Predictive biomarkers for response to EGFR-directed monoclonal antibodies for advanced squamous cell lung cancer.

Background: Upregulated expression and aberrant activation of the epidermal growth-factor receptor (EGFR) are found in lung cancer, making EGFR a relevant target for non-small-cell lung cancer (NSCLC). Treatment with anti-EGFR monoclonal antibodies (mAbs) is associated with modest improvement in overall survival in patients with squamous cell lung cancer (SqCLC) who have a significant unmet need for effective treatment options. While there is evidence that using EGFR gene copy number, EGFR mutation, and EGFR protein expression as biomarkers can help select patients who respond to treatment, it is important to consider biomarkers for response in patients treated with combination therapies that include EGFR mAbs. Design: Randomized trials of EGFR-directed mAbs cetuximab and necitumumab in combination with chemotherapy, immunotherapy, or antiangiogenic therapy in patients with advanced NSCLC, including SqCLC, were searched in the literature. Results of associations of potential biomarkers and outcomes were summarized. Results: Data from phase III clinical trials indicate that patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein (H-score of ≥200) and/or gene copy numbers of EGFR (e.g. ≥40% cells with ≥4 EGFR copies as detected by fluorescence in situ hybridization; gene amplification in ≥10% of analyzed cells) derive greater therapeutic benefits from EGFR-directed mAbs. Biomarker data are limited for EGFR mAbs used in combination with immunotherapy and are absent when used in combination with antiangiogenic agents. Conclusions: Therapy with EGFR-directed mAbs in combination with chemotherapy is associated with greater clinical benefits in patients with NSCLC, including SqCLC, whose tumors express high levels of EGFR protein and/or have increased EGFR gene copy number. These data support validating the role of these as biomarkers to identify those patients who derive the greatest clinical benefit from EGFR mAb therapy. However, data on biomarkers for EGFR-directed mAbs combined with immunotherapy or antiangiogenic agents remain limited.

Relationship between efficacy outcomes and weight gain during treatment of advanced, non-squamous, non-small-cell lung cancer patients.

BACKGROUND: Unintentional weight loss occurs among advanced non-small-cell lung cancer (NSCLC) patients and is associated with worse survival. Small studies have suggested that weight gain during treatment is associated with superior survival. PATIENTS AND METHODS: A retrospective analysis analyzed data from three international phase III studies comprising 2301 advanced, non-squamous NSCLC patients who received a platinum-based, first-line doublet, with or without bevacizumab and maintenance therapy. Body weight was recorded before and after treatment by each study's schedule. The relationship between weight gain and overall survival (OS) and progression-free survival (PFS) was assessed using log-rank test and adjusted Cox modeling. Logistic regression assessed the association between baseline covariates and post-baseline weight gain. RESULTS: Four hundred and twenty-one (18.3%) patients had >5% weight gain after baseline. More than half of the weight gain cohort exhibited initial weight gain by 3 weeks. The median OS was 16.7 months versus 10.7 months for the >5% versus ≤5% weight gain subgroup (n = 1880) (P < 0.001). PFS was 6.9 versus 4.8 months, respectively (P < 0.001). Differences in overall tumor response rate (50.8% versus 25.4%, respectively) and disease control rate (tumor response or stable disease) (91.5% versus 63.6%, respectively) were also significant (P < 0.001). The Cox modeling revealed the >5% subgroup had longer survival [hazard ratio (HR) = 0.54, 95% confidence interval (CI) 0.47-0.62; P < 0.001] than the ≤5% subgroup after adjusting for baseline factors. Similar significant results were found for PFS (HR = 0.59, 95% CI 0.52-0.67; P < 0.001). Unadjusted logistic regression indicated a significant association between weight gain (>5% versus ≤5%) and age, and BMI. CONCLUSIONS: Weight gain during treatment may be an early indicator of clinical benefit. If confirmed in prospective studies, monitoring weight change may provide important information regarding survival outcomes in NSCLC and may provide ideas for new therapeutic strategies.

