Gefitinib in definitive management of esophageal or gastroesophageal junction cancer: a retrospective analysis of two clinical trials.

The role of epidermal growth factor receptor inhibition in resectable esophageal/gastroesophageal junction (E/GEJ) cancer is uncertain. Results from two Cleveland Clinic trials of concurrent chemoradiotherapy (CCRT) and surgery are updated and retrospectively compared, the second study differing only by the addition of gefitinib (G) to the treatment regimen. Eligibility required a diagnosis of E/GEJ squamous cell or adenocarcinoma, with an endoscopic ultrasound stage of at least T3, N1, or M1a (American Joint Committee on Cancer 6th). Patients in both trials received 5-fluorouracil (1000 mg/m(2) /day) and cisplatin (20 mg/m(2) /day) as continuous infusions over days 1-4 along with 30 Gy radiation at 1.5 Gy bid. Surgery followed in 4-6 weeks; identical CCRT was given 6-10 weeks later. The second trial added G, 250 mg/day, on day 1 for 4 weeks, and again with postoperative CCRT for 2 years. Preliminary results and comparisons have been previously published. Clinical characteristics were similar between the 80 patients on the G trial (2003-2006) and the 93 patients on the no-G trial (1999-2003). Minimum follow-up for all patients was 5 years. Multivariable analyses comparing the G versus no-G patients and adjusting for statistically significant covariates demonstrated improved overall survival (hazard ratio [HR] 0.64, 95% confidence interval [CI] = 0.45-0.91, P = 0.012), recurrence-free survival (HR 0.61, 95% CI = 0.43-0.86, P = 0.006), and distant recurrence (HR 0.68, 95% CI = 0.45-1.00, P = 0.05), but not locoregional recurrence. Although this retrospective comparison can only be considered exploratory, it suggests that G may improve clinical outcomes when combined with CCRT and surgery in the definitive treatment of E/GEJ cancer.

Clinicopathologic features and treatment outcomes of patients with human epidermal growth factor receptor 2-positive adenocarcinoma of the esophagus and gastroesophageal junction.

Human epidermal growth factor receptor 2 (HER2) is overexpressed in 21% of gastric and 33% of gastroesophageal junction (GEJ) adenocarcinomas. Trastuzumab has been approved for metastatic HER2-positive gastric/GEJ cancer in combination with chemotherapy. This retrospective analysis was undertaken to better define the clinicopathologic features, treatment outcomes, and prognosis in patients with HER2-positive adenocarcinoma of the esophagus/GEJ. Pathologic specimens from 156 patients with adenocarcinoma of the esophagus/GEJ treated on clinical trials with chemoradiation and surgery were tested for HER2. Seventy-six patients also received 2 years of gefitinib. Baseline characteristics and treatment outcomes of the HER2-positive and negative patients were compared both in aggregate and separately for each of the two trials. Of 156 patients, 135 had sufficient pathologic material available for HER2 assessment. HER2 positivity was found in 23%; 28% with GEJ primaries and 15% with esophageal primaries (P= 0.10). There was no statistical difference in clinicopathologic features between HER2-positive and negative patients except HER2-negative tumors were more likely to be poorly differentiated (P < 0.001). Locoregional recurrence, distant metastatic recurrence, any recurrence, and overall survival were also statistically similar between the HER2-positive and the HER2-negative groups, in both the entire cohort and in the gefitinib-treated subset. Except for tumor differentiation, HER2-positive and negative patients with adenocarcinoma of the esophagus and GEJ do not differ in clinicopathologic characteristics and treatment outcomes. Given the demonstrated benefit of trastuzumab in HER2-positive gastric cancer and the similar incidence of HER2 overexpression in esophageal/GEJ adenocarcinoma, further evaluation of HER2-directed therapy in this disease seems indicated.

Influence of killer immunoglobulin-like receptor/HLA ligand matching on achievement of T-cell complete donor chimerism in related donor nonmyeloablative allogeneic hematopoietic stem cell transplantation.

