A phase II study of concomitant hyperfractionated radiation therapy and double dose intra-arterial cisplatin for squamous cell carcinoma of the head and neck

This successor phase II study evaluates the tolerability and efficacy of concomitant hyperfractionated radiation therapy (HFX-RT) and double dose intra-arterial (IA) cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In doing so, this study represents further resurgence of the potential use of IA chemotherapy in the management of SCCHN. This has been enabled by the evolution of angiographic catheter/microcatherter technology. Between 1997 and 1999, 24 patients with locally advanced T4/T3 SCCHN were treated with HFX-RT (76.8- 81.6 Gy at 1.2 Gy bid over 6-7 weeks) and high-dose IA cisplatin (150mg/m2 given at the start of and during RT boost treatment [start of week 6 and 7]). Twenty-two patients (92%) had T4 disease and 14 (58%) N2/ N3 disease. Acute toxicity was limited to two grade 4 (8%) and 19 grade 3 (79%) mucosal events; and single grade 3 hematologic, infectious and skin events. Eight patients (33%) were unable to receive the second planned dose of IA cisplatin. Twenty-two patients had complete response (92%) at the primary site. Among 17 patients with positive neck disease 12 (71%) achieved complete response in the neck. Follow-up ranges from 7-30 months (median = 18 months) with 14 patients alive without disease, 2 alive with disease, 7 dead of disease and 1 dead of intercurrent disease. While concomitant HFX-RT and double dose IA cisplatin as used in this study is associated with encouraging response rates in this highly unfavorable subset of patients with locally advanced SCCHN it was not feasible. Future investigation of this novel treatment strategy utilizing modern angiographic catheter/microcatherter technology will involve a single dose of IA cisplatin with HFX-RT and dose intensification using neoadjuvant therapy.     

Concurrent weekly cisplatin and radiotherapy in routine management of cervical cancer: a report on patient compliance and acute toxicity

PURPOSE: To evaluate patient compliance and acute toxicity accompanying concurrent weekly cisplatin and radiotherapy (RT) in the routine management of cervical cancer. METHODS AND MATERIALS: Locally advanced or high-risk early-stage cervical cancer patients treated with RT and concurrent weekly cisplatin at a dose of 40 mg/m(2) i.v. (maximum dose, 70 mg) for five cycles. Definitive RT included whole pelvis external beam RT to the International Commission on Radiation Units and Measurements reference dose of 40 Gy plus a 10-Gy boost to the parametrium and two brachytherapy applications of 20 Gy to point A each. Postoperative RT consisted of pelvic external beam RT to the International Commission on Radiation Units and Measurements reference dose of 50 Gy and one brachytherapy application of 30 Gy at a depth of 0.5 cm from the applicator surface. RESULTS: Included in this analysis were 112 consecutive cervical cancer patients treated at one institution with concurrent cisplatin and RT between May 1999 and September 2002. The median age was 48 years (range, 28-79 years). Definitive RT was administered to 57 International Federation of Gynecology and Obstetrics "bulky" Stage IB or IIB-IVA patients, and 53 patients underwent postoperative RT; 2 patients underwent RT for stump carcinoma. All but 2 patients (both administered definitive RT) completed RT. A total of 454 cisplatin cycles were administered (median 4 cycles/patient, range 1-6). Overall, 74% of patients received at least four cycles of cisplatin. The planned five cisplatin cycles were administered to 50 patients (45%); 42% were irradiated definitively and 47% postoperatively. The full and timely planned cisplatin dose was administered to 29 patients (26%). For 29% of patients, the interval between cycles was prolonged because of toxicity (n = 11; 10%) or for reasons not related to toxicity (n = 10; 9%). Of the 112 patients, 62 (55%) did not undergo the planned five cycles of cisplatin because of treatment toxicity (n = 35; 31%) or noncompliance with the treatment schedule because of delayed administration of the first cycle or omission of a cycle for reasons other than toxicity (n = 23; 21%). The most common side effects resulting in chemotherapy discontinuation included GI complications (n = 7) and impaired renal function (n = 5). Of the 112 patients, 49 (44%) experienced Grade 1 or 2 leukopenia and 6 (5%) Grade 3 or 4 leukopenia. CONCLUSION: Our results show that pelvic RT combined with weekly cisplatin in cervical cancer patients is accompanied by considerable acute toxicity. Furthermore, a number of patients were unable to comply with the treatment schedule owing to reasons unrelated to treatment toxicity. Thus, administration of the full chemotherapy dose may be difficult, although the delivery of planned RT was generally not compromised. Additional follow-up is needed to assess the late toxicity of combined modality treatment.     

