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Exposure to ionizing radiation increases the risk of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but such risks are not known in well-differentiated thyroid cancer (WDTC) patients treated with radioactive iodine (RAI). A total of 148 215 WDTC patients were identified from Surveillance, Epidemiology and End Results registries between 1973 and 2014, of whom 54% underwent definitive thyroidectomy and 46% received adjuvant RAI. With a median follow-up of 6.6 years, 77 and 66 WDTC patients developed MDS and MPN, respectively. Excess absolute risks for MDS and MPN from RAI treatment when compared to background rates in the US population were 6.6 and 8.1 cases per 100 000 person-years, respectively. Compared to background population rates, relative risks of developing MDS (3.85 (95% confidence interval, 1.7-7.6); P=0.0005) and MPN (3.13 (1.1-6.8); P=0.012) were significantly elevated in the second and third year following adjuvant RAI therapy, but not after thyroidectomy alone. The increased risk was significantly associated with WDTC size ⩾2 cm or regional disease. Development of MDS was associated with shorter median overall survival in WDTC survivors (10.3 vs 22.5 years; P<0.001). These data suggest that RAI treatment for WDTC is associated with increased risk of MDS with short latency and poor survival.

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., (© 2014 International Society for Diseases of the Esophagus.)

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (© 2012 Copyright the Authors. Journal compilation © 2012, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus.)

Our objectives were to determine the likelihood of true folate deficiency among patients tested for this disorder, to identify whether there were differences between the clinical indications for folate testing in folate-normal and folate-deficient patients and to assess the impact of a diagnosis of folate deficiency on patient management. The results of all blood samples analyzed for serum and erythrocyte folate levels during the year 2001 at the Cleveland Clinic Foundation were retrieved. Folate deficient patients were identified and their medical charts were reviewed to determine the indications, patient characteristics, and impact of this diagnosis on patient management. For comparison, medical chart review was also conducted on a control group composed of an equal number of randomly selected patients with normal serum folate values. A total of 6024 (4689 serum and 1335 erythrocyte) samples from 4985 patients were collected. In the study, 77 (1.6%) of the serum folate levels, from 74 patients, were identified as low. When compared with the control group, patients with low serum folate levels had lower hemoglobin and a greater red cell distribution width. Mean corpuscular volume, however, did not differ between the two groups. No significant differences in the clinical indications for serum folate level determinations could be identified. Only 39 of the 74 patients with low serum folate levels were given folate replacement, representing only 0.9% of the clinically suspected and tested patients. We conclude that determination of serum folate level infrequently led to appropriate folate replacement therapy. Moreover, even when suspected, true folic acid deficiency is rare and clinical indications are not helpful in diagnosis.

Objective: Experience with treatment and outcome of superficial adenocarcinoma of the esophagus is limited. The purpose of this study was to evaluate the results of surgical management and identify predictors of survival., Methods: Between September 1985 and December 1999, 122 patients underwent resection. Eighty-nine percent were men (mean age 63 +/- 10 years; range 35-83 years). Sixty (49%) patients were in endoscopic surveillance programs and 48 (39%) had the preoperative diagnosis of high-grade dysplasia. Forced expiratory volume in 1 second was less than 2 L in 12 (12%). Seventy-five (61%) patients underwent transhiatal esophagectomy. Pathologic stage was N1 in 8 (7%). Pulmonary complications necessitating reintubation (respiratory failure) occurred in 10 (8%) patients. Time-related survival models were developed for decision-making (preoperative), prognosis (operative), and hospital care (postoperative)., Results: Operative mortality was 2.5%. Survival at 1, 5, and 10 years was 89%, 77%, and 68%. Preoperative decision-making factors associated with ideal outcome were 1-second forced expiratory volume of more than 2 L, surveillance, preoperative diagnosis of high-grade dysplasia, and planned transhiatal esophagectomy. Prognosis was decreased in younger patients and in those with N1 disease. Postoperative respiratory failure increased mortality., Conclusions: Surgery is the treatment of choice for superficial adenocarcinoma of the esophagus. The ideal patient has a preoperative diagnosis of high-grade dysplasia found at surveillance, good pulmonary function, and undergoes a transhiatal esophagectomy. Discovery of N1 disease or development of postoperative respiratory failure reduces the benefits of surgery.

Background: The incidence of hypothyroidism was assessed retrospectively from a data base of 155 patients with head and neck carcinoma who were treated at the Cleveland Clinic Foundation between 1990 and 1997., Methods: One hundred patients were randomized between radiotherapy (RT) (66-72 grays in single daily fractions) and RT with concurrent chemotherapy (CT) using 5-fluorouracil and cisplatin. An additional 55 patients received RT and CT without randomization. Primary site surgery was performed for tumor persistence or recurrence and included a thyroidectomy in nine patients. These nine patients, along with three patients who had hypothyroidism prior to treatment, were excluded from the analysis. At regular intervals after the completion of treatment, all patients were evaluated for the development of hypothyroidism, defined as a serum thyroid-stimulating hormone (TSH) level > 5.5 microU/mL., Results: With a median follow-up for 143 evaluable patients of 4.4 years (range, 1.5-9.2 years), the 5-year Kaplan-Meier projected incidence rate of hypothyroidism was 48%, and the 8-year projected incidence rate was 67%. The median time to the development of hypothyroidism was 1.4 years (range, 0.3-7.2 years). The likelihood of developing hypothyroidism could not be predicted according to age, gender, primary site, tumor or lymph node status, overall stage, RT dosage to the primary site or to the neck, or inclusion of CT in the treatment plan. Only race proved predictive, with no African-American patients developing hypothyroidism (P = 0.02)., Conclusions: The authors conclude that the incidence rate of hypothyroidism after patients undergo RT for head and neck carcinoma is higher than generally reported and that TSH screening after treatment appears justified., (Copyright 2001 American Cancer Society.)

Hypothesis: P53 and Ki-67 status will predict response to treatment, organ preservation, and survival in patients with advanced squamous cell cancers of the head and neck treated with chemoradiotherapy (CRT)., Study Design: Retrospective analysis of p53 and Ki-67 status from the CRT arm of a randomized, controlled trial (n = 50) and from patients receiving the same treatment but not enrolled in the trial (n = 55)., Methods: P53 and Ki-67 status were established from archived tissue samples using immunohistochemical (IHC) staining. Tumors were positive for p53 (p53+) when more than 2% of cells stained for p53 and were positive for Ki-67 (Ki-67+) when any cell stained for Ki-67. End points were tumor response, tumor recurrence, survival status, and organ preservation at last follow-up, and time to events. Predictive models were calculated for each outcome., Results: Neither marker predicted tumor response to treatment. P53+ status was associated with tumor recurrence (P =.003) and locoregional recurrence (P =.003). Adjusting for time to event, p53+ status was significantly related to a lower recurrence-free survival (P =.004), lower disease-specific survival (P =.04), lower overall survival with primary site preservation (P =.03), and lower disease-specific survival with primary site preservation (P =.003). Multivariate analysis revealed that p53+ status was significantly related to a lower recurrence-free survival (P =.01, risk ratio [RR] = 3.65) and lower disease-specific survival with organ preservation (P =.02, RR = 3.41). Ki-67+ status was not related to any variables. However, multivariate analysis revealed that Ki-67+ was significantly related to a lower overall survival (P =.05, RR = 2.03). The combination of both markers negative (p53-/Ki-67-) was associated with a lower incidence of tumor recurrence (P =.02), lower locoregional recurrence (P =.01), and fewer second primary lesions (P =.04). Adjusting for time to event, p53-/Ki-67- status was significantly related to a higher recurrence-free survival (P =.02), higher disease-specific survival with primary site preservation (P =.02), and higher overall survival with primary site preservation (P =.02). Multivariate analysis revealed that p53-/Ki-67- status was significantly related to a higher overall survival with site preservation (P =.01, RR = 2.78)., Conclusions: P53 and Ki-67 status appear to be related to the various survival end points considered in this study. However, this relation does not seem to be sufficient to warrant treatment modifications. Closer follow-up may be justified in both p53+ and Ki67+ patients to detect recurrence or a second primary at an earlier stage, possibly improving survival.