Achievement of complete donor chimerism (CDC) after allogeneic nonmyeloablative hematopoietic stem cell transplantation (NMHSCT) is important for preventing graft rejection and for generating a graft-vs-malignancy effect. The alloreactivity of NK cells and some T-cell subsets is mediated through the interaction of their killer immunoglobulin-like receptors (KIRs) with target cell HLA/KIR ligands. The influence of KIR matching on the achievement of T-cell CDC after NMHSCT has not been previously described. We analyzed 31 patients undergoing T-cell replete related donor NMHSCT following fludarabine and 200 cGy TBI. Recipient inhibitory KIR genotype and donor HLA/KIR ligand matches were used to generate an inhibitory KIR score from 1 to 4 based upon the potential number of recipient inhibitory KIRs that could be engaged with donor HLA/KIR ligands. Patients with a score of 1 were less likely to achieve T-cell CDC (P=0.016) and more likely to develop graft rejection (P=0.011) than those with scores greater than 1. Thus, patients with lower inhibitory KIR scores may have more active anti-donor immune effector cells that may reduce donor chimerism. Conversely, patients with greater inhibitory KIR scores may have less active NK cell and T-cell populations, which may make them more likely to achieve CDC.

Survival of AML patients receiving HLA-matched sibling donor allogeneic bone marrow transplantation correlates with HLA-Cw ligand groups for killer immunoglobulin-like receptors.

The reactivity of natural killer cells and some T-cell populations is regulated by killer immunoglobulin-like receptors (KIR) interactions with target cell HLA class I molecules. Such interactions have been suggested to influence outcomes after allogeneic hematopoietic stem cell transplantation, particularly for myeloid malignancies and with T-cell depletion. Donor KIR genotypes and recipient HLA KIR ligands were analyzed in 60 AML patients receiving T-cell replete, HLA-matched-related donor allogeneic bone marrow transplants. Patients were categorized according to their HLA inhibitory KIR ligand groups by determining whether or not they expressed: HLA-A3 or -A11; HLA-Bw4 and HLA-Cw groups (homozygous C1, homozygous C2 or heterozygous C1/C2). Heterozygous C1/C2 patients had significantly worse survival than those homozygous for C1 or C2 (5.8 vs 43.5 months, respectively, P=0.018) and the C1/C2 group had a higher relapse rate (47 vs 31%, respectively, P=0.048). Multivariate analysis found C1/C2 status to be an independent predictor for mortality (P=0.007, HR 2.54, confidence interval 1.29-5.00). C1/C2 heterozygosity was also associated with a delayed time to platelet engraftment, particularly for those with concurrent HLA-Bw4 expression (P=0.003). Since C1/C2 heterozygotes have a greater opportunity to engage inhibitory KIRs than do C1 or C2 homozygotes, they may more effectively inhibit KIR-positive NK- and T-cell populations involved in graft vs leukemia responses.

Autologous hematopoietic stem cell transplantation in peripheral T-cell lymphoma using a uniform high-dose regimen.

The role of high-dose therapy and autologous stem cell transplantation (ASCT) for patients with peripheral T-cell lymphoma (PTCL) is poorly defined. Comparisons of outcomes between PTCL and B-cell non-Hodgkin's lymphoma (NHL) have yielded conflicting results, in part due to the rarity and heterogeneity of PTCL. Some retrospective studies have found comparable survival rates for patients with T- and B-cell NHL. In this study, we report our single-center experience of ASCT over one decade using a uniform chemotherapy-only high-dose regimen. Thirty-two patients with PTCL-unspecified (PTCL-u; 11 patients) and anaplastic large-cell lymphoma (21 patients) underwent autologous stem cell transplant, mostly for relapsed or refractory disease. The preparative regimen consisted of busulfan, etoposide and cyclophosphamide. Kaplan-Meier 5-year overall survival (OS) and relapse-free survival (RFS) are 34 and 18%, respectively. These results suggest a poor outcome for patients with PTCL after ASCT, and new therapies for T-cell lymphoma are needed.

Effect of prior rituximab on high-dose therapy and autologous stem cell transplantation in follicular lymphoma.

