Design and fabrication of a nanofibrous polycaprolactone tubular nerve guide for peripheral nerve tissue engineering using a two-pole electrospinning system.

Nerve guidance conduits are considered to be the new generation of scaffolds designed for nerve disorders. A tubular construct with a highly aligned fibrous structure, mimicking the endoneurium layer surrounding inner axons of a nerve fascicle, is a suitable candidate for a nerve guide. In this paper a new approach for the fabrication of 3D tubular nerve guides is introduced using simulation of a two-pole electrospinning system and describing its mechanism. The structure of this scaffold is then optimized using the Taguchi statistical method and after morphological studies by scanning electron microscopy, the crystallinity, tensile strength and protein adsorption of these highly aligned fibres are investigated, comparing them with semi-aligned and random fibres produced via conventional mandrel electrospinning. Cell attachment, proliferation and migration of PC12 neuronal like cells are studied on highly aligned, semi aligned and random structures, and morphological change and elongation are observed in PC12 cells. The results of these studies suggest that conduits fabricated using two-pole electrospinning are a suitable and promising scaffold for peripheral and even spinal nerve regeneration. This nerve guide has a great potential for further advanced modifications and regeneration in higher levels.

Multidisciplinary treatment of olfactory neuroblastoma: Patterns of failure and management of recurrence.

PURPOSE: Esthesioneuroblastoma is an uncommon malignancy of the head and neck for which there is no defined treatment protocol. The purpose of this study is to report our experience with the treatment and patterns of failure of this disease. METHODS AND MATERIALS: From 1994 to 2012, 37 previously unreported patients with esthesioneuroblastoma were evaluated, and 32 eventually treated for cure at 2 academic medical centers. All patients were staged with Kadish criteria. The mean and median follow-ups were 96.1 and 76.5 months respectively (range 6-240 months). RESULTS: The Kadish stage was A in 6 patients, B in 13 patients, and C in 13 patients. Four patients were initially treated with concurrent chemo-radiation therapy. Twenty-eight patients were treated with primary surgery. Two (2) underwent open medial maxillectomy and 26 underwent craniofacial resection (open - 17, endoscopic - 9). Three patients received curative surgical resection only. Seven patients failed either within the cranial axis or distantly, 6 of the 7 are dead of disease, 10-194 months following initial treatment. Six patients had isolated neck recurrences, 4/6 were salvaged with neck dissection and additional chemo-radiation and remain alive 30-194 months following initial treatment. Estimated overall survival rate at 10 years was 78% based on Kadish and T stages. CONCLUSION: In this retrospective analysis of 32 patients, Kadish stage C and stage T3/T4 tumors were associated with worse outcome. Total radiation dose of 60 Gy, margin status, patient age, were not found to have significant prognostic value.

Impact of tumor volume-directed involved field radiation therapy integrated in the management of recurrent ovarian cancer.

OBJECTIVES: Assess the role of involved field radiation therapy (IFRT) in recurrent ovarian cancer. METHODS: Thirty-five patients with a diagnosis of epithelial ovarian cancer received radiation therapy at LUMC between 1991 and 2001. Of these, 20 received tumor volume-directed IFRT for localized extraperitoneal recurrences (either as consolidation following debulking surgery or as attempted salvage if unresectable) and form the basis of this report. All patients were heavily pretreated with multiple chemotherapy regimens. Eleven patients had optimal debulking of their recurrences prior to radiation. IFRT was primarily with external beam (median dose 50.4 Gy). Appropriate statistical analyses evaluated association among disease-free (DFS), overall survival (OS), local recurrence-free (LRFS), and various prognostic factors. LRFS was defined as freedom from in-field recurrences and was considered as a measure of effectiveness of radiotherapy. RESULTS: Of 20 patients, 17 had a complete response after RT. The actuarial LRFS, OS, and DFS at 5 years from date of radiation were 66%, 34%, and 34%, respectively. The LRFS at 3 years was 89% for those with optimal resection vs. 42% for those with gross residual/unresectable tumor, which was significantly better (P = 0.04). The corresponding 3-year DFS was 72% vs. 22% and 5-year OS was 50% vs. 19%, respectively. Acute complication of RT was mild, half had Grade 1-2 gastrointestinal (GI) toxicity, three patients had Grade 3-4 late GI effects. CONCLUSION: IFRT is effective in controlling localized recurrences of ovarian cancer, especially after they are optimally debulked (89% local control and 50% 5-year overall survival in this subgroup), and is relatively well tolerated in these heavily pretreated patients.

