The fate of patients with locally advanced bladder cancer treated conservatively with neoadjuvant chemotherapy, extensive transurethral resection and radiotherapy: 10-year experience

PURPOSE: We assess the results of bladder preservation for infiltrating bladder cancer. The potential for neoadjuvant chemotherapy followed by extensive transurethral resection and radiotherapy was evaluated in 40 patients with T2-T4a G2-G3 bladder carcinoma. MATERIALS AND METHODS: From 1983 to 1995, 40 patients with bladder cancer underwent bladder sparing treatment, consisting of neoadjuvant chemotherapy, extensive transurethral resection and radiotherapy. Most patients had T3G3 cancer. A deep transurethral resection biopsy was performed before and after chemotherapy, and an extensive transurethral resection was repeated at the end of radiotherapy. Of the patients 30 received cisplatin and methotrexate and 10 also received vinblastine. Total dose of radiotherapy was 60 to 65 Gy. Recurrent superficial tumors were treated transurethrally. Radical cystectomy was considered for persistent or recurrent invasive disease. RESULTS: Complete response occurred in 19 patients (47.5%) after chemotherapy, and in 8 patients after transurethral resection and radiotherapy (67.5%). Within 10 years 8 responding patients (30%) had local recurrences and 3 underwent cystectomy. Of the patients 14 (35%) are alive, including 13 with no evidence of disease (mean survival 65 months), 5 died of unrelated disease and 21 (52.5%) died of distant metastases (mean survival 28 months). Of the 21 patients 14 had residual tumor after radiotherapy, 3 presented with distant metastases after vesical infiltrating recurrence and 4 had distant metastases in the absence of locoregional recurrence. In 22 patients (55%) the bladder was salvaged. Patients with complete response to chemotherapy had a low risk for recurrent infiltrating tumors and metastases. CONCLUSIONS: Complete tumor control was maintained at 5 years in more than 50% of the patients treated conservatively. Bladder salvage is feasible in select patients.     

Results of salvage abdominoperineal resection for anal cancer after radiotherapy

PURPOSE: Nonsurgical treatment of anal cancer by radiotherapy alone or combined with chemotherapy is the standard therapy for epidermoid carcinoma of the anal canal. Surgery is only recommended for treatment failures. Very few studies have been devoted to the outcome of this salvage surgery. The aim of this study is to evaluate these results. METHODS: A retrospective review from 1986 to 1995 revealed 21 patients with residual or recurrent anal canal carcinoma after initial radiotherapy, operated on by abdominoperineal resection. Patients were reviewed as to age, gender, initial treatment, any symptoms of recurrence, duration until recurrence, any diagnosis imaging, treatment, and outcome. RESULTS: None of these 21 patients had known lymph node involvement or metastases at radiotherapy or at salvage abdominoperineal resection. Eleven patients had residual disease (positive biopsy less than 6 months after the end of radiotherapy) and 10 had tumor recurrence (more than 6 months after cessation of treatment). Recurrence occurred at a mean of 15 (range, 9-41) months after radiotherapy. All 21 patients underwent an abdominoperineal resection. Pathologic examination of the 21 specimens showed complete excision in all cases except one and lymph node metastases in two cases. There was no perioperative mortality. The mean follow-up after surgery was 40 months; no patients were lost to follow-up. Of the 21 patients, 10 died and 11 lived, of whom 9 are disease free. The overall survival rate at three years after salvage abdominoperineal resection was 58 percent. The overall survival rate for patients with residual disease (vs. recurrence) at three years was 72 percent (vs. 29 percent) and at five years was 60 percent (vs. 0 percent; P = 0.06). CONCLUSIONS: Salvage abdominoperineal resection for anal cancer can be expected to yield a number of survivors from residual disease, but the low rate of survival after abdominoperineal resection for recurrent disease suggests the need for additional postoperative treatment if salvage abdominoperineal resection is performed.     

Second lung cancers in patients successfully treated for lung cancer

The rate of developing second lung cancers and other aerodigestive tumors in patients who have been treated for both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) is approximately 10-fold higher than other adult smokers. The risk of second lung cancers in patients surviving resection of NSCLC is approximately 1% to 2% per year. The series reported show that the patients who develop second NSCLCs tend to have early-stage NSCLC (predominantly stage I and II). The survival of patients after the second resection of lung cancer is similar to that of patients presenting with initial NSCLC. The risk of second lung cancers in patients surviving SCLC is 2% to 14% per patient per year and increases two- to seven-fold with the passage of time from 2 to 10 years. The risk of second lung cancers in patients treated for SCLC appears to be higher than that found in patients with NSCLC who were treated only with surgical resection. In addition, the chances of successful resection of second primary NSCLCs in patients who were treated for SCLC is much less than that for patients with metachronous lung cancers after an initial NSCLC. Patients treated for SCLC who continue to smoke cigarettes increase their rate of developing second lung cancers. The contribution of chest radiation and chemotherapy administration to the risk of developing second lung tumors remain to be defined but may be responsible for some of the increased risk in patients treated for SCLC compared to patients undergoing a surgical resection for NSCLC.     