PTEN and PIK3CA gene copy numbers and poor outcomes in non-small cell lung cancer patients with gefitinib therapy.

METHODS: Fluorescent in situ hybridisation analyses of PTEN, PIK3CA, EGFR and CEN7 were performed on tumour specimens from patients treated on the expanded access gefitinib trial. Progression-free survival (PFS) and overall survival (OS) were correlated with outcomes in all patients and EGFR wild-type patients. RESULTS: Progression-free survival (hazard ratio=2.54, P<0.001) and OS (hazard ratio=4.04, P<0.001) were significantly shorter in patients whose tumours had all of the following molecular patterns: CEN7 <4 copies per cell, PTEN loss (<2 copies in at least 20% of cells), and PIK3CA gain (>2 copies in at least 40% of cells) both in all and EGFR wild-type only patients. CONCLUSION: The combination of low CEN7 copy number, PTEN loss, and PI3KCA gain may be useful for identifying NSCLC patients unlikely to benefit from treatment with EGFR (TKIs), specifically in wild-type EGFR cases.

Phase II trial of cisplatin, etoposide, and 5-fluorouracil in advanced non-small-cell lung cancer: an Eastern Cooperative Oncology Group Study (PB586).

Advanced non-small-cell lung cancer (NSCLC) remains an incurable disease despite significant progress in chemotherapy. We conducted a phase II clinical trial to investigate the efficacy and toxicity of a cisplatin, etoposide, and 5-fluorouracil (5-FU) combination in advanced metastatic and/or recurrent NSCLC. Forty patients with advanced, recurrent, or metastatic, measurable NSCLC were treated with cisplatin, 60 mg/m2 intravenously (i.v.) on day 1; etoposide, 120 mg/m2/day i.v. on days 1, 2, and 3; and 5-FU. 1,000 mg/m2/day i.v. continuous infusion on days 1 through 5. Treatment was administered in 4-week cycles. Thirty patients had distant metastases and were previously untreated, and 10 patients had recurrent disease after prior treatment with either surgery (1 patient), radiation therapy (5 patients), or both treatments (4 patients). Twenty-nine patients were evaluable for response. Seven (24%) patients achieved a partial remission (PR), 18 (62%) had stable disease (SD), and 8 (14%) had progressive disease (PD). Overall median survival was 7.9 months (range, 0.4-27.4 months). Patients who achieved a PR had a median survival of 23.5 months (9.3-27.4 months). In contrast, patients with SD had a median survival of 9.9 months (2.5-25.3 months), and patients with PD had a median survival of 2.1 months (1-9.3 months). Median duration of response of 27.1 weeks (4.9-76.5 weeks) for patients with PR, and time to progression was 13.4 weeks (3.7-54.5 weeks) for patients with SD. Toxicity was primarily hematologic and gastrointestinal, and there were three deaths due to infection. The combination of cisplatin, 5-FU, and etoposide as administered in this study appears to have considerable toxicity and does not appear to be superior to other cisplatin-containing regimens used for the treatment of advanced NSCLC.

A randomized Phase II study of interleukin-2 with and without beta-interferon for patients with advanced non-small cell lung cancer: an Eastern Cooperative Oncology Group study (PZ586).

Interleukin-2 (IL-2) and beta-interferon (beta-IFN) are biologic agents with antitumor activity observed in preclinical models. Some studies of patients with advanced non-small cell lung cancer treated with IL-2 report relatively long survival, despite low response rates. Seventy-six evaluable patients with stage IV non-small cell lung cancer were treated in a randomized Phase II study with either IL-2 alone or IL-2 plus beta-IFN. Patients received either IL-2 at 6 x 10(6) Cetus units/m2 3 days weekly or the combination of IL-2 at 5 x 10(6) Cetus units/m2 plus beta-IFN at 6 x 10(6) units/m2, both given 3 days weekly. Both biologic agents were administered by intravenous bolus injection on an outpatient basis. Objective responses were observed in 3/76 (4%)) patients. Grade 4 toxicity occurred in 3/39 patients treated with IL-2 alone, and in 4/37 patients treated with IL-2 plus beta-IFN. An additional lethal respiratory toxicity occurred in a patient who received IL-2 plus beta-IFN. The median survival of all patients treated on this study was 33 weeks. Despite producing only a 4% objective response rate. IL-2 appears to have a favorable impact on survival comparable to chemotherapy. The role for this immune therapy in the management of non-small cell lung cancer requires further study.