Background: Multimodality treatments for patients with squamous cell head and neck carcinoma often produce significant mucositis and dysphagia, mandating enteral nutritional support. Patient preference has resulted in the increasing use of percutaneous endoscopic gastrostomy (PEG) tubes rather than nasogastric (NG) tubes. Anecdotal observations of prolonged PEG dependence and of a need for pharyngoesophageal dilatation in PEG patients prompted a retrospective review of the use of both types of feeding tubes., Methods: Patients who were treated on clinical trials of radiotherapy or chemoradiotherapy for squamous cell head and neck carcinoma between 1989 and 1997 were reviewed retrospectively. Data were gathered regarding demographics, primary tumor site, T and N classifications, and the need for feeding tube placement. In patients requiring feeding tubes, the type and duration of the feeding tube, the need for tracheostomy, the need for pharyngoesophageal dilatation, and the degree of mucositis and dysphagia at baseline and at 1 month, 3 months, 6 months, and 12 months after beginning treatment were recorded. Comparisons were then made between the NG and the PEG groups., Results: Ninety-one feeding tubes were placed in 158 patients over the 8-year interval. A hypopharyngeal primary site, female gender, a T4 primary tumor, and treatment with chemoradiotherapy were predictive of a need for feeding tube placement. NG tubes were placed in 29 patients, and PEG tubes were placed in 62 patients. PEG patients had more dysphagia at 3 months (59% vs. 30%, respectively; P = 0.015) and at 6 months (30% vs. 8%, respectively; P = 0.029) than NG patients. The median tube duration was 28 weeks for PEG patients compared with 8 weeks for NG patients, (P < 0.001). Twenty-three percent of PEG patients needed pharyngoesophageal dilatation compared with 4% of NG patients (P = 0.022). These end points could not be correlated with age, stage, primary tumor site, or tracheostomy placement., Conclusions: Although patients treated for head and neck carcinoma find that the PEG tube is a more acceptable route for enteral nutrition than the NG tube, in the authors' experience, a PEG tube was required for longer periods of time and was associated with more persistent dysphagia and an increased need for pharyngoesophageal dilatation. A randomized prospective trial is needed to test these observations., (Copyright 2001 American Cancer Society.)

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.

The rarity of most primary skull base carcinomas and sarcomas has prevented a careful examination of the role of chemotherapy in these diseases. For advanced nasopharyngeal cancer, however, convincing data have now been generated supporting the role of systemic chemotherapy in conjunction with definitive locoregional treatment. Chemotherapy also seems to have a role in the management of other squamous cell head and neck cancers, and its use concurrently with radiation may be appropriate when extension to the base of the skull is identified. The role of chemotherapy in the management of the other skull base neoplasms remains less well established. Existing evidence is little more than anecdotal, and the use of systemic chemotherapy should generally be restricted to the palliative treatment setting. The ultimate role of this intervention in the aggressive sinonasal undifferentiated carcinomas and primary neuroendocrine carcinomas is unknown, but for these diseases, chemotherapy is a reasonable addition to locoregional treatment.

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.

Objective: This study evaluates the cost-effectiveness of various imaging and biopsy strategies for characterizing adrenal masses in patients with newly diagnosed non-small cell carcinoma of the lung., Materials and Methods: A decision-analysis model was used to compare the cost-effectiveness of nine strategies. Initial imaging included unenhanced CT using an adenoma or nonadenoma threshold of 0 or 10 H or in- and opposed-phase MR imaging. When initial imaging did not confirm an adenoma, CT-guided biopsy or subsequent imaging was performed. Medicare reimbursement was used as a surrogate of cost. Net costs were calculated as the difference in costs between two limbs of the decision tree. Net benefits were calculated as the difference between strategies and were calculated for life expectancy in years. MR imaging, CT, and biopsy accuracy, average life expectancy, and surgical mortality rates were based on the literature., Results: The base case analysis determined that the most cost-effective strategy was CT with an adenoma or nonadenoma threshold of 10 H followed by MR imaging, if necessary. CT with a threshold of 0 H followed by biopsy, if necessary, was the least costly. The incremental cost-effectiveness ratio between these two strategies was $16,370 per year of life gained., Conclusion: Unenhanced CT using a 10 H threshold followed by MR imaging, if needed, was the most cost-effective strategy for evaluating an adrenal mass in a patient with newly diagnosed non-small cell lung cancer.

Background: The current study presents mature results from a Phase III randomized trial comparing radiation therapy and concurrent chemoradiotherapy in patients with resectable American Joint Committee on Cancer Stage III and IV disease., Methods: One hundred patients were randomized to receive either radiation therapy alone (Arm A) (at a dose of between 66-72 grays [Gy] at 1.8-2 Gy per day) and the identical radiation therapy with concurrent chemotherapy (Arm B) (5-fluorouracil, 1000 mg/m(2)/day, and cisplatin, 20 mg/m(2)/day, both given as continuous intravenous infusions over 4 days beginning on Days 1 and 22 of the radiation therapy). Primary site resection was planned for patients with residual or recurrent local disease. Cervical lymph node dissection was performed for regional persistent disease or recurrence, or if N2-3 disease was present at the time of presentation., Results: After completing all therapy including surgery, 82% of the patients in Arm A and 98% of the patients in Arm B had been rendered disease free (P = 0.02). At a median follow-up of 5 years (range, 3-8 years), the 5-year Kaplan-Meier projections for overall survival for Arm A versus Arm B were 48% versus 50% (P = 0.55). Kaplan-Meier projections for the recurrence free interval were 51% versus 62% (P = 0.04), projections for a distant metastasis free interval were 75% versus 84% (P = 0. 09), projections for overall survival with primary site preservation were 34% versus 42% (P = 0.004), and projections for local control without surgical resection were 45% versus 77% (P < 0.001). Salvage surgery proved to be successful in 63% and 73%, respectively, of the Arm A and Arm B patients with primary site failure. Unrelated death while free of disease occurred in 22% and 32%, respectively, of Arm A and Arm B patients (P = 0.26)., Conclusions: The addition of concurrent chemotherapy to definitive radiation in patients with resectable Stage III and IV squamous cell carcinoma of the head and neck improves the likelihood of disease clearance, a recurrence free interval, and primary site preservation. However, overall survival does not appear to be improved, reflecting both effective surgical salvage after local recurrence and competing causes of death., (Copyright 2000 American Cancer Society.)

