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Study objective: To evaluate the effects of induction concurrent chemoradiotherapy (cCRT) on pulmonary function and postoperative acute respiratory complications (PARCs). Design: A retrospective review of our patients treated with induction [...]

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/[m.sup.2]/day) and 5-fluorouracil (1000 mg/[m.sup.2]/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/[m.sup.2]/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 multi-modality treatment, suggest that excellent locoregional control and long term, disease free survival can be achieved in selected patients with proximal esophageal cancer. Cancer 1994; 74:1680-5.

Squamous cell cancers of the head and neck are generally responsive to chemotherapy, radiation, or both. However, not all schedules of treatment work equally well. To evaluate the relative effectiveness of two schedules of combination radiation and chemotherapy, 48 patients with locally confined squamous cell carcinoma of the head and neck were randomly assigned to one of two experimental groups. The first group received chemotherapy and radiotherapy simultaneously, followed by another course of simultaneous chemo- and radiotherapy. The second, or sequential, group, received chemotherapy first, followed by radiotherapy. Chemotherapy consisted of cycles of 5-fluorouracil and cisplatin; radiotherapy consisted of a total of 6,000 cGy (a Gy, or Gary, is 1 joule of energy absorbed per kilogram of tissue). Patients who achieved complete remission after the first treatment cycle did not receive surgery; in addition, five patients either had unresectable tumors or refused surgery. The data indicate an improved relapse-free survival rate for the patients who received simultaneous treatment. However, it is too early to determine if the relapse-free survival will translate into significantly improved overall survival. The toxicity of the two treatment schedules was comparable, although the simultaneous chemo- and radiotherapy group had more inflammation of the mucous membranes and greater weight loss. The study demonstrates that simultaneous chemo- and radiotherapy may provide an advantage for treating squamous cell carcinoma of the head and neck. Furthermore, the study found that the appropriate scheduling of treatment can reduce the need for surgery without affecting the patient's relapse-free survival. (Consumer Summary produced by Reliance Medical Information, Inc.)

Primary squamous cell carcinoma (SqCC) of the thyroid gland is an extremely rare, highly aggressive malignancy associated with locally advanced disease and frequent metastases to regional lymph nodes and distant sites. There are no standardized guidelines for treating primary thyroid SqCC because of its rarity, but some investigators have recommended staging and treating it as a variant of anaplastic thyroid carcinoma. Prognosis, however, remains poor with minimal response to treatment and an estimated median survival of 6 to 14 months. We report a case of primary SqCC of the thyroid that was successfully treated with aggressive locoregional resection followed by concurrent radical dose radiotherapy and cisplatin-based chemotherapy. The patient remains free of disease more than 4 years after surgery and adjuvant chemoradiation. Because of potential prognostic and management implications, it is crucial to make an accurate pathologic diagnosis of primary SqCC of the thyroid and distinguish it from metastatic squamous carcinoma and other primary thyroid malignancies with squamous features. A thorough clinicopathologic diagnostic workup including immunohistochemistry, computed tomography scan, and endoscopy is mandatory. In this case, treatment similar to the standard management used for patients with locally advanced mucosal head and neck squamous cancer led to a successful outcome.

Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma have high survival when treated with radiotherapy plus cisplatin. Whether replacement of cisplatin with cetuximab—an antibody against the epidermal growth factor receptor—can preserve high survival and reduce treatment toxicity is unknown. We investigated whether cetuximab would maintain a high proportion of patient survival and reduce acute and late toxicity.

Squamous cell carcinoma (SCC) of the orbit is almost uniformly the result of local invasion from a cutaneous primary, extension by perineural invasion, or the result of metastasis. This is owed to the lack of native squamous epithelium in the orbit. After review of the literature, to date, only 6 reports of 8 patients with primary orbital SCC exist. Of those cases, only 2 reported non-apical orbital SCC. There are 2 reports of orbital SCC after retina surgery with proposed transplanted conjunctival epithelium and subsequent malignant transformation of a conjunctival cyst. The initial signs and symptoms can be vague and lead to delay in diagnosis. We present a case of primary orbital SCC and discuss the workup, imaging, and multidisciplinary management of this rare condition.

