Trimodality therapy for superior sulcus non-small cell lung cancer: Southwest Oncology Group-Intergroup Trial S0220.

BACKGROUND: Although preoperative chemotherapy (cisplatin-etoposide) and radiotherapy, followed by surgical resection, is considered a standard of care for superior sulcus cancers, treatment is rigorous and relapse limits long-term survival. The Southwest Oncology Group-Intergroup Trial S0220 was designed to incorporate an active systemic agent, docetaxel, as consolidation therapy. METHODS: Patients with histologically proven and radiologically defined T3 to 4, N0 to 1, M0 superior sulcus non-small cell lung cancer underwent induction therapy with cisplatin-etoposide, concurrently with thoracic radiotherapy at 45 Gy. Nonprogressing patients underwent surgical resection within 7 weeks. Consolidation consisted of docetaxel every 3 weeks for 3 doses. The accrual goal was 45 eligible patients. The primary objective was feasibility. RESULTS: Of 46 patients registered, 44 were eligible and assessable; 38 (86%) completed induction, 29 (66%) underwent surgical resection, and 20 (45% of eligible, 69% surgical, and 91% of those initiating consolidation therapy) completed consolidation docetaxel; 28 of 29 (97%) underwent a complete (R0) resection; 2 (7%) died of adult respiratory distress syndrome. In resected patients, 21 of 29 (72%) had a pathologic complete or nearly complete response. The known site of first recurrence was local in 2, local-systemic in 1, and systemic in 10, with 7 in the brain only. The 3-year progression-free survival was 56%, and 3-year overall survival was 61%. CONCLUSIONS: Although trimodality therapy provides excellent R0 and local control, only 66% of patients underwent surgical resection and only 45% completed the treatment regimen. Even in this subset, distant recurrence continues to be a major problem, particularly brain-only relapse. Future strategies to improve treatment outcomes in this patient population must increase the effectiveness of systemic therapy and reduce the incidence of brain-only metastases.

Multicenter trial of EC145 in advanced, folate-receptor positive adenocarcinoma of the lung.

BACKGROUND: EC145 is a novel folate-receptor targeted agent consisting of a folate molecule linked to a vinca alkaloid. EC20 is a technetium-labeled folate that assesses the presence of folate receptors (FR) in vivo. The objective of this study was to determine the activity of EC145 in patients with chemotherapy refractory lung adenocarcinoma, whose tumors expressed the FR as determined by EC20 imaging. METHODS: Patients with advanced adenocarcinoma of the lung, Eastern Cooperative Oncology Group performance status 0 to 2, normal organ function, those who had progressed after at least two prior cytotoxic regimens, and with EC 20 uptake in at least one index lesion were eligible. The primary objective of the study was the ability to receive four or more cycles of therapy. RESULTS: Sixty patients were screened and 43 patients were enrolled. Eleven patients (26%) received more than four cycles (95% confidence interval [CI] 14%, 41%), and one patient had partial response (response rate (RR) = 2.3%, 95% CI 0%, 12%). Patients in whom all target tumor lesions expressed FR by EC 20 scans had a trend toward superior results in terms of clinical benefit response (50% versus 14.3 %; p = 0.10) and survival (47.2 weeks versus 14.9 weeks [HR = 0.539, p = 0.101]) compared with those in whom at least one but not all target lesions were positive for FR (FR+). CONCLUSION: EC145 demonstrated clinical activity with a good toxicity profile in this population. Uniform uptake of EC20 may predict activity of EC145 and be useful for prospective selection of patients in future trials.

Phase II trial of imatinib maintenance therapy after irinotecan and cisplatin in patients with c-Kit-positive, extensive-stage small-cell lung cancer.

