Esophageal Cancer Clinical Practice Guidelines.
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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
Jack Roth
Publications and source records attributed to Jack Roth.
Gastric Cancer Clinical Practice Guidelines.
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Antineoplastic Combined Chemotherapy Protocols↗
Induction chemotherapy improved outcomes of patients with resectable esophageal cancer who received chemoradiotherapy followed by surgery.
PURPOSE: To investigate the effect of induction chemotherapy (CHT) before trimodality therapy on the outcome of patients with resectable cancer of the esophagus. METHODS AND MATERIALS: This retrospective study included 81 consecutive patients with resectable cancer of the esophagus who received neoadjuvant chemoradiotherapy followed by esophagectomy between January 1990 and December 1998 (inclusive). Thirty-nine patients underwent chemoradiotherapy followed by esophagectomy (CHT/RT+S), 42 received additional induction CHT followed by CHT/RT+S (CHT+CHT/RT+S). Of the 81 patients, 47 were entered in institutional or national prospective trials (6 in the CHT/RT+S and 41 in the CHT+CHT/RT+S group). Induction CHT consisted of three courses of 5-fluorouracil (5-FU), cisplatin, and paclitaxel given in 28-day cycles in 37 patients (88.1%). Concurrent CHT was 5-FU and platinum based. The median radiation dose for patients treated with CHT/RT+S was 30 Gy (range, 30-50.4 Gy) delivered in a median of 10 fractions (range, 10-28 fractions) and 45 Gy (range, 30-45 Gy) in a median of 25 fractions (range, 10-25 fractions) for patients treated with CHT+CHT/RT+S. Esophagectomy was performed 6-8 weeks after completion of concurrent chemoradiotherapy. Most patients underwent transthoracic esophagectomy (n = 66, 82.5%). RESULTS: The pretreatment characteristics were well balanced between the two groups except for age. The median follow-up time was 29 months (22 months for the CHT/RT+S group and 38.5 months for the CHT+CHT/RT+S group) for all patients and 49 months for living patients. The actuarial overall survival (OS), disease-free survival (DFS), locoregional control (LRC), and distant metastasis-free survival (DMFS) rate at 5 years for the entire group was 46%, 36.6%, 70.7%, and 53.2%, respectively. Statistically significant differences in the OS, DFS, and LRC rates between the two groups were detected. Specifically, the 5-year OS rate was 22.8% and 71.1% in the CHT/RT+S and CHT+CHT/RT+S group (p = 0.0001), respectively. The 5-year DFS rate was 27.6% and 56.6% in the CHT/RT+S and CHT+CHT/RT+S group (p = 0.003), respectively. The 5-year LRC rate was 64.2% and 85.6% in the CHT/RT+S and CHT+CHT/RT+S group (p = 0.007), respectively. The difference in the DMFS rate between the two groups was statistically significant, with a 2- and 5-year actuarial rate of 63.9% and 51.9%, respectively, in the CHT/RT+S group and 76.9% and 74.1%, respectively, in the CHT+CHT/RT+S group (p = 0.04). The statistically significant differences persisted when patients who received >/=45 Gy in each group were compared. Among those patients, the 5-year OS, DFS, LRC, and DMFS rates were 23.1%, 15.4%, 58.6%, and 39.2%, respectively, for those receiving CHT/RT+S, and 71.4% (p = 0.001), 55.8% (p = 0.0008), 84.6% (p = 0.005), and 77.3% (p = 0.009), respectively, for those receiving CHT+CHT/RT+S. The pathologic complete response (pCR) rate was greater in the CHT+CHT/RT+S group compared with in the CHT/RT+S group (p = 0.008). In univariate analysis, young age, good Karnofsky performance status, Stage II disease, total radiation dose, multiple drug regimen for concurrent CHT, pCR, R0 resection, distant disease progression, and CHT+CHT/RT+S treatment proved to be prognostic factors for OS. Lower esophageal/gastroesophageal junction tumor location, pCR, R0 resection, and CHT+CHT/RT+S treatment were favorable prognostic factors for LRC. Neither the total radiation dose nor multiple drugs for concurrent CHT were negative prognostic factors for LRC. In multivariate analysis, pCR, R0 resection, and treatment with CHT+CHT/RT+S were independent positive