Geriatric Assessment and Functional Decline in Older Patients with Lung Cancer.

PURPOSE: Older patients with lung cancer are a heterogeneous population making treatment decisions complex. This study aims to evaluate the value of geriatric assessment (GA) as well as the evolution of functional status (FS) in older patients with lung cancer, and to identify predictors associated with functional decline and overall survival (OS). METHODS: At baseline, GA was performed in patients ≥70 years with newly diagnosed lung cancer. FS measured by activities of daily living (ADL) and instrumental activities of daily living (IADL) was reassessed at follow-up to define functional decline and OS was collected. Predictors for functional decline and OS were determined. RESULTS: Two hundred and forty-five patients were included in this study. At baseline, GA deficiencies were present in all domains and ADL and IADL were impaired in 51 and 63% of patients, respectively. At follow-up, functional decline in ADL was observed in 23% and in IADL in 45% of patients. In multivariable analysis, radiotherapy was predictive for ADL decline. No other predictors for ADL or IADL decline were identified. Stage and baseline performance status were predictive for OS. CONCLUSIONS: Older patients with lung cancer present with multiple deficiencies covering all geriatric domains. During treatment, functional decline is observed in almost half of the patients. None of the specific domains of the GA were predictive for functional decline or survival, probably because of the high impact of the aggressiveness of this tumor type leading to a poor prognosis.

Phase II study of stereotactic body radiotherapy to primary tumor and metastatic locations in oligometastatic nonsmall-cell lung cancer patients.

BACKGROUND: Stereotactic body radiotherapy (SBRT) has emerged as a treatment modality in patients presenting with oligometastatic nonsmall-cell lung cancer (NSCLC). SBRT is used as a local consolidative treatment to metastatic disease sites. The majority of patients included in SBRT trials for oligometastatic NSCLC have controlled primary tumors and brain metastases. PATIENTS AND METHODS: Oligometastatic NSCLC patients with ≤5 metastatic lesions were included in a prospective phase II trial to evaluate efficacy and toxicity of SBRT to all disease sites, primary tumor and metastatic locations. SBRT to a dose of 50 Gy in 10 fractions was delivered. Positron emission tomography-computed tomography (PET-CT) was carried out at baseline and 3 months after SBRT to evaluate the metabolic response rate according to PET Response Criteria in Solid Tumors (PERCIST). The progression-free survival (PFS) and overall survival (OS) were calculated using Kaplan-Meier method from start of chemotherapy or radiotherapy. Side-effects were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. RESULTS: Twenty-six patients received SBRT after induction chemotherapy (n = 17) or as a primary treatment (n = 9). Median follow-up was 16.4 months. Overall metabolic response rate was 60% with seven patients (30%) achieving a complete metabolic remission and 7 (30%) a partial metabolic response. Any acute grade 2 toxicity was observed in four patients (15%) and grade 3 pulmonary toxicity in two patients (8%). Median PFS and OS were 11.2 and 23 months. The 1-year PFS and 1-year OS rate were 45% and 67%, respectively. CONCLUSION: SBRT to all disease sites, primary tumor and metastatic locations, in oligometastatic NSCLC patients produced an acceptable median PFS of 11.2 months.

Zoledronic acid in patients with stage IIIA/B NSCLC: results of a randomized, phase III study.

BACKGROUND: Bone metastases are common in patients with advanced non-small-cell lung cancer (NSCLC) and can have devastating consequences. Preventing or delaying bone metastases may improve outcomes. PATIENTS AND METHODS: This study evaluated whether zoledronic acid (ZOL) delayed disease progression or recurrence in patients with controlled stage IIIA/B NSCLC after first-line therapy. Patients received vitamin D and calcium supplementation and were randomized to i.v. ZOL (every 3-4 weeks) or no treatment (control). The primary end point was progression-free survival (PFS). RESULTS: No significant intergroup differences were observed in PFS or overall survival (OS). Median PFS was 9.0 months with ZOL versus 11.3 months for control. Fifteen ZOL-treated (6.6%) and 19 control patients (9.0%) developed bone metastases. Estimated 1-year OS was 81.8% for each group. ZOL safety profile was consistent with previous clinical data, but with higher discontinuations versus control. Fifteen ZOL-treated (6.6%) and five control patients (2.3%) had renal adverse events. Two cases of osteonecrosis of the jaw were reported. CONCLUSIONS: ZOL did not significantly affect PFS or OS in stage IIIA/B NSCLC patients with controlled disease, with a trend toward worsening PFS in the longer-term follow-up. Few patients experienced bone metastases, possibly limiting the potential ZOL impact on disease course.