Phase II evaluation of paclitaxel in combination with carboplatin in advanced head and neck carcinoma.

BACKGROUND: Two-thirds of patients with squamous cell carcinomas of the head and neck (SCCHN) at diagnosis have advanced disease with projected 5-year survival rates of 30%. In those patients with distant metastatic or previously treated recurrent disease, response rate to the standard regimen of cisplatin and 5-fluorouracil is approximately 30%. The authors investigated the use of paclitaxel and carboplatin in a limited Phase II study in recurrent or metastatic SCCHN to evaluate tumor response, time to progression, survival, and toxicities of this regimen. METHODS: Patients with recurrent or metastatic SCCHN not amenable to further surgical or radiation therapy were treated with 200 mg/m(2) by 3-hour infusion of paclitaxel followed by carboplatin at an area under the concentration time curve of 6 mg/mL/minute via a 20-30-minute infusion every 3 weeks. RESULTS: Thirty-seven patients were enrolled. Ninety-five percent of patients had received prior surgery and postoperative radiotherapy. The overall response rate was 27% (95% confidence interval, 13-41%) with 1 complete and 9 PRs. Median survival of all patients was 4.9 months, and 1-year survival rate was 16%. There was a 43% response rate and 15.7-month median survival rate in patients with only distant metastatic disease and 38% response rate and a 4.5-month median survival in patients with locoregional and metastatic disease. The response rate for patients with only locoregional recurrence was 7% with a median survival of 4.8 months. Grade 3-4 myelotoxicity occurred in 24% of cycles administered. There were two treatment-related deaths due to neutropenic fever and one additional death on study may have been caused by treatment-induced thrombocytopenia. CONCLUSIONS: The combination of paclitaxel and carboplatin is significantly myelotoxic and ineffective in patients with previously treated locoregionally recurrent SCCHN, whereas it deserves further evaluation in those patients with distant metastatic disease alone. In those patients with locoregional disease, other more innovative treatments are needed.

Patterns of spread in recurrent head and neck squamous cell carcinoma.

OBJECTIVE: To examine the pattern of spread regarding recurrent disease in primary head and neck squamous cell carcinoma. STUDY DESIGN AND SETTING: A retrospective study reviewed 128 patients who underwent primary tumor resection and postoperative radiation and/or chemoradiation for squamous cell carcinoma at Loyola University Medical Center from July 1993 to August 1998. Patterns of spread of recurrent disease were grouped according to site of recurrence and compared with the histopathology. RESULTS: Of 128 patients, 40 (32%) had recurrent disease, 22 (17%) died without disease, and 66 (51%) are disease free. Although the recurrences in patients who were N0 were primarily local-regional (8/11), the majority of recurrences in patients that were N+ with extracapsular nodal spread involved distant sites (18/24); 17/18 involved metastasis to the lung. SIGNIFICANCE: This study gives the first report at our institution of patterns of spread in recurrent head and neck squamous cell cancer and compares these patterns within subgroups of patients based on the extent of neck disease at the time of primary surgical resection. CONCLUSION: Not only was there a higher rate of recurrent disease in patients with extracapsular nodal spread, there was a much higher involvement of distant metastatic sites as opposed to local-regional recurrence more often seen with the N0 neck. The most common site of distant metastasis was the lung.

Parotid-sparing irradiation for cancer of the oral cavity: maintenance of oral nutrition and body weight by preserving parotid function.

