Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099.

PURPOSE: The Southwest Oncology Group (SWOG) coordinated an Intergroup study with the participation of Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. MATERIALS AND METHODS: Radiotherapy was administered in both arms: 1.8- to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total dose of 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS: Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P < .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P < .001). CONCLUSION: We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.

Organ preservation for advanced resectable cancer of the base of tongue and hypopharynx: a Southwest Oncology Group Trial.

PURPOSE: The Southwest Oncology Group designed a phase II trial for patients with base of tongue or hypopharyngeal cancer to evaluate the complete histologic response rate at the primary site after induction chemotherapy followed by chemoradiotherapy for responders. Secondary end points were the rate of organ preservation and the need for salvage surgery. PATIENTS AND METHODS: Fifty-nine eligible patients were enrolled; 37 had base of tongue cancer, and 22 had hypopharynx cancer. Forty-two percent had stage III disease, and 58% had stage IV disease. Induction chemotherapy was two cycles of cisplatin 100 mg/m(2) and fluorouracil 1,000 mg/m(2)/d for 5 days. Patients who had a greater than 50% response at the primary site were treated with radiation 72Gy and concurrent cisplatin 100 mg/m(2) for three cycles. Patients with less than partial response at the primary had immediate salvage surgery. RESULTS: Forty-five patients (76%) had a greater than 50% response at the primary after induction chemotherapy; 43 went on to receive definitive chemoradiotherapy. Thirty-two patients (54%) achieved a histologic complete response at the primary site, and an additional nine patients had a complete clinical response, but biopsy was not done. Seventy-five percent of patients did not require surgery at the primary tumor site. The 3-year overall survival was 64%. The 3-year progression-free survival with organ preservation was 52%. CONCLUSION: Patients with base of tongue or hypopharyngeal cancer treated with this regimen of induction chemotherapy followed by definitive chemoradiotherapy have a good rate of organ preservation without compromise of survival.

Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099.

PURPOSE: The Southwest Oncology Group (SWOG) coordinated an Intergroup study with the participation of Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. MATERIALS AND METHODS: Radiotherapy was administered in both arms: 1.8- to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total dose of 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS: Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P < .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P < .001). CONCLUSION: We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.

Concurrent chemotherapy/radiotherapy for limited small-cell lung carcinoma: a Southwest Oncology Group Study.

The Southwest Oncology Group (SWOG) has conducted a phase II study to explore the efficacy and toxicity of initial, concurrent use of radiation therapy with cisplatin, etoposide (VP-16), and vincristine in limited-stage small-cell carcinoma of the lung. Two courses of cisplatin, VP-16, and vincristine chemotherapy were given with concurrent radiotherapy (XRT) to the primary tumor to a total dose of 4,500 cGy. Elective brain XRT was given to all patients concurrent with a third course of cisplatin/VP-16 therapy. Consolidation chemotherapy consisting of vincristine, methotrexate, and VP-16 alternating with Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) and cyclophosphamide, was given for 12 weeks following the initial induction chemotherapy/XRT program. Patients with a complete response had all therapy discontinued. Among 154 eligible patients treated, the complete response rate was 56%, with a partial response rate of 27%. The median survival is 17.5 months with an estimated 30% survival rate at 4 years from initiation of treatment. Combined modality toxicities were acceptable with the predominant toxicity being moderate to severe leukopenia and mild radiation esophagitis. The results of this treatment program appear superior to any previously reported by our group and compare favorably to those in the literature at large.

Concurrent chemotherapy and radiotherapy for limited small-cell carcinoma of the lung: a Southwest Oncology Group Study.

This pilot study in limited-stage small-cell carcinoma of the lung using concurrent cisplatin (Platinol) and etoposide (VePesid) chemotherapy with radiotherapy has yielded a high complete response rate in 23 of 40 patients evaluable for response. Five of these responders have survived greater than 2 years off all therapy with a stable, high performance status. Median survival of all patients is 18 months. Toxicity has been acceptable, the most common being neutropenia. Radiation toxicities include 17 of 40 patients experiencing mild to moderate esophagitis, with one severe toxicity; and three of 40 patients developing mild to moderate radiation pneumonitis. The high complete remission observed with this program and the long tumor-free interval seen off maintenance therapy deserve further exploration. Toxicities appear only moderately greater than with other programs currently utilized.

Computed tomography in the management of bladder carcinoma.

Between 1978 and 1980, 30 patients were evaluated by computed tomography (CT). CT differed from clinical stage in 10 of 30 patients (30%). In 9 of the 10 patients the change in stage resulted because of extravesical extension or involvement of the prostate. Seventeen patients underwent pre-operative irradiation, and CT scans done post-irradiation showed a decrease in tumor stage in 5 patients (33%). The accuracy of CT in detecting nodal involvement was limited with an overall accuracy of 65%. CT has limited value in staging of bladder cancer.