Changing preferences for information and participation in the last phase of life: a longitudinal study among newly diagnosed advanced lung cancer patients.

PURPOSE: The objective is to explore changes over time in the information and participation preferences of newly diagnosed stage IIIb/IV non-small-cell lung cancer patients. METHODS: Patients were recruited by physicians in 13 hospitals and interviewed every 2 months until the fourth and every 4 months until the sixth interview. RESULTS: Sixty-seven patients were interviewed three times. Over a period of 4 months from diagnosis, half of patients changed their information preferences for palliative care and end-of-life decisions with a possible or certain life-shortening effect (ELDs, e.g., non-treatment decisions) in both directions, from not wanting to wanting the information, but also--and as much--from wanting to no longer wanting it. The latter were more likely to be in a better physical condition. Preferences for participation in medical decision making also changed: 50% to 78%, depending on the type of decision (general, treatment, transfer or ELD), changed their preference towards wanting more or less participation. Pain seemed to be a trigger for patients wanting more involvement, which contrasts with studies suggesting that patients who are more ill tend to give up more control. CONCLUSIONS: Doctors should regularly ask their advanced lung cancer patients how much information and participation they want because preferences do change in unexpected ways.

Complete metabolic tumour response, assessed by 18-fluorodeoxyglucose positron emission tomography (18FDG-PET), after induction chemotherapy predicts a favourable outcome in patients with locally advanced non-small cell lung cancer (NSCLC).

BACKGROUND: 18FDG-PET and multislice computerized axial tomography (CT) scan are used for diagnosis, staging and response evaluation in NSCLC patients. The correlation between the response assessment by both imaging techniques and survival was assessed in patients with unresectable stage III NSCLC treated with induction chemotherapy followed by consolidation radiotherapy. METHODS: Thirty-one patients, enrolled in a phase II study evaluating the efficacy and toxicity of a novel triplet induction chemotherapy (paclitaxel, carboplatin and gemcitabine) (PACCAGE) before consolidation radiotherapy, were evaluated by CT and 18FDG-PET at baseline and after three cycles of chemotherapy. The correlation between CT and 18FDG-PET response and time to progression and overall survival was analyzed using the Kaplan-Meier estimates of survival and the log rank test. RESULTS: Ten patients with a complete response (CR) on 18FDG-PET had a significantly longer time to progression and overall survival than patients with a non-CR (median 19.9 months versus 9.8 months, p=0.026, and median >49 months versus 14.4 months, p=0.004, respectively). Twenty patients with a partial CT response (PR) had a significantly longer time to progression (median 15 months versus 9.4 months, p=0.001) than patients with a non-PR but the difference in overall survival only showed a trend (23.3 months versus 14.4 months, p=0.093). CONCLUSIONS: A CR on 18FDG-PET following induction chemotherapy for locally advanced, unresectable NSCLC seems to be a more powerful prognostic marker for survival compared to PR on CT.

Tolerance of adjuvant letrozole outside of clinical trials.