IMPORTANCE: Late toxic effects are common after definitive radiotherapy and chemoradiotherapy for oropharynx cancer and are considered a significant contributor to decreased quality of life for survivors. The incidence of severe late toxic effects may be reduced by modern narrow-margin image-guided intensity-modulated radiotherapy (IG-IMRT), current supportive care improvements, and the changing epidemiology of oropharynx cancer. OBJECTIVE: Assess the incidence of severe late toxic effects after modern definitive non-operative treatment for oropharynx cancer. DESIGN, SETTING, AND PARTICIPANTS: For this single-institution retrospective review, 156 patients with stage I-IVB squamous cell carcinoma of the oropharynx treated between April 2009 and February 2015 at a tertiary-referral academic multidisciplinary head and neck practice were recruited. INTERVENTIONS: Definitive narrow-margin IG-IMRT to a dose of 66 Gy (to convert milligray to rad, multiply by 0.1) or higher with or without concurrent cisplatin. MAIN OUTCOMES AND MEASURES: The primary outcome was the prospectively collected 2-year cumulative incidence of severe late toxic effects (Common Terminology Criteria for Adverse Events grade 3 or higher) occurring 3 months or more after radiotherapy. Toxic effect end points investigated included esophageal stricture requiring dilation, aspiration pneumonia hospitalization, vocal dysfunction, delayed feeding tube insertions, and osteoradionecrosis. Feeding tube dependence at 1 year was also considered a severe late toxic effect. Secondary outcomes collected include physician-reported grade 2 or higher neck fibrosis and xerostomia. The competing risks of recurrence and death were accounted for using the Gray method. RESULTS: One-hundred fifty-six patients (median [range] age, 58 [37-96] years) were identified; 130 patients (83%) were HPV positive. Concurrent cisplatin was delivered in 131 patients (84%) and 5 patients (3%) underwent an adjuvant neck dissection. The median (range) follow-up for survivors was 22 (4-73) months from diagnosis. The projected 2-year locoregional control was 93% (95% CI, 88.4%-97.6%) and overall survival was 88% (95% CI, 82.2%-94.0%). Thirty-eight patients (23%) required a feeding tube during treatment. The cumulative incidence of severe late toxic effects adjusted for competing risks at 2-year posttreatment was 2.3% (95% CI, 0%-5.6%). One patient required free-flap reconstruction for grade 3 osteoradionecrosis at 47 months. At 1 year, 2 patients (1%) experienced grade 2 neck fibrosis and 38 patients (23%) experienced grade 2 xerostomia. CONCLUSIONS AND RELEVANCE: These results suggest that severe late toxic effects after modern definitive IG-IMRT, with or without cisplatin, for oropharynx cancer is likely uncommon. The importance of late toxic effect reduction in current and future investigational strategies, including clinical trials, should be considered.

IMPORTANCE: Nonsurgical treatment of advanced supraglottic laryngeal cancer is widely used as part of a larynx preservation protocol. However, recent studies have suggested that nonsurgical treatment may be associated with inferior survival. Furthermore, it is not clear whether preservation of the larynx provides superior voice or swallowing function in the long term. OBJECTIVE: To test the hypothesis that surgical treatment of advanced-stage squamous cell carcinoma of the supraglottic larynx is associated with superior overall survival (OS), freedom from recurrence (FFR), and noninferior voice and swallowing function. DESIGN, SETTING, AND PARTICIPANTS: Retrospective medical record review of patients treated for stage III or IV squamous cell carcinoma of the supraglottic larynx between January 1990 and June 2013 at a tertiary referral center: 97 patients underwent surgical treatment and 138, nonsurgical treatment. Exclusion criteria included prior definitive treatment for laryngeal cancer or evidence of distant metastatic disease at presentation. The median follow-up for all 235 patients was 63 months. INTERVENTIONS: Surgical or nonsurgical therapy. MAIN OUTCOMES AND MEASURES: Freedom from recurrence (FFR), OS, larynx preservation, voice graded from 1 to 5, and swallowing graded from 1 to 6 using our voice and swallowing function scales. RESULTS: Surgical treatment was associated with superior FFR (5-year FFR: 75% vs 55%; P = .006) but not OS (5-year OS: 52% vs 52%; P = .61). The larynx was preserved in 83% of patients in the nonsurgical group vs 42% of patients in the surgical group (P < .001). Voice function was superior in the nonsurgical group at all time points through 5 years after treatment (mean voice score, 3.8 vs 2.6; P < .001). Swallowing function was comparable between surgical and nonsurgical groups. Multivariable analysis revealed that advanced age (hazard ratio [HR], 1.43 per 10-year increment; 95% CI, 1.19-1.72) and clinical N stage (HR, 1.17 per 1-level increment; 95% CI, 1.05-1.30) were associated with worse OS, while treatment with chemotherapy was associated with superior OS (HR, 0.61; 95% CI, 0.41-0.92). CONCLUSIONS AND RELEVANCE: Compared with surgical treatment, nonsurgical treatment as part of a larynx preservation protocol is associated with a higher likelihood of recurrence but has similar OS and should continue to be viewed as a viable alternative for the treatment of advanced supraglottic laryngeal cancer.