Role of computed tomography in the evaluation and management of carcinoma of the prostate.

Between January 1978 to March 1980, 25 patients with biopsy-proven prostate carcinoma were evaluated by computerized tomography (CT). CT differed from clinical stage in 7 of 25 patients (28%). In 6 of the 7 patients, change in stage resulted because of demonstration of extracapsular extension and/or pelvic lymph node involvement. Twelve of the 25 patients (48%) underwent surgery with histological confirmation of CT findings. Ct identified nodal involvement accurately in 10 of 12 patients (83%). We recommend use of CT for initial staging, treatment planning and assessment of response in the management of prostate cancer.

Comparison of single, fractionated and hyperfractionated irradiation on the development of normal tissue damage in rat lung.

The effect of fractionated thoracic irradiation on the development of normal tissue damage in rats was compared to that produced by single doses. Animals received a single dose of 15 Gy, 30 Gy in 10 daily fractions of 3 Gy each (fractionation), or 30 Gy in 30 fractions of 1 Gy each 3 times a day (hyperfractionation). The treatments produced minimal lethality since a total of only 6 animals died between days 273 and 475 after the initiation of treatment, with no difference in survival observed between the control and any of the 3 treated groups. Despite the lack of lethality, evidence of lung damage was obtained by histological examination. At times less than 180 days after treatment, the lungs of animals receiving a single dose of 15 Gy displayed more severe changes than did animals from either fractionation group. At longer times after treatment (days 261 and 475), the histological appearances within each group were changed, collagen deposits and fibrosis being the most significant observations. Animals that had received either single doses or fractionated doses had more of the pulmonary parenchyma involved than did animals that had received hyperfractionated doses. We conclude that, in the rat lung model, a total radiation dose of 30 Gy fractionated over 14 days produces no more acute lethality nor damage to lung tissue than does 15 Gy delivered as a single dose. However, long-term effects as evidenced by deposits of collagen and development of fibrosis are significantly reduced by hyperfractionation when compared to single doses and daily fractionation.

Dosimetric analysis in brachytherapy of carcinoma of the cervix.

Brachytherapy plays an essential role in the definitive radiation treatment of cervical carcinoma. The dosimetry of intracavitary irradiation is complex in that the optimum doses that can be delivered are dictated not only by the volume and extent of tumor but also by the close vicinity of dose-limiting structures, such as the small and large intestines, rectum, and bladder. To facilitate understanding of the relationships between the various dosimetric parameters involved, a retrospective analysis of 50 randomly chosen intracavitary insertions with Cesium-137 in 41 patients performed at our institution between 1975 and 1985 was carried out. All 50 cases utilized Fletcher-Suit-Delcos applicators and only the insertions using three sources in the tandem and one in each of the ovoids were included in this analysis. Using the AP and lateral radiographs and the lymphatic trapezoid, the reference points were obtained and transferred digitally to the treatment planning computer, and computerized dosimetry performed. In addition to the specified reference points, points were added and modified to obtain more complete information. The doses at the specified points were normalized to the average dose at AT, a reference point 2 cm superior to external os and 2 cm lateral to the tandem, and expressed as a percentage. It was noted that the average dose at the closest bladder point was 103 +/- 41% of the dose at AT, the maximum rectal dose 77 +/- 29% of the dose at AT and the maximum small bowel dose 65 +/- 16% of that at AT. The analysis of percent contribution of various sources to different reference points revealed that the dose to point AT was equally contributed to by all sources; bladder and rectal doses were mainly contributed to by the lowermost uterine and ovoid sources. Our analysis may provide a model for optimizing brachytherapy in cervical carcinoma.

Univariate and multivariate statistical analysis of high-grade gliomas: the relationship of radiation dose and other prognostic factors.