Autologous stem-cell transplantation (ASCT) has been used in follicular lymphoma (FL) to achieve durable responses in first remission or in the relapsed or refractory settings. Addition of rituximab to chemotherapy for FL has been shown to improve survival. The impact of prior therapy with rituximab upon the effectiveness of high-dose therapy (HDT) and ASCT in patients with FL is unknown. We retrospectively reviewed consecutive patients with FL who underwent HDT and ASCT. Patients were categorized according to prior therapy with rituximab. Outcomes were compared between groups in all patients and in a well-matched subset. In all 35 patients received prior rituximab and 71 rituximab-naive patients were analyzed. The rituximab-naive group had a median overall survival (OS) that was not reached during follow-up, with a median relapse-free (RFS) survival of 49.9 months. The prior rituximab group also did not reach median OS and had a median RFS of 24.6 months. Survivals were not significantly different in this group or in the well-matched subset. In conclusion, these results suggest that the use of rituximab-based regimens for the treatment of FL does not compromise the effectiveness of HDT and ASCT as a salvage strategy in patients with FL.

Allogeneic BMT and patient eligibility based on psychosocial criteria: a survey of BMT professionals.

BMT professionals were compared regarding their willingness to proceed with allogeneic BMT given select psychosocial issues. A questionnaire was sent to 660 physician members of ASBMT, 92 social work members of BMT Special Interest Group, Association of Oncology Social Work, and 626 nurse members of BMT Special Interest Group, Oncology Nursing Society; 597 responded with a response rate of 43.5%. Items included background information, followed by 17 case vignettes; each represented a different psychosocial issue to which respondents indicated whether or not they would recommend proceeding with allogeneic BMT. In every vignette, at least 10% of respondents indicated they would not proceed. In six vignettes, at least 64% indicated do not proceed: suicidal ideation (86.8%), uses addictive illicit drugs (81.7%), history of noncompliance (80.5%), no lay caregiver (69.3%), alcoholic (64.8%), and mild dementia/Alzheimer's (64.4%). In 10 vignettes, at least 73% indicated proceed. On four vignettes, professional subgroups differed in their recommendation on whether or not to proceed with allogeneic BMT. Qualitative data suggest that this decision is contingent on the perceived acuity, severity, and currency of the psychosocial issue, patient ability to comply with treatment given the issue, and its manageability as a risk factor for treatment related vulnerability and outcomes.

Does paclitaxel improve the chemoradiotherapy of locoregionally advanced esophageal cancer? A nonrandomized comparison with fluorouracil-based therapy.

PURPOSE: A phase II trial of accelerated fractionation radiation with concurrent cisplatin and paclitaxel chemotherapy was performed to investigate the role of the paclitaxel, when substituted for fluorouracil (5-FU), in the chemoradiotherapy of esophageal cancer. PATIENTS AND METHODS: Patients with an esophageal ultrasound stage of T(3) or N(1) or M(1) (nodal) esophageal cancer were treated with two courses of a cisplatin infusion (20 mg/m(2)/d for 4 days) and paclitaxel (175 mg/m(2) over 24 hours) concurrent with a split course of accelerated fractionation radiation (1.5 Gy bid to a total dose of 45 Gy). Surgical resection was performed 4 to 6 weeks later followed by a single identical postoperative course of chemoradiotherapy (24 Gy) in patients with significant residual tumor at surgery. Toxicity and results of this treatment were retrospectively compared with our previous 5-FU and cisplatin chemoradiotherapy experience. RESULTS: Between September 1995 and July 1997, 40 patients were entered onto this study. Although dysphagia proved worse in our 5-FU-treated patients, profound leukopenia and a need for unplanned hospitalization were significantly more common in the paclitaxel group. Thirty-seven patients (93%) proved resectable for cure. The 3-year projected overall survival is 30%, locoregional control is 81%, and distant metastatic disease control is 44%. When compared with a similarly staged cohort of 5-FU-treated patients, there was no advantage for any survival function studied. CONCLUSION: This paclitaxel-based treatment regimen for locoregionally advanced esophageal cancer produced increased toxicity with no improvement in results when compared with our previous 5-FU experience. Paclitaxel-based treatments must be carefully and prospectively studied before their incorporation into the standard management of esophageal cancer.