Radiation Therapy Oncology Group (RTOG) 88-08 and Eastern Cooperative Oncology Group (ECOG) 4588: preliminary results of a phase III trial in regionally advanced, unresectable non-small-cell lung cancer

BACKGROUND: Regionally advanced, surgically unresectable non-small-cell lung cancer represents a disease with an extremely poor prognosis. External-beam irradiation to the primary tumor and regional lymphatics is generally accepted as standard therapy. The use of more aggressive radiation regimens and the addition of cytotoxic chemotherapy to radiotherapy have yielded conflicting results. Recently, however, results from clinical trials using innovative irradiation delivery techniques or chemotherapy before irradiation have indicated that patients treated with protocols that incorporate these modifications may have higher survival rates than patients receiving standard radiation therapy. PURPOSE: On the basis of these results, the Radiation Therapy Oncology Group (RTOG)-Eastern Cooperative Oncology Group (ECOG) elected to conduct a phase III trial comparing the following regimens: 1) standard radiation therapy, 2) induction chemotherapy followed by standard radiation therapy, and 3) twice-daily radiation therapy. METHODS: Patients with surgically unresectable stage II, IIIA, or IIIB non-small-cell lung cancer were potential candidates. Staging was nonsurgical. Patients were required to have a Karnofsky performance status of 70 or more and weight loss less than 5% for 3 months prior to entry into the trial, to be older than 18 years of age, and to have no metastatic disease. Of the 490 patients registered in the trial, 452 were eligible. The disease in 95% of the patients was stage IIIA or IIIB. More than two thirds of the patients had a Karnofsky performance status of more than 80. Patients were randomly assigned to receive either 60 Gy of radiation therapy delivered at 2 Gy per fraction, 5 days a week, over a 6-week period (standard radiation therapy); induction chemotherapy consisting of cisplatin (100 mg/m2) on days 1 and 29 and 5 mg/m2 vinblastine per week for 5 consecutive weeks beginning on day 1 with cisplatin, followed by standard radiation therapy starting on day 50; or 69.6 Gy delivered at 1.2 Gy per fraction twice daily (hyperfractionated radiation therapy). RESULTS: Toxicity was acceptable, with four treatment-related deaths. Three patients subsequently died of chronic pulmonary complications. Compliance with protocol treatment was acceptable. One-year survival (%) and median survival (months) were as follows: standard radiation therapy--46%, 11.4 months; chemotherapy plus radiotherapy--60%, 13.8 months; and hyperfractionated radiation therapy--51%, 12.3 months. The chemotherapy plus radiotherapy arm was statistically superior to the other two treatment arms (logrank P = .03). CONCLUSIONS: In "good-risk" patients with surgically unresectable non-small-cell lung cancer, induction chemotherapy followed by irradiation was superior to hyperfractionated radiation therapy or standard radiation therapy alone, yielding a statistically significant short-term survival advantage.     

Pharmacokinetics of tacrolimus (FK506) in primary orthotopic heart transplant patients

STUDY OBJECTIVES: Local recurrence is high when sublobar resection is chosen as primary management of stage I non-small cell lung carcinoma. Postoperative external-beam radiotherapy may reduce this local recurrence problem. A technique of intraoperative brachyradiotherapy following thoracoscopic wedge resection is described as an alternative to adjuvant external-beam radiotherapy for high-risk patients who are not candidates for pulmonary lobectomy. PATIENTS: Fourteen patients with significant impairment in cardiopulmonary function having small peripheral solitary pulmonary nodules underwent video-assisted thoracoscopic (VATS) wedge resection and were found to have non-small cell cancer. Surgical margins were pathologically clear and mediastinal nodes were benign-stage I (T1NO). INTERVENTIONS: A custom polyglyconate mesh (Vicryl) containing 125I seeds was applied to pulmonary resection margins following wedge resection of peripheral lung cancers. A total dose of 100 to 120 Gy at 1 cm was applied to the target area. RESULTS: All patients had histologically clear surgical margins. Postoperative dosimetry confirmed adequate resection margin coverage. There was neither operative mortality nor morbidity related to the VATS wedge resection or the brachytherapy implants. Implants did not migrate, and there were no cases of significant radiation pneumonitis or local recurrence at mean follow-up of 7 months (range, 2 to 12 months). CONCLUSIONS: Intraoperative brachytherapy appears to be a safe and efficient alternative to external-beam radiation therapy when adjuvant radiotherapy is considered following therapeutic wedge resection of stage I (T1NO) lung cancers. The impact on local recurrence, disease-free interval, and survival will require additional follow-up.     