Univariate and multivariate statistical analyses were used to examine the relationships between duration of survival and multiple variables in the presentation and treatment of 82 patients with high-grade gliomas (16 grade 3, 66 grade 4). The median survival time of the eight patients who received less than or equal to 40 Gy to the tumor bed was 16 weeks and was 17 weeks for the three who received between 40 and 50 Gy. Patients who received 50-60 Gy had a median survival time of 62 weeks, compared to 54 weeks in patients who received 60-70 Gy. These differences in median survival time were statistically significant between the extremes (p = 0.0001), as well as between the 40-50 Gy group and the 50-60 Gy group (p = 0.02). However, no significant difference could be detected between the groups receiving 50-60 Gy versus 60-70 Gy. Univariate analysis also identified preoperative performance status, age, histologic grade, extent of surgery, and seizure history as prognostic factors. Cox multivariate analysis was performed to identify variables that were significant in independently predicting duration of survival. Although contemporary studies have shown many variables to be significant in predicting survival, our analysis found that many of them were not independent predictors. The variables which independently predicted improved duration of survival were greater total radiation dose to the tumor bed (p less than 0.0001), superior preoperative performance status (p = 0.003), and grade 3 versus grade 4 (p = 0.04). Younger age at diagnosis was marginally significant (p = 0.07). In the group of 60 patients receiving greater than 50 Gy, a discriminant analysis was also performed. The patients were divided into two groups based on apparent clusters of survival times: greater than or equal to 60 weeks versus less than 60 weeks. The only variable that was found to be predictive of membership in the cluster with longer survival was the presence of seizure activity (p = 0.02). Although univariate and multivariate analyses both showed an apparent statistically significant improvement in survival with increasing total radiation dose to the tumor bed, no additional benefit could be demonstrated for doses greater than 60 Gy.

Ten-year follow-up of Southwest Oncology Group 8269: a phase II trial of concomitant cisplatin-etoposide and daily thoracic radiotherapy in limited small-cell lung cancer.

PURPOSE: To report the long-term follow-up of Southwest Oncology Group-8269, a phase II North American cooperative group trial of concurrent cisplatin, etoposide, vincristine (PEV), and thoracic radiotherapy (TRT) for limited small-cell lung cancer (L-SCLC). METHODS: 114 eligible patients from 47 institutions enrolled between April, 1985 and March 1986. Patients had documented L-SCLC. Induction chemotherapy consisted of three cycles of PEV. TRT was administered at 1.8 Gy/fraction in 25 daily fractions to a total dose of 45 Gy, to begin concomitantly. Consolidative chemotherapy included two cycles of vincristine, methotrexate, etoposide, doxorubicin and cyclophosphamide. Prophylactic cranial irradiation (PCI) was concurrent with the 3rd cycle of chemotherapy. The PCI dose was 30 Gy in 15 fractions of 2 Gy/fraction. RESULTS: As of May 2000, 5 of 114 remain alive and progression-free with a minimum follow-up interval of 13.2 years, as of May 2000. The median follow-up interval is 14.2 years. Thirty eight patients died of causes other than SCLC and five patients are still alive and progression-free. Of the remaining 71 patients dying of SCLC, local failure (LF) occurred in 24% (17 patients), distant metastasis (DM) occurred in 35% (25 patients), simultaneous LF and DM occurred in 25% (18 patients), and was indeterminate in 16% (11 patients). Thus, LF was a component of failure in 49%. Twenty patients had the CNS as the initial site of failure. Eleven patients (10%) developed fatal second primary cancers, including two with acute myelogenous leukemia, two with squamous cell lung cancer, one each with breast, pancreas, prostate, renal cell, and myelodysplasia. One patient developed both a melanoma and non-Hodgkin's lymphoma. CONCLUSION: There are long-term survivors with concomitant TRT and PEV. LF and DM are common. Pattern of failure suggests needs to improve local and systemic control.

Concurrent chemotherapy and radiation therapy in advanced head and neck cancer.

A combination of radiation therapy and cis-platinum (25 mg/m2 i.v.) day 1, vincristine (1 mg i.v.) day 2, and bleomycin (15 U i.v.) day 4 was given concomitantly to 14 patients with advanced inoperable head and neck cancer and one patient with local recurrence. Radiation therapy consisted of 70 Gy to the involved areas and 50 Gy to adjacent uninvolved areas at 1.8 Gy per fraction. The overall response rate was 100%. Nine patients (60%) achieved a complete response, and six patients achieved a partial response. One patient appeared to have increasing disease, but biopsies have shown only fibrosis. The survival is 8 of 15 (53%), with a median follow-up time of 24 months. Most significant toxicity was anorexia and weight loss. Other toxicity consisted of peripheral neuropathy (1 patient), mild transient elevation of creatinine (1 patient), hypothyroidism (1 patient), and mild pulmonary toxicity (2 patients). Mucositis occurred in all patients, requiring interruption of therapy (2-14 days).

A unique nasopharynx brachytherapy technique.

To deliver a curative dose of radiation therapy to the nasopharynx using either external beam radiotherapy or conventional brachytherapy, it is often necessary to expose a large volume of normal tissue. Tolerance of normal tissue also limits the dose of radiation given for salvage therapy in failed nasopharyngeal carcinoma. A unique brachytherapy technique with associated treatment planning is presented as an alternative method of treatment. This technique combines a single linear cesium-137 source inserted in the nasopharynx via a modified cuffed endotracheal tube, in conjunction with a plaque of iridium-192 ribbons applied in the form of a modified upper denture appliance. This method allows additional treatment to the primary area while neither exposing more normal tissue than necessary nor exceeding tolerance doses to surrounding structures.