BACKGROUND: The prognosis for patients with extensive-stage small-cell lung cancer remains poor. This trial was designed to evaluate irinotecan/cisplatin plus maintenance imatinib in patients with c-Kit-positive disease (the transmembrane receptor c-Kit is the product of the c-KIT protooncogene). PATIENTS AND METHODS: Immunohistochemistry for c-Kit was performed before enrollment. Treatment consisted of irinotecan 65 mg/m2 on days 1 and 8 plus cisplatin 60 mg/m2 on day 1 and every 21 days for 4 cycles. Imatinib was administered at 400 mg twice a day until progression or unacceptable toxicity occurred. RESULTS: Fourteen patients were enrolled. Slow accrual led to early study termination. Six patients did not begin treatment with imatinib because of disease progression, persistent toxicity, or referral for radiation therapy. Eight patients had a partial response with irinotecan/cisplatin and received imatinib. The median number of weeks on imatinib was 6.1 (range, 4.1-25.1 weeks). Reasons for imatinib discontinuation included disease progression (n = 7) and persistent neutropenia (n = 1). No objective responses to imatinib were evident, but 3 patients (21%) exhibited stable disease for 12, 15, and 25 weeks. The median progression-free survival was 4.3 months (95% CI, 2.9-4.8 months). The median overall survival was 7.8 months (95% CI, 5.7-10.0 months). The irinotecan/cisplatin regimen was well tolerated (grade 1/2 neutropenia, 29%; anemia, 43%; thrombocytopenia, 14%; and diarrhea, 29%), except in 1 patient with grade 3 vomiting. Imatinib toxicity included grade 1/2 nausea in 50% of the patients, peripheral edema in 75% of the patients, grade 3 fatigue in 13% of the patients, and neutropenia in 13% of the patients. CONCLUSION: Despite the selection of tumors expressing c-Kit, imatinib did not appear to delay disease progression after response to chemotherapy. However, this trial was underpowered because of its early termination. Although disease stability with imatinib was evident in 3 patients and the therapy was well tolerated, this approach does not appear to warrant further clinical study.

Phase II trial of fenretinide (NSC 374551) in patients with recurrent small cell lung cancer.

BACKGROUND: Alterations in retinoid signaling appear to be involved in the pathogenesis of small cell lung cancer (SCLC). Fenretinide [N-(4-hydroxyphenyl)retinamide], a synthetic retinoid, inhibits the growth of SCLC cells in vitro via the induction of apoptosis. Since these data suggested that SCLC is the adult solid tumor that is most susceptible to fenretinide, a trial to evaluate the clinical activity of fenretinide in patients with SCLC was considered the definitive test of its clinical potential in adult oncology. METHODS: Patients with progressive SCLC after one or two prior chemotherapy regimens and a performance status of 0-2 were eligible for the study. Patients with stable, treated brain metastases were eligible. Fenretinide 900 mg/m(2) twice daily was administered orally on days 1-7 of each 21-day cycle. Blood and saliva were collected pre-treatment and on day 7 of cycle 1 to measure fenretinide and retinol levels by high-pressure liquid chromatography (HPLC). RESULTS: Nineteen patients were enrolled. Fifteen patients had one prior chemotherapy regimen and four patients had two prior regimens. The median time from diagnosis to enrollment was 10 months. A median of two cycles of fenretinide was administered. There were no objective responses, but four of 17 evaluable patients (24%) had stable disease after 2-17 cycles. The median time to treatment failure was 5.7 weeks overall, while the four patients with stable disease demonstrated treatment failure at 11, 13, 19, and 52 weeks. Median survival was 25 weeks, with one patient alive 22 months after the start of treatment. The 1-year survival rate was 29%. Toxicity included mild, reversible visual changes (haziness, altered night vision), grade 1-3 nausea/vomiting, and grade 1-2 diarrhea. The mean day 7 plasma fenretinide level was 2.90 +/- 1.66 µg/ml (7.40 +/- 4.25 muM; n = 14). The mean pre-treatment and day 7 plasma retinol levels were 0.47 +/- 0.16 µg/ml and 0.05 +/- 0.07 µg/ml (n = 8), respectively. The mean day 7 salivary fenretinide level was 0.08 +/- 0.18 µg/ml, with no correlation between salivary and plasma drug levels. CONCLUSIONS: Fenretinide is well tolerated in patients with SCLC and stabilization of disease was noted in 24% of patients with this aggressive disease. However, after the first stage of enrollment, the response rate did not meet criteria to proceed with full trial accrual. Plasma concentrations of fenretinide that induce cytotoxicity in vitro in SCLC cell lines are clinically achievable, but there were no objective responses. Non-invasive drug monitoring using saliva underestimates systemic exposure.