predictive factors for OS, and distant recurrences were negative predictive factors for OS. R0 resection, CHT+CHT/RT+S treatment, and lower esophageal/gastroesophageal junction tumor location were positive predictive factors for LRC. The radiation dose was not identified as an independent prognostic factor for either OS or LRC in the multivariate analysis. Meaningful multivariate analysis could not be performed when the multiple drug vperformed when the multiple drug variable was included in the model because of the small number of patients. CONCLUSION: Significantly greater LRC, DFS, OS, and DMFS were found in patients treated with CHT+CHT/RT+S compared with those treated with CHT/RT+S. The pCR rate was significantly higher in the CHT+CHT/RT+S group. Induction CHT was an independent favorable prognostic factor for both LRC and OS for the population included in this study. Our data suggest that a randomized trial comparing CHT+CHT/RT+S and CHT/RT+S is warranted to assess further the merits of this treatment in patients with this currently very lethal cancer.
Adult↗
Equivalent outcome of patients with clinical Stage IIIA non-small-cell lung cancer treated with concurrent chemoradiation compared with induction chemotherapy followed by surgical resection.
PURPOSE: To compare the outcome of induction chemotherapy followed by surgery (C/S) and concurrent chemoradiotherapy (CRT) for clinical Stage IIIA non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Between 1990 and 2000, 107 patients underwent either induction C/S (n = 55) or concurrent CRT (n = 52) for clinical Stage IIIA NSCLC at The University of Texas M. D. Anderson Cancer Center. Patient and tumor characteristics were balanced in the two treatment groups with respect to T and N stage, race, median age, performance status, weight loss, and histologic findings. In the C/S group, induction chemotherapy included two to four cycles of cisplatin-based chemotherapy followed by lobectomy and mediastinal lymph node dissection. Postoperative RT was delivered in 35 patients, with referral for RT made at the discretion of the treating physician. CRT consisted of three cycles of cisplatin-based chemotherapy given every 3 weeks concurrent with RT to 60-63 Gy in 30-35 fractions in 27 patients and 69.6 Gy in 58 fractions (b.i.d.) in 25 patients. Local control, overall disease-free survival, and distant metastasis-free survival rates were calculated using the Kaplan-Meier method. The median follow-up duration was 20 months in all patients and 32 months in surviving patients. RESULTS: No statistically significant differences were found in the end points measured in the two treatment groups. Specifically, the median survival time was 31 and 27 months and the 5-year overall survival rate was 33% and 30% in the C/S and CRT groups, respectively. Likewise, the 5-year local control (58% vs. 61%), disease-free (24% vs. 23%), and distant metastasis-free (44% vs. 36%) survival rates in the two groups were not significantly different. In the C/S group, postoperative RT significantly improved the 5-year local control rate from 33.8% to 81.5% (p = 0.007) but did not significantly improve overall survival. Additionally, patients in the C/S group whose disease responded to induction chemotherapy had a significantly improved 5-year overall survival rate (50%) compared with those who had stable or progressive disease (16%, p = 0001). CONCLUSION: Treatment of Stage IIIA NSCLC using either induction C/S or CRT resulted in similar outcomes in terms of local control and median overall, 5-year overall, distant metastasis-free, and disease-free survival. However, patients undergoing induction C/S often needed postoperative RT to achieve local control equivalent to that achieved with concurrent CRT. Advances in radiation-based treatment as reflected in this study have resulted in similar outcomes compared with modern induction C/S. To improve survival, however, newer systemic agents that reduce and control distant metastasis are required.
Antineoplastic Combined Chemotherapy Protocols↗
The risk of second primary tumors after resection of stage I nonsmall cell lung cancer.