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.

Purpose: To evaluate the usefulness of neoadjuvant chemotherapy and radiation therapy before esophagectomy for invasive cancer of the esophagus or gastroesophageal junction (GEJ)., Materials and Methods: The authors conducted a retrospective analysis of 154 patients who underwent esophagectomy for invasive cancer between September 1, 1991, and December 31, 1995. The end points evaluated were overall, disease-free, local-regional relapse-free, and systemic relapse-free survival., Results: Seventy of the 154 patients received neoadjuvant combined-modality therapy (CMT) consisting of concurrent cisplatin and fluorouracil administration and accelerated, hyperfractionated radiation therapy. The remaining 84 patients underwent immediate esophagectomy. With a median follow-up of 34.7 months, the 3-year overall, disease-free, and distant metastatic relapse-free survival rates were 38.0%, 41.9%, and 56.0%, respectively. Although neoadjuvant therapy did not appear to prevent distant metastases, there was a dramatic effect on local control. After CMT, the 5-year local control rate was 90% compared to 64% after surgery (P < .001). Tumors in the GEJ recurred more frequently (P = .01); however, multivariate analysis showed CMT was the only independent predictor of local control. Postoperative mortality was 15.7% after CMT versus 5.9% without CMT (P = .05)., Conclusion: Local control of esophageal cancer is excellent following neoadjuvant chemotherapy and radiation therapy. However, the effects of CMT on overall and disease-free survival are less clear due to significant differences between the treatment groups.

Induction chemotherapy can produce response rates of 60% to 90%, which are complete in 20% to 50% of previously untreated patients with squamous cell head and neck cancer. It was hoped that this dramatic chemotherapy-induced tumor shrinkage would result in more successful locoregional treatment and prove useful in disease management. Despite many promising phase II studies of neoadjuvant chemotherapy, a large number of well-controlled phase III trials have shown no survival benefit. Distant metastases may be reduced, however, and organ preservation seems more likely with this method of treatment. An understanding of the benefits of chemotherapy in this disease must recognize the multiple reasons why these patients die, and the need for greater sophistication in our endpoint analysis.

Mature results are reported from a phase II trial of accelerated induction chemoradiotherapy and surgical resection for stage III non-small-cell lung cancer whose prognosis is poor. Surgically staged patients with poor prognosis stage III non-small-cell lung cancer were eligible for this study. Four-day continuous intravenous infusions of cisplatin 20 mg/m2/day, 5-fluorouracil 1,000 mg/m2/day, and etoposide 75 mg/m2/day were given concurrently with accelerated fractionation radiation therapy, 1.5 Gy twice a day, to a total dose of 27 Gy. Surgical resection followed in 4 weeks. Identical postoperative chemotherapy and concurrent radiation to a total dose of 40 to 63 Gy was subsequently given. Between February 1991 and June 1994, 42 eligible and evaluable patients, 23 with stage IIIA disease and 19 with stage IIIB disease, were entered in this trial. Treatment was well tolerated. The pathologic response rate was 40%. This response was complete in 5%. With a median follow-up of 54 months, the Kaplan-Meier 4-year survival estimate is 19%: 26% for stage IIIA and 11% for stage IIIB patients. Patients with a pathologic response, resectable disease, or pathologic downstaging to stage 0, I, or II had a better survival. The 4-year estimates of locoregional and distant disease control are 70% and 19%, respectively. It is concluded that although the ultimate role of concurrent chemoradiotherapy and surgery in stage III non-small-cell lung cancer must await the results of phase III clinical trials, survival and locoregional control in this study appear improved in comparison with historical experience. There is a subset of patients, able to undergo resection with pathologic downstaging, who have a projected survival equivalent to that of patients with more limited disease. Clinical or pathologic tools to identify these patients before treatment would be highly useful.

The role and optimal use of audiometry in monitoring for cisplatin ototoxicity are incompletely defined. Audiograms were obtained from 217 patients before treatment with cisplatin-based chemotherapy for cancers of the esophagus, lung, or head and neck. Posttreatment audiometry then was conducted in 53 of these patients. Chemotherapy consisted of two (87%) or three (13%) courses of cisplatin at a dose of 20 mg/m2/day given as a continuous intravenous infusion over 4 days. Simultaneous 5-fluorouracil or paclitaxel also was given, and 38% received concurrent radiation therapy to the head and neck. Air-conduction thresholds for each ear were obtained at 250, 500, 1000, 2000, 4000, 6000, and 8000 Hz. Three three-frequency pure-tone averages (PTA) also were calculated. Framingham gender-specific, age-adjusted norms were used, beginning at age 60 to correct for presbycusis, and the upper limit of normal was calculated as the greater of the Framingham mean plus twice the standard error, or 25 dB. Hearing abnormality was defined as a threshold >10 dB above the norm for any PTA, or >20 dB above the norm for any individual frequency. Hearing loss was defined as an elevation over baseline threshold of >10 dB for any PTA or >20 dB for any individual frequency. Of the 217 patients who underwent baseline testing, 57 (26%) were found to have hearing abnormality in excess of the expected presbycusis. Post-cisplatin audiograms demonstrated hearing loss in 19 of the 53 retested patients (36%) when compared with their own baseline. As determined by tympanometry, none of these subjects had a conductive component to their hearing loss. These observations were independent of the duration of follow-up after treatment and of the total dose of cisplatin administered. The authors conclude that significant preexisting hearing abnormality is common in this patient population and that, even after low-dose cisplatin administration, additional hearing loss occurs frequently. Baseline testing is mandatory if follow-up studies are to be adequately interpreted.

Objective: Endoscopic ultrasound (EUS) provides important information in the initial staging of patients with esophageal cancer. With recent modifications in chemoradiotherapy protocols, a significant number of patients have no residual tumor at esophagectomy. The high surgical morbidity and mortality might be avoided if complete response to chemoradiotherapy could be predicted. Previously published clinical trials, with relatively small patient numbers, have suggested that EUS may accurately stage esophageal cancer after chemoradiotherapy. The aim of this study was to verify the accuracy of EUS in staging esophageal cancer after effective chemoradiotherapy., Methods: EUS staging was performed before and after concurrent cisplatin, 5-fluorouracil, and hyperfractionated radiotherapy in 59 patients with newly diagnosed esophageal cancer. All patients underwent subsequent esophagectomy and pathological staging. The accuracy of preoperative, postchemoradiotherapy EUS was evaluated in a retrospective fashion by comparison to pathological staging., Results: After chemoradiotherapy, 18 patients (31%) had no residual disease at pathological staging (T0N0). However, EUS correctly predicted complete response to chemoradiotherapy (T0N0) in only three patients (17%). The accuracy of postchemoradiotherapy EUS for pathological T stage was only 37%, and its sensitivity for N1 disease was only 38%. EUS was unable to distinguish postradiation fibrosis and inflammation from residual tumor., Conclusion: When aggressive preoperative chemoradiotherapy is provided to patients with esophageal cancer, the predictive value of postchemoradiotherapy EUS is inadequate for use in clinical decision making.