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.     

Supradose intra-arterial cisplatin and concurrent radiation therapy for the treatment of stage IV head and neck squamous cell carcinoma is feasible and efficacious in a multi-institutional setting: results of Radiation Therapy Oncology Group Trial 9615.

PURPOSE: To determine the feasibility of high-dose intra-arterial (IA) cisplatin and concurrent radiation therapy (RT) for head and neck squamous cell carcinoma in the multi-institutional setting (Multi-RADPLAT). PATIENTS AND METHODS: Eligibility included T4 squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received cisplatin (150 mg/m(2) IA with sodium thiosulfate 9 g/m(2) intravenous [IV], followed by 12 g/m(2) IV over 6 hours, weekly for 4 weeks) and concurrent RT (70 Gy, 2.0 Gy/fraction, daily for 5 days over 7 weeks). Between May 1997 and December 1999, 67 patients from three experienced and eight inexperienced centers were enrolled, of whom 61 were eligible for analysis. RESULTS: Multi-RADPLAT was feasible (ie, three or four infusions of IA cisplatin and full dose of RT) in 53 patients (87%). The complete response (CR) rate was 85% at the primary site and 88% at nodal regions, and the overall CR rate was 80%. At a median follow-up of 3.9 years for alive patients (range, 0.9 to 6.1 years), the estimated 1-year and 2-year locoregional tumor control rates are 66% and 57%, respectively. The estimated 1-year and 2-year survival rates are 72% and 63%, respectively. The estimated 1-year and 2-year disease-free survival rates are 62% and 46%, respectively. The rates of grade 4 and 5 toxicities at the experienced and the inexperienced institutions were 14% and 0% v 47% and 4%, respectively. CONCLUSION: This intensive treatment regimen for head and neck cancer is feasible and effective in a multi-institutional setting.     

Phase II study of concurrent chemoradiotherapy with capecitabine and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck

We aimed to evaluate the efficacy and safety of concurrent chemoradiotherapy with capecitabine and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In total, 37 patients with stage III or IV SCCHN were enrolled on the study. The chemotherapy consisted of two cycles of intravenous cisplatin of 80 mg m(-2) on day 1 and oral capecitabine 825 mg m(-2) twice daily from day 1 to day 14 at 3-week intervals. The radiotherapy (1.8-2.0 Gy 1 fraction day(-1) to a total dose of 70-70.2 Gy) was delivered to the primary tumour site and neck. The primary tumour sites were as follows: oral cavity (n=6), oropharynx (n=11), hypopharynx (n=8), larynx (n=3), nasopharynx (n=6), and paranasal sinus (n=3). After the chemoradiotherapy, 29 complete responses (78.4%) and 6 partial responses (16.2%) were confirmed. Grade 3 or 4 neutropenia occurred only in two patients, plus grade 3 febrile neutropenia was observed only in one patient. At a median follow-up duration of 19.8 months, the estimated overall survival and progression-free survival rate at 2-year was 76.8 and 57.9%, respectively. Concurrent chemoradiotherapy with capecitabine and cisplatin was found to be well tolerated and effective in patients with locally advanced SCCHN.     

Concurrent weekly cisplatin plus external beam radiotherapy and high-dose rate brachytherapy for advanced cervical cancer: a control cohort comparison with radiation alone on treatment outcome and complications

PURPOSE: To test, though a control-cohort study, the hypothesis that concurrent chemoradiotherapy (CCRT) using weekly cisplatin, plus high-dose rate intracavitary brachytherapy (HDRICB) is superior to radiation (RT) alone in patients with advanced cervical cancer. METHODS AND MATERIALS: A total of 171 patients with Stage IIB-III cervical cancer were enrolled in this study. Seventy patients were treated with CCRT and the results were compared with those of 101 patients who had been treated with RT using the same protocol at an early period. RT consisted of 45 Gy in 25 fractions to the whole pelvis, followed by a 12.6-Gy boost to the parametrium. Four courses of HDRICB using 6.0 Gy to Point A were performed. Chemotherapy consisted of weekly cisplatin at a dose of 40 mg/m(2) for 5-6 cycles. RESULTS: The 4-year actuarial survival was 74% for the CCRT group and 68% for the RT group (p = 0.60). The 4-year pelvic relapse-free survival was 87% for the CCRT group and 85% for the RT group (p = 0.37). The 4-year distant metastases-free survival was 75% for the CCRT group and 76% for the RT group (p = 0.44). The cumulative incidence of gastrointestinal and genitourinary injuries of grade 3 or above was 14.3% for the CCRT group and 7.9% for the RT group (p = 0.19). CONCLUSION: This study did not show a survival benefit of CCRT with weekly cisplatin and HDRICB for Stage II-III cervical cancer, nor did it demonstrate a significant increase of late complications when comparing with RT alone.     