The purpose of this study was to assess the nutritional benefit of parotid-sparing irradiation, comparing the body weights of patients irradiated with parotid-sparing technique versus those irradiated with bilateral opposed photon beams, including both parotid glands in the radiation fields. One hundred fourteen patients with cancer of the oral cavity were irradiated with curative intent. Two-dimensional radiotherapy techniques sparing at least one parotid gland from the radiation beams were used to treat 31 patients (parotid-sparing techniques). Eighty-three patients were irradiated using bilateral opposed photon beams, which included both parotid glands (bilateral technique). Body weight during and after irradiation, treatment outcome, and survival were compared. Patients treated with parotid-sparing techniques maintained their nutritional intake and baseline body weight during and after irradiation. Patients treated with the bilateral technique that included both parotid glands had poor nutritional intake, leading to a more than 10% decline in their initial body weight; these patients did not regain their body weight during the 2-year follow-up period. Primary tumor control rate was higher for patients treated with parotid-sparing techniques than for patients who had both parotid glands irradiated (70% versus 48%; p = 0.05). This difference is because a higher percentage of patients treated with parotid-sparing techniques had early-stage tumors (54%) compared with patients treated with the bilateral technique (24%). When analyzed according to the tumor stage, the primary tumor control rates for patients treated with parotid-sparing techniques and for patients treated with the bilateral technique showed no difference; control rates were 93% and 87% (p = 1.00) for early-stage tumors and 42% and 36% (p = 0.75) for advanced-stage tumors, respectively. Nodal control rates in the ipsilateral side of the neck and in the contralateral side of the neck for patients treated with parotid-sparing techniques and with the bilateral technique were not significantly different-74% versus 76% (p = 0.86) and 70% versus 82% (p = 0.21), respectively. Sparing at least one parotid gland during irradiation of patients with head and neck cancer will preserve parotid function and prevent xerostomia. Patients treated with parotid-sparing techniques were able to maintain their oral nutrition and body weight, compared with patients who had both parotid glands irradiated. A higher percentage of patients treated with parotid-sparing techniques had early-stage tumors, resulting in higher rates of primary tumor control and survival in this group of patients.

Stomal recurrence in patients with T1 glottic cancer after salvage laryngectomy for radiotherapy failures: role of p53 overexpression and subglottic extension.

The role of p53 overexpression in the development of stomal recurrence was studied in patients with T1 glottic cancer who had undergone salvage laryngectomy after primary radiotherapy failure (first recurrence). The role of subglottic extension of the recurrent tumor in the development of stomal recurrence was also studied. One hundred fourteen patients with T1 squamous cell carcinoma of the glottic larynx were irradiated with curative intent. A local recurrence (first recurrence) developed in 23 patients (20%), and salvage laryngectomy was performed for 20 of these patients. No postlaryngectomy radiation therapy was included in the treatment of recurrences. Several risk factors thought to be significant in the development of stomal recurrence were analyzed in these 20 patients. Prognostic factors analyzed include: p53 overexpression in the preradiation biopsy specimen, subglottic extension of the first recurrence, thyroid cartilage and lymph node involvement at the time of first recurrence, emergency tracheostomy performed before salvage laryngectomy, and the laryngectomy procedure performed for first recurrence. Presence of p53 protein in the preradiation biopsy specimen of laryngeal cancer did not show any adverse effect on the development of stomal recurrence. Stomal recurrence developed in 27% of patients with positive biopsies and in 20% of patients with negative biopsies (p = 1.00). Subglottic extension of the first recurrence was associated with an increased incidence of stomal recurrence. Rates of stomal recurrence were 6% in patients without subglottic extension and 100% in patients with subglottic extension (p = 0.001). All other risk factors studied showed no effect on stomal recurrence. In this study, p53 overexpression showed no effect on the development of stomal recurrence after salvage laryngectomy in patients with T1 glottic cancer. Conversely, subglottic extension of the recurrence was found to be strongly associated with stomal recurrence. All other factors analyzed showed no effect on stomal recurrence.

Matching tomographic IMRT fields with static photon fields.

The matching of abutting radiation fields presents a challenging problem in radiation therapy. Due to sharp penumbra of linear accelerator beams, small (1-2 mm) errors in field positioning can lead to large (>30%) hot or cold spots in the abutment region. With head and neck immobilization devices (thermoplastic mask/aquaplast) an average setup error of 3 mm has been reported. Therefore hot or cold spots approaching 50% of the prescription dose may occur along the matchline. Although abutting radiation fields have been investigated for static fields, there is no reported study regarding matching of tomographic IMRT and static fields. Compared to static fields, the matching of tomographic IMRT fields with static fields is more complicated. Since IMRT and static fields are planned on separate treatment planning computers, the dose in the abutment region is not specified. In addition, commonly used techniques for matching fields, such as feathering of junctions, are not practical. We have developed a method that substantially reduces dose inhomogeneity in the abutment region. In this method, a "buffer zone" around the matchline was created and was included as part of the target for both IMRT and static field plans. In both fields, a small dose gradient (< or =3%/mm) in the buffer zone was created. In the IMRT plan, the buffer zone was divided into three sections with dose varying from 83% to 25% of prescription dose. The static field dose profile was modified using either a specially designed physical (hard) or a dynamic (soft) wedge. When these modified fields were matched, the combined dose in the abutment region varied by < or =10% in the presence of setup errors spanning 4 mm (+/-2 mm) when the hard wedge was used and 10 mm (+/-5 mm) with the soft wedge.