Induction chemoradiotherapy before esophagectomy for esophageal carcinoma seems to improve patient survival. Given the toxicity of this regimen, it would be useful to predict those patients likely to benefit. p53 is known to mediate apoptosis in response to DNA damage, but there are few data evaluating the relationship between p53 expression and chemoradiosensitivity in human tissues. We immunohistochemically evaluated p53 protein expression in 95 biopsy specimens from patients with esophageal carcinoma before chemoradiotherapy. p53 expression was correlated to the pathologic response identified in subsequent esophagectomy specimens. p53 immunoreactivity was recorded semiquantitatively using the following scale: neg, < 5%; 1+, 5-25%; 2+, 26-50%; 3+, 51-75%; 4+, > or = 76%. Pathologic response in esophagectomy specimens was categorized as overt residual tumor (ORT), minimal residual tumor, and no residual tumor. Of the 95 patients, 64 had adenocarcinoma, and 31 had squamous cell carcinoma. Of those with adenocarcinoma, 46 (72%) of 64 were positive for p53. Thirty-seven (80%) of 46 p53+ patients had ORT, compared with 4 (22%) of 18 p53- patients (P < .001). There was no correlation between the degree of p53 staining and pathologic response. Of those with squamous cell carcinoma, 13 (42%) of 18 were positive for p53. Three (23%) of 13 p53+ patients had ORT, compared with 4 (22%) of 18 p53- patients (P = .96). Our data indicate that overexpression of p53 protein is associated with decreased responsiveness to induction chemoradiotherapy in patients with esophageal adenocarcinoma but that no such association exists in patients with esophageal squamous cell carcinoma.

Background: Since 1989, 105 patients with squamous head and neck cancer have been treated with combined chemoradiotherapy., Objective: To examine the effectiveness of using combined chemoradiotherapy on patients with squamous head and neck cancer., Design: Eight-year (1989-1997) single-institution evaluation of 105 patients., Methods: Treatment consisted of fluorouracil, 1000 mg/m2 per day, and cisplatin, 20 mg/m2 per day, both given as continuous infusions during 4 days beginning on day 1 and 22 of a concurrent radiotherapy course. Radiation was given in single daily fractions of 1.8 to 2 Gy, to a total dose of 66 to 72 Gy. Salvage surgery was performed for any residual or recurrent locoregional disease. Planned neck dissection was recommended for all patients with N2+ neck disease, irrespective of clinical response., Results: The 105-patient cohort consisted of 79 men and 26 women. The primary site was identified in the oral cavity in 6, oropharynx in 46, larynx in 30, and hypopharynx in 20 patients. Two patients had multiple primaries and 1 patient had an unknown primary. There were 4 patients with stage II, 24 with stage III, and 77 with stage IV disease. Grade 3 and 4 chemoradiotherapy toxic effects included mucositis in 88% of patients, cutaneous reaction in 50%, neutropenia in 49%, thrombocytopenia in 12%, and nausea in 5%. There were no deaths secondary to treatment. The mean weight loss was 12% of initial body weight. To date, primary site persistence or recurrence has occurred in only 14 patients (13%). With a mean follow-up of 39 months, 66 patients (63%) are alive and free of disease. The Kaplan-Meier 4-year projected overall survival is 60% with a disease-specific survival of 74%, a distant metastasis-free survival of 84%, and an overall survival with primary site preserved of 54%., Conclusions: This chemoradiotherapy regimen, although toxic, is tolerable with appropriate supportive intervention. Locoregional and distant control are likely. Primary site conservation is possible in most patients. Chemoradiotherapy appears to have an emerging role in the primary management of head and neck cancer.

Background: This study assessed toxicity, tumor response, disease control, and survival after short-course induction chemoradiotherapy and surgical resection in patients with stage III non-small-cell lung carcinoma., Methods: Forty-five patients with stage III non-small-cell lung carcinoma received 12-day induction therapy of a 96-hour continuous infusion of cisplatin (20 mg/m2 per day), 24-hour infusion of paclitaxel (175 mg/m2), and concurrent accelerated fractionation radiation therapy (1.5 Gy twice daily) to a dose of 30 Gy. Surgical resection was scheduled for 4 weeks later. Postoperatively, a second identical course of chemotherapy and concurrent radiation therapy (30 to 33 Gy) was given., Results: Induction toxicity resulted in hospitalization of 18 (40%) patients for neutropenic fever. No induction deaths occurred. Of 40 (89%) patients who underwent thoracotomy, resection for cure was possible in 32 (71%) patients. Pathologic response was noted in 21 (47%) patients, and 14 (31%) were downstaged to mediastinal node negative (stage 0, I, or II). At a median follow-up of 19 months, 24 patients were alive, 10 with recurrent disease. Of 21 deaths, 16 were from recurrent disease, three were from treatment, and two were unrelated. Recurrent disease was distant in 21 patients, distant and locoregional in 2, and locoregional in 3. The Kaplan-Meier projected 24-month survival is 49%. Projected 24-month survival is 61% for stage IIIA, 17% for stage IIIB (p = 0.035); 84% for pathologic responders, 22% for nonresponders (p<0.001); 83% for downstaged patients (stage 0, I, or II), 33% for those not downstaged (p = 0.005); and 63% for resectable patients, 14% for unresectable patients (p = 0.007)., Conclusions: We conclude that short-course neoadjuvant therapy with paclitaxel (1) has manageable toxicity and a low treatment mortality, (2) results in good tumor response and downstaging, (3) provides excellent locoregional control with most recurrences being distant, and (4) has improved the median survival compared with historical controls. Survival was better in stage IIIA patients, resectable patients, pathologic responders, and patients downstaged to mediastinal node negative disease (stage 0, I, or II).

Background: Patients with clinically localized, intermediate- or high-grade non-Hodgkin's lymphoma usually receive initial treatment with a doxorubicin-containing regimen such as cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Pilot studies suggest that eight cycles of CHOP alone or three cycles of CHOP followed by involved-field radiotherapy are effective in such patients., Methods: We compared these two approaches in a prospective, randomized, multi-institutional study. The end points were progression-free survival, overall survival, and life-threatening or fatal toxic effects. Two hundred eligible patients were randomly assigned to receive CHOP plus radiotherapy, and 201 received CHOP alone., Results: Patients treated with three cycles of CHOP plus radiotherapy had significantly better progression-free survival (P=0.03) and overall survival (P=0.02) than patients treated with CHOP alone. The five-year estimates of progression-free survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 77 percent and 64 percent, respectively. The five-year estimates of overall survival for patients receiving CHOP plus radiotherapy and for patients receiving CHOP alone were 82 percent and 72 percent, respectively. The adverse effects included one death in each treatment group. Life-threatening toxic effects of any type were seen in 61 of 200 patients treated with CHOP plus radiotherapy and in 80 of 201 patients treated with CHOP alone (P=0.06). The left ventricular function was decreased in seven patients who received CHOP alone, whereas no cardiac events were recorded in the group receiving CHOP plus radiotherapy (P=0.02)., Conclusions: Three cycles of CHOP followed by involved-field radiotherapy are superior to eight cycles of CHOP alone for the treatment of localized intermediate- and high-grade non-Hodgkin's lymphoma.

