Harvey I. Pass

Randomized trial of neoadjuvant therapy for lung cancer: Interim analysis

The role of neoadjuvant chemotherapy in stage IIIa non-small cell lung cancer remains undefined. Since 1987, 27 patients with non-small cell lung cancer, all with histologically confirmed metastases to the ipsilateral mediastinal lymph nodes, have been enrolled in an ongoing prospective, randomized trial at our institution. Thirteen patients have been randomized to preoperative etoposide-platinum (EP) chemotherapy-surgery-postoperative EP, and 14 other patients have been randomized to surgery-postoperative mediastinal irradiation (SRT). Both groups are similar in sex, age, weight loss, tumor location, preoperative pulmonary function, physiologic grade, and tumor histology. Eight of the 13 EP patients have responded as evidenced by a 50% or greater radiographic tumor shrinkage after two cycles. Complete tumor and nodal resection rates were similar: 11/13 EP patients versus 12/14 SRT patients. There was no operative mortality for the 27 patients. Median potential follow-up is 29.9 months for the EP group and 34.9 months for the SRT group. Preliminary results suggest a trend toward increased survival time for the EP group (median, 28.7 months) versus the SRT group (median, 15.6 months) (p2 = 0.095). Eleven of 12 resected SRT patients have had recurrence versus 8 of 11 resected EP patients. Time to recurrence reveals no significant differences between the two groups but a trend toward increased disease-free interval in the EP group (12.7 months versus 5.8 months, EP versus SRT). This interim analysis demonstrates the feasibility of such a trial; however, despite the trends, definitive conclusions await further accrual and study maturation.

Results of lung metastasectomy from breast cancer: prognostic criteria on the basis of 467 cases of the International Registry of Lung Metastases.

OBJECTIVE Metastatic breast cancer is still defined as an incurable disease. Although the prognosis after resection of isolated metastases to the lung is much better than after chemotherapy most oncologists and gynecologists disapprove of lung metastasectomy. METHODS In order to summarize the experience of pulmonary metastatic surgery and to achieve more relevant data by an increased number of cases, we evaluate the data of the International Registry of Lung Metastases of 467 patients having lung metastases from breast cancer with regard to long-term survival and prognostic factors. RESULTS In 84% a complete metastatic resection was possible. The survival rates are 38% after 5 years, 22% after 10 years, and 20% after 15 years. Prognostic factors are a disease-free interval of > or = 36 months with 5-year survival of 45%, a 10-year survival of 26% and a 15-year survival of 21% (P=0.0001), solitary lung metastasis is associated with a survival rate of 44% after 5 years and of 23% after 10 and 15 years, but this is not statistically significant compared to multiple metastases. When establishing prognostic groups as suggested by Pastorino and the International Registry of Lung Metastases based on the risk factors disease-free interval, number of metastases and complete resection the group with the best prognosis showed 5-year survival of 50%, 10- and 15-year survival of 26% with a median survival of 59 months. CONCLUSION Considering the low morbidity and mortality rate, we think that lung metastasectomy today is the best treatment option in selected cases of lung metastases from breast cancer.

Phase III randomized trial of surgery with or without intraoperative photodynamic therapy and postoperative immunochemotherapy for malignant pleural mesothelioma

AbstractBackground: Patients with malignant pleural mesothelioma (MPM) usually die of progressive local disease. This report describes the results of a Phase III trial comparing maximum debulking surgery and postoperative cisplatin, interferon α-2b, and tamoxifen (CIT) immunochemotherapy with and without intraoperative photodynamic therapy (PDT) to determine (1) whether such a multimodal approach can be performed with minimum morbidity and mortality in malignant pleural mesothelioma (MPM), and (2) whether first-generation (i.e., 630-nm laser light, Photofrin II) intrapleural PDT impacts on local recurrence or survival. Methods: From July 1993 to June 1996, 63 patients with localized MPM were randomized to either PDT or no PDT. The tumors of 15 patients could not be debulked to 5 mm. Patients assigned to PDT (n=25) and no PDT (n=23) were similar with respect to age, sex, tumor volume, and histology. Results: The type of resection (11 pleurectomies and 14 pneumonectomies vs. 12 pleurectomies and 11 pneumonectomies), length postoperative stay, and ICU time were comparable (PDT vs. no PDT). There was one operative death (hemorrhage), and each group had two bronchopleural fistulas. Postoperative staging divided patients into the following categories: stage I: PDT, 2, no PDT, 2; stage II: PDT, 2, no PDT, 2; stage III, PDT, 21; no PDT, 17; stage IV, PDT, 0; 0; no PDT, 2. Comparable numbers of CIT cycles were delivered. Median survival for the 15 non-debulked patients was 7.2 months, compared to 14 months for the 48 patients on protocol. There were no differences in median survival (14.4 vs. 14.1 months) or median progression-free time (8.5 vs. 7.7 months), and sites of first recurrence were similar. Conclusions: Aggressive multimodal therapy can be delivered for patients with higher stage MPM. First-generation PDT does not prolong survival or increase local control for MPM.