External-bean megavoltage radiation therapy in the treatment of post-radical prostatectomy residual or recurrent tumor preliminary results

High dose, external-beam megavoltage radiation therapy was administered to 21 patients because of incomplete excision (11 patients) or palpable local recurrence (10 patients) following radical prostatectomy. Of the 21 patients 8 were alive without clinical evidence of cancer for 29 to 97 months after radiation therapy. The best survival was in the 11 patients referred because of incomplete excision. Of these 11 patients 9 were alive, 6 without cancer, and 2 were dead of intercurrent disease without evidence of cancer. Of the 10 patients with palpable local recurrence 2 were alive without evidence neoplasm, while 2 died of intercurrent disease without cancer. Acute treatment-associated symptoms occurred in 11 of the 21 patients. Generally, these symptoms were mild and responded to conservative, symptomatic management. Two serious complications were recorded.     

Adjuvant radiotherapy and chemotherapy for stage II or IIIA non-small-cell lung cancer after complete resection. Provincial Lung Cancer Disease Site Group

GUIDELINE QUESTIONS: 1) Does the use of postoperative, adjuvant radiotherapy or chemotherapy, alone or in combination, improve survival rates among patients with completely resected, pathologically confirmed stage II or IIIA non-small-cell lung cancer (NSCLC)? 2) Does the use of radiotherapy reduce the risk of local recurrence among patients with completely resected stage II or IIIA NSCLC? OBJECTIVE: To make recommendations about the use of postoperative adjuvant radiotherapy and chemotherapy in the treatment of patients with completely resected stage II or IIIA NSCLC. OUTCOMES: Overall survival and disease-free survival are the primary outcomes of interest. A secondary outcome of interest is local disease control. PERSPECTIVES (VALUES): Evidence was collected and reviewed by 4 members of the Lung Cancer Disease Site Group (Lung Cancer DSG) of the Cancer Care Ontario Practice Guidelines Initiative. The evidence-based recommendation resulting from this review was approved by the Lung Cancer DSG, which comprises medical oncologists, radiation oncologists, pathologists, surgeons and a medical sociologist. A community representative was present at 1 meeting during which the recommendation was discussed. QUALITY OF EVIDENCE: One meta-analysis and 22 randomized controlled trials (RCTs) were published between 1962 and 1996. The RCTs compared surgery plus radiotherapy with surgery alone; surgery plus adjuvant chemotherapy with surgery alone; surgery plus radiotherapy with surgery plus both chemotherapy and radiotherapy. Many studies included patients with stage IIIB NSCLC; some included patients with incompletely resected stage I NSCLC or with small cell lung cancer (maximum 10%). Older studies used chemotherapy or radiation that would now be considered inferior according to current standards of practice. BENEFITS: There was no survival benefit with adjuvant radiotherapy alone, although 3 RCTs reported a reduction in the rate of local recurrence among patients treated with adjuvant radiotherapy. The meta-analysis showed that postoperative, cisplatin-based chemotherapy alone reduced the relative risk of death by 13% (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.74 to 1.02); in combination with radiotherapy it resulted in a 6% reduction in the relative risk of death (HR 0.94, 95% CI 0.79 to 1.11). HARMS: Postoperative adjuvant chemotherapy with alkylating agents was found in the meta-analysis to increase the relative risk of death by 15%. A study involving prolonged adjuvant chemotherapy (busulfan or cytoxan daily for 2 years) reported that 4 of 726 patients had hematologic malignancies. In 1 study, only 53% of patients received all 4 cycles of chemotherapy with cyclophosphamide-doxorubicin-cisplatin (CAP); in another, 22% of patients refused therapy with CAP because of nausea and vomiting. PRACTICE GUIDELINE: There is evidence from RCTs that postoperative radiotherapy reduces rates of local recurrence by 11% to 18% (or 1.6 to 19-fold) among patients with completely resected, pathologically confirmed stage II or IIIA NSCLC. Therefore, if the outcome of interest is a reduction in the frequency of local tumour recurrence, radiotherapy is recommended. However, there is no evidence of a survival benefit from postoperative radiotherapy alone. In a meta-analysis, postoperative chemotherapy with or without radiotherapy resulted in a slightly reduced (statistically nonsignificant) risk of death among patients with surgically resected stage II or IIIA NSCLC. The survival benefit was small and achieved only with chemotherapy regimens that produced substantial toxic effects and that are no longer used. Newer chemotherapy regimens are currently being evaluated as adjuvant therapy, but there is insufficient evidence of benefit at this time to recommend them. Therefore, if the outcome of interest is survival, there is insufficient evidence to recommend current chemotherapy regimens with or without radiotherapy as postoperative, adjuvant the     