Retreatment of recurrent invasive thymoma with platinum, doxorubicin, and cyclophosphamide.

Invasive thymoma recently has been shown to be sensitive to combination chemotherapy and in some cases to be relatively indolent. Two cases of extensive thymoma which responded to primary treatment with a combination of a platinum compound (carboplatin or cisplatin), doxorubicin (Adriamycin), and cyclophosphamide (or PAC) are described. Tumor progression occurred 14 (case 1) and 60 months (case 2) after completion of initial PAC therapy and was treated with the same regimen resulting in a second remission, which lasted 6 months in case 1 and is continuing at 8 months in case 2. Similar reports of secondary responses using the same chemotherapy have been described in breast, lung, and ovarian cancers, as well as in Hodgkin's lymphomas. Our observations suggest that retreatment with the same platinum-based regimen should be considered in patients who have progressive thymomas following a previous chemotherapeutic response and a disease-free interval of greater than 12 months.

Phase II study of ifosfamide, carboplatin, and oral etoposide chemotherapy for extensive-disease small-cell lung cancer: an Eastern Cooperative Oncology Group pilot study.

PURPOSE: A phase II study of ifosfamide, carboplatin, and prolonged oral administration of etoposide (ICE) in patients with untreated extensive-disease (ED) small-cell lung cancer (SCLC) was conducted to assess toxicities, response, and median survival. PATIENTS AND METHODS: Between July 1990 and August 1992, 35 patients were treated. ICE doses were ifosfamide 5 g/m2 by 24-hour continuous intravenous (CIV) infusion with mesna on day 1, carboplatin 300 mg/m2 intravenously (IV) on day 1, and etoposide 50 mg/m2 orally on days 1 to 21 every 4 weeks for up to six to eight cycles (schedule I). Because of severe hematologic toxicity in the first 18 patients, the last 17 patients received ifosfamide 3.75 mg/m2 IV on day 1, carboplatin 300 mg/m2 IV on day 1, and etoposide 50 mg orally on days 1 to 14 (schedule II). RESULTS: Nine of 18 patients (50%) on schedule I had 13 episodes of severe hematologic toxicity (one death), and only two (11%) received full doses on cycle 2. However, with schedule II, only four of 17 patients (24%) developed severe hematologic toxicity, and eight (47%) received full doses on cycle 2. Objective responses were observed in 29 of 35 patients (83%) (schedule 1, 16 of 18 patients [89%]; schedule II, 13 of 17 patients [76%]). There were eight (23%) complete responses (CRs) and 21 (60%) partial responses (PRs). The median survival duration was 8.3 months, and 1- and 2-year survival rates were 37% and 14%, respectively. CONCLUSION: ICE with oral etoposide has comparable activity with other regimens in ED SCLC. However, the 2-year survival rate may be higher and ICE with the lower doses of schedule II could be given safely with acceptable toxicity. Further studies of ICE compared with standard two-drug regimens are warranted.

EST 2582 phase II trial of cisplatin in metastatic or recurrent thymoma.

In 1982 there were four reports of cisplatin-induced remissions of invasive thymoma. These observations led the Eastern Cooperative Oncology Group (ECOG) to conduct a Phase II trial of cisplatin (50 mg/m2 intravenously every 3 weeks). During a 4-year period 24 patients were entered on this trial; 3 were excluded because review of histologic material failed to confirm the presence of thymoma. The characteristics of the remaining 21 patients were as follows: median age, 51; males/females, 11/10; ECOG performance status, 0-1/2-3, 16/5; previous treatment with chemotherapy, 3; previous surgery, 20; previous radiation, 15; weight loss, < 5%/ > or = 5%: 17/4. One patient was eliminated from response analysis because of failure to return for follow-up tumor measurements. The following responses were observed in the remaining 20 patients. Partial remission, 2 (10%); stable disease, 8 (40%); and progression, 10 (50%). The median survival was 76 weeks, and the 2-year survival rate was 39%. Four patients experienced severe nausea and vomiting, but life-threatening and lethal toxicities were not observed. Cisplatin given at this dose was relatively ineffective in producing tumor regression in recurrent or metastatic thymoma.