BACKGROUND: The incidence of second primary lung cancers (SPLC) after resection of nonsmall cell lung cancer (NSCLC) is estimated to be 1% to 4% per patient year. The overall effect of SPLC on survival after resection of stage I NSCLC is unknown. Here we report the incidence, management, and outcome of SPLC in a large prospective cohort of patients who underwent careful follow-up. METHODS: National Cancer Institute Intergroup Trial NCI #I91-0001 examined the effectiveness of isotretinoin A for chemoprevention of second primary tumors, the primary endpoint in that trial. Prospective data from patients randomly assigned to the placebo arm were analyzed. RESULTS: Five hundred sixty-nine patients underwent complete resection of pathologic stage I NSCLC. The median follow-up was 5.9 years. Second primary tumors developed in 88 (15%) patients. Of these, 49 (56%) were SPLC (incidence = 1.99/100 patient-years), with a median interval from initial surgery of 4.2 years. Second primary lung cancer never developed in patients who had never smoked (n = 44, p = 0.046; never versus ever smokers). Current smokers had a higher incidence of SPLC than former smokers (hazard ratio = 1.91, p = 0.03). Age, sex, stage, histology, tumor location and initial surgery had no effect on SPLC development. Despite semiannual follow-up with chest radiographs, 12 (24%) patients had metastatic disease at the time of diagnosis of SPLC. Surgical resection was performed in 31 (63%) SPLC patients. Median survival was 4.1 years in those who underwent surgery and 1.4 years in those who did not (p = 0.003). Overall SPLC-related mortality in the original cohort was 3.7%. CONCLUSIONS: Patients who undergo surgery for SPLC can achieve prolonged survival. Despite close follow-up however many patients with SPLC present with advanced disease. That indicates a need for continued lifelong postoperative surveillance.
Carcinoma, Non-Small-Cell Lung↗
Irinotecan/cisplatin followed by 5-FU/paclitaxel/radiotherapy and surgery in esophageal cancer.
Local-regional carcinoma of the esophagus is often diagnosed in advanced stages because the diagnosis is established when symptoms are severe. The prognosis of patients with local-regional carcinoma of the esophagus continues to be grim. While preoperative chemoradiotherapy increases the fraction of patients who achieve pathologic complete response, that percentage is approximately 25%. In an attempt to increase the number of patients with either no cancer in the surgical specimen or only microscopic cancer, we adopted a three-step strategy. The current study utilized up to two 6-week cycles of induction chemotherapy with irinotecan (CPT-11, Camptosar) and cisplatin as step 1. This was followed by concurrent radiotherapy and chemotherapy with continuous infusion fluorouracil (5-FU) and paclitaxel as step 2. Once the patients recovered from chemoradiotherapy, a preoperative evaluation was performed and surgery was attempted. All patients signed an informed consent prior to their participation on the study. A total of 43 patients were enrolled. The baseline endoscopic ultrasonography revealed that 36 patients had a T3 tumor, five patients had a T2 tumor, and two had a T1 tumor. Twenty-seven patients had node-positive cancer (N1). Thirty-nine (91%) of the 43 patients underwent surgery; all had an R0 (curative) resection. A pathologic complete response was noted in 12 of the 39 patients. In addition, 17 patients had only microscopic (< 10%) viable cancer in the specimen. Therefore, a significant pathologic response was seen in 29 (74%) of 39 taken to surgery or 29 (67%) of all 43 patients enrolled on the study. With a median follow up beyond 25 months, 20 patients remain alive and 12 patients remain free of cancer. Our preliminary data suggest that the proportion of patients with significant pathologic response can be increased by using the three-step strategy.
Adult↗
Resection of advanced thoracic malignancies requiring cardiopulmonary bypass.
