Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non--small-cell lung cancer: a Southwest Oncology Group trial.

PURPOSE: This randomized trial was designed to determine whether paclitaxel plus carboplatin (PC) offered a survival advantage over vinorelbine plus cisplatin (VC) for patients with advanced non--small-cell lung cancer. Secondary objectives were to compare toxicity, tolerability, quality of life (QOL), and resource utilization. PATIENTS AND METHODS: Two hundred two patients received VC (vinorelbine 25 mg/m(2)/wk and cisplatin 100 mg/m(2)/d, day 1 every 28 days) and 206 patients received PC (paclitaxel 225 mg/m(2) over 3 hours with carboplatin area under the curve of 6, day 1 every 21 days). Patients completed QOL questionnaires at baseline, 13 weeks, and 25 weeks. Resource utilization forms were completed at five time points through 24 months. RESULTS: Patient characteristics were similar between the groups. The objective response rate was 28% in the VC arm and 25% in the PC arm. Median survival was 8 months in both arms, with 1-year survival rates of 36% and 38%, respectively. Grade 3 and 4 leukopenia (P =.002) and neutropenia (P =.008) occurred more frequently on the VC arm. Grade 3 nausea and vomiting were higher on the VC arm (P =.001, P =.007), and grade 3 peripheral neuropathy was higher on the PC arm (P <.001). More patients on the VC arm discontinued therapy because of toxicity (P =.001). No difference in QOL was observed. Overall costs on the PC arm were higher than on the VC arm because of drug costs. CONCLUSION: PC is equally efficacious as VC for the treatment of advanced non--small-cell lung cancer. PC is less toxic and better tolerated but more expensive than VC. New treatment strategies should be pursued.

19F-MRS studies of fluorinated drugs in humans.

The use of 19F-NMR as a noninvasive probe to measure directly the pharmacokinetics of drugs at their target (effector) site(s) is illustrated in this article by human studies with 5-fluorouracil (5-FU). This drug, and several of its metabolites, have been measured in vivo in animals and in patients using standard clinical MRI systems. Using a pharmacokinetic imaging approach the parameter that can be measured most readily is the tumoral t(1/2) of 5-FU. Patients whose tumoral t(1/2) of 5-FU is equal to/greater than 20 min are designated as "trappers", and those whose tumoral t(1/2) of 5-FU is less are nontrappers. Trapping of 5-FU in tumors is a necessary, albeit not a sufficient condition, for response. Problems associated with the technical aspects of these measurements have been discussed, as well as how modulators and other agents will affect the tumoral t(1/2) of 5-FU. The rationale for the biological processes underlying the fate of 5-FU in humans has been illustrated with the use of a 12 compartment model, where several of the steps have been discussed and the consequences of their inhibition/stimulation related to the noninvasive studies that can be performed with modulators of the action of 5-FU. These 19F-NMR studies have now been extended to other fluoropyrimidines, some of which are prodrugs of 5-FU, and others where the fluorine atoms are on the ribose ring. These studies also reveal information that has both scientific and clinical significance. The studies presented here illustrate some of the potential and some of the usefulness of 19F-MRS in patient management and in drug development. It is a technique that has proven itself.

Enhancement of fluorouracil uptake in human colorectal and gastric cancers by interferon or by high-dose methotrexate: An in vivo human study using noninvasive (19)F-magnetic resonance spectroscopy.

PURPOSE: To study whether two modulators, high-dose methotrexate (MTX) and interferon alfa-2a (IFNalpha-2a) will alter the intratumoral pharmacokinetics of fluorouracil (5-FU). PATIENTS AND METHODS: Five patients, two with gastric cancer and three with colorectal cancer, who had metastatic tumor nodules in their livers were studied dynamically in vivo after 5-FU injection. In a magnetic resonance imaging unit, noninvasive (19)F-magnetic resonance spectroscopy (MRS) was used to detect (19)F signals from 5-FU and its metabolites. RESULTS: The intratumoral half-life (t(1/2)) of 5-FU in these tumors ranged from 18.8 minutes to 42.3 minutes. Four of the five patients exhibited increases in the t(1/2) of 5-FU after intravenous (IV) administration of MTX or IFNalpha-2a. In the two patients with gastric cancer who received IV high-dose MTX followed by IV 5-FU, increases were seen in either the total t(1/2) of 5-FU (41.8%) or in the t(1/2) of the alpha phase (150%). In the three patients with colorectal cancer who received IV IFNalpha-2a followed by IV 5-FU, the two patients with partial responses had increases in the t(1/2) of 5-FU of 41% and 30.2%, whereas the nonresponder had a nonsignificant increase (5.6%) in the t(1/2) of 5-FU. CONCLUSIONS: These results document that the in vivo modulation of the tumoral pharmacokinetics of 5-FU can be measured noninvasively by (19)F-MRS and suggest that such information correlates with subsequent clinical outcomes. The findings also indicate that IFNalpha-2a and high-dose MTX can increase the intratumoral 5-FU in some patients. Such information, obtained prospectively in vivo, may assist in better individual cancer patient management and in developing novel drug combinations.