Justification for evaluating new anticancer drugs in selected untreated patients with extensive-stage small-cell lung cancer: an Eastern Cooperative Oncology Group randomized study.

BACKGROUND: Studies have shown that response to a given chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer is superior to that in patients previously treated with other regimens. This finding raises the question of whether it is necessary and ethical to study the effects of new anticancer agents in untreated patients. Such studies appear to be the best test for drug development, but there has been no evaluation of whether survival of untreated patients, whose cancer is sensitive to established drugs, is adversely affected in trials of new drugs. PURPOSE: This randomized study of untreated patients with extensive-stage small-cell lung cancer was designed (a) to compare the survival of patients treated with either effective standard chemotherapy or an investigational anticancer drug as initial therapy and (b) to evaluate response rates and toxic effects of such therapies. METHODS: Eighty-six patients were randomly assigned to receive, as initial therapy, either the standard CAV regimen--cyclophosphamide (1000 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg/m2) every 3 weeks--or the phase II drug menogaril (200 mg/m2) every 4 weeks. Treatment after induction therapy varied, depending on patient response, but nonresponders and those with disease progression received salvage chemotherapy--etoposide (120 mg/m2 on days 1, 2, and 3) and cisplatin (60 mg/m2 on day 1), repeated every 3 weeks. RESULTS: Of the 43 patients on CAV, 42% responded (eight complete responses and 10 partial responses); 5% of the 43 on menogaril responded (two partial responses) (P = .0001). Twelve (22%) of 54 patients responded to salvage chemotherapy (five complete responses and seven partial responses). Within 3 months from start of treatment, twelve patients died--3 patients in the CAV group and nine patients in the menogaril group (P = .12). The estimated median survival was 37 weeks with menogaril and 45 weeks with CAV (P = .28). At 6 months, survival was 76.7% for the CAV group and 67.4% for the menogaril group. At 12 months, survival rates were 24.4% and 27.9%, respectively. Confidence intervals (95%) for the differences between the proportions surviving in the two groups were -9%-28% at 6 months and -25%-14% at 12 months. Use of CAV resulted in significantly higher occurrence of severe and life-threatening treatment-related complications (P = .002). CONCLUSION: The confidence intervals for the differences in survival are too wide to conclude that evaluation of a new drug in untreated patients with extensive-stage small-cell lung cancer is or is not harmful. The data do suggest, however, that use of this study design may have no adverse effect on survival.

Mediastinal tumors.

Of the many types of tumors located in the mediastinal compartments, most are metastatic. The most common adult tumor in the anterior compartment is thymoma. A number of important cytogenetic, immunohistochemical, and molecular analytical observations have been reported over the past year regarding this tumor. In addition, reports on the multimodality management of thymoma have raised important issues regarding the prognostic significance of selected pretreatment parameters. Of special interest are reports which may clarify differences which may exist between thymic carcinoma, a separate pathologic entity, and thymoma. Finally, important observations regarding the association of hematologic malignancies with germ cell tumors of the mediastinum have been made in the past year. The following review summarizes pertinent progress in the above-mentioned areas and cites interesting reports pertaining to less common mediastinal tumors of the posterior and middle mediastinum.

Preoperative radiation therapy in regionally localized stage III non-small cell lung carcinoma: long-term results and patterns of failure.