Phase II study of celecoxib and docetaxel in non-small cell lung cancer (NSCLC) patients with progression after platinum-based therapy.

INTRODUCTION: To evaluate the efficacy and toxicity of the combination of celecoxib and docetaxel in patients with advanced non-small cell lung cancer after failure of platinum-based therapy. METHODS: Patients with relapsed non-small cell lung cancer received celecoxib 400 mg orally twice daily beginning 7 days before the first cycle of docetaxel and the celecoxib was continued with no interruption. Docetaxel 75 mg/m2 was administered intravenously on a 21-day cycle. The primary end point of the study was the 6-month survival rate. RESULTS: Twenty-four patients were enrolled and twenty patients were treated (median age 60, M:F 16:8). Most patients had a baseline performance status of 1. The objective response rate was 10% (95% confidence interval [CI], 0-25%) and the 6-month survival rate was 59% (95% CI 37-80%). Median survival time was 6.9 months (95% CI, 2.8-15.2 months) and the 1- and 2-year survival rates were 36% (95% CI, 15-57%) and 1% (95% CI, 0-10%), respectively. The most frequent grade > or =3 adverse events were neutropenia (58%) and neutropenic fever (21%) which resulted in early closure of the trial. CONCLUSIONS: The addition of celecoxib to docetaxel did not seem to improve the response rate and survival compared with docetaxel alone. The combination demonstrated considerable neutropenia and complications from febrile neutropenia that suggests celecoxib may enhance the marrow toxicity of docetaxel.

Phase II study of docetaxel and celecoxib, a cyclooxygenase-2 inhibitor, in elderly or poor performance status (PS2) patients with advanced non-small cell lung cancer.

INTRODUCTION: The utility of two-drug chemotherapy regimens in elderly or performance status (PS 2) patients with advanced non-small cell lung cancer (NSCLC) remains to be established. Preclinical studies suggested that celecoxib, a Cyclooxygenase-2 inhibitor, has antitumor activity in NSCLC and can enhance the activity of chemotherapy drugs. We conducted a phase II study to evaluate the efficacy of the combination of weekly docetaxel and celecoxib in advanced NSCLC patients, who were either elderly (> or =70 years) or PS2. METHODS: Patients with stage IIIB (with pleural effusion) or IV NSCLC who were > or =70 years and had a PS of 0-2 or patients of any age with a PS of 2 were included. Patients should have been off any nonsteroidal anti-inflammatory drug for 30 continuous days before study enrollment. Patients were treated with weekly docetaxel 36 mg/m i.v. on days 1, 8, 15 of a 28 day cycle and Celecoxib 400 mg po twice daily. Disease assessment was performed after every two cycles. The study design required 39 patients. RESULTS: Study was terminated after 34 patients were enrolled due to safety concerns regarding celecoxib. Thirty patients were evaluable. The response rate was 15%. The median progression free survival and median survival were 2.3 months and 5.0 months, respectively. The median survival of patients > or =70 years old with a PS of 0-1 was 8.3 months and the median survival of PS2 patients was 2.8 months. The combination was well tolerated with fatigue as the most common adverse effect. Two patients developed arterial thrombotic events. CONCLUSION: In these 'special populations' of patients with advanced NSCLC, the addition of celecoxib to docetaxel did not seem to improve the outcome compared with single agent docetaxel.

Gemcitabine and cisplatin in unresectable malignant mesothelioma of the pleura: a phase II study of the Southwest Oncology Group (SWOG 9810).