Contribution of an induction treatment in the surgical treatment of locally advanced non-small-cell cancers

From October 1988 to July 1990, 18 patients with marginally resectable non-small cell cancer (10 stage IIIa and 8 stage IIIb) were entered in a phase-II trial combining induction therapy with a subsequent thoracotomy. Induction therapy included 2 courses of chemotherapy (5-FU and cisplatinum) and radiotherapy (30 Gray in split course). Partial response was observed in 10 patients, and minimal response in 3. Thoracotomy disclosed unresectability in 3 patients. Fifteen complete resections consisted in 1 lobectomy and 14 pneumonectomies. There were no operative deaths (30 days). Postoperative recovery was uneventful in 3 patients with exploratory thoracotomy and in 1 patient with lobectomy. Following pneumonectomy, we observed 2 bronchopleural fistulae and 1 empyema. On pathology, 10 patients were stage IIIa, and 3 were stage I, whereas no residual tumor was found in 2 patients. During follow-up, local recurrence occurred in 2, and metastases in 8. On December 31st, 1993, 3 patients were alive at 44, 52, and 62 months respectively. Nine patients had died from cancer, and 3 from unrelated causes. Estimated survival was 66.7% at 1 year, 33.3% at 3 years, and 20% at 5 years. We conclude that induction therapy allowed satisfactory resection for marginally resectable tumors. Operative morbidity was increased in this group. However, the 5-year survival was similar to resectable stage IIIa cancer.     

Detection of hibernated myocardium using intracoronary technetium-99m-sestamibi

Fifty-two of 2,315 patients (2.4%) with non-small cell lung cancer (NSLC) treated with radiation therapy at the Mallinckrodt Institute of Radiology and St. Luke's Hospital between 1975 and 1988 presented with local recurrence after definitive surgery. No patient received radiation therapy after surgery as part of initial treatment and none had evidence of distant metastases at the time of local recurrence. The median time to first recurrence was 14 months. At recurrence, patients presented with disease in the bronchial stump (eight patients), ipsilateral lung parenchyma (10), chest wall (six), regional lymph nodes (five), or some combination thereof (23). Sixty-five percent of patients had histologic evidence of recurrence. Radiation therapy consisted of > 5,000 cGy in conventional fractionation to areas of gross disease in 35 of 52 patients. Of 15 patients receiving > 6,000 cGy, 13 had a favorable--complete (CR) or partial (PR) response--tumor response to radiation therapy. Among these patients, local control was achieved in 70% of patients with marginal recurrences (i.e., stump, parenchyma, or chest wall) and in 50% with nodal recurrences. The median survival after radiation therapy for all patients was 8.5 months. The best indicators for long-term survival were the interval from initial surgery to first recurrence and tumor response to radiation therapy.     

Phase I trial of docetaxel and cisplatin in previously untreated patients with advanced non-small-cell lung cancer

PURPOSE: To determine the maximum-tolerated doses (MTDs), principal toxicities, and pharmacokinetics of the combination of docetaxel and cisplatin administered every 3 weeks to patients with advanced non-small-cell lung cancer (NSCLC) who have not received prior chemotherapy and to recommend a dose for phase II studies. PATIENTS AND METHODS: Patients with advanced NSCLC and performance status 0 to 2 who had not received prior chemotherapy received docetaxel over 1 hour followed by cisplatin over 1 hour with hydration. Dose levels studied were (docetaxel/cisplatin) 50/75, 75/75, 75/100, and 100/75 mg/m2 repeated every 3 weeks. Colony-stimulating factor (CSF) support was not used. Pharmacokinetics of docetaxel and cisplatin were studied in the first cycle of therapy. Most patients (79%) had metastatic disease or intrathoracic recurrence after prior radiation and/or surgery. RESULTS: Of 24 patients entered, all were assessable for toxicity and 18 for response. The MTD schedules were docetaxel 75 mg/m2 with cisplatin 100 mg/m2 (dose-limiting toxicities [DLTs] in five of six patients), and docetaxel 100 mg/m2 with cisplatin 75 mg/m2 (DLTs in two of two patients, including one fatal toxicity). Limiting toxicities were febrile neutropenia and nonhematologic, principally diarrhea and renal. Two patients had neutropenic enterocolitis. Pharmacokinetics of both drugs were consistent with results from single-agent studies, which suggests no major pharmacokinetic interaction. Neutropenia was related to docetaxel area under the plasma concentration-versus-time curve (AUC). An alternative schedule was investigated, with cisplatin being administered over 3 hours commencing 3 hours after docetaxel, but toxicity did not appear to be less. Independently reviewed responses occurred in eight of 18 patients (44%; 95% confidence interval, 22% to 69%), most following 75 mg/m2 of both drugs. CONCLUSION: Docetaxel 75 mg/m2 over 1 hour followed by cisplatin 75 mg/m2 over 1 hour is recommended for phase II studies. The responses seen in this phase I study suggest a high degree of activity of this combination in previously untreated advanced NSCLC.     