The use of concurrent chemotherapy and radiation, or chemoradiation, has become the focus of increasing interest in the management of patients with squamous-cell head and neck cancer. Randomized trials comparing radiation therapy alone with radiation and single chemotherapeutic agents given concurrently have suggested benefit for several different drugs. Randomized multiagent chemoradiotherapeutic trials have been approached somewhat more tentatively in view of the anticipated additional toxicity. Nonetheless, several studies have been reported, and a more consistent survival benefit with chemoradiotherapy has been observed. Treatment regimens using rapidly alternating chemotherapy and radiation schedules have also resulted in an improvement in survival. Although these kinds of aggressive treatment approaches produce significant incidences of morbidity and may not be appropriate for all patients, a role for chemoradiotherapy in the definitive management of this disease is being defined.

Objective: To determine the incidence of minor and major complications in patients with squamous cell carcinoma of the upper aerodigestive tract who require surgical salvage or planned neck dissection after an initial treatment regimen with radiotherapy or concurrent chemoradiotherapy for organ preservation., Design: The medical records of 100 patients treated in a phase 3 trial comparing radiotherapy alone with concurrent chemoradiotherapy for stage III and IV head and neck squamous cell carcinoma were reviewed. Fifty-four patients underwent 59 surgical procedures. Twenty-nine planned neck dissections were performed for persistent neck disease or initial stage N2 or greater. For persistent or recurrent disease at the primary site, 30 salvage operations were performed., Setting: Academic tertiary care referral center., Results: Complications occurred in 15 (46%) of the 33 procedures in the radiation-only group and 12 (46%) of the 26 procedures in the chemoradiotherapy group. Major complications occurred in 4 (12%) of the procedures in the radiation-only group and 3 (12%) of the procedures in the chemoradiotherapy group. The incidence of minor complications was 33% and 35% in the radiation-only and chemoradiotherapy groups, respectively. The major complication rate for salvage operations did not differ between the radiation-only and chemoradiotherapy groups (16% and 27%, respectively; P=.79 by chi2 test). The incidence of major complications in planned neck dissections was 7% of the radiation-only group and 0% of the chemoradiotherapy group., Conclusions: After radiation or concurrent chemoradiotherapy, surgery can be performed with an acceptable rate of major complications. Adding chemotherapy did not increase the incidence of surgical complications. These results differ from other reports in the literature.

Background: The depth of tumor invasion (T) and regional lymph node status (N) are two factors that define the stage of an esophageal carcinoma. However, the arrangement of staging groups assumes that these factors are independent variables. A retrospective review of 359 consecutive patients undergoing esophageal resection was conducted to define the relationship between T and N and to determine whether T is a significant predictor of regional lymph node metastasis (N1)., Methods: Primary treatment was operation without preoperative therapy. There were 295 (82%) adenocarcinomas, 55 (15%) squamous cell carcinomas, and 9 (3%) adenosquamous carcinomas. T status was Tis in 29 (8%) patients, T1 in 65 (18%), T2 in 37 (10%), T3 in 219 (61%), and T4 in 9 (3%). N status was N0 in 161 (45%) patients and N1 in 198 (55%). M status was M0 in 327 (91%) patients and M1 in 32 (9%). Stage was 0 in 29 (8%) patients, I in 58 (16%), IIA in 70 (20%), IIB in 22 (6%), III in 148 (41%), and IV in 32 (9%)., Results: The likelihood of N1 disease occurring with increasing T was tested using the trend test. The percentage of patients with N1 disease is 0% for Tis, 11% for T1, 43% for T2, 77% for T3, and 67% for T4 (p < 0.001). This relationship existed for both adenocarcinoma and squamous cell carcinoma. Multivariable analysis identified increasing T, adenocarcinoma, and lack of well-differentiated histologic features as significant predictors of N1 disease. Compared with a T1 patient, a T2 patient is 6 times more likely to have N1 disease, a T3 patient 23 times, and a T4 patient 35 times., Conclusions: We conclude that for patients with esophageal carcinoma, T is an important predictor of N and this association should be included with other established factors used in clinical staging and treatment decisions.

Recent changes in the epidemiology of esophageal carcinoma now recognize adenocarcinoma as the predominant histologic cell type. Barrett's esophagus and dysplasia in this epithelium identify patients who are at risk of developing invasive adenocarcinoma. This neoplasm is not a single entity with a consistently poor prognosis, and disease stage is important for determining therapy. These findings offer the potential for further development of therapeutic regimens. Endoscopic esophageal ultrasound is an accurate and reproducible staging tool. It allows the physician to determine clinical stage and modify treatment. T2 N0 M0 or lesser stage tumors have acceptable surgical cure rates, and patients should undergo immediate resection. Patients with more advanced T3 or N1 tumors have a potential for cure but do poorly with surgery alone. These patients should be considered for multimodality therapy. Palliative therapy should be given to patients with hematogenous metastatic disease. Treatment stratification by stage proves that esophageal carcinoma is not a uniformly fatal disease without hope for cure.

Background: A phase III randomized comparison of radiotherapy alone versus combination chemotherapy and concurrent continuous-course radiotherapy was performed at the Cleveland Clinic Foundation., Methods: Between March 1990 and June 1995, 100 patients with resectable stage III and IV squamous cell head and neck cancer were randomized to either Arm A: radiotherapy alone, 68-72 Gy at 1.8-2.0 Gy per day; or to Arm B: the identical radiotherapy with concurrent chemotherapy. Chemotherapy consisted of 5-fluorouracil, 1000 mg/m2/day, and cisplatin 20 mg/m2/ day, both given as continuous intravenous infusions over 4 days beginning on day 1 and day 22 of the radiotherapy. At 50-55 Gy, patients were clinically reassessed. If a response was evident, radiotherapy was completed. In non-responding patients, however, radiotherapy was terminated and surgery recommended. After completion of all treatment, salvage surgery was performed, if possible, for any residual primary or nodal disease or for any subsequent locoregional recurrence., Results: Except for an overrepresentation of T1 patients on Arm A, the treatment arms were equivalent. Toxicity was greater in the patients on Arm B with a higher incidence of grade III and IV neutropenia, thrombocytopenia, cutaneous reaction, and mucositis. Feeding tubes were also required more often, and weight loss was greater on the chemotherapy arm. No toxic deaths occurred. With a median follow-up of 36 months, the Kaplan-Meier 3-year projections of relapse-free survival are 52% for Arm A and 67% for Arm B (p = .03), and the likelihood of developing hematogenous metastases is 21% for Arm A and 10% for Arm B (p = .04). Although overall survival is not significantly different, overall survival with successful primary site preservation was 35% for Arm A and 57% for Arm B (p = .02). This difference remains statistically significant in the subsets of patients with laryngeal and hypopharyngeal primaries but not in patients with oropharyngeal primaries., Conclusions: Continuous-course radiotherapy and concurrent combination chemotherapy is an intensive, toxic but tolerable treatment regimen, which, when compared with radio therapy alone, can produce an improvement in relapse-free survival, a decrease in distant metastases, and an improvement in overall survival with successful primary site preservation.