IMPORTANCE: Important differences exist in the pattern and timing of distant metastases between human papillomavirus–initiated (HPV+) and HPV− oropharyngeal squamous cell carcinoma (OPSCC). However, our understanding of the natural history of distant metastases in HPV+ OPSCC and its implications for surveillance is limited. OBJECTIVE: To investigate the rate, pattern, and timing of distant metastases in advanced-stage OPSCC treated definitively with concomitant chemoradiotherapy. DESIGN, SETTING, AND PARTICIPANTS: In a retrospective review, we identified 291 patients with pathologically diagnosed stages III to IVB OPSCC and known HPV status from a tumor registry at the Cleveland Clinic. Patients were treated from January 1, 1996, through December 31, 2013. Details of treatment failure and the natural history of the disease were retrieved from the electronic medical records. INTERVENTIONS: All patients were treated with definitive concomitant chemoradiotherapy. MAIN OUTCOMES AND MEASURES: The primary outcome was the rate and timing of distant metastases. Secondary outcomes included the pattern of distant failure and survival after distant metastases. RESULTS: Thirty-seven patients developed distant metastatic disease after definitive treatment, including 28 of 252 patients with HPV+ disease and 9 of 39 patients with HPV− disease. The 3-year projected distant control rate was higher in the HPV+ group (88% vs 74%; P = .01). The median time to develop distant metastases was also longer after the completion of treatment for HPV+ disease compared with HPV− disease (16.4 vs 7.2 months; P = .008). We detected a trend in patients with HPV+ disease for more distant metastatic sites involved than in those with HPV− disease (2.04 vs 1.33 sites; P = .09). Although the lung was the most common distant site involved in HPV+ and HPV− disease (HPV+ group, 23 of 28 patients [82%]; HPV− group, 7 of 9 patients [78%]), the HPV+ group had metastases to several subsets atypical for head and neck squamous cell carcinoma, including the brain, kidney, skin, skeletal muscle, and axillary lymph nodes in 2 patients each and in the intra-abdominal lymph nodes in 3 patients. The rate of 3-year overall survival was higher in the HPV+ group (89.9% vs 62.0%; P < .001), as was the median survival after the occurrence of distant metastases regardless of additional treatment (25.6 vs 11.1 months; P < .001). CONCLUSIONS AND RELEVANCE: This retrospective review suggests that distant metastases in patients with HPV+ OPSCC occurs significantly later after completion of chemoradiotherapy than in patients with HPV− disease. Human papillomavirus–initiated OPSCC also appears to involve a greater number of subsites and metastatic sites infrequently seen in head and neck squamous cell carcinoma. Distant metastatic disease in HPV+ OPSCC has unique characteristics and a natural history that may require alternative surveillance strategies.

Salivary gland malignancies are a rare and heterogeneous group of tumors with considerable variability in their natural history. Historically they have been treated with surgery and radiation therapy. It is only recently that there has been any growth in our understanding of these diseases and their management, and this progress will be reviewed.

Several different approaches have been tested in an effort to integrate chemotherapy into definitive non-operative management of squamous cell head and neck cancer. In phase III randomized trials and in meta-analyses, the concomitant use of chemotherapy and radiation has proven to be the most consistently successful, and to produce both locoregional control and survival benefits, when compared to radiation therapy alone. Large, multi-institutional and cooperative group studies have now established high-dose single-agent cisplatin and concurrent radiation therapy as the standard of care for patients with advanced nasopharynx cancer, for patients with unresectable head and neck tumors, and as a postoperative adjuvant for patients with high-risk pathologic features. This same treatment regimen also has been demonstrated to be the most effective multi-modality treatment strategy for larynx preservation. Future investigation will focus on optimizing the concomitant chemotherapy and radiotherapy schedules used, integrating targeted agents into these established treatment schedules, addressing the problem of distant metastases, minimizing both acute and late toxicities, and identifying the most appropriate patient populations for this kind of aggressive treatment.