Carboplatin skin testing: a skin-testing protocol for predicting hypersensitivity to carboplatin chemotherapy.

PURPOSE: A high incidence of moderate to severe hypersensitivity reactions (HRs) is noted in patients who have been treated with multiple courses of carboplatin. Presently, there is no reliable way to predict which patients may be at risk for this potentially severe adverse reaction. We developed a skin-test protocol to identify patients at high risk for HR to carboplatin chemotherapy. PATIENTS AND METHODS: Patients undergoing more than seven courses of carboplatin received a 0.02-mL intradermal injection of an undiluted aliquot of their planned carboplatin infusion 1 hour before each course of the agent. A positive skin test was prospectively defined as that resulting in a wheel of at least 5 mm with a surrounding flare. We recently reported a 27% incidence of HRs in patients receiving more than seven courses of carboplatin. These patients served as historical controls for the current study. RESULTS: Forty-seven patients with recurrent ovarian or primary peritoneal carcinoma receiving carboplatin were skin tested. Thirteen of 47 patients (28%) manifested a positive skin test at a median of nine total courses of carboplatin (range, eight to 17 courses). This rate of skin-test positivity was not significantly different from the incidence of documented HR reported in a historical control group (P =.89), suggesting comparable populations. A negative skin test accurately predicted the absence of HR in 166 of 168 courses of chemotherapy. Only two of 47 patients (4%) experienced a HR after a negative skin test. Thus, administering carboplatin only to patients with a negative skin test may result in a significant reduction in HRs relative to historical controls (P =.002). CONCLUSION: An easily performed skin test appears to predict patients in whom carboplatin may be safely administered. Treatment modifications based on the results of skin testing may reduce the incidence of HRs in patients receiving repeated courses of carboplatin.

Influence of a randomized clinical trial on practice by participating investigators: lessons from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT). CAVEAT I and II Investigators.

OBJECTIVES: We sought to determine whether the results of the first Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT-I) influenced subsequent practice patterns among the investigators. BACKGROUND: CAVEAT-I demonstrated that directional coronary atherectomy (DCA) resulted in higher rates of early complications at a higher cost and with no clinical benefit. We sought to determine whether these results influenced subsequent use of procedures among CAVEAT-I investigators. METHODS: We compared the results of a week-long registry of all coronary interventions performed at 35 CAVEAT-I sites in 1994 with those of a similar registry obtained in 1992 before the trial, the results of which were published in 1993. For control purposes, the use of procedures was studied at 24 additional sites to provide insight into practice at hospitals not participating in the trial. A total of 1,465 interventions were analyzed. RESULTS: Ninety-four percent of CAVEAT-I sites responded. Utilization rates differed between CAVEAT-I and CAVEAT-I follow-up (p < 0.001). Balloon angioplasty decreased from 83.8% to 68.5%, DCA increased slightly from 10.7% to 14.1%, and the use of other devices increased from 5.4% to 17.5%. Stand-alone balloon use was more prevalent at nonparticipating control sites than at sites that took part in CAVEAT-I (p < 0.001). CONCLUSIONS: Paradoxically, despite the negative findings of CAVEAT-I, there was a noteworthy trend toward an increase in the use of DCA and other devices at CAVEAT-I sites. Our findings suggest that among investigators in the trial, there may have been a lack of influence of trial data on clinical practice patterns 1 year after publication of the results. Ethics of protocol: Both CAVEAT I and II were approved by the Institutional Review Board at each study site.

The impact of ursodeoxycholic acid on cancer, dysplasia and mortality in ulcerative colitis patients with primary sclerosing cholangitis.