Background: Treating the neck after organ-preservation treatment with radiotherapy or chemoradiotherapy can be problematic., Methods: To develop management guidelines, we reviewed the results of a 100-patient phase-3 trial that had compared outcome after radiotherapy alone with outcome after chemoradiotherapy for head and neck cancer. Patients were randomly assigned to receive radiotherapy alone or concurrent chemoradiotherapy. After completing therapy, patients were reassessed, and surgery was recommended for persistent disease at the primary site or neck and for all patients with stage N2-3 neck nodes regardless of clinical response., Results: Of the 47 patients with stage NO-1, 43 had a complete response (CR); of the 18 N1 patients, all but 4 had a CR. One of these 4, as well as 5 others among the NO-1 patients, underwent neck dissection (n = 6). No disease was found on pathologic examination, and no patient had neck recurrence. Of the remaining 41 N0-1 patients, 3 had disease progression and received no further therapy. Of the 38 others, 4 had neck recurrence, with 3 recurring at the primary site. Of the 53 with stage N2-3, 23 had less than a complete response (

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.

Background: To test the hypothesis that the cytoprotectant amifostine attenuates the thrombocytopenia produced by carboplatin, the authors performed a randomized trial comparing treatment with carboplatin alone versus the combination of amifostine and carboplatin., Methods: Patients with refractory or carboplatin-sensitive malignancies were randomized to receive either carboplatin, 500 mg/m2 alone or carboplatin, 500 mg/m2 in conjunction with 2 doses of amifostine of 910 mg/m2 each., Results: Fifty-five patients with a variety of malignancies were entered on this study. One patient withdrew from each arm prior to the administration of any therapy, leaving 30 evaluable patients treated with carboplatin alone and 23 treated with the combination of amifostine and carboplatin. For 82 cycles of therapy with amifostine plus carboplatin, the median platelet nadir was 127 x 10(9)/L while the median platelet nadir was 88 x 10(9)/L over the 80 courses of therapy with carboplatin alone (P = 0.023). The median platelet nadir after the first cycle of therapy was 144 x 10(9)/L for patients treated with amifostine plus carboplatin and 85 x 10(9)/L for patients treated with carboplatin alone (P = 0.24). The median survival for 9 patients with advanced nonsmall cell lung carcinoma treated with carboplatin alone was 39 weeks whereas the median survival for 12 such patients treated with amifostine plus carboplatin was 52 weeks (P = 0.116)., Conclusions: These data support the hypothesis that amifostine attenuates the myelosuppression of carboplatin. Additional studies of amifostine in combination with carboplatin-containing chemotherapy regimens are warranted.

Treatment of esophageal carcinoma requires the realization that this neoplasm is not a single entity with a uniformly poor prognosis. As with any other malignancy, disease stage has prognostic and therapeutic importance. Patients with stage T1-2,N0,M0 or lower tumors have acceptable surgical cure rates and should undergo immediate resection. Patients with more advanced tumors (T3 or N1) are still potentially curable but do poorly with surgery alone. These patients should be considered for multimodality therapy. Patients with hematogenous metastatic disease should be treated with palliative intent. Endoscopic ultrasound (EUS), an accurate, reproducible staging tool, allows for clinical staging of these patients and modification of treatment at the time of diagnosis. Our experience at The Cleveland Clinic Foundation using this algorithm of surgery alone in patients with EUS-defined early-stage carcinomas and multimodality therapy in patients with EUS-staged locally advanced disease is described.

Tobacco and alcohol abuse are the major known risk factors for the development of squamous cell head and neck cancer (SCHNC). Information about this disease in nonsmokers, however, is limited. We retrospectively studied a group of 59 tobacco nonusers with SCHNC, diagnosed since 1986 at the Cleveland Clinic Foundation (CCF). Two objectives were defined: (a) to characterize this nonsmoking population of patients and identify any significant differences compared with a control population consisting of all patients diagnosed with SCHNC at the CCF between 1986 and 1993 and (b) to determine the prevalence of exposure to environmental tobacco smoke in this nonsmoking group of patients with SCHNC and compare it with the environmental tobacco-smoke exposure in a second, control population of non-SCHNC, nonsmoking patients matched for age, race, sex, and alcohol use. The group of nonsmoking patients with SCHNC was notable for only rare alcohol abuse, a preponderance of whites, and relatively fewer laryngeal primary tumors. There were significantly more women and more tongue primaries. When compared with the control population without cancer, the nonsmoking patients had a significantly higher risk of exposure to environmental tobacco smoke both in the home and in the workplace. We conclude that the tobacco nonuser who develops SCHNC is likely to be female and white and to have a primary tongue cancer. A significant association with environmental tobacco smoke exposure is suggested by our data.

The results in 9 patients with unresectable recurrent squamous cell cancer of the head and neck who were treated with aggressive concurrent chemoradiotherapy are reported. Treatment consisted of one or two courses of chemotherapy with 5-fluorouracil 1000 mg/m2/day and cisplatin 20 mg/m2/day, both given as 4-day continuous intravenous infusions, concurrent with radiation therapy. Salvage radiation doses between 30 and 70 Gy were administered. Seven patients had previously undergone an attempt at curative surgery, and 7 had been treated with radiation doses between 52 and 72 Gy. The recurrent disease was locally confined in 3, locoregional in 5, and locoregional with metastases in 1 of the 9 patients. Treatment toxicity was significant and included mucositis, nausea/vomiting, and granulocytopenia, but there were no toxic deaths. Complete tumor clearance was possible in 6 of these 9 patients, and 5 patients remain disease-free at 41+, 43+, 45+, 47+, and 50+ months. Of these 5 patients, 4 had previously been treated with both surgery and radiation, while 1 had only undergone surgery. We conclude that aggressive chemotherapy and concurrent (re)irradiation can be given to patients with unresectable, recurrent, squamous cell cancer of the head and neck. Treatment is tolerable, and disease-free long-term survival is possible. Careful patient selection, however, is required.

Objective: Stage II esophageal carcinomas are a heterogeneous group of uncommon malignant tumors that include both node-negative (IIA; T2 N0 M0 and T3 N0 M0) and node-positive (IIB; T1 N1 M0 and T2 N1 M0) carcinomas. The purpose of this study was to evaluate this heterogeneity and to identify predictors of improved survival., Results: Ninety-four of 345 patients undergoing esophageal resection at the Cleveland Clinic Foundation between 1985 and 1994 had stage 11 carcinomas; 70 stage IIA (24 T2 N0 M0 and 46 T3 N0 M0) and 24 stage IIB (9 T1 N1 M0 and 15 T2 N1 M0). Pathologic stage and T and N status were the only identifiable predictors of survival. Stage IIA survival was significantly better than stage IIB (p = 0.01). T2 N0 M0 survival was not different from T1 N0 M0 survival (p = 0.83). T3 N0 M0 survival was significantly worse than T1 N0 M0 (p = 0.03) and intermediate between T2 N0 M0 survival (p = 0.06) and T1 N1 M0 and T2 N1 M0 survivals (p = 0.07). T1 N1 M0 and T2 N1 M0 survival was not significantly different from T3 N1 M0 survival (p = 0.63)., Conclusions: (1) N1 disease is the principal predictor of reduced survival and N1 is independent of T. Therefore the distinction between T1 N1 M0, T2 N1 M0, and T3 N1 M0 carcinomas is not warranted. (2) N0 disease is the principal predictor of improved survival but N0 is not independent of T. T1 N0 M0 and T2 N0 M0 survivals are similar and therefore distinction between these subgroups is not warranted. T3 N0 M0 survival is intermediate between T1 N0 M0 and T2 N0 M0 carcinomas and between T1 N1 M0, T2 N1 M0, and T3 N1 M0 carcinomas. Therefore stratification by T for N0 carcinomas is warranted.