PURPOSE: The purpose of this open-label phase II SWOG study was to evaluate the activity of gemcitabine (Gemzar; Eli Lilly, Indiana, USA) and cisplatin combination therapy, in patients with unresectable malignant mesothelioma of the pleura. PATIENTS AND METHODS: Fifty eligible chemotherapy naïve patients with histologically proven malignant mesothelioma of the pleura, and a SWOG performance status 0-2 were enrolled between February 1999 and August 2000. Treatment consisted of gemcitabine 1000mg/m(2) and cisplatin 30mg/m(2) on days 1, 8 and 15 of a 28-day cycle, until progression of disease or two cycles beyond complete response. RESULTS: Using SWOG response criteria, one patient had a confirmed complete response and five patients had a confirmed partial response, for a total response rate of 12% (95% CI 5-24%). All the responses were seen in patients with epithelioid or unspecified histology. Stable disease was seen in 25 patients (50%). The median overall survival was 10 months (95% CI 7-15 months), with a median progression-free survival of 6 months. Sixteen patients experienced Grade 4 toxicity. Twelve of these Grade 4 toxicities were hematologic. There were no treatment-related deaths. CONCLUSIONS: Cisplatin-gemcitabine combination chemotherapy has modest activity with an acceptable toxicity profile, as first line treatment for patients with malignant mesothelioma.

Mature results of a phase II trial of gemcitabine/paclitaxel given every 2 weeks in patients with advanced non-small-cell lung cancer.

PURPOSE: This phase II study evaluated the efficacy and toxicity of gemcitabine/paclitaxel given every 2 weeks in patients with advanced-stage non-small-cell lung cancer. Treatment with 1 previous chemotherapy regimen was allowed. Patients received gemcitabine 3000 mg/m(2) intravenously over 30 minutes and paclitaxel 150 mg/m(2) over 3 hours every 2 weeks. PATIENTS AND METHODS: Forty-five patients were enrolled: 31 patients were chemotherapy naive and 14 patients were previously treated. The median age was 61 years, and the majority of patients had adenocarcinoma and stage IV disease. The minimum follow-up was 4.5 years. The response rate was 27% for all 45 patients and 32% for the 38 patients who were response evaluable. RESULTS: The response rate was 26% (31% response evaluable) for the patients who were chemotherapy-naive and 29% (33% response evaluable) for the patients who were previously treated. For the entire group, the median time to progression was 3.3 months; median overall survival was 9.4 months, and the 1-year and 2-year survival rates were 38% and 13%, respectively. The overall survival and time to progression durations were not significantly different between patients who were chemotherapy-naive and patients who were previously treated. The toxicities associated with treatment were minimal, with only 1 episode of grade 4 neutropenia and a low incidence of significant nonhematologic toxicity. CONCLUSION: Gemcitabine/paclitaxel is active in the treatment of non-small-cell lung cancer. The every-2-week schedule is likely to be responsible for the low level of toxicity seen with this regimen and could be used as the basis for the addition of other agents in future clinical trials.

Induction chemoradiation and surgical resection for superior sulcus non-small-cell lung carcinomas: long-term results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160).

PURPOSE: Traditional treatment for superior sulcus non-small-cell lung cancers (SS NSCLC), radiation plus surgery, yields a 50% rate of complete resection and a 30% 5-year survival. On the basis of improved outcomes in other subsets of stage III NSCLC, this trial tested the feasibility of induction chemoradiotherapy for SS NSCLC. PATIENTS AND METHODS: Patients with T3-4, N0-1 SS NSCLC received two cycles of cisplatin and etoposide concurrently with radiation (45 Gy). Patients with stable or responding disease underwent thoracotomy. All patients received two more cycles of chemotherapy. Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed by Cox regression analysis. RESULTS: From April 1995 to November 1999, 110 eligible patients (76 men, 34 women) were entered onto the study (78 T3, 32 T4 tumors). Induction therapy was completed by 104 (95%) patients. Of 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had complete resection. Pathologic complete response (CR) or minimal microscopic disease was seen in 61 (56%) resection specimens. Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Pathologic CR led to better survival than when any residual disease was present (P = .02). Disease progression occurred mainly in distant sites. CONCLUSION: This combined-modality approach is feasible and is associated with high rates of complete resection and pathologic CR in both T3 and T4 tumors. Local control and overall survival seem markedly improved relative to previous studies of radiation plus resection.