Squamous cell head and neck cancer is a relatively uncommon malignancy in North America. Nonetheless, it has been of considerable interest to medical oncologists because of its remarkable sensitivity to systemic chemotherapy. Even in patients with relapsed or metastatic disease, meaningful tumour shrinkage can be achieved with systemic therapy. This has led to the performance of carefully conducted clinical trials exploring the role of systemic chemotherapy, not only in the palliative setting, but as part of definitive multi-modality treatment. Chemotherapy has been used as the initial (or induction) treatment, as an adjuvant treatment after definitive surgery and/or radiation, and concurrent with both definitive and adjuvant radiation therapy. Evidence-based conclusions have been drawn from these clinical trials and have led to significant changes in the current standards of care for this disease. In this article, the available data supporting the use of systemic chemotherapy as palliative treatment, and as part of the definitive management for this disease will be reviewed.

The role of neck dissection (ND) after definitive chemoradiotherapy for squamous cell head and neck cancer is incompletely defined. We retrospectively reviewed 109 patients with N2–N3 disease treated with chemoradiotherapy to identify predictors of a clinical complete response in the neck (CCR-neck), pathologic complete response after ND (PCR-neck), and regional failure. All patients were given 4-day continuous infusions of 5-fluorouracil (1000 mg/m²/d) and cisplatin (20 mg/m²/d) during the first and fourth weeks of either once daily (n = 68) or twice daily (n = 41) radiation therapy. ND was considered for all patients after completion of chemoradiotherapy and was performed in 32 of the 65 patients achieving a CCR-neck after chemoradiotherapy and in all 44 patients with residual clinical evidence of neck disease. CCR-neck, PCR-neck, and regional failure were then correlated with potential predictors, including T, N, largest lymph node size (<3 cm, ≥3 cm), primary tumor site, and radiation fractionation schedule. Achievement of a CCR-neck was predicted by N, N2 vs N3 (53 of 80 vs 12 of 29, p = .019) and by largest lymph node size, <3 cm vs ≥3 cm (19 of 25 vs 46 of 84, p = .06). Achievement of a PCR-neck could not be predicted by any clinical parameter. Regional failure occurred both in patients undergoing ND and those not dissected (5 of 76 vs 4 of 33, p = .33) and proved more likely only in the ND patients with residual positive pathology compared with those achieving a PCR-neck (5 of 25 vs 0 of 51, p < .001). Primary site was not a useful predictor of CCR-neck, PCR-neck, or regional failure. Most importantly, CCR-neck (vs <CCR-neck) did not predict either a PCR-neck (24 of 32 vs 27 of 44, p = .21) or regional failure (5 of 65 vs 4 of 44, p = .80). After chemoradiotherapy, clinical parameters do not identify those patients with residual neck node disease or those at risk for regional failure, suggesting that ND be considered for all N2–N3 patients. © 2003 Wiley Periodicals, Inc. Head and Neck 25: 791–798, 2003

There are over 200,000 cases of brain metastases (BrM) every year, but very few are from esophageal cancer primaries. In order to determine predictors for outcome of these patients, the authors conducted a retrospective review of twenty-seven patients with BrM from esophageal carcinoma diagnosed at the Cleveland Clinic Foundation between 1991 and 2001. For the entire cohort, median follow-up and median survival was 3.6 months and 3.6 months, respectively. On univariate analysis, patients with Karnofsky Performance Status (KPS) ≥ 70, low recursive partitioning analysis score, single BrM, no systemic disease, and aggressive treatment [surgery, stereotactic radiosurgery (SRS) + whole brain radiation (WBRT), SRS + surgery + WBRT, surgery + WBRT)] had a significantly improved survival. In a multivariate model, patients with higher KPS and aggressive treatment had improved survival. The 1-year survival for the WBRT alone group and the aggressive treatment group was 6%, and 36% respectively. We conclude that based on the data presented here, patients with BrM from esophageal cancer have poor outcome. Aggressive treatment and favorable KPS are associated with longer survival for selected patients. We recommend esophageal cancer patients with BrM be enrolled in clinical trials to better delineate the role of treatment and potentially improve results.