New therapeutic strategies for the treatment and prevention of head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is an aggressive epithelial malignancy that is now the sixth most common neoplasm in the world today. Approximately 50,000 cases in the United States and more than 500,000 cases worldwide will be diagnosed in 2000 [1]. Despite numerous advances in treatment utilising the most recent protocols for surgery, radiation and chemotherapy, the long-term survival has remained at less than 50% over the past 40 years [2]. This poor long-term survival is due to a number of variables including delayed diagnosis as well as the frequent development of multiple primary tumours. Therefore, in addition to early detection, continued emphasis must be placed on preventing the development of new primaries as well as establishing more effective treatments for individuals who present with advanced disease. This review will summarise some of the recent advances in the realms of chemotherapy and radiation therapy. In addition, it will discuss the present status of chemoprevention in HNSCC. Finally, we will discuss the rationale for the use of anti-angiogenic agents as one possible means of developing new chemopreventive protocols that result in reduced toxicity while maintaining similar clinical efficacies.

Improvement of tomographic intensity modulated radiotherapy dose distributions using periodic shifting of arc abutment regions.

Based on the study of treatment arc positioning versus target length, a method that allowed periodic shift of arc abutment regions through the course of intensity modulated radiotherapy (IMRT) was developed. In this method, two treatment plans were developed for the same tumor. The first plan contained the original target (Planning Target Volume as defined by radiation oncologist) and the second one contained a modified target. The modification of the original target consisted of simply increasing its length, adding a small extension to it, or creating a distant pseudo target. These modifications cause arc abutment regions in the second plan to be shifted relative to their positions in the first plan. Different methods of target modification were investigated because in some cases (for instance, when a critical structure might overlap with the target extension) a simple extension of the target would cause an unacceptable irradiation of the sensitive structures. The dose prescribed to the modified portion of the target varied from 10% to 100% of the original target dose. It was found that a clinically significant shift (> or =5 mm) in abutment region locations occurred when the dose prescribed to the extended portion of the target was > or =95% of the original target dose. On the other hand, the pseudo target required only approximately 10% to 20% of the original target dose to produce the same shift in arc positions. Results of the film dosimetry showed that when a single plan was used for the treatment delivery, the dose nonuniformity was 17% and 25% of the prescribed dose with 0.5 and 1 mm errors in couch indexing, respectively. The dose nonuniformity was reduced by at least half when two plans were used for IMRT delivery.

Nonsurgical treatment of advanced metastatic cervical disease in cancer of the larynx.

Historically, patients with advanced cervical adenopathy (N2 or N3) have between a 20 and 30% chance of surviving their disease at 5 years from treatment. Despite attempts at more aggressive surgical resection, including resection and reconstruction of the carotid artery, patients with advanced cervical adenopathy remain at the highest risk for the development of local recurrences and distant metastases. This chapter will review the current limitations of surgical resectability for advanced neck disease, discuss the evolution of combined chemoradiation therapy for these patients, and finally present promising recent technological advances in radiation oncology which will have significant impact on the treatment of these patients.

Evaluation of a standard breast tangent technique: a dose-volume analysis of tangential irradiation using three-dimensional tools.

PURPOSE: A thorough dose-volume analysis of a standard tangential radiation technique has not been published. We evaluated the adequacy of a tangential radiation technique in delivering dose to the breast and regional lymphatics, as well as dose delivered to underlying critical structures. METHODS AND MATERIALS: Treatment plans of 25 consecutive women with breast cancer undergoing lumpectomy and adjuvant breast radiotherapy were studied. Patients underwent two-dimensional (2D) treatment planning followed by treatment with standard breast tangents. These 2D plans were reconstructed without modification on our three-dimensional treatment planning system and analyzed with regard to dose-volume parameters. RESULTS: Adequate coverage of the breast (defined as 95% of the target receiving at least 95% of the prescribed dose) was achieved in 16 of 25 patients, with all patients having at least 85% of the breast volume treated to 95% of the prescribed dose. Only 1 patient (4%) had adequate coverage of the Level I axilla, and no patient had adequate coverage of the Level II axilla, Level III axilla, or the internal mammary lymph nodes. CONCLUSION: Three-dimensional treatment planning is superior in quantification of the dose received by the breast, regional lymphatics, and critical structures. The standard breast tangent technique delivers an adequate dose to the breast but does not therapeutically treat the regional lymph nodes in the majority of patients. If coverage of the axilla or internal mammary lymph nodes is desired, alternate beam arrangements or treatment fields will be necessary.