Primary tumors of the thoracic skeleton

From 1975 to 1990, eighty-nine primary tumors of the thoracic skeleton; ribs, sternum, scapula, clavicle, and thoracic spine, were treated. Forty-four tumors (49%) were benign lesions. Forty-five tumors were malignant and were proportionately distributed amongst the five sites. The most common malignancies were Ewing's sarcomas, chondrosarcomas, plasmacytomas, osteogenic sarcomas, and lymphomas. All patients with Ewing's sarcomas were treated with combination chemotherapy, surgical resection, and radiation therapy for those with residual disease after surgery. Only one patient has died of disease. Patients with primary chondrosarcomas were treated by surgery alone and all are free of disease or have died without disease. Patients with solitary plasmacytomas or primary lymphomas of bone were treated with radiation therapy initially. Half the patients developed systemic disease. The patients with osteogenic sarcomas included several with radiation induced lesions and Paget's osteosarcoma and all but one died of disease.     

Regional chemotherapy with hemofiltration: a rationale for a different treatment approach to advanced pancreatic cancer

BACKGROUND/AIMS: Since 1989, thirty-two patients with advanced, intra-abdominal pancreatic cancer were treated with regional chemotherapy in combination with extracorporeal hemofiltration. PATIENTS and METHODS: Eleven patients had locally advanced, unresectable cancer, and ten had advanced disease with liver metastases. Three patients had developed liver metastases following a radical resection. One patient had an incomplete resection with local residual disease, and a second had developed a local recurrence after a radical resection. One patient had an unresectable cystadenocarcinoma. Five patients had failed prior systemic therapies for unresectable pancreatic cancer. The patients underwent 85 treatments with regional chemotherapy plus hemofiltration, an average of 2.7 treatments per patient. RESULTS: Of 21 patients treated primarily with regional chemotherapy plus hemofiltration, there were two complete responses (9%) and eight partial responses (38%), an overall total response rate of 47%. The average survival for patients with Stage II/III localized, unresectable disease is 13 months and that for Stage IV unresectable disease with liver metastases is 9 months. CONCLUSIONS: Patients with recurrent disease following a radical resection or having failed prior systemic therapies generally had no benefit from regional chemotherapy plus hemofiltration.     

Radiotherapy and concurrent chemotherapy for the treatment of locally advanced head and neck squamous cell carcinoma

PURPOSE: To determine whether combination 5-fluorouracil, cisplatin, and interferon alfa, an active regimen in advanced esophageal cancer, is efficacious as induction therapy before esophagectomy. MATERIALS AND METHODS: Forty-four patients with potentially resectable esophageal/gastroesophageal junction adenocarcinoma or squamous cell carcinoma were entered into a phase I/II study of this chemotherapeutic regimen and concurrent external-beam radiotherapy before resection. The initial 16 patients were treated with prolonged-infusion 5-fluorouracil (300 mg/m2 on days 1 to 28), cisplatin (20 mg/m2 on days 1 to 5 and 24 to 28), interferon alfa (3 x 10(6) U/m2 intravenously on days 1 to 5 and 24 to 28; subcutaneous injection every other day on days 6 to 23), and radiation (4000 cGy). The subsequent 28 patients were treated over 21 days with two modifications: dose escalation of 5-fluorouracil (250 to 350 mg/m2) and double-fractionated radiotherapy to a total dose of 4500 cGy. RESULTS: Forty-one patients completed chemoradiotherapy and were evaluable for toxicity. Adverse events were substantial but tolerable, and most toxic episodes were hematologic and gastrointestinal. Three patients died, and one patient had progressive disease before resection. Of the 37 patients eligible for curative resection, 36 had all gross tumor removed. Thirty-three (80%) patients had a major pathologic response: 10 (24%) with no residual tumor and 23 with only microscopic residual tumor. Median survival for all patients was 27 months and for responders was 36 months. CONCLUSIONS: This combination regimen is active but yields results similar to those of other chemoradiotherapy phase II trials; therefore, the contribution of interferon alfa to treatment efficacy remains uncertain. The true worth of preoperative chemoradiotherapy is unknown pending results of phase III trials.     