BACKGROUND: Colorectal cancer in primary sclerosing cholangitis patients with ulcerative colitis is mostly right-sided where concentrations of carcinogenic secondary bile acids are highest. AIM: To investigate whether ursodeoxycholic acid could be chemopreventive for colorectal cancer. METHODS: A historical cohort study was performed on primary sclerosing cholangitis patients with ulcerative colitis where the 28 patients (cases) who were treated with ursodeoxycholic acid for at least 6 months (mean 3.4 +/- 2.7 years) were compared with the 92 patients (controls) who were not treated with ursodeoxycholic acid. The primary outcomes were colorectal cancer and dysplasia. The secondary outcome was overall mortality. RESULTS: The cumulative incidence of dysplasia or cancer was not significantly different between cases and controls (P = 0.17 by log-rank test). The adjusted relative risk for cases of developing dysplasia or cancer was 0.59 (95% CI 0.26-1.36). The cumulative mortality was significantly different between groups (P = 0.02 by log-rank test). The adjusted relative risk for cases of death was 0.44 (95% CI 0.22-0.90). CONCLUSION: In ulcerative colitis patients with primary sclerosing cholangitis, ursodeoxycholic acid did not reduce the risk of developing cancer or dysplasia. However, ursodeoxycholic acid may reduce mortality.

Outcomes after autologous SCT in lymphoma patients grouped by weight.

Obesity continues to be an increasing global health issue contributing to the complexity of chemotherapy dosing in the field of SCT. Investigation into the optimal dosing weight used to calculate chemotherapy doses in obese patients undergoing SCT is limited and inconclusive. Our single-center, retrospective study compared safety and efficacy outcomes by body mass index (BMI) for 476 adult lymphoma patients who underwent auto-SCT with a myeloablative chemotherapeutic regimen of BU, CY and etoposide dosed using adjusted body weight. Three weight groups categorized based on BMI were defined: normal/underweight ⩽24.9 kg/m(2), overweight 25-29.9 kg/m(2) and obese ⩾30 kg/m(2). Severity of mucositis, incidence of secondary malignancy, incidence of bacteremia and median hospital length of stay did not differ among the groups. The median times to absolute neutrophil count and platelet recovery were 10 days (P=0.75) and 14 days (P=0.17), respectively. Obese patients had a lower 100-day mortality compared with other weight groups, although this did not translate into an OS benefit. OS and disease relapse were similar among the groups. Our study demonstrates that use of adjusted body weight to calculate chemotherapy doses does not negatively have an impact on outcomes in obese patients undergoing auto-SCT with BU, CY and etoposide.

It is not just IMRT: Human papillomavirus related oropharynx squamous cell carcinoma is associated with better swallowing outcomes after definitive chemoradiotherapy.

OBJECTIVES: Long term swallowing dysfunction in patients with oropharynx squamous cell carcinoma (OPSCC) treated with concurrent chemoradiation (CRT) is declining. While the use of intensity modulated radiotherapy (IMRT) is commonly believed to be a potential cause, we hypothesize that the increasing incidence of human papillomavirus (HPV) related disease may also favorably impact this outcome. MATERIALS AND METHODS: We reviewed 130 HPV+ and 17 HPV- patients with stage III-IV OPSCC treated exclusively with conventional 3-field radiotherapy with chemotherapy between 2002 and 2010. The rates of normal diet, limited diet (significant restrictions in the types of foods eaten, and/or requiring nutritional supplementation for weight maintenance) and feeding tube dependence (FTD) were compared between HPV+ and HPV- patients. Cox proportional hazards modeling were used to perform univariate analysis (UVA) to examine predictors of a combined endpoint of dietary limitation, which included limited diet and/or FTD. These outcomes were also compared to our previously reported cohort of OPSCC patients treated between 1989 and 2002 to assess changes in toxicity over time given the changing disease epidemiology, in the setting of identical treatment regimens. RESULTS: With a median follow-up of 55 months, HPV+ patients more frequently had resumed a normal diet (87% vs. 65%) at last follow up and had lower rates of limited diet (9% vs. 18%) and FTD (4% vs. 18%) compared to HPV- patients (p=0.02). HPV status was the only significant predictor of reduced swallowing dysfunction on UVA (HR 0.19; p=0.008). When compared to our 1989-2002 cohort, patients treated between 2002 and 2010 had less FTD (7.5% vs. 34%, p<0.001) and dietary limitations (26% vs.46%, p<0.001) at 6 months post treatment. CONCLUSIONS: HPV+ patients with OPSCC have reduced late swallowing dysfunction after chemoradiation compared to HPV- patients. The changing epidemiology of OPSCC may play a role in toxicity reduction in these patients, independent of the increasing use of IMRT.