Nuclear Estrogen Receptor β in Lung Cancer: Expression and Survival Differences by Sex

Purpose: A role for estrogens in determining lung cancer risk and prognosis is suggested by reported sex differences in susceptibility and survival. Archival lung tissue was evaluated for the presence of nuclear estrogen receptor (ER)-α and ER-β and the relationship between ER status, subject characteristics, and survival. Experimental Design: Paraffin-embedded lung tumor samples were obtained from 214 women and 64 men from two population-based, case-control studies as were 10 normal lung autopsy samples from patients without cancer. Nuclear ER-α and ER-β expression was determined by immunohistochemistry. Logistic regression was used to identify factors associated with ER positivity and Cox proportional hazards models were used to measure survival differences by ER status. Results: Neither tumor (0 of 94) nor normal (0 of 10) lung tissue stained positive for ER-α. Nuclear ER-β positivity was present in 61% of tumor tissue samples (170 of 278; 70.3% in men and 58.3% in women) and 20% of normal tissue samples (2 of 10; P = 0.01). In multivariate analyses, females were 46% less likely to have ER-β–positive tumors than males (odds ratio, 0.54; 95% confidence interval, 0.27-1.08). This relationship was stronger and statistically significant in adenocarcinomas (odds ratio, 0.40; 95% confidence interval, 0.18-0.89). Women with ER-β–positive tumors had a nonsignificant 73% (P = 0.1) increase in mortality, whereas men with ER-β–positive tumors had a significant 55% (P = 0.04) reduction in mortality compared with those with ER-β–negative tumors. Conclusions: This study suggests differential expression by sex and influence on survival in men of nuclear ER-β in lung cancer, particularly in adenocarcinomas.

Comparison of Median Sternotomy and Thoracotomy for Resection of Pulmonary Metastases in Patients with Adult Soft-Tissue Sarcomas

Thoracotomy and median sternotomy have both been advocated for resection of pulmonary metastases, and the advantages of each approach remain disputed. Patients with adult soft-tissue sarcomas undergoing resection of pulmonary metastases at the National Cancer Institute were studied retrospectively to assess the results of each surgical approach. Between 1981 and 1984, 65 patients underwent 78 sternotomies (7 lobectomies, 71 wedge resections); a mean of 9.5 nodules were resected per patient (range, 1 to 61). Resection of all nodules was accomplished in 60 of 71 explorations (84%) in patients with documented metastases. Benign lesions were found during 7 explorations (9%). Thirteen of 30 patients (43%) with unilateral metastases on linear tomography (LT), 45% (9 of 20) of patients with unilateral metastases on computed tomography (CT), and 38% (5 of 13) of patients with unilateral metastases on both CT and LT had bilateral metastases at sternotomy. Survival by type of incision was compared for 84 patients who underwent complete resection of their metastases (42 by sternotomy and 42 by thoracotomy); the minimum follow-up was two years. The groups did not differ significantly with respect to prognostic variables (tumor doubling time, disease-free interval, or number of nodules resected). There was no significant difference in actuarial survival between the two groups. The complication rate was 15% for the sternotomy group and 10% for the thoracotomy group (difference not significant). There were no operative deaths. Median sternotomy results in detection of unsuspected bilateral metastases and avoidance of a second operative procedure, but it does not increase operative morbidity or mortality or compromise overall patient survival.

Preoperative Tumor Volume Is Associated With Outcome In Malignant Pleural Mesothelioma

OBJECTIVES Our objective was to analyze the impact of preoperative and postresection solid tumor volumes on outcomes in 47 of 48 consecutive patients undergoing resection for malignant pleural mesothelioma who were treated prospectively and randomized to photodynamic therapy or no photodynamic therapy. METHODS From July 1993 to June 1996, 48 patients with malignant pleural mesothelioma had cytoreductive debulking to 5 mm or less residual tumor by extrapleural pneumonectomy (n = 25) or pleurectomy/decortication (n = 23). Three-dimensional computed tomographic reconstructions of preresection and postresection solid tumor were prospectively performed and the disease was staged postoperatively according to the new International Mesothelioma Interest Group staging. RESULTS Median survival for all patients is 14.4 months (extrapleural pneumonectomy, 11 months; pleurectomy/decortication, 22 months; p2 = 0.07). Median survival for preoperative volume less than 100 was 22 months versus 11 months if more than 100 cc, p2 = 0.03. Median survival for postoperative volume less than 9 cc was 25 months versus 9 months if more than 9 cc, p2 = 0.0002. Thirty-two of forty-seven (68%) had positive N1 or N2 nodes. Tumor volumes associated with negative nodes were significantly smaller (median 51 cc) than those with positive nodes (median 166 cc, p2 = 0.01). Progressively higher stage was associated with higher median preoperative volume: stage I, 4 cc; stage II, 94 cc; stage III, 143 cc; stage IV, 505 cc; p2 = 0.007 for stage I versus II versus III versus IV. Patients with preoperative tumor volumes greater than 52 cc had shorter progression-free intervals (8 months) than those 51 cc or less (11 months; p2 = 0.02). CONCLUSIONS Preresection tumor volume is representative of T status in malignant pleural mesothelioma and can predict overall and progression-free survival, as well as postoperative stage. Large volumes are associated with nodal spread, and postresection residual tumor burden may predict outcome.