Docetaxel, cisplatin, and fluorouracil induction chemotherapy followed by accelerated fractionation/concomitant boost radiation and concurrent cisplatin in patients with advanced squamous cell head and neck cancer: A Southwest Oncology Group phase II trial (S0216).

BACKGROUND: In an effort to optimize nonoperative therapy in patients with locoregionally advanced head and neck squamous cell cancer, the Southwest Oncology Group conducted a phase II trial combining 3-drug taxane-containing induction chemotherapy with accelerated fractionation/concomitant boost radiation and concomitant single-agent cisplatin. METHODS: Two induction courses using docetaxel (75 mg/m(2) on day 1), cisplatin (100 mg/m(2) on day 1), and fluorouracil (1000 mg/m(2)/day continuous intravenous infusion days 1-4) were given, with an interval of 21 days. Patients who were stable or responded to the chemotherapy received definitive accelerated fractionation/concomitant boost radiation with concurrent cisplatin (100 mg/m(2)) on days 1 and 22 of radiation. RESULTS: There were 74 eligible and evaluable patients enrolled between March 1, 2003, and August 15, 2004; 52 (70%) had stage IV disease. At least 1 grade 3-4 toxicity was experienced by 63 patients (85%) during induction. A total of 61 patients completed induction and began concurrent chemoradiotherapy; 50 (68%) completed all planned treatment. At least 1 grade 3-4 toxicity was noted in 53 of the 58 patients (91%) evaluated for toxicity from concurrent chemoradiotherapy. Two patients died during induction, and 2 during chemoradiation. With a median follow-up of 36 months (range, 14-50), the 2-year and 3-year overall survival estimates were 70% and 64%, with 2-year and 3-year progression-free survival estimates of 66% and 61%, respectively. CONCLUSIONS: Three-drug induction chemotherapy followed by accelerated fractionation/concomitant boost radiation and concurrent cisplatin is toxic but feasible within a cooperative group. In this patient cohort with advanced head and neck squamous cell cancer, overall and progression-free survivals were encouraging, justifying further study of this approach.

Cancers of the maxillary sinus.

Maxillary sinus cancers are rare as compared with cancers of other sites. Because the onset is insidious, they are at an advanced stage at diagnosis and therefore present a therapeutic challenge for local control. Traditionally, treatment has been surgery or irradiation, or a combination of the two. Local control and survival, however, remains poor. Numerous chemotherapeutic agents have shown activity against squamous cell cancers of the head and neck. In several studies the use of either neoadjuvant or concurrent chemotherapy has improved local control and survival when compared with historical controls. Randomized studies are needed to confirm the benefit of chemotherapy over the standard forms of surgical and radiation therapy.

Accelerated fractionation radiation therapy for advanced squamous cell carcinoma of the head and neck.

We treated 14 patients who had advanced head and neck cancer with an accelerated fractionation schedule of irradiation consisting of two fractions given 6 hours apart. In the morning a volume of 1.7 Gy was given to an area that encompassed the entire tumor, enlarged lymph nodes, and all areas at risk for microscopic disease. Six hours later, 1.1 Gy was given to an area that included only the tumor and any enlarged lymph nodes, with a 2-cm margin. The treatment was well tolerated; of the 13 patients who completed therapy, six did not require a break in therapy, and seven patients did. The median rest period was 2 days. There was no grade 4 toxicity. Grade 3 toxicity included skin changes (one case), mucositis (two), dysphagia (two), weight loss (three), and a decrease in the hemoglobin level (one case). The response rate in the 13 who completed therapy was 13/13 (100%); 11 of the 13 (83%) had a complete response. Only one of the 11 who achieved a complete response had failure at the primary site. At a median follow-up of 24 months, the absolute survival was 7/13 (54%) and the corrected survival was 7/10 (70%). This technique permits radiation therapy to be given on an accelerated schedule without a planned break in treatment. The overall response rate and survival at 2 years was excellent.

Radiation therapy for early glottic carcinomas.

From 1973 to 1978, 30 cases of early glottic cancers (TINOMO) were treated in the Department of Radiation Therapy, University of Kansas Medical Center. All 30 patients have a minimal follow-up of three years with a mean of 50.2 months, and 26 (86.7%) are alive with no evidence of disease. Radiation therapy failed in three (10%), two of whom were salvaged by subsequent surgery. Thus the overall control rate was 29/30 (96.7%). We recommend primary radiation therapy for these early lesions, reserving operation for cases of unsuccessful radiotherapy.