A modified method of planning and delivery for dynamic multileaf collimator intensity-modulated radiation therapy.

PURPOSE: To develop a modified planning and delivery technique that reduces dose nonuniformity for tomographic delivery of intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS: The NOMOS-CORVUS system delivers IMRT in a tomographic paradigm. This type of delivery is prone to create multiple dose nonuniformity regions at the arc abutment regions. The modified technique was based on the cyclical behavior of arc positions as a function of a target length. With the modified technique, two plans are developed for the same patient, one with the original target and the second with a slightly increased target length and the abutment regions shifted by approximately 5 mm compared to the first plan. Each plan is designed to deliver half of the target prescription dose delivered on alternate days, resulting in periodic shifts of abutment regions. This method was experimentally tested in phantoms with and without intentionally introduced errors in couch indexing. RESULTS: With the modified technique, the degree of dose nonuniformity was reduced. For example, with 1 mm error in couch indexing, the degree of dose nonuniformity changed from approximately 25% to approximately 12%. CONCLUSION: Use of the modified technique reduces dose nonuniformity due to periodic shifts of abutment regions during treatment delivery.

Final results of phase III trial in regionally advanced unresectable non-small cell lung cancer: Radiation Therapy Oncology Group, Eastern Cooperative Oncology Group, and Southwest Oncology Group.

STUDY OBJECTIVES: The purpose of this phase III clinical trial was to test whether chemotherapy followed by radiation therapy resulted in superior survival to either hyperfractionated radiation or standard radiation in surgically unresectable non-small cell lung cancer. DESIGN: Patients were prospectively randomized to 2 months of cisplatin, vinblastine chemotherapy followed by 60 Gy of radiation at 2.0 Gy per fraction or 1.2 Gy per fraction radiation delivered twice daily to a total dose of 69.6 Gy, or 2.0 Gy per fraction of radiation once daily to 60 Gy. Patients were enrolled from January 1989 through January 1992, and followed for a potential minimum period of 5 years. SETTING: This trial was an intergroup National Cancer Institute-funded trial within the Radiation Therapy Oncology Group, the Eastern Cooperative Oncology Group, and the Southwest Oncology Group. PATIENTS: Patients with surgically unresectable non-small cell lung cancer, clinical stage II, IIIA, and IIIB, were required to have a Karnofsky Performance Status of > or = 70 and a weight loss of < 5% for 3 months before study entry. Four hundred ninety patients were registered on trial, of which 458 patients were eligible. CONCLUSION: Overall survival was statistically superior for the patients receiving chemotherapy and radiation vs the other two arms of the study. The twice-daily radiation therapy arm, although better, was not statistically superior in survival for those patients receiving standard radiation. Median survival for standard radiation was 11.4 months; for chemotherapy and irradiation, 13.2 months; and for hyperfractionated irradiation, 12 months. The respective 5-year survivals were 5% for standard radiation therapy, 8% for chemotherapy followed by radiation therapy, and 6% for hyperfractionated irradiation.

Clinical dose-volume histogram analysis for pneumonitis after 3D treatment for non-small cell lung cancer (NSCLC)