Seventy-four patients from January 1975 through December 1982, with clinical Stage III Mo non-small cell carcinoma of the lung were treated at our Medical Center with a course of pre-operative radiation therapy to be followed by surgical resection. Radiation therapy consisted of delivering a total dose of 40 Gy with 200 cGy per fraction over a period of 4 weeks to the primary tumor in the lung and the regional lymph nodal areas. Surgical resection was attempted 4 weeks later. Fifty-eight percent of the patients had squamous cell carcinoma whereas the remaining had other histologies like adenocarcinoma, large cell carcinoma, or a combination thereof. All the patients except two were followed up to a minimum of 5 years or until death. Sixty-four patients (82%) had T3 tumors whereas mediastinal nodal involvement was found in 41 patients (55%). Fifteen patients (20%) did not have the operation because of tumor progression, patient's refusal or death. All but two surgically treated patients had tumor resection. Of these 19% had histologically negative specimens, 9 patients (16%) had microscopic disease only, and 37 patients had gross residual disease at the time of surgery. The actuarial 5-year survival and recurrence-free survival rates for the entire group were 20% and 24%, respectively. Patients with a pathologic response had an actuarial recurrence-free survival rate of 53% at 5 years whereas only 17% of those with gross residual disease at surgery had remained recurrence-free at 5 years. One-half of the patients with clinically uninvolved nodes were living recurrence-free at 5 years whereas only 20% of the patients with N2 disease did so. The patterns of failure according to the histology and stage of the disease will be presented.

Neoadjuvant treatment in locally advanced non-small cell lung cancer.

Any neoadjuvant or preoperative treatment program that would increase survival in clinically advanced non-small cell lung cancer (NSCLC) patients would be of significant benefit. In addition to improving patient survival, the program should be associated with minimal toxicity and surgical mortality. The rationale for any preoperative program is that the ability to resect the advanced cancer will be enhanced and micrometastasis will be eradicated. We have analyzed 323 patients enrolled in various types of neoadjuvant and preoperative studies. Review of this data indicates that cisplatin containing regimens produce relatively high responder rates in locally advanced NSCLC patients, resectability rate can be increased by a neoadjuvant program and chemotherapeutic toxicity and operative mortality are not prohibitive. Survival data frequently includes T3N0-1 patients, but there does appear to be increased survival at 3 and 4 years. These studies remain experimental and continued analysis is necessary before they can be accepted as standard therapy for clinically advanced NSCLC cancer.

Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: a study of the Eastern Cooperative Oncology Group.

During the last decade, the Eastern Cooperative Oncology Group (ECOG) has studied a series of combination chemotherapy regimens in metastatic (stage IV) non-small-cell lung cancer (NSCLC). In January 1984, the ECOG activated a randomized study, EST 1583, which concluded the evaluation of combination regimens in phase III trials and initiated the evaluation of single agents exclusively in previously untreated patients. The treatment regimens in EST 1583 consisted of: (1) mitomycin, vinblastine, and cisplatin (MVP); (2) vinblastine and cisplatin (VP); (3) MVP alternating with the regimen cyclophosphamide, doxorubicin, methotrexate, and procarbazine (CAMP); (4) carboplatin followed by the MVP regimen at the time of progression; and (5) iproplatin followed by MVP at the time of progression. From January 1984 to July 1985, 743 patients were entered on this trial and 699 fulfilled the eligibility requirements. The following objective response rates (complete plus partial remissions) were observed: first-line MVP, 20%; VP, 13%; MVP/CAMP, 13%; carboplatin, 9%; iproplatin, 6%; and second-line MVP, 6%. First-line MVP produced a significantly higher response rate than the other treatments (P = .03) adjusted for prognostic variables. Using analyses that were adjusted for prognostic covariates, survival for patients treated on a given regimen was compared with survival for all remaining patients. These analyses showed that treatment with carboplatin was associated with longer survival (median survival time, 31.7 weeks; P = .008) while initial treatment with MVP was associated with a trend for shorter survival (median survival time, 22.7 weeks; P = .09). It should be noted that none of these regimens appear to have produced a clinically meaningful prolongation of survival. Similar analyses evaluating time to progression disclosed that carboplatin-treated patients had a significantly longer time to progression (median time to progression, 29 weeks) than all remaining patients (P = .01). Life-threatening and lethal toxicities (toxicity grades 4 and 5) were greater on the combination regimens than on the single agents (P less than .0001). Based on these results, current group-wide ECOG trials in stage IV NSCLC consist of randomized phase II trials evaluating single agents.