Recently aromatase inhibitors have become a standard care as an adjuvant treatment for many postmenopausal patients with hormone receptor positive early breast cancer. Adjuvant letrozole was made available either immediately postoperative, after 2-3 years of tamoxifen, or as an extended treatment after 5 years of tamoxifen. Between October 2003 and October 2005, we analyzed the subjective tolerance in 185 postoperative early breast cancer patients receiving letrozole outside of a clinical trial. The most prominent toxicity was musculoskeletal pain. In addition hot flushes, increased fatigue, nausea, vomiting, anorexia, mood disturbances, vaginal dryness, hair loss and rash were also recorded. In contrast to the prospective randomized clinical trials, a high drop-out rate of 20% was documented, mainly due to aromatase inhibitor-associated arthralgia syndrome interfering significantly with the daily life of our patients. Although adjuvant aromatase inhibitors have proven to be generally superior to tamoxifen in the adjuvant setting, it is important to focus attention on the tolerance during the adjuvant therapy and to balance this against the potential benefit in individual patients. Alternative options including switching to tamoxifen remain available.

The Relationship between a New Biomarker of Vagal Neuroimmunomodulation and Survival in Two Fatal Cancers.

BACKGROUND: The vagus nerve may slow tumor progression because it inhibits inflammation. This study examined the relationship between a new vagal neuroimmunomodulation (NIM) index and survival in fatal cancers. METHOD: We retroactively derived markers of vagal nerve activity indexed by heart rate variability (HRV), specifically the root mean square of successive differences (RMSSD), from patients' electrocardiograms near diagnosis. The NIM index was the ratio of RMSSD to C-reactive protein levels (RMSSD/CRP). Sample 1 included 202 Belgian patients with advanced pancreatic cancer (PC), while sample 2 included 71 Belgian patients with non-small cell lung cancer (NSCLC). In both samples, we examined the overall survival, while in sample 2, we additionally examined the survival time in deceased patients. RESULTS: In PC patients, in a multivariate Cox regression controlling for confounders, the NIM index had a protective relative risk (RR) of 0.68 and 95% confidence interval (95% CI) of 0.51-0.92. In NSCLC patients, the NIM index also had a protective RR of 0.53 and 95% CI of 0.32-0.88. Finally, in NSCLC, patients with a higher NIM index survived more days (475.2) than those with lower NIM (285.1) (p < 0.05). CONCLUSIONS: The NIM index, reflecting vagal modulation of inflammation, may be a new independent prognostic biomarker in fatal cancers.

A novel triplet regimen with paclitaxel, carboplatin and gemcitabine (PACCAGE) as induction chemotherapy for locally advanced unresectable non small cell lung cancer (NSCLC).

UNLABELLED: Phase II study of 3 cycles of triplet induction chemotherapy (response, toxicity) followed by radiotherapy in locally advanced non small cell lung cancer (NSCLC). BACKGROUND: Patients with locally advanced inoperable non-small cell lung cancer are currently treated with concomitant or sequential chemotherapy and radiotherapy. However, the outcome of existing treatment modalities is unsatisfactory. Development of new strategies including more efficient systemic chemotherapy is warranted. OBJECTIVE: To study the antitumour activity and toxicity of a triplet combination of paclitaxel, carboplatin and gemcitabine as induction chemotherapy before radiotherapy, in locally advanced NSCLC and to evaluate time to progression and survival. METHODS: Three cycles of paclitaxel (175 mg/m(2) by 3h infusion on day 1), carboplatin (AUC 5mg/(mlmin) by IV bolus on day 1) and gemcitabine (1000 mg/m(2) by IV bolus on day 1 and 8) were administered every 3 weeks in reasonably fit patients. Fractionated radiotherapy with curative intent was initiated 4 weeks after the last chemotherapy administration. Toxicity was assessed weekly during cycle 1 and on day 1 and 8 in cycles 2 and 3. Response evaluation was performed at the end of cycle 3. RESULTS: Forty-eight patients (20 stage IIIA and 28 stage IIIB) received a total of 134 cycles of chemotherapy. Forty-two patients received the intended 3 cycles. Thirty patients obtained an objective response (1 complete and 29 partial response) or 62.5% on the intent to treat analysis (95% confidence interval: 49-76%). None of the responders became eligible for surgery. The median time to progression and survival for all patients was 10.1 and 15.7 month, respectively. A significant difference was observed in survival parameters between stage IIIA and stage IIIB patients. Haematological toxicity grade 3/4, mainly neutropenia and thrombocytopenia, was most prominent on day 15 of the treatment cycles. Haematological support by means of recombinant erythropoietin, red blood cell or platelet transfusion, filgrastim administration or a combination was needed in 21 patients. None of the patients discontinued chemotherapy because of haematotoxicity. Grade 3/4 non-haematological toxicity leading to chemotherapy withdrawal occurred early during induction (2 and 1 in cycles 1 and 2, respectively). CONCLUSION: Three cycles of the novel triplet combination of paclitaxel, carboplatin and gemcitabine (PACCAGE) is an active and feasible induction regimen for patients with locally advanced inoperable NSCLC. Neutropenia and to a lesser extent thrombocytopenia represent the main haematological toxicity. Whether this triplet regimen can improve outcome when compared to specific cisplatin doublet regimens should be evaluated in a phase III study.