Characteristics of non-participants and reasons for non-participation in a population survey in Kin-Hu, Kinmen

We analyzed the pattern of failure and clinicopathologic factors influencing the disease-free survival of 78 patients who died after macroscopic curative resection for pancreatic cancer. Local recurrence was a component of failure in 56 patients (71.8%) and hepatic recurrence in 48 (61.5%), both accounting for 97% of the total recurrence rate. About 95% of recurrences occurred by 24 months after operation. Median disease-free survival time was 8 months, and cumulative 1-, 3-, and 5-year actuarial disease-free survival rates were 66%, 7%, and 3%, respectively. Multivariate analysis showed that tumor grade (p = 0.04), microscopic radicality of resection (p = 0.04), lymph node status (p = 0.01), and size of the tumor (p = 0.005) were independent predictors of disease-free survival. Patterns of failure and disease-free survival were not statistically influenced by the type of surgical procedure performed. Median survival time from the detection of recurrence until death was 7 months for local recurrence versus 3 months for hepatic or local plus hepatic recurrence (p < 0.05). From our experience and the data collected from the literature, it appears that surgery alone is an inadequate treatment for cure in patients with pancreatic carcinoma. Effective adjuvant therapies are needed to improve locoregional control of pancreatic cancer after surgical resection.     

Accelerated-interrupted radiation therapy given concurrently with chemotherapy for locally advanced non-small cell lung cancer

PURPOSE: To evaluate the efficacy of multidrug chemotherapy combined with accelerated radiation therapy in the treatment of localized but unresectable non-small cell lung cancer. PATIENTS AND METHODS: Between September 1990 and February 1993, 35 patients with Stage III (15 IIIA & 20 IIIB) non-small cell lung cancer were entered on a protocol using combined accelerated radiation therapy and chemotherapy. Radiation therapy consisted of 55.6 Gy in 30 fractions (1.8 Gy bid for 5 consecutive days given in 3 weeks [total of 15 days], every other week). Chemotherapy consisted of cisplatin (10 mg/m2), vinblastine (4 mg/m2), 6-thioguanine (40 mg bid), and 5-fluorouracil (400 mg/m2 as continuous infusion) given concomitantly with radiation therapy. Approximately 3 weeks following completion of radiation therapy, two cycles of consolidation chemotherapy were given, consisting of two doses of cisplatin (120 mg/m2) 4 weeks apart and six doses of vinblastine (4 mg/m2) given on two consecutive days every other week for 3 weeks. RESULTS: Six patients were still alive at last follow-up; for them the median follow-up time is 47 months (range, 39-55.8). The median survival time is 17.5 months. The 1-, 2-, 3- and 4.5-year survival rates are 69%, 37%, 20% and 17%, respectively. Overall response rate is 63%, with 51.5% partial response and 11.5% complete response rates. Esophagitis occurred as follows: Grade 4 = 0, Grade 3 = 1, Grade 2 = 6, and Grade 1 = 13. No patient developed Grade 3 or 4 acute respiratory toxicity. Significant hematologic toxicity occurred as follows: 37% Grade 3 and 31% Grade 4 leukopenia. Radiation pneumonitis occurred in two patients. DISCUSSION: The regimen tested in this protocol appears to be very well tolerated with minimal pulmonary or esophageal toxicity. This, coupled with the shortened course of radiation therapy and the ability to deliver the combined radiation and chemotherapy portion of the treatment on an outpatient basis most of the time, has made multi-modality treatment for this malignancy much easier and more convenient for patients. In addition, the favorable survival in this group of patients with locally advanced disease is very encouraging and warrants further study.     

Use of concurrent chemotherapy, accelerated fractionation radiation, and surgery for patients with esophageal carcinoma

BACKGROUND: The results of a Phase II study of concurrent chemotherapy and accelerated fractionation radiation therapy followed by surgical resection for patients with both adenocarcinoma and squamous cell carcinoma of the esophagus are presented. Pretreatment and postinduction staging were correlated with pathologic findings at surgery to assess the role of surgical resection and the predictive value of noninvasive staging techniques. METHODS: Patients received 2 induction courses with 4-day continuous intravenous infusions of cisplatin (20 mg/m2/day) and 5-fluorouracil (1000 mg/m2/day) beginning on Day 1 and Day 21, concurrent with a split course of accelerated fractionation radiation (1.5 grays [Gy] twice daily, to a total dose of 45 Gy). All patients were subsequently referred for surgical resection. A single, identical postoperative course of chemotherapy and 24 Gy accelerated fractionation radiation was planned for patients with residual tumor at surgery. RESULTS: Seventy-four patients were entered on this study; 72 patients were considered eligible and evaluable. Induction toxicity included nausea (85%), increased dysphagia (90%), neutropenia (<1000/mm3) (43%), thrombocytopenia (<20,000/mm3) (10%), and reversible nephrotoxicity (8%). Sixty-seven patients (93%) underwent surgery, and 65 (90%) were found to have resectable tumors. Twelve of these patients (18%) died perioperatively, and 18 (27%) had no residual pathologic evidence of disease. Resolution of symptoms and normalization of radiographic studies, endoscopy, or esophageal ultrasound did not identify pathologic complete responders accurately. No patient completing induction therapy and surgery experienced a locoregional recurrence. The Kaplan-Meier 4-year projected recurrence free and overall survival rates were 49% and 44%, respectively. CONCLUSIONS: Although this regimen is feasible, there was significant preoperative toxicity and perioperative mortality. Nonetheless, the recurrence free and overall survival rates were encouraging. However, no staging tool can predict a pathologic complete response after induction therapy accurately, suggesting a continued need for surgical resection.     