Preoperative chemotherapy and irradiation for stage III non-small cell lung cancer.

Surgical therapy for stage III non-small cell lung cancer (NSCLC) has not resulted in substantial long-term survival. Neoadjuvant treatment programs that could down-stage the tumor and achieve increased long-term survival would be of obvious benefit. We have used preoperative simultaneous chemotherapy and irradiation in 85 patients with clinical stage III non-small cell lung cancer considered candidates for surgical resection. One group of 56 patients was treated with cisplatin, 5-fluorouracil, and simultaneous irradiation for five days every other week for a total of four cycles. After treatment, 39 patients underwent resection, and the operative mortality was 2 (5%) of 39. A second trial was undertaken in which etoposide (VP-16) was added because of its synergism with cisplatin. In this group, 29 patients were considered to have potentially resectable disease, and 23 underwent thoracotomy with 1 operative death (4%). Of the total of 62 patients having thoracotomy, 60 underwent resection (97%). Complications were major, and there were four bronchopleural fistulas. For the 85 patients eligible for surgical intervention in these two groups of patients, the Kaplan-Meier median survival estimate is 40% at 3 years. The median survival of the 62 patients having thoracotomy is 36.6 months. Combination preoperative chemotherapy and irradiation is feasible with acceptable toxicity and operative mortality in patients with clinical stage III non-small cell lung cancer. Prospective randomized studies are suggested for further evaluation of this treatment program.

A pilot study of the Functional Living Index-Cancer (FLIC) Scale for the assessment of quality of life for metastatic lung cancer patients. An Eastern Cooperative Oncology Group study.

Quality of life is an important factor in the assessment of cancer therapy, but it is difficult to define and measure. The Functional Living Index-Cancer (FLIC) was designed specifically for cancer patients under treatment. The Eastern Cooperative Oncology Group (ECOG) mounted a pilot study to assess the feasibility and sensitivity of the patient-oriented FLIC scale for assessment of quality of life. The results of this study show that the FLIC scores correlate with the functional status of patients on treatment: high scores on the FLIC prior to therapy were found to correlate with good performance status (p = 0.0001), and decreases in the FLIC score during therapy correlated with a decline in performance status (p = 0.0001), with poor performance status (p = 0.0002), and greater than 5% recent weight loss (p = 0.004). However, there was poor compliance to completion of the instrument, indicating a need for future research into this aspect of assessing quality of life in the cooperative group setting.

Sequential hormone therapy for advanced breast cancer.

Sequential hormone therapy for advanced breast cancer can offer significant and prolonged disease control with minimal morbidity. Predictors of response to sequential hormone therapy have not previously been identified. Sixty postmenopausal women with advanced or recurrent breast cancer treated with sequential megestrol acetate and tamoxifen were evaluated to identify factors which predict response to sequential therapy. The response rate to first-line therapy was 28% (17/60). Forty-seven percent of patients who responded to the first therapy responded to the second (8/17). Four of 16 patients (25%) who failed the first hormone therapy responded to the second. The response rate to a second hormone therapy was 25% (15/60). Chi-square tests were used to test the association between a response to sequential hormonal therapy and prior chemotherapy, age at first hormone trial, number of sites of disease, dominant site of disease, sequence of hormonal therapy, second response on the basis of first response, presence of soft tissue disease or bone disease alone, and receptor value. A one-tailed Fisher exact probability test revealed that a greater proportion of receptor-positive patients exhibited positive responses to sequential hormonal therapies than did receptor-negative patients. All of the patients who responded to a second hormonal therapy were estrogen receptor (ER)- and progestogen receptor (PgR)-positive. Fisher exact probability tests revealed a statistically significant association between response to initial hormone therapy and response to a subsequent hormone trial. This study suggests that patients who fail their initial hormone trial should be considered for a second hormonal trial if they are ER- and PR-positive.