Background: The detection of superficial esophageal carcinomas by surveillance endoscopy and the downstaging of advanced carcinomas to superficial carcinomas by induction therapy have increased the number of patients with these carcinomas undergoing resection. The natural history of these carcinomas is not well defined., Methods: To evaluate the results of surgical resection and identify predictors of improved survival, a retrospective review of (1) patients with superficial esophageal carcinoma at presentation (SECP) and (2) patients with advanced carcinomas that were downstaged to no residual carcinoma or superficial esophageal carcinoma after induction therapy (SECD) was conducted., Results: There were 54 patients with SECP (19 Tis and 35 T1). Survival was significantly better for patients with Tis carcinomas (85.3% at 5 years) and patients with intramucosal T1 carcinomas (79.4%) than for patients with submucosal T1 carcinomas (16.3%) (p = 0.007 and p = 0.045, respectively). Survival at 5 years for the 49 patients without regional lymph node metastases (N0) was 65.2%, whereas none of the 5 patients with regional lymph node metastases (N1) have survived more than 3 years (p = 0.054), and 3 died of recurrent disease. There were 21 patients with SECD (13 T0, 2 Tis, and 6 T1). Survival at 4 years was 58.2%. In this group, survival was not related to depth of tumor invasion (p = 0.76) or regional lymph node status (p = 0.68)., Conclusions: We conclude that (1) patients with Tis and intramucosal T1 SECP have a significantly better survival than those with submucosal T1 SECP, (2) patients with N0 SECP have a significantly better survival than those with N1 SECP, and (3) survival of patients with SECD is not related to depth of tumor invasion or regional lymph node status.

Background: Induction therapy and resection may improve the survival of patients with poor prognosis stage III non-small cell lung cancer, at the cost of significant treatment prolongation. The purpose of this study was to assess toxicity, response, and survival of an accelerated induction regimen and resection in poor prognosis stage III non-small cell lung cancer., Methods: Forty-two surgically staged patients with poor prognosis stage III non-small cell lung cancer received 11 days of induction treatment consisting of 96 hours of continuous chemotherapy infusions of cisplatin (20 mg.m-2.day-2), 5 fluorouracil (1,000 mg.m-2.day-2), and etoposide (75 mg.m-2.day-2) concurrent with accelerated fractionation radiation therapy (1.5 Gy twice a day, to a dose of 27 Gy). Induction was followed in 4 weeks by resection. Postoperatively, a second course of continuous chemotherapy and concurrent accelerated fractionation radiation therapy (postoperative dose 13 to 36 Gy) was given., Results: Despite some degree of induction toxicity in all patients there was only one induction death (2.4%). A clinical partial response was seen in 24 patients (57%). Thirty-six patients (86%) underwent thoracotomy, and resection was possible in 33 (79%). Pathologic downstaging was seen in 17 patients (40%), and 2 patients (5%) had no residual carcinoma at operation. There were 11 postoperative complications (31%) and 4 postoperative deaths (11%). Thirteen patients (31%) are alive and disease-free, 24 (57%) have persistent disease or have recurred (15 distant, 5 locoregional, 4 both), and 9 patients are alive with disease. The median survival is 21 months and the 2-year Kaplan-Meier survival is 43%, with no differences identified between stages IIIA and IIIB patients (p = 0.63)., Conclusions: We conclude that accelerated induction therapy and resection in poor prognosis stage III non-small cell lung cancer (1) is toxic, with a 12% treatment mortality; (2) is effective with a 79% resection rate and 40% pathologic downstaging rate; (3) provides excellent local control; (4) may prolong survival; and (5) is of value in stage IIIB as well as stage IIIA patients.

The results of several randomized trials suggest a marginal survival benefit for patients with metastatic non-small cell lung cancer after treatment with chemotherapy. This intervention, however, has not become standard therapy. Toxicity, cost, and inconvenience have led many physicians to question whether chemotherapy has even a palliative role in this disease. Furthermore, it is well established that patients with a poor performance status, who are most in need of symptomatic palliation, are also those who are least likely to benefit and most likely to experience treatment-related toxicity. Nonetheless, evidence of a symptomatic benefit from combination chemotherapy has been presented. Indeed, symptomatic palliation can result even in the absence of a conventionally defined chemotherapy-induced response. Phase III trials supporting the palliative value of chemotherapy, however, have been limited and inconclusive. Fortunately, other palliative treatment modalities exist. These interventions should be carefully integrated with chemotherapy when an overall treatment plan appropriate for an individual patient is being developed. In addition to the symptomatic needs of each individual, this treatment plan must also address both physician and patient biases.

Concurrent radiation therapy and chemotherapy is a promising approach to the treatment of squamous cell head and neck cancer. Toxicity, however, has required either scheduled breaks in radiation therapy administration or compromise in chemotherapy dose intensity. We describe the toxicity and results in 19 patients treated at diagnosis with a continuous course of radiation therapy and intensive concurrent combination chemotherapy using 5-fluorouracil and cisplatin. Toxicity among these 19 patients was significant, including mucositis, myelosuppression, and weight loss, and aggressive supportive efforts were required. No toxic deaths occurred, however. At the end of treatment, all patients had achieved complete control of their primary-site tumor. Primary-site resection was not required in any patient for tumor control, but neck dissections were performed in selected individuals with involved nodes at diagnosis. No patient recurred at the primary site and only a single patient recurred in the neck. We conclude that this chemoradiotherapy schedule is very effective, albeit toxic. Toxicity, however, can be managed with appropriate aggressive supportive measures. Confirmation of these encouraging treatment results will require performance of a randomized clinical trial.

Background: Proximal esophageal cancer has been a disease associated with relatively poor treatment success, partly due to advanced disease at presentation and the morbidity of the surgery required. Therefore, most patients receive palliative radiation therapy, and disease control is poor., Methods: Between July 1990 and December 1992, nine consecutive patients with proximal esophageal squamous cell carcinoma were treated with aggressive concurrent chemoradiotherapy followed by surgical resection. Treatment consisted of cisplatin (20 mg/m2/day) and 5-fluorouracil (1000 mg/m2/day), both given as continuous intravenous infusions over 4 days concurrent with accelerated fractionation external beam radiation therapy (150 cGy twice a day to a dose of 2400 cGy). Three weeks after beginning treatment, a second course of chemotherapy and accelerated fractionation radiation therapy was administered to a total preoperative radiation therapy dose of 4500 cGy. After restaging of their disease, patients next underwent surgical resection. A single postoperative course of chemotherapy and 2400 cGy of concurrent accelerated fractionation radiation therapy was administered to those patients with residual tumor in the resection specimen. Two of these nine patients also were given 4-day etoposide infusions (75 mg/m2/day) as part of their chemotherapy and received lower induction radiation therapy doses., Results: Although significant toxicity was experienced, there were no deaths attributable to the chemoradiotherapy and only one perioperative death. All nine patients underwent surgery; five required pharyngolaryngoesophagectomy. No residual tumor was found in the resection specimen in three of the nine patients. Continuous locoregional tumor control was achieved in all patients. Only two developed distant metastases., Conclusions: These results, using aggressive multimodality treatment, suggest that excellent locoregional control and long term, disease free survival can be achieved in selected patients with proximal esophageal cancer.