Paclitaxel in combination chemotherapy with radiotherapy in patients with unresectable stage III non-small-cell lung cancer

PURPOSE: The addition of combination chemotherapy to standard radiation therapy has improved treatment for locally unresectable non-small-cell lung cancer. In this phase II study, we evaluated the toxicity and efficacy of a novel chemotherapy regimen that included paclitaxel, cisplatin, and etoposide plus concurrent radiation therapy in this group of patients. PATIENTS AND METHODS: Thirty-three patients with previously untreated, unresectable stage III non-small-cell lung cancer (stage IIIA, 11 patients; stage IIIB, 22 patients) initially received two courses of chemotherapy, which included paclitaxel 135 mg/m2 by 1-hour infusion on day 1, cisplatin 60 mg/m/ intravenously (i.v.) on day 2, and etoposide 100 mg/m2 i.v. on days 1, 2 and 3. On week 6, radiation therapy (60 Gy in 30 fractions) was initiated in conjunction with two additional courses of chemotherapy: paclitaxel 135 mg/m2 i.v. by 1-hour infusion on day 1, cisplatin 5 mg/m2 i.v. on days 2- to 10, and etoposide 25 mg/m2 on days 1 to 10. RESULTS: This combined modality program was feasible and well tolerated by most patients. During the two courses of induction chemotherapy, grade 3 or 4 myelosuppression occurred in only six patients (18%). Esophagitis was common during combined modality therapy (grade 3, 10 patients; grade 4 five patients). Forty-two percent of patients had partial response after two courses of induction therapy, and 82% of patients had an objective response at completion of therapy. Twelve patients (36%) had a complete response. Nineteen patients remain progression-free at a median of 8 months; the median survival time has not been reached. CONCLUSION: This paclitaxel-containing combined modality therapy is feasible and highly active in patients with inoperable stage III lung cancer. Esophagitis is the most common severe toxicity with this program. Further studies with paclitaxel-containing combination regimens in patients with stage III non-small-cell lung cancer are indicated.     

Advantage of post-operative oral administration of UFT (tegafur and uracil) for completely resected p-stage I-IIIa non-small cell lung cancer (NSCLC)

OBJECTIVE: Although adjuvant therapy after surgery for non-small cell lung cancer (NSCLC) has been reported to be ineffective, it has been recently reported in prospective randomised studies conducted by two different groups in Japan that oral administration of a 5-fluorouracil (5-FU) derivative drug, UFT (a combination drug of tegafur and uracil) can improve the post-operative survival [The Study Group of Adjuvant Chemotherapy for Lung Cancer (Chubu, Japan). A randomized trial of postoperative adjuvant chemotherapy in non-small cell lung cancer (the second cooperative study). Eu J Surg Oncol 1995;21:69-77; Wada, H., Hitomi, S., Teramatsu, T, West Japan Study Group for Lung Cancer Surgery. Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. J Clin Oncol 1996;14:1048-1054]. To examine the efficacy of UFT as post-operative adjuvant therapy, a retrospective study was performed. METHODS: A total of 655 consecutive patients who underwent complete tumor resection for pathologic stage I-IIIa, NSCLC at the Department of Thoracic Surgery, Chest Disease Research Institute, Kyoto University between 1976 and 1992 were retrospectively reviewed. As post-operative adjuvant therapy, UFT was administrated to 98 patients (UFT group), and was not administered to the other 557 patients (Control group). RESULTS: The 5-year survival rate of the UFT group was 76.5%, which was significantly better than that of the Control group (5-year survival rate: 58.6%, P = 0.005). Stratified with pathologic stage, the efficacy of UFT was seen in the p-stage I disease (5-year survival rate: 88.6% for the UFT group, 72.0% for the Control group, P = 0.013) and in the p-stage IIIa, pN2 disease (5-year survival rate: 54.3% for the UFT group, 37.5% for the Control group, P = 0.037). Multivariate analysis of the prognostic factors also revealed the efficacy of UFT (P = 0.004, 95% confidence interval of relative risk: 0.325-0.840). Post-operative intravenous chemotherapy or radiation therapy did not prove to be significant factors affecting the prognosis. CONCLUSIONS: Efficacy of oral administration of UFT as post-operative adjuvant therapy for completely resected NSCLC was proposed. To confirm the efficacy, a prospective randomized study for a more homogenous patient group is needed.     