A unique radiation scheme for the treatment of high-grade non-metastatic soft tissue sarcoma: the detroit medical center experience.

PURPOSE: This is the initial report on the utilization of combined photon irradiation followed by a neutron boost irradiation for the initial management of patients with high-grade non-metastatic soft tissue sarcoma (STS). We present data on local control, complications, disease-free survival and overall survival in patients at high risk for local relapse. METHODS AND MATERIALS: Between 1/1/1995 and 10/31/02, twenty-three patients with high-grade non-metastatic soft tissue sarcoma were referred to the Department of Radiation Oncology at the Detroit Medical Center. These patients were referred for consultation due to surgical margin status (tumor within 3mm of surgical margin (n=11)), or gross residual disease (n=12). There were 14 males and nine females whose ages ranged from 12 to 75 at the time of diagnosis (med=44 years). The most common histology was malignant fibrous histiocytoma (n=6), followed by liposarcoma (n=5), synovial sarcoma (n=4), and angiosarcoma (n=2). Twenty-one of 23 patients also received multi-agent multi-cyclic cyto-reductive therapy. Treatment consisted of initial daily photon irradiation delivered either using twice daily fractions of 120 cGy (n=10) or once daily 200 cGy/fx (n=13).Total photon dose was 36-39.6 Gy. Neutron irradiation was initiated immediately following the photon irradiation and consisted of fraction sizes of 1.0-1.25NGy to a total dose of 6-10 NGy. The neutrons were given once daily. Follow-up is calculated from the day of last radiation treatment. RESULTS: No patient has been lost to follow-up, which has ranged from 18 to 82 months (med=36 months). To date there have been two local relapses and three patients with distant disease development without local relapse. Each of the patients with distant disease has died. The local failures occurred at 9 and 12 months. The 36-month local control is 91%. Thirtysix month disease-free survival was 78%. Overall survival at 36 months was 87%. Three patients had unusual complications consisting of delayed wound healing, and in one of these patients a fracture of the tibia has been noted. CONCLUSION: The use of this unique radiation sequence post-surgically in patients at high risk for local relapse has resulted in an exciting 36-month local control rate of 91%. The 3-year disease-free survival of 78% and overall survival rate of 87% are exciting but need to mature. The low complication rate is similar to that reported in other large institutional series that have not utilized neutrons. We continue to evaluate the role of combined photon and once-off neutron irradiation in the treatment of patients with high-grade STS that are risk for local recurrence.

The role of irradiation in the management of locally recurrent non-metastatic soft tissue sarcoma of extremity/trunkal locations.