Modification of cell surface carbohydrates and invasive behavior by an alkyl lysophospholipid.

The effect of the alkyl lysophospholipid racemic-1-O-octadecyl-2-O-methyl glycero-3-phosphocholine on the expression of cell surface carbohydrates of four matched pairs of normal and malignant cells was studied using chromatographic techniques. After treatment with alkyl lysophospholipid, glycopeptides proteolytically derived from normal and malignant cells displayed a shift in the size distribution profiles obtained by gel filtration. These drug-induced changes in molecular weight distribution were expressed most strongly in untransformed cells and resembled the carbohydrate alterations found after their malignant transformation. Desialylation abolished the effect of alkyl lysophospholipid, thus suggesting an increased amount of sialic acid in the surface carbohydrates of drug-treated cells. Chromatography of glycopeptides on concanavalin A-Sepharose, Ricinus communis agglutinin I-agarose, and Bio-Gel P-4 columns excluded a higher degree of branching but suggested addition of extra terminal sialic acid residues as the major cause of the observed alterations. Alkyl lysophospholipid stimulated glycoprotein sialylation of normal cells to the level observed in malignant cells, thus inducing a "malignant-like" surface phenotype. The drug-induced carbohydrate changes in normal chick heart tissue prevented its being invaded by tumor cells when tested in an organotypic assay. The alkyl lysophospholipid thus appears to modulate in a nontoxic fashion the expression of surface molecules implicated in various cellular interactions including invasiveness.

Effect of cancer-related and drug-induced alterations in surface carbohydrates on the invasive capacity of mouse and rat cells.

The effect of alterations in cell surface carbohydrates on invasion of mouse and rat cells into embryonic chick heart fragments in organ culture was studied. Matching pairs of malignant and nonmalignant cells, including all categories of carcinogenic induction (i.e., viral, chemical, or oncogenic), were compared for their alterations in cell surface carbohydrates and invasive behavior. Glycopeptides derived from the surface of malignant cells expressed cancer-related changes in carbohydrate composition, demonstrated by gel filtration chromatography as a shift in size distribution in comparison with those from nonmalignant counterparts. This phenotypic property strictly correlated with the acquisition of the invasive capacity. Morphological transformation of cells without simultaneous alteration in surface carbohydrates was, however, insufficient for invasion. To test the possible mechanistic role of altered surface carbohydrates in the invasive capacity of cells, the surface molecules of noninvasive cells were modified by incubation with an alkyl-lysophospholipid (racemic 1-O-octadecyl-2-O-methyl glycero-3-phosphocholine). Alkyl-lysophospholipid induced an increase in surface sialylation resembling the changes found in malignant and invasive cells. After pretreatment with alkyl-lysophospholipid, morphologically transformed but nonmalignant and noninvasive cells became able to invade chick heart tissue. These findings indicate that alterations in cell surface carbohydrates, induced by entirely different mechanisms, endowed cells with invasive capacity.

Sequential administration of epirubicin and paclitaxel for advanced breast cancer. A phase I randomised trial.