Phase II trial: concurrent radio-chemotherapy with weekly docetaxel for advanced squamous cell carcinoma of head and neck

Abstract Introduction: Standard fractionation radiation therapy (RT) combined with concomitant chemotherapy (CT) based on cisplatin schemes is actually the standard treatment for locally advanced non-resectable squamous cell carcinoma of head and neck (SCCHN). The appearance of taxoids has introduced a new kind of treatment with high antitumoral power. The aim of this study is to add more information about the role of this new approach. Materials and methods: Twenty-six patients with locally advanced non-resectable SCCHN were recruited at six institutions in Spain, between January 2001 and January 2003. Docetaxel was administered weekly, for 6 weeks, concurrently with RT. Results: The mean total delivered dose of RT was 70’2 Gy (range 64-74 Gy). The median and mean duration of time were 63 days and 61 days (range 49-103 days) respectively. After a median time control of 19 months (range 3.3-42.2 months), the response rate was 83.4%. The median time to local progression was 16.4 months (95% confidence interval [CI]=4.4-28.4 months). The median survival time was 26.9 months, with one- and two-year overall survival of 66.9% (95% CI=48.1-85.7%) and 57.5% (95% CI=37.3-77.7%) respectively. The median duration time response was 15.1 months (95% CI=3.7-26.5 months). The median time until treatment failure was 9.4 months (95% CI=4.7-14.1). Incidence of grade III-IV mucositis was 88%, neutropenia 72% and skin toxicity 92% (24% grade III-IV). The incidence of severe late toxicity (grade III and IV) due to RT/CT was 31.4%. Conclusions: Although therapeutics results are equivalent to cisplatin schemes of concurrent CT-RT, mucositis and cutaneous toxicity registered in this trial must be considered as limiting factors to application of this new approach.     

Phase II feasibility study of concurrent radiotherapy and gemcitabine in chemonaive patients with squamous cell carcinoma of the head and neck: long-term follow up data.

BACKGROUND: Radiotherapy (RT) with concurrent chemotherapy is the current standard of care for patients with unresectable locally advanced squamous cell carcinoma of the head and neck (SCCHN). Gemcitabine (GEM) is a potent radiosensitizer and in addition has activity as an anticancer agent in SCCHN. PATIENTS AND METHODS: Twenty-six patients with locally far advanced SCCHN were enrolled in a chemoradiation feasibility study between November 1998 and September 2003. Use was made of conventionally fractionated RT and GEM 100 mg/m(2), which was given within 2 h prior to radiotherapy on a weekly basis starting on day 1 of RT. Response was assessed according to WHO criteria, toxicity according to NCI-CTC version 2. RESULTS: The patients received a median of 7 (2-8) weekly cycles of gemcitabine and a median cumulative RT dose of 70 Gy (66-84.75). Hematologic toxicity was mild, but non-hematologic toxicity was severe: grade 3-4 stomatitis occurred in 85% of patients, dermatitis in 69%, pharyngitis/esophagitis in 81% and 80% of the patients needed a feeding tube during treatment. All 22 evaluable patients responded (50% complete, 50% partial). Median follow up of the surviving patients is 46 months. Median disease-free and overall survival is 13 months and 19 months, respectively; 27% of the patients are alive without evidence of recurrence beyond 3 years. CONCLUSIONS: Conventionally fractionated RT in combination with GEM 100 mg/m(2) weekly is feasible and highly active in the treatment of locally advanced SCCHN. In particular, long-term local control rate is promising. Acute mucosal toxicities are significant but manageable. Long-term toxicity interferes with normal food intake.     

Using plasma transforming growth factor beta-1 during radiotherapy to select patients for dose escalation.