A phase I study of Foscan-mediated photodynamic therapy and surgery in patients with mesothelioma

BACKGROUND Photodynamic therapy (PDT) is a light-based cancer treatment that, in the correct setting, can be delivered intraoperatively as an adjuvant therapy. A phase I clinical trial combining surgical debulking with Foscan-mediated PDT was performed in patients with malignant pleural mesothelioma. The purpose of the study was to define the toxicities and to determine the maximally tolerated dose (MTD) of Foscan-mediated PDT. METHODS A total of 26 patients completed treatment. Tumor debulking was accomplished with either an extrapleural pneumonectomy (7 patients) or a lung-sparing pleurectomy-decortication (19 patients). Patients were injected with Foscan before surgery, and 652 nm light was delivered intraoperatively after completion of surgical debulking. Four light sensors were placed in the chest, allowing delivery of light to a uniform measured dose throughout the hemithorax. RESULTS Four dose levels were explored. The MTD was 0.1 mg/kg of Foscan injected 6 days before surgery in combination with 10 J x cm(-2) 652 nm light. Dose limiting toxicity at the next higher dose was a systemic capillary leak syndrome leading to death in 2 of 3 patients treated at that dose. Other PDT-related toxicities included wound burns and skin photosensitivity. In all, 14 patients were treated at the MTD without significant complications. CONCLUSIONS Foscan-mediated PDT can be safely combined with surgery at the established MTD. Unlike most other surgery-based multimodal treatments for mesothelioma, Foscan-mediated PDT affords the option, in selected patients, of accomplishing tumor debulking with a lung-sparing procedure rather than an extrapleural pneumonectomy. A phase II study is warranted.

Gene expression profiles predict survival and progression of pleural mesothelioma

Purpose: Clinical outcomes for malignant pleural mesothelioma (MPM) patients having surgery are imprecisely predicted by histopathology and intraoperative staging. We hypothesized that gene expression profiles could predict time to progression and survival in surgically cytoreduced pleural mesothelioma of all stages. Experimental Design: Gene expression analyses from 21 MPM patients having cytoreductions and identical postoperative adjuvant therapy were performed using the U95 Affymetrix gene chip. Using both dChip and SAM, neural networks constructed a common 27 gene classifier, which was associated with either the high-risk and low-risk group of patients. Data were validated using real-time PCR and immunohistochemical staining. The 27 gene classifier was also used for validation in a separate set of 17 MPM patients from another institution. Results: The groups predicted by the gene classifier recapitulated the actual time to progression and survival of the test set with 95.2% accuracy using 10-fold cross-validation. Clinical outcomes were independent of histology, and heterogeneity of progression and survival in early stage patients was defined by the classifier. The gene classifier had a 76% accuracy in the separate validation set of MPMs. Conclusions: These data suggest that pretherapy gene expression analysis of mesothelioma biopsies may predict which patients may benefit from a surgical approach.

Kaposi's Sarcoma Causing Pulmonary Infiltrates and Respiratory Failure in the Acquired Immunodeficiency Syndrome

Although an aggressive form of Kaposis sarcoma often develops in patients with the acquired immunodeficiency syndrome, most patients die due to opportunistic infections rather than the direct effects of this tumor. Because Kaposis sarcoma has caused pulmonary dysfunction in a number of our patients, we attempted to characterize features of pulmonary dysfunction induced by Kaposis sarcoma. In 66 patients with Kaposis sarcoma treated between 1982 and 1984 there were 30 episodes of pulmonary dysfunction that resulted in a biopsy. Six episodes were due to pulmonary Kaposis sarcoma alone, and 6 additional episodes were due to Kaposis sarcoma and associated opportunistic infections. Clinical and radiologic features of pulmonary Kaposis sarcoma an infection were indistinguishable. Pulmonary Kaposis sarcoma could only be documented in large tissue sections available from open-lung biopsy or autopsy samples. Because chemotherapy or radiation therapy appears to provide palliation, clinicians should recognize Kaposis sarcoma as a cause of pulmonary disease in patients with the acquired immunodeficiency syndrome.

Sarcomatoid mesothelioma and its histological mimics: a comparative immunohistochemical study

Aims:  Differentiating sarcomatoid mesothelioma from other pleural‐based spindle cell tumours by light microscopy can be challenging, especially in a biopsy. The role of immunohistochemistry in this differential diagnosis is not as well defined as it is for distinguishing epithelioid mesothelioma from adenocarcinoma. In this study, we investigate the utility of diagnostic immunohistochemistry for distinguishing sarcomatoid mesothelioma from its histological mimics, high‐grade sarcoma and pulmonary sarcomatoid carcinoma.