PURPOSE: To identify a clinically relevant and available parameter upon which to identify non-small cell lung cancer (NSCLC) patients at risk for pneumonitis when treated with three-dimensional (3D) radiation therapy. METHODS AND MATERIALS: Between January 1991 and October 1995, 99 patients were treated definitively for inoperable NSCLC. Patients were selected for good performance status (96%) and absence of weight loss (82%). All patients had full 3D treatment planning (including total lung dose-volume histograms [DVHs]) prior to treatment delivery. The total lung DVH parameters were compared with the incidence and grade of pneumonitis after treatment. RESULTS: Univariate analysis revealed the percent of the total lung volume exceeding 20 Gy (V20), the effective volume (Veff) and the total lung volume mean dose, and location of the tumor primary (upper versus lower lobes) to be statistically significant relative to the development of > or = Grade 2 pneumonitis. Multivariate analysis revealed the V20 to be the single independent predictor of pneumonitis. CONCLUSIONS: The V20 from the total lung DVH is a useful parameter easily obtained from most 3D treatment planning systems. The V20 may be useful in comparing competing treatment plans to evaluate the risk of pneumonitis for our individual patient treatment and may also be a useful parameter upon which to stratify patients or prospective dose escalation trials.

Simultaneous superficial hyperthermia and external radiotherapy: report of thermal dosimetry and tolerance to treatment.

BACKGROUND: In vitro and animal studies indicate that a moderate temperature of 41 degrees C maintained for approximately 1 h will provide radiosensitization if radiation (RT) and hyperthermia (HT) are delivered simultaneously, but not with sequential treatment. A minimum tumour temperature of 41 degrees C is a more feasible goal than the goal of >42 degrees C needed for sequential treatment. METHODS AND MATERIALS: Forty-four patients with 47 recurrent superficial cancers received simultaneous external beam radiotherapy and superficial hyperthermia on successive IRB approved phase I/II studies. All lesions had failed previous therapy, 35 were previously irradiated (mean dose 52.7 Gy). Hyperthermia was delivered with 915 MHz microwave or 1-3.5 MHz ultrasound using commercially available applicators. The average dimensions of 19 lesions treated with microwave were 4.7 x 3.6 x 1.7 cm and the average dimensions of 28 lesions treated with ultrasound were 8.0 x 6.1 x 2.9 cm. The most common sites were chest wall (15 cases) and head and neck (21 cases). Temperatures were monitored at an average of six intratumoral locations using multisensor probes. The median number of hyperthermia treatments was three and the median radiation dose 30 Gy. Radiation dose per fraction was 4 Gy with hyperthermia and 2 Gy or 4 Gy (depending on protocol) on non-hyperthermia days. RESULTS: Six different measures of minimum monitored temperature and duration were found to be highly correlated with each other. There was nearly a one-to-one correspondence between minimum tumour time at or above 41 degrees C (Min t41) and minimum tumour Sapareto Dewey equivalent time at 42 degrees C (Min teq42). After four sessions 63% of cases had a per session average Sapareto Dewey equivalent time at 41 degrees C which exceeded 60 min in all monitored tumour locations. The complete and partial response rate in evaluable lesions were respectively 21/41 (51%) and 7/41 (17%) and were best correlated with site (chest wall showing best response). Toxicity consisted of 10/47 (21%) slow healing soft tissue ulcers which healed in all cases but required a median of 7 months. The most important predictors for chronic ulceration were cumulative radiation dose >80 Gy and complete response to treatment. CONCLUSIONS: Minimum tumour temperatures maintained for durations compatible in vitro with thermal radiosensitization (if RT and HT are delivered simultaneously) are clinically feasible and tolerable for broad but superficial lesions amenable to externally applied ultrasound or microwave hyperthermia. The current in-house protocol is evaluating the impact of more than four hyperthermia sessions on the overall thermal dose distribution and toxicity.

Addition of chemotherapy to radiation therapy alters failure patterns by cell type within non-small cell carcinoma of lung (NSCCL): analysis of radiation therapy oncology group (RTOG) trials.