Non-invasive 19F-NMRS of 5-fluorouracil in pharmacokinetics and pharmacodynamic studies.

Knowledge of the exact dose and rate at which an antitumor agent is delivered to its target site is postulated to be crucial to proper patient management. It is now possible to obtain such information using non-invasive 19F-NMRS (nuclear magnetic resonance spectroscopy) following the administration of 5-fluorouracil (5-FU). We have performed such studies in 103 patients with breast, colorectal and other tumors. Measurable 19F signals were detected in 99 of these patients (92.5%). Estimation of the tumoral t1/2 of 5-FU in these patients revealed that 51 of them (51.5%) exhibited a tumoral t1/2 greater than 20 min, a value we had characterized as indicating drug trapping in the tumor. Of these patients, 46 who received regimen bolus 5-FU 600 mg/m2 with leucovorin for their treatment have been evaluated. In these patients, the association between trapping and response remains very high (p<.000001). None of the non-trappers responded to chemotherapy, whereas 70% of the evaluable trappers responded. Details are presented here on the methodology of NMRS data acquisition and on their pharmacokinetic analysis. The potential mechanisms underlying the trapping effect appear to be predicated primarily on transport processes. Suggestions are presented on how such pharmacokinetic imaging studies may extend both our understanding of the mechanism of action of 5-FU, and how they could be used to optimize patient treatment.

Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small-cell lung cancer: mature results of Southwest Oncology Group phase II study 8805.

PURPOSE: To assess the feasibility of concurrent chemotherapy and irradiation (chemoRT) followed by surgery in locally advanced non-small-cell lung cancer (NSCLC) in a cooperative group setting, and to estimate response, resection rates, relapse patterns, and survival for stage subsets IIIA(N2) versus IIIB. PATIENTS AND METHODS: Biopsy proof of either positive N2 nodes (IIIAN2) or of N3 nodes or T4 primary lesions (IIIB) was required. Induction was two cycles of cisplatin and etoposide plus concurrent chest RT to 45 Gy. Resection was attempted if response or stable disease occurred. A chemoRT boost was given if either unresectable disease or positive margins or nodes was found. RESULTS: The median follow-up time for 126 eligible patients [75 stage IIIA(N2) and 51 IIIB] was 2.4 years. The objective response rate to induction was 59%, and 29% were stable. Resectability was 85% for the IIIA(N2) group eligible for surgery and 80% for the IIIB group. Reversible grade 4 toxicity occurred in 13% of patients. There were 13 treatment-related deaths (10%) and 19 others (15%) died of causes not related to toxicity or tumor. Of 65 relapses, 11% were only locoregional and 61% were only distant. There were 26 brain relapses, of which 19 were the sole site or cause of death. There was no survival difference (P = .81) between stage IIIA(N2) versus stage IIIB (median survivals, 13 and 17 months; 2-year survival rates, 37% and 39%; 3-year survival rates, 27% and 24%). The strongest predictor of long-term survival after thoracotomy was absence of tumor in the mediastinal nodes at surgery (median survivals, 30 v 10 months; 3-year survival rates, 44% v 18%; P = .0005). CONCLUSION: This trimodality approach was feasible in this Southwest Oncology Group (SWOG) study, with an encouraging 26% 3-year survival rate. An Intergroup study is currently being conducted to determine whether surgery adds more to the risk or to the benefit of chemoRT.

Association of intratumoral pharmacokinetics of fluorouracil with clinical response.

In-vivo fluorine-19 nuclear magnetic resonance spectroscopy (NMRS) allows non-invasive, real-time, chemical identification of specific fluorinated compounds inside human tumours after administration of fluorouracil (5-fluorouracil). Kinetic measures of the administered drug and metabolites allow estimation of the tumoral half-life of fluorouracil. We studied 57 patients by 19F NMRS immediately after they had received 600 mg/m2 fluorouracil intravenously. Serial spectra were acquired with the surface coil positioned on the skin above the tumour. We defined an intratumoral half-life of fluorouracil of 20 min or more as indicating trapping of the drug, based on the blood half-life of 8-12 min. 19 patients had intratumoral half-lives indicating trapping of fluorouracil, 27 had half-lives less than 20 min, and 11 had no detectable fluorouracil in their tumours. 8 of 9 evaluable patients whose tumours showed trapping had partial responses to chemotherapy that included fluorouracil compared with only 2 of 25 patients whose tumours did not trap the drug (p = 0.000021). 19F NMRS can identify patients likely to respond to chemotherapy with fluorouracil and could be used clinically to tailor optimum treatment.