Forty-six previously untreated patients with advanced breast cancer were eligible for the present randomised phase I study. It aimed to evaluate the toxicity and activity of a therapeutic sequence with epirubicin on day 1 followed by paclitaxel on day 2 (sequence A) or the reverse sequence, ie., paclitaxel on day 1 followed by epirubicin on day 2 (sequence B). The starting doses of epirubicin and paclitaxel, administered either according to sequence A or B, (level 1 cohort) were 90 mg/m2 and 175 mg/m2, respectively. Per cohort of 3 patients, the dose of paclitaxel was increased by 25 mg/m2 (levels 2 and 4) and of epirubicin by 10 mg/m2 (levels 3 and 5). Treatment was repeated with 3-week intervals. The maximal tolerated dose (MTD) was achieved at level 1 in sequence B (paclitaxel first) and level 3 (epirubicin 100 mg/m2 followed by paclitaxel 200 mg m2) in sequence A. Dose limiting toxicity (DLT) was neutropenia (+/- febrile) in both sequences. Cardiac events occurred in 28% of the patients; significant decrease in left ventricular ejection function (LVEF) was observed in 8/33 and in 2/13 patients in sequence A and B, respectively. This was associated with 5 and 1 cardiac heart failure (CHF), respectively. In 43 evaluable patients, 10 CR and 25 PR were observed (overall response rate 81%). In the 20 patients with locally advanced disease (LABC), the respective numbers were 7 CR and 11 PR; in the 23 metastatic (MBC) patients, 3 CR and 14 PR were recorded. The median survival of the both groups was not reached at 33 + months. In conclusion , the combination of epirubicin and paclitaxel has significant activity in breast cancer. The recommended sequence of both drugs in combination therapy, mainly to avoid neutropenia, is epirubicin day 1 followed by paclitaxel on day 2. Cardiac toxicity remains problematic in either sequence of administration.

Role of the host tissue in the anti-invasive activity of the alkyllysophospholipid, ET-18-OCH3, in vitro.

The alkyllysophospholipid, racemic-l-O-octadecyl-2-O-methylglycero-3- phosphocholine (ET-18-OCH3) was previously shown to inhibit invasion of malignant cells into precultured heart fragments (PHF) in vitro. In particular, pretreatment of PHF with 10 micrograms ET-18-OCH3 for 48 h was sufficient to induce in the host tissue resistance towards invasion by mouse MO4 cells. Resistance was obvious when MO4 cells were confronted either immediately (the pretreatment experiment) or after withdrawal of the drug 7 days prior to confrontation (the reversibility experiment). In the present study, the survival of PHF cells in the pretreatment and reversibility experiments was similar to that of untreated PHF cells as determined by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) test and by the PHF explantation test. The effective anti-invasive concentration was 6 micrograms/ml in the pretreatment experiment while 3 micrograms/ml was sufficient to inhibit invasion in the reversibility experiment. Induction of resistance towards invasion in pretreated PHF was shown to occur not only with MO4 cells but also with mouse LLC-H61 Lewis lung carcinoma and mouse BW-O-Li1 T-lymphoma cells. The increase in molecular weight of N-linked cell surface glycosylpeptides (N-GP) of PHF was apparent in the pretreatment experiment and was enhanced in the reversibility experiment. This effect was completely abolished in cells obtained from pretreated PHF which were converted into a cell suspension and further cultured as a monolayer on tissue culture plastic without drug for 7 days. The results reported here provide additional evidence for the causal involvement of N-GP of the PHF host tissue in the anti-invasive activity of ET-18-OCH3 in vitro.

Is adjuvant treatment with vinblastine effective in reducing the occurrence of distant metastasis in limited squamous cell lung cancer? A randomized study.