PURPOSE: The ability to prescribe treatment based on relative risks for normal tissue injury has important implications for oncologists. In non-small-cell lung cancer, increasing the dose of radiation may improve local control and survival. Changes in plasma transforming growth factor beta (TGFbeta) levels during radiotherapy (RT) may identify patients at low risk for complications in whom higher doses of radiation could be safely delivered. PATIENT AND METHODS: Patients with locally advanced or medically inoperable non-small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved nodes to a dose of 73.6 Gy (1.6 Gy twice daily). If the plasma TGFbeta level was normal after 73.6 Gy, additional twice daily RT was delivered to successively higher total doses. The maximum-tolerated dose was defined as the highest radiation dose at which < or = one grade 4 (life-threatening) late toxicity and < or = two grade 3 to 4 (severe life-threatening) late toxicities occurred. RESULTS: Thirty-eight patients were enrolled. Median follow-up was 16 months. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGFbeta levels. Fourteen patients whose TGFbeta levels were normal after 73.6 Gy were escalated to 80 Gy (n = 8) and 86.4 Gy (n = 6). In the 86.4-Gy group, dose-limiting toxicity was reached because there were two (33%) grade 3 late toxicities. CONCLUSION: It is feasible to use plasma TGFbeta levels to select patients for RT dose escalation for non-small-cell lung cancer. The maximum-tolerated dose using this approach is 86.4 Gy.     

Concomitant chemoradiation versus radical radiotherapy in advanced squamous cell carcinoma of oropharynx and nasopharynx using weekly cisplatin: a phase II randomized trial

BackgroundTo know the effectiveness and tolerance of weekly cisplatin added to radiotherapy (RT) in advanced carcinoma of oropharynx and nasopharynx.Patients and methodsStage II–IV cancer patients were randomly assigned to either radical RT, 70 Gy/35 fractions over 7 weeks (RT arm), or chemoradiotherapy (CRT), cisplatin 40 mg/m² weekly for seven doses plus RT. Primary end points were (i) the responses, (ii) toxicity profile, and (iii) overall survival (OS) in two groups. Study period was from June 2003 to July 2005.ResultsOne hundred and fifty-three patients were randomly allocated to the study, 76 in RT arm and 77 in CRT arm. Seventy-one in each arm completed the planned treatment; complete response (CR): 67.1% versus 80.5% in RT and CRT arms (P = 0.04). Grade III and IV toxicity were 16% and 40% in RT and CRT arms, respectively (P = 0.01). There were frequent treatment interruptions (9.3% versus 28.9%; P = 0.003) and hospitalization (20% versus 40.8%) in the CRT group. OS was superior in the CRT arm (P = 0.02): 27 months [95% confidence interval (CI) 15.2–36.8] for RT versus not reached for CRT. Three-year OS was 42% for RT and 62% for CRT group. CRT and CR were independent prognostic factors.ConclusionThis trial on Indian head and neck squamous cell carcinoma patients confirms that the use of weekly cisplatin is safe and CRT is superior to RT alone resulting in higher OS.     

A phase I trial of weekly docetaxel and cisplatinum combined to concurrent hyperfractionated radiotherapy for non-small cell lung cancer and squamous cell carcinoma of head and neck

We conducted a phase I study to evaluate the activity and tolerability of concurrent docetaxel and cisplatinum radiosensitization with hyperfractionated irradiation, in patients with advanced non-small cell lung cancer (NSCLC) and squamous cell carcinoma of the head and neck (SCCHN). Nine patients (5 stage III(A) and 4 III(B)) with NSCLC, and 15 with SCCHN (10 stage III and 5 IV) were treated with a b.i.d. hyperfractionated (HF) radiotherapy schedule. The normalized total dose for alpha/beta ratio = 10 Gy was 69.6 Gy for NSCLC and 80.5 Gy for SCCHN patients. The standard dose of cisplatin (10 mg/m(2)) was given combined to docetaxel on a weekly basis. The docetaxel starting dose level was 10 mg/m(2)/week and was escalated by 3 mg/m(2) increments in cohorts of 8 patients (5 SCCHN and 3 NSCLC). DLT (grade 3 malaise) was observed in 4 out of 8 patients treated at the 16 mg/m(2)/week docetaxel dose level. The 13 mg/m(2)/week docetaxel dose level was defined as the MTD causing grade 3 mucositis in 4 out of 8 patients. In total 4 (17%) patients developed grade 3 neutropenia. G-CSF support was given in 1/8, 4/8, and 5/8 patients treated at the 10, 13 and 16 mg/m(2) docetaxel dose levels respectively. Fatigue was the most common adverse event (5/24: 21%) and was responsible for more than 1 week treatment delay in 4 out of 8 patients treated at the 16 mg/m(2)/week docetaxel dose level. Nine (3 NSCLC and 6 SCCHN patients: 37.5%) had treatment delay of 1 week, while 7 (3 NSCLC and 4 SCCHN: 29%) had delays of 2 weeks for combined chemoradiation sequelae. Acute hypersensitivity reactions occurred in 3 (12.5%) patients, and grade 3 mucositis in 2/8, 5/8 and 6/8 patients, treated at 10, 13 and 16 mg/m(2)/week docetaxel dose levels respectively. The overall response rate was 79% (CI = 63-96%) with 33% and 53% CRs for NSCLC and SCCHN patients respectively. There were 3 deaths among 9 NSCLC and 4 among 15 SCCHN patients. Local and/or distant disease recurrences were shown in 4 NSCLC and in 6 SCCHN patients; 5 NSCLC and 9 SCCHN patients are alive with no evidence of tumor progression at 8.5 months mean follow-up time. Radiosensitization with docetaxel and cisplatin given concurrently with HF (b.i.d.) radiotherapy on a weekly basis is a promising approach and the recommended dose for further phase II studies is 10 mg/m(2)/week for both drugs. The antitumor activity shown was significant in both types of tumors. The incorporation of docetaxel in chemoradiotherapy regimens for future treatment of squamous cell carcinoma of the lung and head and neck, merits evaluation in phase II and III trials.     