Liposomal daunorubicin treatment of HIV-associated Kaposi's sarcoma.

Compared with conventional chemotherapy, use of liposomes loaded with therapeutic agents is less toxic and more effective in experimental tumours in vivo. We have assessed efficacy and toxicity of liposomal daunorubicin (40 mg/m2 every 2 weeks) in 25 patients with HIV-associated Kaposi's sarcoma of poor prognosis. In 24 evaluable patients, there were 2 complete remissions (8.3%) and 13 partial remissions (54.2%). 5 of 11 patients with doxorubicin-resistant Kaposi's sarcoma had partial remissions. Median duration of response was 12 weeks. Quality of life improved after treatment with a response rate of 71% for physical performance and 74% for emotion. Myelosuppression was the commonest adverse event. Vomiting, stomatitis, and alopecia were rare and mild. Liposomal daunorubicin is safe and effective in HIV-associated Kaposi's sarcoma and improves quality of life. The treatment is effective even in patients resistant to other chemotherapy.

Human tumor fluorouracil trapping: clinical correlations of in vivo 19F nuclear magnetic resonance spectroscopy pharmacokinetics.

We previously reported that fluorouracil (5FU) accumulation and metabolism in human livers and tumors can be studied by in vivo nuclear magnetic resonance spectroscopy (NMRS). We have extended these observations by evaluating the pharmacokinetics of 5FU in the tumors of 11 patients with carcinoma of the breast, colon, endometrium, cervix, and kidney, using 19F-NMRS in a 1.5 Magnetom (Siemens Medical Systems, Cerrito, CA) magnetic resonance imaging unit (MRI). These NMRS measurements detected a long-lived tumor pool of 5FU in six of 11 tumors in our patients including carcinomas in the pelvis, breast, lung, and liver. The half-life (T1/2) of this tumor pool of "trapped" 5FU was 0.33 to 1.3 hours (20 to 78 minutes), much longer than the T1/2 of 5FU in blood (5 to 15 minutes). Neither the anabolites of 5FU (fluorinated nucleosides, nucleotides, 5FU-RNA, or 5FU-thymidylate synthase) nor the catabolites (eg, fluorobetaalanine [FBAL]) were detectable by 19F NMRS. Patient response to chemotherapy appeared to correlate with the extent of trapping of free 5FU in the human tumors: in the seven patients receiving 5FU, or 5FU or FUdR plus leucovorin, four of four patients whose tumors trapped 5FU responded to fluorinated pyrimidine chemotherapy, whereas three patients in whom there was a failure to detect tumor trapping were resistant to 5FU. We conclude that NMRS is clinically feasible, and enables investigators to study 5FU pharmacokinetics and metabolism in tumors in vivo. 19F-NMRS of 5FU allows for in vivo evaluation of 5FU metabolic modulation and might be able to guide therapeutic decisions.

Preliminary report: imaging of Kaposi sarcoma and lymphoma in AIDS with indium-111-labelled liposomes.

Kaposi sarcoma and malignant lymphoma were successfully imaged with high purity liposomes containing indium-111 in two patients with AIDS. Gamma camera images of the patient with Kaposi sarcoma showed four discrete lesions along the left foot and calf with no foci along the right foot, and no uptake into clinically enlarged but non-neoplastic lymph nodes. The spread of the Kaposi sarcoma was proximal along the leg. The neoplastic cervical lymph nodes in the second patient who had large-cell diffuse intermediate grade lymphoma were also imaged successfully. Since Kaposi sarcoma and lymphoma frequently involve occult sites, liposome imaging may prove useful in the diagnosis and management of these diseases.

Tumor trapping of 5-fluorouracil: in vivo 19F NMR spectroscopic pharmacokinetics in tumor-bearing humans and rabbits.