Hepatic tumor radioembolization in a rat model using radioactive rhenium (186Re/188Re) glass microspheres.

PURPOSE: The aim of this study was to fully characterize newly developed radioactive rhenium glass microspheres in vivo by determining their biodistribution, stability, antitumor effect, and toxicity after hepatic arterial injection in a syngeneic rat hepatoma model. The dose response of the tumors to increasing amounts of radioactive 186Re and 188Re microspheres was also determined. METHODS AND MATERIALS: Rhenium glass microspheres were made radioactive by neutron activation and then injected into the hepatic artery of Sprague-Dawley rats containing 1-week-old Novikoff hepatomas. The biodistribution of the radioactivity and tumor growth were determined 1 h and 14 days after injection. RESULTS: Examination of the biodistribution indicated a time-dependent, up to 7-fold increase in Novikoff hepatoma uptake as compared to healthy liver tissue uptake. After 14 days, the average T:L ratio was 1.97. Tumor growth in the rats receiving radioactive microspheres was significantly lower than in the group receiving nonradioactive microspheres (142% vs. 4824%, p = 0.048). Immediately after injection, 0.065% of the injected radioactivity was measured in the thyroid; it decreased to background levels within 24 h. CONCLUSION: Radioactive rhenium microspheres are effective in diminishing tumor growth without altering hepatic enzyme levels. The microspheres are safe with respect to their radiation dose to healthy tissue and radiation release in vivo and can be directly imaged in the body with a gamma camera. Furthermore, rhenium microspheres have an advantage over pure beta-emitting microspheres in terms of preparation and neutron-activation time. In sum, this novel radiopharmaceutical may provide an innovative and cost-effective approach for the treatment of nonresectable liver cancer.

Cell cycle phase specificity in the potentiation of etoposide-induced DNA damage and apoptosis by KN-62, an inhibitor of calcium-calmodulin-dependent enzymes.

The cell cycle phase-dependent induction of DNA damage and apoptosis by etoposide (VP-16) and its modulation by 1-[N,O-bis(1, 5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-piperazine (KN-62), an inhibitor of calcium-calmodulin-dependent enzymes, were examined in sensitive (HL-60/S) and VP-16-resistant (HL-60/DOX0.05) HL-60 cells. Cells from exponential-phase cultures were enriched by centrifugal elutriation into G(1), S, and G(2)+M fractions. Modulation of VP-16-induced apoptosis by KN-62 in HL-60/S cells was apparent only in the S phase at the IC(50) concentration. However, in the HL-60/DOX0.05 cells, significant (P < 0.001) potentiation of VP-16-induced apoptosis by a non-cytotoxic concentration of 2 microM KN-62 was apparent in cells in the G(1), S, and G(2)+M phases, as well as over the entire concentration range tested. VP-16-induced apoptosis and its potentiation by a non-cytotoxic concentration of 2 microM KN-62 were correlative with drug-stabilized DNA cleavable complex formation based on a band depletion assay. In agreement with the results on apoptosis in the resistant HL-60/DOX0.05 cells, the enhanced depletion of the alpha and beta isoforms of topoisomerase II by VP-16 + KN-62 was observed in G(1), S, and G(2)+M cells. Results suggest that the effects of KN-62 in reversing resistance are based on its role as a potent sensitizer of VP-16-induced DNA damage and apoptosis in a cell cycle phase-independent manner.

Is resection of pulmonary and hepatic metastases warranted in patients with colorectal cancer?