Phase I trial of concurrent chemoradiotherapy with docetaxel, cisplatin and 5-fluorouracil (TPF) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN)

The aim of this study was to evaluate the efficacy and toxicity of a concurrent chemoradiotherapy using docetaxel, cisplatin and 5-fluorouracil (5-FU) (TPF) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In total, 19 patients with previously untreated stage III-IV SCCHN were entered onto this trial. Patients received two cycles of chemotherapy. Cycles were repeated every 4 weeks. The starting doses (dose level 1) were docetaxel 60 mg m(-2), cisplatin 70 mg m(-2), and 5-day continuous infusion of 5-FU 600 mg m(-2) day(-1). Radiation was targeted to begin on the first day of chemotherapy, day 1. The total radiation dose to the primary tumour site and neck lymph nodes was between 63.0 and 74.0 Gy. At least three patients were examined at each dose level before advancing to the next level. The maximum-tolerated dose (MTD) of this regimen was docetaxel 60 mg m(-2), cisplatin 60 mg m(-2) and 5-FU 600 mg m(-2) day(-1). The main toxicities were mucositis (grade 3 and 4, 79%), leukocytopenia (grade 3 and 4, 53%), neutropenia (grade 3 and 4, 42%), anaemia (grade 3, 16%), liver dysfunction (grade 3, 11%) and renal dysfunction (grade 2, 11%). The overall response rate was 100%, including 84% complete responses (CRs). This concurrent chemoradiotherapy with TPF was safe and well tolerated. The high CR rate justifies further evaluation of this chemoradiotherapy modality in advanced SCCHN patients.     

Phase II study of neoadjuvant carboplatin and paclitaxel followed by radiotherapy and concurrent cisplatin in patients with locoregionally advanced nasopharyngeal carcinoma: therapeutic monitoring with plasma Epstein-Barr virus DNA.

PURPOSE: To assess the efficacy of neoadjuvant paclitaxel and carboplatin (TC) followed by concurrent cisplatin and radiotherapy (RT) in patients with locoregionally advanced nasopharyngeal carcinoma (NPC) and to monitor treatment response with plasma Epstein-Barr virus (EBV) DNA. PATIENTS AND METHODS: Thirty-one patients with International Union Against Cancer stages III and IV undifferentiated NPC had two cycles of paclitaxel (70 mg/m2 on days 1, 8, and 15) and carboplatin (area under the curve 6 mg/mL/min on day 1) on a 3-weekly cycle, followed by 6 to 8 weeks of cisplatin (40 mg/m2 weekly) and RT at 66 Gy in 2-Gy fractions. Plasma EBV DNA was measured serially using the real-time quantitative polymerase chain reaction method. Results All patients completed planned treatment. Response to neoadjuvant TC was as follows: 12 patients (39%) achieved partial response (PR) and 18 achieved (58%) complete response (CR) in regional nodes; five patients (16%) achieved PR and no patients achieved CR in nasopharynx. At 6 weeks after RT, one patient (3%) achieved PR and 30 patients (97%) achieved CR in regional nodes, and 31 patients (100%) achieved CR in nasopharynx; 29 patients (93%) had EBV DNA level of less than 500 copies/mL. Neoadjuvant TC was well tolerated, and the most common acute toxicity of cisplatin plus RT was grade 3 mucositis (55%). At median follow-up of 33.7 months (range, 7 to 39.3 months), six distant and three locoregional failures occurred. Plasma EBV DNA level increased significantly in eight of nine patients who experienced treatment failure but did not increase in those who did not. The 2-year overall and progression-free survival rates were 91.8% and 78.5%, respectively. CONCLUSION This strategy was feasible and resulted in excellent local tumor control. Serial plasma EBV DNA provides a noninvasive method of monitoring response in NPC.     