Modification of the effects of cytotoxic chemotherapy on the immune responses of cancer patients with a nonsteroidal, antiinflammatory drug, piroxicam. A pilot study of the Eastern Cooperative Oncology Group.

We have attempted to modify the manner in which chemotherapy influences immune function in lung cancer patients by adding the nonsteroidal, antiinflammatory drug (NSAID) piroxicam to a cytotoxic drug treatment regimen. Eighteen previously untreated patients with lung cancer received cytotoxic chemotherapy with mitomycin-C (10 mg/m2), vinblastine (6 mg/m2), and cis-platinum (40 mg/m2) (MVP) on day 1 of a 21-day treatment cycle; 12/18 patients also received piroxicam (20 mg/day) beginning 10 days prior to MVP and persisting throughout the 21-day treatment cycle. In vitro tests included (a) phytohemagglutinin (PHA) responsiveness in the presence of indomethacin or interleukin-2 (IL-2), (b) natural killer cell (NK) function, and (c) PHA-induced IL-2 synthesis. In the 6 patients treated with MVP alone, depressed PHA reactivity was found pretherapy, which was augmented by indomethacin, but not by IL-2; this was associated with impaired production of IL-2. By days 7-14, PHA reactivity, IL-2 responsiveness, and IL-2 production rebounded to normal. By days 14-21, PHA reactivity had declined once again in association with increased indomethacin-regulation and impaired IL-2 responsiveness and production. In the 12 patients who received MVP plus piroxicam, PHA and IL-2 assays improved by days 7-14 and indomethacin-regulation was normal; moreover, this improvement persisted throughout the 21-day treatment cycle. Immunological rebound persisted through as many as 3 consecutive 21-day MVP plus piroxicam treatment cycles in patients who were continuously monitored. In contrast to these results, piroxicam did not alter the way chemotherapy affected NK function. These results demonstrate that the immunomodulatory effects of cytotoxic chemotherapy can be modified or ameliorated by adding an NSAID to the cytotoxic drug treatment regimen; for certain functions, such as mitogen-stimulated blastogenesis or IL-2 production, sustained immunological rebound without immunosuppression can be achieved by this maneuver.

Hormone receptor studies in axillary metastases from occult breast cancers.

The authors describe 11 patients with occult breast carcinoma, who initially presented with axillary nodal metastases of unknown origin. In all 11 cases, physical examination and mammography results were normal. Steroid hormone receptor studies were done on tissue from all 11 axillary masses and 2 masses underwent lactalbumin staining as well. In 8 of the 11 patients these studies were positive, suggesting breast as the primary tumor site. Estrogen (30 to 445 fmol/g) or progesterone (30 to 1059 fmol/g) receptors, or both, were positive in seven cases. Although a breast carcinoma was subsequently found in all 11 patients, receptor studies on the primary tumor could not be done in every instance. The authors concluded that performing steroid hormone receptor assays on axillary metastases from occult tumors not only may provide information regarding the identity of the primary tumor but also may be the sole opportunity to determine its hormone receptor status.

Simultaneous cisplatin fluorouracil infusion and radiation followed by surgical resection in regionally localized stage III, non-small cell lung cancer.

Sixty-four patients with stage III (M omicron) non-small cell lung cancer were treated with cisplatin fluorouracil infusion chemotherapy and simultaneous radiation therapy for 5 days every other week. A total of 4 cycles (40 Gy) was followed by attempted surgical resection. Clinical response to the preoperative treatment included 5 (8%) complete and 32 (48%) partial responses. Thirty-nine (61%) underwent the planned operation, and in 9 (23%) of these patients the resected specimens were histologically negative. Clinical assessment failed to predict histological response. With 17 months median follow-up (range, 2.4-29 months), estimated 1-year survival was 61% and median survival was 16 months for all patients.