BACKGROUND: Patients who have had initial curative intent therapy for non-metastatic soft tissue sarcoma, and who subsequently relapse at the initial site without evidence of metastatic disease, have various options regarding local treatment. The treatment options available will be determined by the extent of relapse, previous therapy rendered, and patient characteristics. We reported on a series of 31 patients treated initially with only surgery for extremity/trunkal high-grade soft tissue sarcoma and then seen for recurrence at our institution between 1980 and 1999. Local re-treatment consisted of combined modality therapy, most often aggressive surgical debulking/resection and irradiation, in an effort to reduce the need for amputation and, where anatomically allowable, to maintain a functional limb. We report our results in re-establishing local control, subsequent survival, and complication rates. METHODS: Thirty-one patients with locally recurrent, non-metastatic high-grade soft tissue sarcoma, (excluding extraabdominal desmoid) were retrospectively reviewed to determine local control, survival, and complication rates associated with the relapsed disease. All patients had multimodality re-treatment most often utilizing aggressive surgical debulking and irradiation. The irradiation consisted of either external beam alone, brachytherapy alone, or a combination of external beam and brachytherapy. Nine patients also received multi-agent, multi-cycle chemotherapy using various regimens. In addition, the impact of surgical margin at the time of re-resection (gross versus microscopic disease), radiation treatment type, total radiation dose delivered, size of relapse, histological sub-type, sex and age, were evaluated to determine if they had any impact on the re-establishment of local control and subsequent survival. RESULTS: Local control was re-established in 25 of 31 (80.6%) patients. Two additional patients with isolated local relapse after irradiation were salvaged with amputation and remain NED at last follow-up. With these patients a total of 27/31 (87%) are now with local control. At last follow-up, which ranged from 23 to 192 months, 23 of 31 (74%) remained alive. Of the eight patients who have died, four had evidence of local and distant failure. Two additional patients died of distant failure while the treated sites remained in local control and two patients, both NED, died of intracurrent processes. Follow-up for those patients who had re-established local control has ranged from 23 to 192 months (median=60.5 months). Time to local failure following re-treatment ranged between 3 and 72 months following re-treatment (median=12 months). Five patients had significant treatment related complications. Included are two patients in which amputation was required due to local recurrences. Two patients developed a soft tissue necrosis and one patient had a wound healing problem that resolved with conservative management. No statistical significance in the development of local control could be found based on surgical margin status, total dose of irradiation (greater or less than 60 Gy), size of recurrence (greater than 5 cm), histological sub-type, sex, or age (greater than 50 years). There was a trend for negative impact for those patients receiving only external beam irradiation. CONCLUSION: Selective locally recurrent, non-metastatic soft tissue sarcoma of the extremity/trunkal regions should still be considered eligible for aggressive limb-sparing therapy. Our experience suggests that a majority of patients re-establish local control following aggressive surgical resection/debulking and irradiation and this appears to be durable in its nature. The role of chemotherapy in this group of patients remains investigational. In a surprising finding, one patient re-relapsed in the re-treatment site at 72 months, thus justifying continued strict surveillance not only in the primary site but also for subsequent metastatic disease.

The role of postoperative irradiation in the treatment of locally recurrent incompletely resected extra-abdominal desmoid tumors.

BACKGROUND: To define the efficacy of postoperative irradiation in patients with recurrent extra-abdominal desmoid tumors in whom surgical intervention has resulted in microscopically or grossly positive surgical margins. METHODS: A retrospective analysis was performed on all patients referred to the department of radiation oncology at the Detroit Medical Center with a diagnosis of recurrent extra-abdominal desmoid tumor. This analysis includes all patients seen from 1 January 1990 through 31 December 1999. A total of 11 patients were treated to 13 sites. Ten had microscopically positive margins and three had gross residual disease. Three patients were noted to have multifocal disease at the time of initial representation. Local control, survival, follow-up, and subsequent development of new tumors are measured from the last day of treatment with irradiation. RESULTS: Thirteen sites were treated. Seven patients had received chemotherapy/hormonal therapy prior to surgery and/or irradiation. The most commonly used drug was tamoxifen (n=6). The type of radiation delivered included external beam irradiation alone (n=3), combined external beam irradiation and brachytherapy (n=4), brachytherapy alone (n=3) and 252-Cf neutron brachytherapy alone (n=3). Follow-up has ranged from 29 to 115 months (median=76 months). Three patients have failed locally at 17, 24 and 29 months. One of these was treated for gross residual disease. No patient has died of tumor-related causes. Salvage at the failed sites was possible in twom of three with re-irradiation using external neutrons and/or aggressive surgical intervention and systemic therapy. Complications were most often noted to include decrease range in motion, especially in joint areas, and skin reactions which were normal in presentation. In one site there was development soft tissue necrosis. CONCLUSION: Based on our experience we recommend postoperative irradiation for all recurrent extra-abdominal desmoid lesions with microscopically or grossly positive surgical margins. Furthermore, patients with recurrent desmoid tumors involving the bony structures of the hand or feet are poor candidates for brachytherapy alone. For patients with extremity lesions, brachytherapy may be a reasonable treatment option provided adequate margins around the tumor bed are covered. The continued recommended use of irradiation in this group of patients is warranted.