High-dose-rate brachytherapy boost following concurrent chemoradiotherapy for esophageal carcinoma.

PURPOSE: To assess the efficacy, toxicity, and the optimum dose of high-dose-rate brachytherapy following chemoradiotherapy (CRT) compared with a historical group of patients treated with a combination of external beam and brachytherapy (RT alone). METHODS AND MATERIALS: Fifty-three patients with localized esophageal cancer received concurrent chemoradiotherapy followed by brachytherapy. The chemotherapy regimen was a combination of cisplatin 60 mg/m2 on day 1 and fluorouracil 600 mg/m2 continuous infusion from days 1-4 during the first and last week of external irradiation. Radiotherapy consisted of external irradiation to a total dose of 40-61 Gy (median 50 Gy) and brachytherapy to 8-24 Gy (median 16 Gy) in 2-4 fractions. RESULTS: Acute toxicity was well tolerated. A fistula occurred in one patient 1 week after completion of external irradiation. Local control was achieved in 32/53 (60%) compared with 42% of the RT group (p = 0.029). Local control rates of the CRT group were significantly better than those of the RT group in Stages II and III. Late toxicity (esophageal ulceration and strictures) occurred in 18 (34%) of the CRT group compared with 12% in the RT group (p = 0.013). Severe late toxicity (RTOG/EORTC criteria Grade 3-4) occurred in six patients (15%) whose chemotherapy was followed by 16-24 Gy via brachytherapy compared with 2.5% in the RT group (p = 0.010). CONCLUSION: Combined chemoradiotherapy and brachytherapy boost achieved better local control than radiotherapy alone. However, a high level of severe late toxicity was observed especially with 16-24 Gy via brachytherapy.     

Radiotherapy and cisplatin in metastatic squamous cell carcinoma of an unknown primary tumor localized to the neck. A phase II study.

13 male and 8 female patients with metastatic squamous cell carcinoma (SCC) of an unknown primary tumor localized to the neck were treated with radiotherapy (RT) and cisplatin (CDDP). There were 12 (58%) and 9 (42%) patients, while no patient had N1 disease. All patients underwent biopsy. RT was given to all possible sites of the primary tumor (nasopharynx, pyriform sinus, and the base of the tongue). The RT dosage planned for the whole neck or supraclavicular area was 45 Gy, increasing to 60-70 Gy on the metastatic site. CDDP was given at a dose of 30 mg/m2, once weekly during the RT course. We observed 15 (72%) complete responses (CR) and 3 (14%) partial responses, while 3 (14%) patients did not respond to therapy. 12 (58%) patients are with no evidence of disease (NED) currently. The median survival time was 34+ months (range, 18+ to 50+ months). We observed two groups of toxicities: gastrointestinal and kidney toxicity. The majority of patients experienced grade 3 (RTOG) toxicity and no patient experienced grade 4 toxicity. This treatment appears to be effective and suitable for patients with metastatic SCC of an unknown primary tumor localized to the neck.     

Capecitabine and radiation therapy preceded and followed by combination chemotherapy in advanced pancreatic cancer