OBJECTIVES: Patients with malignancies involving cardiac structures have limited therapeutic options and significant risk of mortality. The decision to offer radical palliative or curative resection must be made only after consideration of the substantial surgical risks. The purpose of this retrospective study was to determine the feasibility and benefits of resection with cardiopulmonary bypass (CPB) of metastatic or non-cardiac primary malignancies extending directly into or metastasizing to the heart in select patients. Our results were examined to assess the risks and benefits of such radical therapy. METHODS: We retrospectively reviewed patient charts and identified all patients with malignancies involving the cardiac chamber or great vessels (excluding renal carcinomas with caval extension) or with substantial cardiac compression who had undergone resection with CPB at The University of Texas M.D. Anderson Cancer Center between January 1995 and July 2000. We evaluated demographic data, symptomatology, tumor characteristics, and outcomes. RESULTS: Nineteen patients (six males and 13 females; median age of patients, 47 years; age range, 17-67 years) were included in the study. Eleven patients underwent surgery with curative intent, and eight underwent surgery with palliative intent. Seventeen patients had tumors that required CPB because their tumors directly involved the heart and/or great vessels (nine sarcomas, seven epithelial carcinomas, and one unclassified), and two patients (both with sarcomas) required CPB to relieve tumor tamponade. The technique included CPB (n=5), CPB with diastolic arrest (n=12), and CPB with hypothermic circulatory arrest (n=2). Five patients underwent concomitant pneumonectomy, and three underwent lobectomy. Two patients (11%) died in the hospital after resection with palliative intent. Of the 11 patients who underwent resection with curative intent, ten (91%) had complete resections. The median time in the intensive care unit was 5.3 days (range, 0-37 days) and the median length of hospital stay was 17.2 days (range, 0-107 days). Major complications occurred in 11 patients (58%); the most common major complications were pneumonia (n=7 patients), mediastinal hematoma (n=4 patients), and acute respiratory distress syndrome (n=2 patients). The median follow-up duration was 27 months. The overall 1- and 2-year survival rates were 65 and 45%, respectively. CONCLUSIONS: Extensive thoracic tumors involving cardiac structures can be resected with acceptable risk. When resection was performed with curative intent, excellent 1- and 2-year cumulative survival rates were achieved. Although resection with palliative intent was associated with greater mortality rates, some patients survived for 1 and 2 years. The use of CPB in selected patients with thoracic malignancies should be considered, especially when complete resection can be achieved.
Adolescent↗
TAD: a web interface and database for tissue microarrays.
Tissue microarrays are increasingly important tools that bring high-throughput technology to traditional pathology laboratories. In many cases, each spot on a tissue microarray is scored by a skilled pathologist and recorded manually. TAD consists of an Active Server Page web interface to a relational database that automates recording scores and linking them with clinical data for future interpretation. TAD is an open source application that can be installed locally.
Computational Biology↗
Bax and Bak promote apoptosis by modulating endoplasmic reticular and mitochondrial Ca2+ stores.
Alterations in intracellular Ca(2+) homeostasis and cytochrome c release from mitochondria have been implicated in the regulation of apoptosis, but the relationship between these events remains unclear. Here we report that enforced expression of either Bax or Bak via adenoviral gene delivery results in the accumulation of the proteins in the endoplasmic reticulum (ER) and mitochondria, resulting in early caspase-independent BCL-2-sensitive release of the ER Ca(2+) pool and subsequent Ca(2+) accumulation in mitochondria. The inhibition of ER-to-mitochondrial Ca(2+) transport with a specific inhibitor of mitochondrial Ca(2+) uptake attenuates cytochrome c release and downstream biochemical events associated with apoptosis. Bax and Bak also directly sensitize mitochondria to cytochrome c release induced by immediate emptying of ER Ca(2+) pool. Our results demonstrate that the effects of the "multidomain" proapoptotic BCL-2 family members Bak and Bax involve direct effects on the endoplasmic reticular Ca(2+) pool with subsequent sensitization of mitochondria to calcium-mediated fluxes and cytochrome c release. These effects modulate the kinetics of cytochrome c release and apoptosis.
Apoptosis↗