In order to study the usefulness of treatment with vinblastine (VLB) in the prevention of cancer metastasis in squamous cell lung cancer, 50 patients with locoregional disease were randomized to receive either locoregional RT alone (group A) or a weekly intravenous bolus injection of VLB (6 mg/m2) concurrently with and after locoregional radiotherapy (RT) (55 Gy in 6 weeks) until the appearance of metastases (group B). Neither the incidence of death with metastases, metastasis-free survival (MFS) nor overall survival (S) were significantly affected by treatment with the drug. However, due to the limited number of patients in each group, the power of the statistical test was such to allow only the detection of differences in MFS and S to or more than 80 per cent at the P = 0.05 level. Local tumor response was significantly superior in group B (P less than 0.05). Acute toxicity (dysphagia, myelosuppression) during RT was significantly worse in group B. During long-term therapy with VLB, mild polyneuropathy developed in the majority of patients in group B. Furthermore, seven patients discontinued treatment with VLB during maintenance due to compliance (4) and excessive neurotoxicity (3). This treatment schedule with VLB is not recommended for patients with locoregional squamous cell lung cancer as significant toxicity is present during and after RT and significant increase in MFS and S is lacking. Because of an apparent increase in local response, the combination of VLB and RT merits further investigation in those tumors where local tumor control is crucial.

Decreased fucose incorporation in cell surface carbohydrates is associated with inhibition of invasion.

Invasion of malignant MO4 cells into embryonic chick heart fragments in an organ culture assay was arrested for at least 7 days when the temperature was lowered to 28 degrees C. Prolonged culturing of MO4 cells at 28 degrees C on tissue culture substrates showed no recuperation of fucose incorporation into cell surface glycopeptides. However, invasion was restored after 10 days of organ culture in confrontation with chick heart tissue at 28 degrees C. A histoautoradiographic study showed that the regained capability to invade was accompanied by an increase in fucose labeling of the MO4 cells in the invading areas. At 28 degrees C the incorporation of [3H]fucose into total cell protein was drastically reduced, whereas [3H]leucine incorporation as a measure for protein synthesis was less affected. Cell surface glycopeptides, metabolically labeled with either fucose or glucosamine at 28 degrees C, showed a time-dependent decrease in the incorporation of fucose but not of glucosamine and no changes in overall size distribution. Low temperature did not reduce fucosyltransferase activity but the relative accumulation of fucose-1-P suggested inhibited conversion towards GDP-fucose. Moreover, mouse L cells which were incapable of invading chick heart tissue appeared also deficient in fucose incorporation, owing to low levels of fucosyltransferase activity. According to the results, fucosylation of surface carbohydrates may be required for invasive capacity and restored in MO4 cells invading at 28 degrees C by metabolic cooperation with the host tissue.

Evidence for abrogation of oncogene-induced radioresistance of mammary cancer cells by hexadecylphosphocholine in vitro.

Hexadecylphosphocholine (HePC), an experimental and clinical antitumour agent of the alkyllysophospholipid group, was tested for its radiosensitising effect on a panel of nine human mammary cancer cell lines in vitro. Growth inhibition by ionising radiation and recovery from it were not influenced by pretreatment with HePC in most cases, except for two cell lines expressing an activated ras oncogene. In the latter we found an enhanced radioresistance that was abolished by pretreatment with HePC. Our results suggest that HePC may act as a radiosensitiser for cells carrying an activated ras oncogene.

Additive pulmonary toxicity with melphalan and busulfan therapy.

We report a 59-year-old patient with chronic myeloid leukemia, who developed severe interstitial lung fibrosis after short term and sequential treatment with melphalan and busulfan. The probable additive toxicity of both agents on the pulmonary tissue is discussed.

Methylprednisolone as an antiemetic drug. A randomised double blind study.

To evaluate the antiemetic efficacy of high-dose methylprednisolone (MP) in previously untreated cancer patients receiving cisplatin (CPDD) for the first time, we performed a randomized double blind study. MP or a placebo (PLB) was administered six times during each course of chemotherapy. The first dose was 500 mg and all others, 250 mg. A total of 30 patients were included and studied during three chemotherapy courses. No significant differences were found between the MP- and PLB-treated group with respect to the number of emetic episodes and degree of nausea. There was also no difference for pain, appetite, nausea, vomiting, sleep, weakness, or energy level as analyzed by the use of a Linear Analog Self-Assessment (LASA) scale up to 7 days after chemotherapy. On the other hand, the assessment of well-being, anxiety, and mood favored the PLB group. We conclude that high-dose MP used as a single antiemetic medication against CPDD-induced nausea and vomiting is of only limited value or none at all.