The natural history of squamous cell head and neck cancer is well understood. Locoregional approaches to salvage therapy for this disease have curative potential, primarily because distant metastases are uncommon. Before proceeding with salvage treatment, however, clinicians should identify the extent of disease and determine whether the treatment intent is curative or palliative. Because of the associated morbidity, surgery should be considered only in patients for whom cure of recurrent disease is feasible. Radiation therapy may be indicated in patients whose disease recurs after surgery and in selected patients in whom initial radiation has failed. Single-agent and combination chemotherapy, in particular the combination of cisplatin and 5-fluorouracil, has achieved overall response rates of 30% to 40% in patients with recurrent disease. However, cure after salvage chemotherapy has not been achieved. Until salvage treatment regimens capable of achieving significant long-term survival are identified, symptomatic palliation will remain the main treatment goal in this patient population.

Nineteen patients with clinical stage I malignant pleural mesothelioma were treated with aggressive multimodality therapy. Nine patients underwent pleurectomy and decortication followed by immediate intrapleural chemotherapy with cisplatin and mitomycin C. Ten patients required pleuropneumonectomy followed within 1 week to 2 weeks by intrapleural administration of cisplatin (100 mg). Four to 8 weeks after operation, 15 patients underwent postoperative adjuvant cisplatin-based systemic chemotherapy. There were three postoperative complications (16%) requiring reoperation and one postoperative death (5%). Intrapleural chemotherapy was well tolerated with no complications. Systemic chemotherapy was poorly tolerated, and there was one chemotherapy-related death. Sixteen patients (84%) experienced good to excellent palliation. Three patients are currently alive with no evidence of recurrent disease at 10, 35, and 43 months. The median overall survival was 13 months and the median disease-free survival, 11 months. Overall and disease-free 3-year survivals were 17% and 22%, respectively. Patients with epithelial malignant pleural mesothelioma had significantly better overall survival (p = 0.037) and disease-free survival (p = 0.02) than patients with sarcomatous or biphasic malignant pleural mesothelioma. We conclude that despite major toxicity, in select patients with clinical stage I malignant pleural mesothelioma, aggressive multimodality therapy offers effective palliation and occasional long-term disease-free survival.

A preoperative induction chemotherapy regimen consisting of two monthly courses of etoposide, doxorubicin, and cisplatin was given to 13 patients with nonmetastatic adenocarcinoma of the distal esophagus or gastroesophageal junction. Esophageal ultrasound examination was performed both before chemotherapy and again before surgery. Induction chemotherapy was poorly tolerated with 10 of the 13 patients experiencing at least one episode of severe neutropenia. Two of the 13 patients refused the second course of treatment. A symptomatic response to chemotherapy, defined as a reduction in the presenting symptom, was noted in 10 of the 13 patients (77%). Endoscopic improvement occurred in 9 of the 13 patients (69%). Esophageal ultrasound evidence of a reduction in either T or N stage was noted in only 2 of the 13 patients (15%), however, and neither of these responses was confirmed pathologically. Clinical evidence of disease progression was noted in 4 patients during chemotherapy. With a median follow-up of 31 months, the relapse-free and overall survivals are 25% and 31%, respectively. Despite significant toxicity, our chemotherapy regimen would be considered successful if assessed by symptomatic or esophagoscopic improvement. Esophageal ultrasound, careful pathologic staging, and our disappointing survival rates, however, suggest limited, if any, value for this approach.

Purpose: The feasibility and success of an intensive chemoradiotherapeutic protocol for patients with locally advanced, unresectable squamous cell head and neck cancer was tested in this limited-institution, Eastern Cooperative Oncology Group phase II pilot study., Materials and Methods: Between December 1987 and September 1989, 57 patients were entered onto this trial. The treatment protocol consisted of three courses of a 4-day continuous fluorouracil infusion, a single cisplatin bolus injection, and concurrent split-course radiotherapy. After 30 Gy of radiation and two chemotherapy courses, patients were evaluated for response and for the possibility of surgical resection., Results: Fifty-five of 57 registered patients are assessable for toxicity and 52 are assessable for response and survival. Toxicity was significant, but tolerable, although there were three toxic deaths. A complete response to this treatment was ultimately achieved by 77% of patients. Twenty-four patients remain relapse-free. The projected Kaplan-Meier 4-year relapse-free survival rate is 45% and the overall survival rate is 49%. Median relapse-free and overall survival durations are 26 and 37 months, respectively. Of the 28 treatment failures, 79% were locoregional. Fourteen patients underwent surgery. Six remain relapse-free., Conclusion: This aggressive concurrent chemoradiotherapy protocol appears feasible within a cooperative group. Treatment results are promising and appear durable. A randomized phase III clinical trial is currently underway.

Methods: Between 1983 and 1989, 42 patients with Stage II, III, and IV, node-negative, squamous cell head and neck cancer were treated with concurrent 5-fluorouracil, cisplatin, and radiation therapy. Two courses of chemotherapy with 30 Gy of concurrent radiation therapy were to be followed in all patients by definitive surgery and then an additional 30 Gy of radiation therapy and one to two courses of chemotherapy. The patients who achieved a complete response to the initial induction treatment, however, did not undergo surgery., Results: After the completion of all therapy, 41 of the 42 patients (98%) were considered disease-free. Only 4 of these 41 had relapses, for a projected Kaplan-Meier disease-free survival rate of 86%. Treatment failure occurred in no patients with Stage II, 1 of 17 patients with Stage III, and 4 of 14 patients with Stage IV disease. Of the 42 patients, 23 (55%) did not require surgery after achieving a complete response to induction therapy, and only 1 of these 23 patients subsequently had a relapse., Conclusions: Although the value of adding chemotherapy to conventional treatment remains unproven in squamous cell head and neck cancer, this treatment schedule appears promising in node-negative disease. Randomized trials will be necessary, however, to validate the efficacy of this approach and confirm the suggestion by the authors that surgery can be avoided in most patients with N0 disease.

A 77-year-old woman with refractory multiple myeloma was treated with a 4-day continuous intravenous infusion of vincristine and doxorubicin and 4 days of oral dexamethasone. Nine days after her second cycle she presented with lethargy and weakness associated with hyponatremia. Evaluation revealed the syndrome of inappropriate secretion of antidiuretic hormone, which was attributed to the vincristine infusion. After normal serum sodium levels returned, further doxorubicin and dexamethasone chemotherapy without vincristine did not produce this complication.