 66%. Survival and PFS were significantly better for patients with smaller tumor volume (stage III), compared with patients with stage IV. Thirteen patients (36%) have elements of local and/or regional failure and 5 patients (14%) have an element of distant metastasis. Neutropenia (25%), mucositis (22%) and vomiting (20%) were the most severe toxicities recorded (grade 3 and 4) during IC while mucositis (36%), dermatitis (28%), anemia (14%) and vomiting (14%) were the most pronouncing toxicities (grade 3 and 4) during CCRT. CONCLUSIONS: IC followed by CCRT treatment program is feasible, tolerable and safe. This strategy improved local control and distant disease control. However combined treatment program have failed to improve survival rates over the historical result of CCRT trials.     

Biweekly escalated, accelerated hyperfractionated radiotherapy with concomitant single-dose mitomycin C results in a high rate of local control in advanced laryngeal and hypopharyngeal cancer

The purpose of this study is to evaluate the efficacy of a dose-escalated, accelerated, and hyperfractionated radiotherapy schedule with a concomitant single dose of mitomycin C in the treatment of patients with advanced laryngeal or hypopharyngeal cancer. Twenty-one previously untreated patients with advanced squamous cell carcinoma (stage III, n = 6; stage IV, n = 15) were treated with a biweekly dose-escalated, accelerated, and hyperfractionated schedule up to a total dose of 74.4 Gy in 54 fractions over 5 weeks. A single dose of intravenous mitomycin C 10 mg/m2 was given on day 30. The median follow-up after treatment of surviving patients is 48 months (range, 28 to 61 months). All patients showed complete tumor control at the primary site when evaluated 2 months after chemoirradiation by laryngomicroscopy or hypopharyngoscopy and radiologic imaging (CT, MRI). Two laryngectomies were carried out after given therapy: 1 for residual cancer and 1 for suspected residual cancer. After a median follow-up of 43 months (range, 28 to 61 months), a local control rate of 70% and disease-free survival (DFS) rate of 60% were achieved in the laryngeal cancer patients; in patients with hypopharyngeal cancer, the corresponding figures were 64% (82% after salvage surgery) and 36%. The results are promising and warrant comparison with other chemoradiotherapy regimens.     

Approaches to preserve larynx function in locally advanced laryngeal and hypopharyngeal cancer

Randomized controlled studies have shown that preservation of the larynx function in patients with advanced resectable laryngeal and hypopharyngeal cancer is possible without compromising survival compared to total laryngectomy (TL). Options for preserving the larynx include function-sparing surgery, radiotherapy alone, induction chemotherapy followed by radiotherapy of responders, and concomitant radiochemotherapy. The current data suggest that induction chemotherapy followed by radiotherapy of responders is an acceptable alternative to TL for patients desiring larynx preservation. Concomitant radiochemotherapy (platinum/5-FU) leads to superior local control and larynx preservation rates compared to induction chemotherapy followed by radiation. The optimal treatment sequence for newer cytotoxic agents is, however, unclear. Such cytotoxic agents and more effective fractionation regimens as well as more advanced surgical techniques are currently evaluated. Predictive tests to successfully stratify patients for the optimal treatment option and more effective systemic therapy are needed to improve therapeutic possibilities and survival.     

A phase II study of concomitant boost radiation plus concurrent weekly cisplatin for locally advanced unresectable head and neck carcinomas.