PURPOSE: The primary objective of this study was to evaluate the tolerance and toxicity of radiation therapy (RT) and capecitabine in patients with advanced, unresectable pancreatic carcinoma. To control micrometastatic disease, combination chemotherapy (gemcitabine and cisplatin) before and after combined modality therapy (CMT) was planned. METHODS AND MATERIALS: Patients with unresectable or metastatic pancreatic cancer were eligible. Gemcitabine 1000 mg/m2 and cisplatin 35 mg/m2 were administered on Days 1 and 8 of a 21-day cycle for two cycles. RT was then given to a dose of 50.4 Gy in 1.8 Gy fractions. Patients were treated with capecitabine 1330 mg/m2 daily during RT. After CMT, two additional cycles of gemcitabine and cisplatin completed the treatment. RESULTS: Twenty-three patients were treated. Eighteen patients completed CMT. One patient was removed from study during CMT for toxicity issues. Treatment delays and dose reductions were common during the final two cycles of gemcitabine and cisplatin as a result of myelosuppression. Median survival was 10.1 months (95% confidence interval [CI] = 7.6, 13.7) for all 23 patients and 12.8 months (95% CI = 8.2, 18.9) for 18 patients without metastasis. CONCLUSION: Combined modality therapy with RT and capecitabine was well tolerated. Chemotherapy after CMT was difficult to complete owing to cumulative myelosuppression. Survival, response, and toxicity were comparable to infusional 5-fluorouracil and RT.     

淋巴结阳性食管癌术后预防性IMRT同期化疗的临床Ⅰ期研究

目的 探讨淋巴结阳性食管癌术后预防性IMRT同期化疗的MTD和缩小靶区的影响。方法 对2007—2011年在我院行根治性手术的33例胸中、下段食管鳞癌伴淋巴结转移患者行术后预防性IMRT同期化疗临床Ⅰ期研究。中位年龄52岁,76%为T₃+T₄期。放疗随机分为60 Gy分30次(2.0 Gy/次)18例、54 Gy分30次(1.8 Gy/次)15例。化疗每周顺铂20 mg/m²+紫杉醇20、30、40、50 mg/m²递增(每阶梯3例),连用5~6周。依据CTCAE3.0标准,DLT为4级白细胞下降或≥3级血红蛋白、血小板下降及≥3级非血液学不良反应。结果 60 Gy分30次(2.0 Gy/次)组,紫杉醇20 mg/m²时1例3级体重下降,增加3例后1例4级白细胞降低,递增实验失败。54 Gy分30次(1.8 Gy/次)组1例紫杉醇过敏中止化疗,其余20~40 mg/m²无DLT,50 mg/m²时2例4级白细胞和3级血小板下降而终止实验;MTD为每周顺铂20 mg/m²+紫杉醇40 mg/m²连用5~6周。缩小靶区后60 Gy分30次(2.0 Gy/次)组12例无DLT,顺利完成递增实验;MTD为每周顺铂20 mg/m²+紫杉醇50 mg/m²连用5~6周。靶区修改前、后平均PTV和残胃D_mean差异有统计学意义(P=0.006、0.013)。结论 淋巴结阳性的胸中、下段食管癌术后预防性IMRT同期紫杉醇+顺铂周方案在合理缩小靶区下是安全、有效的。     

Local radiotherapy for patients with unresectable hepatocellular carcinoma

PURPOSE: To evaluate the response to local radiotherapy (RT) for unresectable hepatocellular carcinoma (HCC) and to analyze the dose-response relationship and the treatment-related morbidities. METHODS AND MATERIALS: Between 1998 and 2002, 59 patients who were treated with localized RT were evaluated. RT was delivered with a curative intent, and the radiation dose was 30-55 Gy (biologic effective dose of 39.0-70.2 Gy(10) using the alpha/beta ratio of 10 Gy) with 2-3 Gy as a daily dose. The tumor response was evaluated by the change in maximum tumor size on serial CT scans, and the morbidity was evaluated by the Common Terminology Criteria for Adverse Events v3.0. RESULTS: An objective tumor response was achieved in 39 of 59 patients (66.1%) with complete response (CR) in 5 patients and partial response (PR) in 34 patients. More than 50 Gy(10) had a significant response; CR or PR was 72.8% with >50 Gy(10) and 46.7% with < or =50 Gy(10) (p = 0.0299). The 2-year overall survival rate after RT was 27.4% (median survival time: 10 months), and this was affected by the tumor response (p = 0.0640); the 2-year overall survival rate after RT was 50.0% for CR and 21.8% for PR. There was no Grade 3 or 4 acute toxicity, and 3 patients (5.1%) developed gastric or duodenal ulcer. CONCLUSIONS: Radiotherapy for unresectable HCC resulted in 66.1% of tumor response with acceptable toxicity, and the radiation dose seems to be a significant prognostic factor in RT response for HCC.     

Accelerated radiotherapy with delayed concomitant boost in locally advanced squamous cell carcinoma of the head and neck.