Objective:Cancer staging is dynamic, reflecting accrual of knowledge and experience in treatment. The objectives of this study were to assess current esophageal cancer staging and to determine whether refinements of classification and stage grouping are necessary. Methods:From 1983 through November 2000, 480 patients underwent esophagectomy without induction therapy. Depth of tumor invasion (T), regional lymph node status (N), distant status (M), number of metastatic regional lymph nodes, and histopathologic type and grade were subjected to survival-tree analysis, multivariable Cox and hazard function analysis, and residual misclassification risk analysis. Results:Inhomogenity of survival was found within and lack of distinction was found between current American Joint Committee on Cancer staging groups, supporting the need for refinement. T1 and N1 were redefined on the basis of survival differences. T1a is intramucosal cancer, T1b is submucosal cancer (P= .008), N1 is 1 or 2 metastatic regional lymph nodes, and N2 is 3 or more metastatic regional lymph nodes (P= .01). Current subclassification of M1 is not warranted (P= .9). Histopathologic type (P= .17) and grade (P= .3) minimally refined staging. Reassignment of staging groups constrained by American Joint Committee on Cancer definitions of stages 0 and IV produced less monotonic, distinctive, and homogeneous survival than free assignment of staging groups. Conclusions:Current American Joint Committee on Cancer staging of esophageal cancer is inadequate. Refinement requires redefinition of T1, N1, and M1 classifications. Stage grouping within the constraints of American Joint Committee on Cancer definitions produces less accurate prognosis than free assignment based on survival data.

Objective:We sought to evaluate the effectiveness of clinical staging of depth of tumor invasion (cT), the relationship of cT to survival, the benefits of downstaging cT, and the role of cT in treatment decisions. Methods:The accuracy of determining T by means of endoscopic ultrasonography and the relationship of cT to survival were assessed in 209 patients undergoing esophagectomy alone for esophageal carcinoma. The benefit of downstaging cT was assessed in 128 patients undergoing induction therapy and esophagectomy. The role of cT in treatment decisions was determined by integrating these results with the results of previous work. Results:Compared with pathologic T (pT), cT was 87% accurate, 82% sensitive, 91% specific, 89% positively predictive, and 86% negatively predictive of tumors confined to (≤T2) or invading beyond (>T2) the esophageal wall. In cN0, increasing cT was predictive of progressively poorer survival. For each category of pT N0, cT accurately predicted survival, except for pT3, which was underestimated (P< .0001). In cN0, downstaging by induction therapy was beneficial only if tumors invaded beyond the wall (≥cT3, P= .0003). In cN1, it was beneficial only when downstaging was synchronous in cT3/T4 (P< .001). Conclusions:cT should be the principal determinant of treatment in cN0. In cN0, if endoscopic ultrasonography identifies tumors of greater than cT2, multimodality therapy should be considered. However, only when cT3/T4 tumors are downstaged to pT2 or less will patients benefit, but their survival will not equal that of patients with tumors of cT2 or less having esophagectomy alone. If endoscopic ultrasonography identifies tumors of cT2 or less, esophagectomy alone should be used because induction therapy might adversely affect survival.

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.

HypothesisP53 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).

The role of chemotherapy in the carcinomas and sarcomas that involve the base of skull is reviewed in this article. An established role exists for cisplatin-based multimodality treatment in the definitive management of nasopharyngeal carcinoma. Extrapolation from data generated for other head and neck squamous cell cancers also suggests a role for concomitant chemotherapy and radiation when these tumors involve the skull base. For the other neoplasms in this region, including the nonsquamous cell cancers of salivary gland and paranasal sinus, and the sarcomas and metastatic tumors, chemotherapy remains a palliative tool with limited overall benefit.

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. (J Thorac Cardiovasc Surg 1999;118:900-7)

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.

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).