PURPOSE: To evaluate the influence of cell type within non-small cell carcinoma of lung (NSCCL) on failure patterns when chemotherapy (CT) is combined with radiation therapy (RT). METHODS AND MATERIALS: Data from 4 RTOG studies including 1415 patients treated with RT alone, and 5 RTOG studies including 350 patients also treated with chemotherapy (RT + CT) were analyzed. Patterns of progression were evaluated for squamous cell carcinoma (SQ) (n = 946), adenocarcinoma (AD) (n = 532) and large cell carcinoma (LC) (n = 287). RESULTS: When treated with RT alone, SQ was more likely to progress at the primary site than LC (26% vs. 20%, p = 0.05). AD and LC were more likely to progress in the brain than SQ (20% and 18% vs. 11%, p = 0.0001 and 0.011, respectively). No differences were found in intrathoracic and distant metastasis by cell type. When treated with RT + CT, AD was less likely to progress at the primary than either SQ or LC (23% vs. 34% and 40%, respectively; p = 0.057 and 0.035). AD was more likely than SQ to metastasize to the brain (16% vs. 8%, p = 0.03), and other distant sites (26% vs. 14%,p = 0.019). No differences were found in intrathoracic metastasis. LC progressed at the primary site more often with RT + CT than with RT alone (40% vs. 20%, p = 0.036). Death with no clinical progression was more likely with SQ than AD or LC for RT alone and RT + CT (p < 0.01). Brain metastasis was altered little by the addition of CT, but other distant metastases were significantly decreased (p < 0.001) in all cell types by the addition of CT. CONCLUSION: CT, although effective in reducing distant metastasis in all types of NSCCL, has different effects on the primary tumor by cell type, and has no effect on brain metastasis or death with no progression. Different treatment strategies should be considered for the different cell types to advance progress with RT + CT in NSCCL.

Response, toxicity, failure patterns, and survival in five Radiation Therapy Oncology Group (RTOG) trials of sequential and/or concurrent chemotherapy and radiotherapy for locally advanced non-small-cell carcinoma of the lung.

PURPOSE: The purpose of this study was to assess response, toxicity, failure patterns, and survival differences in three chemotherapy (ChT)/radiation therapy (RT) sequencing strategies for locally advanced non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: Five completed Radiation Therapy Oncology Group (RTOG) trials for Stage II-IIIA/B inoperable NSCLC patients employed one of the three following strategy groupings: 1) sequential ChT followed by standard RT (60 Gy in 6 weeks); 2) combined sequential and concurrent ChT and standard RT (60 Gy in 6 weeks); or 3) concurrent ChT and hyperfractionated RT (69.6 Gy in 6 weeks). All five trials required KPS > or = 70; two trials (314 patients) required <5% weight loss and three trials (147 patients) had no minimum weight loss requirement. In all five trials the ChT used cisplatin with either vinblastine or oral etoposide. Combining data for the five trials yielded an evaluable group of 461 patients. The three methods of sequencing ChT and RT were evaluated for differences in response, acute and late toxicity, patterns of failure, and survival. Acute toxicity was defined as that occurring within 90 days from the start of RT. Late toxicity was defined as that occurring after 90 days from the start of RT. Acute or late toxicity > or = grade 3 was defined as severe. Site of first failure was recorded by date. In-field failure excluded distant metastasis as a failure and included only tissue in the RT treatment field. Overall progression-free survival (PFS) was defined as survival without evidence of intra- or extrathoracic tumor or death from any cause. RESULTS: Group 1 had a lower overall response rate (63%) compared to either Group 2 (77%) or Group 3 (79%), p = 0.03 and 0.003, respectively. Overall grade 4/5 acute toxicities were nearly equal between groups. The severe nonhematologic acute toxicities were significantly different by strategy group (p < 0.0001). Group 1 and 2 were not statistically different. Group 3 had significantly more patients with severe acute nonhematologic toxicity (55%) than either Group 1 (27%) or 2 (34%) with p < 0.0001 and p = 0.0005, respectively. This was due to a severe acute esophagitis rate of 34% for Group 3 versus 1.3% for Group 1 and 6% for Group 2 (p < 0.0001 for both comparisons). Overall grade 4/5 late toxicities did not differ by group. Severe late nonhematologic toxicities were different by group (p = 0.0098). Group 1 patients had significantly fewer severe late nonhematologic toxicities (14%) compared to patients in Groups 2 (26%) or 3 (28%) (p = 0.046 and 0.038, respectively). Severe late lung toxicity was 10% for Group 1 compared to 21% and 20% for Groups 2 and 3, respectively. Severe late lung toxicities differed by group (p = 0.033), but not severe late esophagitis (p = 0.077). There were no differences between the three strategy groups for patterns of first failure. The in-field failures were higher in Group 2 (71%) compared to Groups 1 (56%) and 3 (55%), p = 0.0478. Pairwise comparisons yielded p-values of 0.068 and 0.015 for Group 2 versus 1 and Group 2 versus 3, respectively. Three-year PFS was better in Group 2 (15%) and 3 (15%) compared to Group 1 (7%), but not statistically significant (p = 0.454). Similarly, in-field PFS was better in Group 2 (17%) and 3 (20%) than Group 1 (9%), but not significant (p = 0.167). There were improvements in 3-year survival for Group 2 (17%) and Group 3 (25%) compared to Group 1 (15%), but the differences were not statistically significant (p = 0.47). The same results were present for patients with less than 5% weight loss and patients with stage IIIA tumors. CONCLUSION: Thus, concurrent ChT and hyperfractionated RT had a higher incidence of severe acute esophageal toxicity. Severe late lung toxicity with concurrent ChT/hyperfractionated RT, as well as with induction ChT followed by concurrent ChT/standard RT, may be greater compared to sequential ChT/RT. (ABSTRACT TRUNCATED)