The pharmacokinetics of 5-fluorouracil (5FU) were studied in vivo in patients with discrete tumors and in rabbits bearing VX2 tumors by using 19F NMR spectroscopy. The human studies were conducted in a 1.5-T Magnetom magnetic resonance imager (Siemens), and the rabbit studies were conducted in a 4.7-T GE/Nicolet 33-cm bore magnet. Free 5FU was detected in the tumors of four of the six patients and in all VX2 tumors but not in normal rabbit tissues. No other metabolites were seen in these tumors, contrary to the extensive catabolism we had previously documented using 19F NMR spectroscopy in both human and animal livers. The tumor pool of free 5FU in those human tumors that trapped 5FU was determined to have a half-life of 0.4-2.1 hr, much longer than expected and significantly longer than the half-life of 5FU in blood (5-15 min), whereas the half-life of trapped 5FU in the VX2 tumors ranged from 1.05 to 1.22 hr. In this initial experience, patient response to chemotherapy may correlate with extent of trapping free 5FU in the human tumors. These studies document that NMR spectroscopy is clinically feasible in vivo, allows noninvasive pharmacokinetic analyses at a drug-target tissue in real time, and may produce therapeutically important information at the time of drug administration. Demonstration of the trapping of 5FU in tumors provides both a model for studying metabolic modulation in experimental tumors (in animals) and a method for testing modulation strategies clinically (in patients).

Clinical responses with active specific intralymphatic immunotherapy for cancer--a phase I-II trial.

We evaluated the method of active specific intralymphatic immunization to treat cancer in 32 patients with various tumor types as part of a broad-based phase I-II evaluation and describe the results of 3 sequential series. In series 1, the patients (n = 13) received 2 or more injections of autologous, cryopreserved, irradiated tumor cells directly into the lymphatic system through the cannulation of a dorsal pedal lymphatic channel. In series 2, the patients (n = 7) received low-dose cyclophosphamide, 300 mg per m2, 3 days before the autologous cell vaccine was administered. Series 3 (12 patients) was similar to series 2 except that the tumor cells were treated with cholesteryl hemisuccinate immediately before irradiation. Patients received from 2 to 6 injections of cells, depending on availability, at 2-week intervals. In all, 91 treatments are evaluated in this study. Clinical responses occurred in 7 of the 32 patients and were seen in all 3 series with about the same frequency. These responses occurred in cases of melanoma, lung cancer, colon cancer, and sarcoma. Regressions occurred in both visceral and subcutaneous sites. There was little toxicity, the chief side effect being local discomfort or inflammation. This experience indicates that active specific intralymphatic immunotherapy is safe, produces antitumor effects, and requires more investigation to increase the frequency and duration of observable tumor regression.

Successful imaging of human cancer with indium-111-labeled phospholipid vesicles.

Twenty-four patients with proven primary and/or metastatic cancer received single intravenous injections of phospholipid vesicles containing 0.5 mCi of Indium-111. Gamma camera scintigraphy 1 to 72 hours later visualized tumors in 22 patients (92%), including carcinomas of breast, lung, colon, prostate, kidney, cervix, thyroid, and soft tissue sarcoma, lymphoma, and melanoma. Tumor sites that were identified included soft tissues, bone, lung, liver, lymph node, and spinal cord. There were only two false-positive images in metastatic sites and four false-negative images in metastatic sites. Overall sensitivity for tumors in 97 individual sites was 85%, whereas specificity was 96%. Unsuspected areas of malignancy were seen in the lumbar subdural space, pleura, liver, thyroid, and lung. Besides tumor accumulations, homogeneous uptake was observed in normal liver and spleen. Radiation doses to these two organs were 2.2 and 2.9 cGy/0.5 mCi In-111, respectively. Whole body radiation dose was 0.3 cGy/0.5 mCi. The use of Indium-111-labeled vesicles permits a wide variety of human tumors in primary and metastatic sites to be imaged without toxicity and with radiation doses comparable to other radionuclide scanning techniques.

In-111-labeled liposomes: dosimetry and tumor depiction.

Neutral phospholipid vesicles (liposomes) were loaded with 0.5 mCi (18.5 MBq) indium-111 and administered to 24 patients with various types of cancer. The median diameter of the liposomes was 77 nm, and lipid dose was 0.78-6.25 mg/kg. Scans obtained 24 and 48 hours after injection of In-111 liposomes showed gradual blood clearance with homogeneous uptake in the normal liver and spleen. Dosimetric estimates for these organs were 2.3 +/- 1.1 and 2.3 +/- 1.4 rad (.02 +/- .01 Gy), respectively, with a whole-body estimate of 0.28 rad (.003 Gy). Radiation dose did not correlate with lipid dose. Total renal excretion of In-111 was less than 2% of the injected dose in all but two patients. Transient eosinophilia occurred in two patients. Tumor was seen in the scans of 22 of 24 patients (unbinded readings). In-111-labeled liposomes may enable the demonstration of suspected or unsuspected sites of tumor.