Nerve-induced histamine release is of little importance in psoriatic skin

To evaluate the efficacy of systemic ifosfamide, cisplatin (CDDP) combination as first line treatment followed by intraperitoneal (IP) chemotherapy with carboplatin (CBCDA) and etoposide as consolidation in patients with stage III and IV epithelial ovarian cancer. A total of 40 patients with stage III and IV ovarian cancer were entered into the study. Ifosfamide 1 g/m2 plus mesna 1 g/m2 was given as six hour infusion daily for six days and CDDP 75 mg/m2 was given on day seven. Patients completing six cycles of systemic therapy underwent second look laparotomy followed by four cycles of IP chemotherapy with CBCDA 300 mg/m2 and etoposide 200 mg/m2. Of the 40 patients entering the protocol 27 patients completed six cycles with a complete remission (CR) of 65% and overall response of 67.5%. Twenty-two patients underwent second look laparotomy with pathological CR in ten patients, microscopic disease in seven and macroscopic disease in five. Eleven patients completed four cycles of IP chemotherapy. At 52 months was the overall survival (OS) was 36%. The disease free survival (DFS) at 45 months was 38%. Factors affecting OS were ascites (p < 0.011), stage (p < 0.04), weight change (p < 0.017), residual disease (p < 0.001), number of chemotherapy cycles (p < 0.0001) and IP chemotherapy (p < 0.006). Presently 35% patients are alive in CR, 15% are alive with disease, one patients has been lost to follow up while 47.5% have died. Of these four patients had progressive disease, seven relapsed, four died due to treatment related complications and two died in CR due to other causes. Subset analysis of 22 patients who had second look laparotomy and completed four cycles of IP chemotherapy revealed a distinct survival advantage. IFOS + CDDP is an effective combination as first time treatment in advanced ovarian cancer. IP chemotherapy is effective as consolidation and seems to provide a significant survival advantage. Further studies with larger number of patients need to be done to confirm these results.     

Acute promyelocytic leukemia: all-trans retinoic acid (ATRA) along with chemotherapy is superior to ATRA alone

This study was conducted to compare the results of treatment of acute promyelocytic leukemia (APL) with all-trans retinoic acid alone (ATRA) or a combination therapy of ATRA followed by chemotherapy. Forty-three patients treated between February 1992 and February 1996 were included in this study. Eighteen patients were treated with ATRA alone and 25 patients were treated with ATRA followed by chemotherapy. The cytogenetic analysis was done in 41 patients at presentation, following treatment, and at follow-up. A complete response (CR) was achieved in 13 (72%) patients on ATRA and 19 (76%) on ATRA followed by chemotherapy. Eleven of 13 patients with response to ATRA alone relapsed with median survival of eight months (range, 1 to 28). One patient died of hepatitis in CR and one patient is alive 2 years after diagnosis. In the combination therapy arm, 10 patients are in CR with a median follow-up of 22 months (range, 6 to 56 months). After achieving a CR, four patients died due to infections during chemotherapy therapy, and only 5 of 19 patients have relapsed. Major cytogenetic response was seen in 8 of the 10 patients in whom cytogenetic data was available after treatment with ATRA at the time of remission. Similarly, 13 of 15 for whom data was available showed a major cytogenetic response after treatment with ATRA plus chemotherapy. Prior to relapse, 80% of the patients had an increase in the percentage of t(15;17) cells in the marrow. Patients with a complete hematological response but no cytogenetic response relapsed within six months. Ten patients died prior to response evaluation. Two patients who received ATRA died of retinoic acid syndrome, one of pneumonia, and one of intracranial hemorrhage. Of the six patients on ATRA and chemotherapy, four died of retinoic acid syndrome (RAS), one of intracranial hemorrhage, and one of left ventricular failure. Only one patient is alive at 24 months following treatment with ATRA alone. The relapse-free survival is 42% at four years for patients treated with ATRA followed by chemotherapy. This trial is a historical comparison of ATRA alone and ATRA with subsequent combination chemotherapy. Nonetheless, the trial shows a significant improvement in the event free survival of patients receiving chemotherapy as consolidation following ATRA.