Failure patterns by prognostic group determined by recursive partitioning analysis (RPA) of 1547 patients on four radiation therapy oncology group (RTOG) studies in inoperable nonsmall-cell lung cancer (NSCLC).

PURPOSE: To identify groups of patients who might benefit from more aggressive systemic or local treatment, based on failure patterns when unresectable NSCLC was treated by radiation therapy (RT) alone. METHODS: From 4 RTOG trials, 1547 patients treated by RT alone were analyzed for patterns of first failure by RPA class defined by prognostic factors, including KPS, weight loss, nodal stage, pleural effusion, age and radiation therapy dose. All patients had NSCLC AJCC Stage II, IIIA, or IIIB, KPS > 50, with no previous RT or chemotherapy. Progressions in the primary (within irradiated fields), thorax (outside irradiated area, but within thorax), brain and distant metastasis other than brain were compared (2-sided) for each failure category by RPA. RESULTS: The RPA classes were 4 distinct subgroups that had significantly different median survivals of 12.6, 8.3, 6.3 and 3.3 months for Classes I, II, III and IV, respectively, (all groups, p = 0.0002). There were 583, 667, 249 and 48 patients in Classes I, II, III and IV, respectively. Primary failure was seen in 27%, 25%, 21% and 10% for Classes I, II, III, and IV, respectively (I vs. IV, p = 0.014; II vs. IV, p = 0.022). Distant metastasis, including brain metastasis, occurred at significantly higher rates among Classes I and II (58% and 54%) than in Classes III and IV (42% and 27%). A higher rate (58%) of death without an identifiable site of failure was found in Class IV than in Classes I, II and III (27%, 28% and 36%, respectively). CONCLUSIONS: The data suggest that physiologic compromise from the intrathoracic disease in Class IV patients is sufficient to cause death before specific sites of failure became evident. Clinical investigations using treatments directed at specific sites of failure could lead to improved outcome for Class I, II and, possibly, Class III patients. Inclusion of Class IV patients in clinical trials may obscure outcomes.

Results of treatment of patients with maxillary sinus carcinoma.

BACKGROUND: Information regarding results of treatment and possible prognostic factors in patients with maxillary sinus carcinoma is limited. METHODS: Between 1969-1995, 48 consecutive patients presented to the study department for curative treatment of maxillary sinus carcinoma. Tumor classification according to the American Joint Committee on Cancer staging system was T1 in 1 patient, T2 in 6 patients, T3 in 17 patients, and T4 in 24 patients. The N classification was NO in 43 patients, N2a in 1 patient, N2b in 3 patients, and N2c in 1 patient. Treatment to the primary site was comprised of surgery (Sx) and radiation therapy (RT) in 37 patients and RT alone in 11 patients. RESULTS: There was a difference in disease free survival between patients who underwent Sx + RT compared with patients who received RT alone; combined therapy results were more favorable. The most common pattern of recurrence was in the primary site, which was found in 22 of 48 patients (45.8%). For patients who underwent Sx + RT, local control at 3 and 5 years was 65.2% and 59.2%, respectively; for patients who received RT alone, local control at both 3 and 5 years was 22.7%. There were 12 late complications found in 8 patients: fistula formation (5 patients), trismus (3 patients), osteonecrosis (1 patient), retinopathy (1 patient), cellulitis (1 patient), and nasal stenosis (1 patient). CONCLUSIONS: The type of treatment to the primary site is an important determinant of disease free survival and local control. Failure at the primary site is the main problem in the curative treatment of patients with maxillary sinus carcinoma; efforts to improve survival in these patients should be directed toward improvement of local control.