BACKGROUND: Conventional management of stage IV colorectal carcinoma is palliative. The value of resecting both liver and lung colorectal metastases that occur in isolation of other sites of metastasis is undetermined. OBJECTIVES: Our objectives were to (1) assess the efficacy of resecting both hepatic and pulmonary metastases, (2) investigate the influence of the sequence and timing of metastases, and (3) identify the profile of patients likely to benefit from both hepatic and pulmonary metastasectomy. PATIENTS AND METHODS: Of 48 patients identified with resection of colorectal cancer and, at some point in time, both liver and lung metastases, 25 patients underwent metastasectomy (resection group). The remaining 23 patients comprised the nonresection group. Risk factors for death were identified by multivariable analyses. RESULTS: Median survival was longer after the last metastatic appearance in the resection group (16 months) than in the nonresection group (6 months; P <.001). The pattern of risk also differed; it peaked at 2 years and then declined in the resection group but was constant in the nonresection group. In the resection group, patients with metachronous resections survived longer after colorectal resection (median, 70 months) than patients with synchronous (median, 22 months) or mixed resections (median, 31 months; P <.001). Risk factors for death included older age, multiple liver metastases, and a short disease-free interval. CONCLUSIONS: Younger patients with solitary metachronous metastases to the liver, then the lung, and long disease-free intervals are more likely to benefit from resection of both liver and lung metastases. Patients with risk factors also had better survival with resection than without resection.

Timed barium esophagogram: A simple physiologic assessment for achalasia.

OBJECTIVE: Success of achalasia therapy is difficult to determine because repeated physiologic study is impractical and symptoms are subjective. Timed barium esophagography directly measures esophageal emptying and is simple to perform. This study (1) evaluates the assessment of myotomy by timed barium esophagography and (2) compares it with premyotomy and postmyotomy symptoms. METHODS: Fifty patients ingested 250 mL low-density barium and had upright films at 1, 2, and 5 minutes premyotomy. Forty-five underwent repeat timed barium esophagography 8 weeks (median) postmyotomy. Premyotomy and postmyotomy height and width of the barium column were compared and related to symptoms. RESULTS: At 1, 2, and 5 minutes premyotomy, median barium column height was 19, 17, and 15 cm, and width was 5.2, 4.8, and 4.5 cm, respectively. Surgery reduced these to 7.0, 5.0, and 1.0 cm and to 3.5, 3.0, and 1.0 cm, respectively (P <.001). Postmyotomy complete esophageal emptying was seen in 29%, 36%, and 49% at 1, 2, and 5 minutes. Postmyotomy height was unrelated (r approximately 0.2) to premyotomy height but was directly related to premyotomy width (r = 0.3-0.5; P <.05); postmyotomy width was directly related to premyotomy width (r approximately 0.6; P <.001). Premyotomy dysphagia was more severe when little change in width occurred from 1 to 5 minutes (r = 0.26, P =.07). Premyotomy regurgitation was more severe the higher the barium column (r approximately 0.4, P <.007). Surgery relieved symptoms in the majority of patients (grade 2-5 dysphagia from 72% to 4%, grade 2-5 regurgitation from 79% to 4%). Postmyotomy symptoms were unrelated to the timed barium esophagogram. CONCLUSIONS: (1) The timed barium esophagogram gives objective confirmation of successful myotomy. (2) Symptoms are unreliable in assessing esophageal emptying.

Esophagectomy with gastric reconstruction for achalasia.

PURPOSE: Achalasia is a degenerative esophageal disorder that may result in esophageal failure necessitating resection for restoration of gastrointestinal function. This study evaluates a protocol of esophageal resection and gastric reconstruction for end-stage achalasia. METHODS: Hospital records, radiographic studies, and resection specimens of patients undergoing esophagectomy and gastric reconstruction were reviewed. Patient outcome was defined by an evaluation of symptoms (early satiety, dysphagia, regurgitation, and reflux), dietary restrictions, and ability to maintain or gain weight. Preoperative, operative, and postoperative variables and pathologic features in the resection specimens were analyzed to determine predictors of outcome. RESULTS: In a 10-year period, 32 patients underwent esophagectomy with gastric reconstruction for achalasia; 30 (94%) underwent elective surgery and 2 (6%), emergency surgery. No postoperative deaths occurred. Of 29 patients completing telephone interviews, 24 (83%) had no or mild dysphagia; 21 (72%), no or mild regurgitation; 20 (69%), no or mild reflux; and 19 (66%), no or mild early satiety. Twenty-four (83%) patients had no or minimal dietary restrictions; 26 (90%) had no or minimal social dietary restrictions. Postoperative weight was not different from preoperative weight. Of 30 patients, 26 (87%) felt better after esophagectomy and 25 (83%) would have the operation again. There were few predictors of outcome. Younger patients were more likely to have dysphagia ( P =.03). CONCLUSIONS: Esophagectomy with gastric reconstruction relieves preoperative dysphasia and regurgitation in the majority of patients. Dietary function and weight maintenance are excellent, attesting to the durability of the procedure in patients with end-stage achalasia.