PURPOSE: To determine the toxicity, maximum tolerated dose (MTD), and clinical effectiveness of a 5-week course of accelerated radiotherapy with delayed concomitant boost in locally advanced squamous cell carcinoma of the head and neck (SCCHN). METHODS AND MATERIALS: Thirty-five patients with untreated T3T4NM0 or TN2 (> 3 cm) N3M0 SCC of the oral cavity, oropharynx, hypopharynx, or larynx were entered in the study between January 1994 and October 1997. The initial target volume was treated with conventional daily fractions. A small field boost covering gross disease was added as a second daily fraction during the last 2 weeks of the 5-week schedule, using a minimum interfraction interval of 6 h. The study was initiated using 180-cGy fractions to deliver a total dose of 63 Gy over 33-35 days. A classical dose escalation strategy was planned to increase the delivered dose in steps using minimum cohorts of three patients, up to a maximum of 70 Gy in 200-cGy fractions. RESULTS: In the dose escalation study, 4 patients were entered at level 1 (63 Gy), 9 at level 2 (65 Gy), and 8 at level 3 (67 Gy). One patient was withdrawn at level 2 because of unstable angina, and 1 at level 3 because of uncontrolled diabetes. One patient at level 3 failed to complete treatment because of radiation toxicity. RTOG Grade 3 mucositis, dermatitis, or pharyngitis was documented in 1 (25%), 5 (63%), and 7 (100%) evaluable patients at levels 1, 2, and 3, respectively. Grade 4 reactions were documented in 1 patient at each level. One patient at level 3 died 5 weeks post-treatment of unknown causes. Two additional patients at level 3 died of progressive disease and RT toxicity. Sixty-five Gy (level 2) was chosen as the MTD. In the MTD study, 14 additional patients were entered at level 2, providing a total of 22 evaluable patients with a median follow-up of 21 months (range 12-41 months). Grade 3 mucositis, dermatitis, or pharyngitis were documented in 11 (50%), 8 (36%), and 6 (27%) patients, respectively. One patient developed Grade 4 mucositis. A complete response was recorded in 16 (77%). Three of 5 patients with uncontrolled disease and 3 of 3 patients with recurrent disease underwent salvage surgery with no postoperative complications. Radiotherapy controlled disease above the clavicles in 14 (68%). Ultimate locoregional control was achieved in 17 (77%). The disease-free, overall, and cause-specific survival of all patients entered at level 2 was 56%, 76%, and 80%, respectively, at 2 years. Late complications have been limited to 3 patients (trismus, chronic mucosal ulcer, and soft tissue necrosis). CONCLUSION: A 5-week course of accelerated radiotherapy with delayed concomitant boost can deliver 65 Gy with acceptable toxicity, encouraging rates of complete response, and locoregional control, and no compromise of salvage surgery in patients with locally advanced SCCHN. The regimen is worthy of further study in a Phase III trial.     

Role of radiation therapy in the combined-modality treatment of patients with extensive disease small-cell lung cancer: A randomized study.

PURPOSE: To investigate the efficacy and toxicity of cisplatin/etoposide (PE) chemotherapy (CHT) with or without accelerated hyperfractionated radiation therapy (ACC HFX RT) and concurrent daily carboplatin/etoposide (CE) in patients with extensive-disease small-cell lung cancer. PATIENTS AND METHODS: A total of 210 patients were treated with three cycles of standard PE. Patients with a complete response (CR) at both the local and distant levels (CR/CR) or a partial response (PR) at the local level and CR at the distant level (PR/CR) received either thoracic ACC HFX RT with 54 Gy in 36 fractions over 18 treatment days in combination with CE followed by two cycles of PE (group 1, n = 55) or an additional four cycles of PE (group 2, n = 54). Patients who experienced less response were treated nonrandomly (groups 3, 4, and 5). All patients with a CR at the distant level received prophylactic cranial irradiation. RESULTS: For 206 assessable patients, the median survival time (MST) was 9 months and the 5-year survival rate was 3.4%. Patients in group 1 had significantly better survival rates than those in group 2 (MST, 17 v 11 months; 5-year survival rate, 9.1% v 3.7%, respectively; P =.041). Local control was also better in group 1, but the difference was only marginally not significant (P =.062). There was no difference in distant metastasis-free survival between groups 1 and 2. Acute high-grade toxicity was higher in group 2 than in group 1. CONCLUSION: The addition of ACC HFX RT to the treatment of the most favorable subset of patients led to improved survival over that obtained with CHT alone.