The effect of pentagastrin on the directional migration of colon adenocarcinoma cells in vitro.

The centrifugal spreading of multicellular aggregates from a DMH induced colon adenocarcinoma cell line from rats was observed in vitro. Various concentrations of pentagastrin were added to the culture medium. Controls included medium alone or culture medium containing different concentrations of either NH4OH or NaOH that were needed to dissolve the pentagastrin. The migration index, the total surface area occupied by the cells after 7 days, and the cell density of the culture were measured. Using 10 micrograms/ml of pentagastrin, the migration idex and the area covered by the cells were increased (P less than 0.01) while the cell density was not. Inhibition of cell division through addition of 5 fluoro-uracil to the culture medium abolished the stimulating effect of pentagastrin although the centrifugal migration was not suppressed by the antimetabolite. These data indicate that a supraphysiological concentration of pentagastrin can stimulate the spreading of colon cancer cell aggregates in vitro by enhanced proliferation.

Ambulatory combination chemotherapy with oral etoposide and cisplatin for advanced non small cell lung carcinoma patients. A phase II study.

Thirty nine male patients with locally advanced and/or extensive non small cell lung cancer (NSCLC) were treated with oral etoposide (240 mg/m2 days 1 to 3) and cisplatin (100 mg/m2 day 4) according to a fully ambulatory schedule. Eight out of 33 (24%) evaluable patients achieved a partial response (PR) and 6 a minor response (MR). Stable disease (SD) was observed in 7 (25%) and progressive disease (P.D.) in 12 (26%). Median survival time (MST) of all patients was 8 months. No difference in MST was observed between limited (LD) and extensive disease (ED) patients. Only overall responding patients (PR + MR + SD) in the E.D. subgroup lived significantly longer than PD patients. Patients with LD did not obtain a significant survival benefit whether or not a response was achieved. The overall toxic cost of the regimen was low and patient tolerance remarkably good. This combination chemotherapy can safely be recommended for ambulatory use and does not seem to compromise heavily the patients' quality of life.

Antiinvasive activity of hexadecylphosphocholine in vitro.

The antiinvasive and related effects of hexadecylphosphocholine (HePC), a newly synthesized antitumor phospholipid, were studied on malignant murine MO4 cells in vitro and compared to the effects produced by racemic - 1 - 0 - octadecyl - 2 - 0 - methylglycero - 3 - phosphocholine (ET-18-OCH3), the prototype of ether lipids. The effects on cell survival produced by both drugs, determined through the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium-bromide test, was moderate at the antiinvasive concentration of 30 micrograms for HePC and 10 micrograms for ET-18-OCH3 per ml. Growth in suspension culture and directional migration from MO4 spheroids explanted on solid substrate was reduced in the presence of 30 micrograms HePC per ml. Invasion of MO4 cells into precultured heart fragments (PHF) was variably inhibited in the presence of 30 micrograms HePC per ml, while the antiinvasive effect on two epithelial lines was more complete. Invasion was also inhibited in PHF pretreated with 30 micrograms HePC and 10 micrograms ET-18-OCH3 per ml for 48 hours followed by confrontation with MO4 spheroids in drug-free medium. This inhibition of invasion was maintained when PHF was pretreated and kept in drug-free medium for 7 days before confrontation with MO4 spheroids. It was our impression that this phenomenon was more obvious with ET-18-OCH3 than with HePC. After pretreatment of PHF followed by 7-day incubation in drug free-medium, a larger shift towards higher molecular weight of the N-linked cell surface glycosylpeptides (N-GP) was observed with ET-18-OCH3 than with HePC. Removal of terminal sialic acid moieties abolished the shift in PHF pretreated with HePC or ET-18-OCH3 followed or not by further incubation in drug-free medium. The antiinvasive effect on the malignant epithelial cells was complete at 30 micrograms HePC per ml. Areas of differentiation in close contact with the PHF were obvious. We concluded that both ET-18-OCH3 and HePC had antiinvasive activity in vitro. For MO4 cells, this antiinvasive activity was less variable with ET-18-OCH3 than with HePC.