BACKGROUND AND PURPOSE: This phase II study evaluated the efficacy and toxicity of weekly cisplatin along with concomitant boost accelerated radiation regimen in patients with locally advanced unresectable head and neck carcinoma. MATERIAL AND METHODS: A total of 94 patients (median age, 58 years) with UICC stage III (n = 19) and IV (n = 75) cancer of the oropharynx, larynx, hypopharynx and oral cavity were included. Patients received radiotherapy with a concomitant boost scheme (1.8 Gy on days 1-40 and 1.5 Gy boost on days 25-40 with a total dose of 72 Gy) and concurrent cisplatin, 40 mg/m(2) weekly, for the first 4 weeks. RESULTS: Most patients (95%) received both radiation and chemotherapy according to protocol. Toxicity was manageable with grade III mucositis and pharyngeal-oesophageal toxicity in 85 and 50% of patients, respectively. Haematological toxicity was mild. Four patients (4%) died due to complications. With a median follow of 41 months, median overall survival and time to progression were 27 and 25 months, respectively. The estimated overall survival at 4 years was 41%. CONCLUSIONS: Concomitant boost accelerated radiation plus concurrent weekly cisplatin is a feasible schedule in patients with locally advanced unresectable head and neck carcinoma, with acceptable toxicity and survival data.     

Combined modality therapy for laryngeal cancer with superselective intra-arterial cisplatin infusion and concomitant radiotherapy

Concomitant radiotherapy and superselective arterial infusion of cisplatin for laryngeal cancer has shown excellent therapeutic outcomes. It is expected to be a reasonable treatment option for laryngeal cancer, especially in locally advanced cases.     

Radiotherapy versus radiotherapy plus cisplatin treatment for locally advanced non small cell lung cancer: preliminary results of a randomized study

Preliminary results of a randomized study (radiotherapy versus radiotherapy plus weekly low-dose cisplatin) are reported. Fifty-four patients (43 evaluable) with stage IIIa-b non small cell lung cancer were randomized. Objective responses (CR + PR) were seen in 62% of the radiotherapy-treated group and in 63% of the group treated with radiotherapy plus cisplatin. No major toxicity was seen. Patient compliance for both treatments was satisfactory.     

鼻咽癌超分割合并缩野加量放射的前瞻性随机研究

目的比较超分割合并缩野加量与常规放射治疗鼻咽癌的局部控制率、生存率和并发症等。材料与方法从１９９０年１０月到１９９２年１月，４８例鼻咽癌患者随机分入超分割合并缩野加量组（研究组）和常规放射组（常规组）。研究组的总剂量为７３～７５Ｇｙ，照射６０次／６周；对照组总剂量为７０．２Ｇｙ，照射３９次／７．５周。总疗程从常规放射的７．５周缩短到６周，总剂量则由７０．２Ｇｙ提高到７４Ｇｙ，获得治疗增益２０％。结果（１）研究组无１例鼻咽部复发而常规组则有６例复发。研究组和常规组的５年局控率分别为１００％和７５．０％（Ｐ＜０．０５）；（２）研究组和常规组的５年生存率分别为６２．５％和５８．３％；（３）研究组的急性粘膜反应明显高于常规组，但能耐受，尚无严重后期并发症发生。结论超分割合并缩野加量治疗鼻咽癌的局控率高于常规放射，且能耐受。     

Three-dimensional photon radiotherapy planning for laryngeal and hypopharyngeal tumours

Three-dimensional absorbed dose distributions have been computed for high-energy photon radiation therapy of laryngeal and hypopharyngeal cancers, using a coaxial pair of opposing lateral beams in fixed positions. Treatment plans obtained under various conditions of irradiation are analyzed and compared for a cobalt-60 gamma unit (GAMMATRON S80, Siemens), photon beams from a 6 MV (CLINAC 1800, VARIAN), an 8 MV (SATURNE, CGR) and a 15 MV (MEVATRON 77, Siemens) linear accelerator. Using open fields a somewhat non-uniform and partly insufficient dose in target volume of interest is obtained with all treatment units if sufficient protection of the spinal cord is provided. The x-ray plans are somewhat superior to the cobalt-60 ones. Depending on the quantum energy and wedge isodose angle, wedging only slightly improves or sometimes moderately decreases the homogeneity of the dose in the target volume. According to these small and/or controversial effects of wedges their application seems unnecessary and/or non-convenient. Simulations show that extreme care is needed in positioning the isocentre: an accuracy of +/- 3 mm is required in the median sagittal plane.