M1a/M1b esophageal carcinoma: clinical relevance.

OBJECTIVE: The 1997 staging system for esophageal carcinoma subdivides distant metastatic disease (M1) into M1a (nonregional lymph node metastases) and M1b (other metastases). This study evaluates the relevance of this classification. METHODS: One hundred forty patients were identified with M1 disease, 36 (26%) M1a and 104 (74%) M1b. The histologic type was adenocarcinoma in 118 (84%), squamous cell in 18 (13%), and adenosquamous in 4 (3%), with a similar distribution for M1a and M1b (P =.3). Forty-five underwent surgery, 28 (78%) with M1a disease and 17 (16%) with M1b disease (P <.001). Chemotherapy and/or radiation therapy was given to 33 (73%) surgical patients and 63 (66%) nonsurgical patients (P =.4), 28 (78%) with M1a disease and 68 (66%) with M1b disease (P =.17). RESULTS: Median and 5-year survivals were 11 months and 6% in patients with M1a disease and 5 months and 2% in those with M1b disease (P =.001). Surgery provided no advantage in M1b (P =.6) or M1a disease (P =.2). Multivariable analysis demonstrated that patients with M1b disease had 1.8 times the mortality risk of those with M1a disease (CI 1.2-2.7, P =.004), and patients without chemotherapy and/or radiotherapy had 2.2 times the mortality risk of those with chemotherapy and/or radiotherapy (CI 1.5-3.2, P <.001). Despite the prevalence of surgery in patients with M1a disease, the analysis suggests that M1a and use of chemotherapy and/or radiotherapy, rather than surgery, account for the small, clinically unimportant differences in survival. CONCLUSIONS: We conclude that (1) although there are statistically significant survival differences between M1a and M1b disease, these differences are not clinically important; (2) chemotherapy and/or radiotherapy is associated with a modest survival benefit; and (3) surgery offers no survival advantage.

N1 esophageal carcinoma: the importance of staging and downstaging.

OBJECTIVE: To evaluate the effects of clinical staging and downstaging by induction chemoradiation therapy in patients with N1 esophageal carcinoma. METHODS: Sixty-nine consecutive patients with regional lymph node metastases (cN1) according to clinical staging received induction therapy before surgery. These were compared to 75 patients both clinically and pathologically N1 (cN1/pN1) who underwent surgery without induction therapy and 79 patients clinically and pathologically not N1 (cN0/pN0) who underwent surgery without induction therapy. Analyses focused on survival and the cost and benefit of therapy. RESULTS: For comparison, the extremes of 5-year survival were 69% for cN0/pN0 patients who underwent surgery alone and 12% for cN1/pN1 patients who underwent surgery alone. Of 69 patients who received induction therapy, 37 were pN0 at resection (downstaged); they had an intermediate survival of 37% at 5 years. Those patients not downstaged with induction therapy had a 12% 5-year survival, similar to patients with cN1/pN1 who underwent surgery alone. After adjusting for the strongest predictors of poor outcome, pN1, and increasing N1 burden, a modest increased risk of death after induction therapy was identified. However, this cost of induction therapy was more than counterbalanced by the benefit of improved survival of downstaging to pN0. CONCLUSIONS: (1) pN1 is the strongest determinant of poor outcome. (2) cN1 patients who are downstaged by induction chemoradiation therapy to pN0 have an intermediate outcome. (3) cN1 patients who are not downstaged by induction therapy have a poor outcome.