Seventeen (10 percent) of 176 patients with small-cell carcinoma of the lung seen at this hospital since 1976 proved to have mixed small-cell and non-small-cell tumors. The presence of a mixed lung cancer was established prior to chemotherapy or irradiation in nine patients. Eight were initially diagnosed as pure small-cell carcinoma but proved to have a mixed tumor at either surgery or autopsy. Of the 17 patients, eight received chemotherapy, and four had a partial response. Six of the 40 autopsies performed on patients with small-cell lung cancer demonstrated intrathoracic tumor which was histologically mixed. Extrathoracic metastases in these patients were heterogeneous and included pure small-cell, pure non-small-cell, and mixed histologic type. We conclude that mixed small-cell and non-small-cell lung cancers are relatively frequent and carry important prognostic and therapeutic implications. Clinical management of patients with small-cell lung cancer should therefore be flexible and tailored to the potential for histologic diversity. Mixed lung cancer in previously untreated patients suggests a common endodermal origin for small-cell and non-small-cell pulmonary tumors.

A phase III randomized comparison of radiotherapy alone versus combination chemotherapy and concurrent continuous-course radiotherapy was performed at the Cleveland Clinic Foundation. 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. 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. Continuous-course radiotherapy and concurrent combination chemotherapy is an intensive, toxic but tolerable treatment regimen, which, when compared with radiotherapy 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. © 1997 John Wiley & Sons, Inc. Head Neck 19: 567–575, 1997.

Treating the neck after organ-preservation treatment with radiotherapy or chemoradiotherapy can be problematic. 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. Of the 47 patients with stage N0–1, 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 N0–1 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 (&lt;CR), and 30 had a CR. In 35 N2–3 patients, neck dissection was performed as planned. Of these 35, 18 had a CR in the neck; 4 had positive nodes on pathologic examination. The other 17 had a &lt;CR in the neck; 8 had positive nodes on pathologic examination. One patient in this group of 17 had regional recurrence after a pathologically negative neck dissection. Of the 18 N2–3 patients who did not undergo planned neck dissection, 6 had tumor progression and had no further therapy. The other 12, all with a CR in the neck, were followed, and 3 had neck recurrence; none successfully salvaged. Despite a CR in 30 N2–3 patients, 7 had persistent disease or eventual neck recurrence. Adding neck dissection minimized neck recurrence (p = .05). In N2–3 patients, disease-specific survival was significantly better in patients with a CR in the neck (p = .002). Disease-specific survival was not affected by neck dissection (p = .40) but was significantly affected by viable tumor in the specimen (p = .03). Based on these results and the realization that it is difficult to follow patients for recurrent neck cancer, that salvage is often unsuccessful, and that patients dying from uncontrollable neck disease have an extremely poor quality of life, we recommend neck dissection for all N2–3 patients regardless of the neck response and for N1 patients without a CR. © 1997 John Wiley & Sons, Inc. Head Neck 19: 559–566, 1997.

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. 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. Seventy-four patients were entered on this study; 72 patients were considered eligible and evaluable. Induction toxicity included nausea (85%), increased dysphagia (90%), neutropenia (&lt;1000/mm³) (43%), thrombocytopenia (&lt;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. 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. Cancer 1997; 80:1011-20. © 1997 American Cancer Society.

• The diagnosis of intramedullary spinal cord metastasis (ISM) is difficult, and treatment is usually ineffective. We review our own experience with ISM as well as the pertinent medical literature, and suggest a practical diagnostic and therapeutic approach. The problem of the diagnosis of ISM is essentially that of the differential diagnosis of a noncompressive myelopathy in a patient with systemic cancer. Most such patients prove to have ISM, meningeal carcinomatosis, radiation myelopathy, or paraneoplastic necrotizing myelopathy. Neurologic features of value in this differential diagnosis are pain, the tempo and mode of progression of symptoms, and tumor cells in the spinal fluid. Oncologic features of value are the location of the primary tumor, the past exposure to therapeutic radiation, cerebral metastases, and the extent of systemic metastatic disease. The myelogram in ISM is either normal or nonspecifically abnormal; therefore, the diagnosis must be made on clinical grounds. Although no single finding is diagnostic of ISM, a careful clinical analysis will lead to the correct diagnosis in most cases. Radiation therapy is effective treatment for ISM, but only if it is administered early, before paraplegia supervenes. Thus, the diagnosis should be made and treatment begun as soon as possible. Intramedullary spinal cord metastasis is often multifocal rather than solitary; therefore, whole-cord rather than local spinal radiation should be given, if possible. If local radiotherapy is chosen, the construction of the portal can be based on the myelogram or, in the event of a normal study, on the clinical localization of the tumor.

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.

No abstract.