Association of the advanced lung cancer inflammation index (ALI) with immune checkpoint inhibitor efficacy in patients with advanced non-small-cell lung cancer.

BACKGROUND: The advanced lung cancer inflammation index [ALI: body mass index × serum albumin/neutrophil-to-lymphocyte ratio (NLR)] reflects systemic host inflammation, and is easily reproducible. We hypothesized that ALI could assist guidance of non-small-cell lung cancer (NSCLC) treatment with immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: This retrospective study included 672 stage IV NSCLC patients treated with programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy in 25 centers in Greece and Germany, and a control cohort of 444 stage IV NSCLC patients treated with platinum-based chemotherapy without subsequent targeted or immunotherapy drugs. The association of clinical outcomes with biomarkers was analyzed with Cox regression models, including cross-validation by calculation of the Harrell's C-index. RESULTS: High ALI values (>18) were significantly associated with longer overall survival (OS) for patients receiving ICI monotherapy [hazard ratio (HR) = 0.402, P < 0.0001, n = 460], but not chemo-immunotherapy (HR = 0.624, P = 0.111, n = 212). Similar positive correlations for ALI were observed for objective response rate (36% versus 24%, P = 0.008) and time-on-treatment (HR = 0.52, P < 0.001), in case of ICI monotherapy only. In the control cohort of chemotherapy, the association between ALI and OS was weaker (HR = 0.694, P = 0.0002), and showed a significant interaction with the type of treatment (ICI monotherapy versus chemotherapy, P < 0.0001) upon combined analysis of the two cohorts. In multivariate analysis, ALI had a stronger predictive effect than NLR, PD-L1 tumor proportion score, lung immune prognostic index, and EPSILoN scores. Among patients with PD-L1 tumor proportion score ≥50% receiving first-line ICI monotherapy, a high ALI score >18 identified a subset with longer OS and time-on-treatment (median 35 and 16 months, respectively), similar to these under chemo-immunotherapy. CONCLUSIONS: The ALI score is a powerful prognostic and predictive biomarker for patients with advanced NSCLC treated with PD-L1 inhibitors alone, but not in combination with chemotherapy. Its association with outcomes appears to be stronger than that of other widely used parameters. For PD-L1-high patients, an ALI score >18 could assist the selection of cases that do not need addition of chemotherapy.

The development of a virtual reality training programme for ophthalmology: repeatability and reproducibility (part of the International Forum for Ophthalmic Simulation Studies).

PURPOSE: To evaluate the variability of performance among novice ophthalmic trainees in a range of repeated tasks using the Eyesi virtual reality (VR) simulator. METHODS: Eighteen subjects undertook three attempts of five cataract specific and generic three-dimensional tasks: continuous curvilinear capsulorhexis, cracking and chopping, cataract navigation, bimanual cataract training, anti-tremor. Scores for each attempt were out of a maximum of 100 points. A non-parametric test was used to analyse the data, where a P-value of <0.05 was considered statistically significant. RESULTS: Highly significant differences were found between the scores achieved in the first attempt and that during the second (P<0.0001) and third (P<0.0001) but not between the second and third attempt (P=0.65). There was no significant variability in the overall score between the users (P=0.1104) or in the difference between their highest and lowest score (P=0.3878). Highly significant differences between tasks were shown both in the overall score (P=0.0001) and in the difference between highest and lowest score (P=0.003). CONCLUSION: This study, which is the first to quantify reproducibility of performance in entry level trainees using a VR tool, demonstrated significant intra-novice variability. The cohort of subjects performed equally overall in the range of tasks (no inter-novice variability) but each showed that performance varies significantly with the complexity of the task when using this high-fidelity instrument.

Sutureless and glue-free conjunctival autograft in pterygium surgery: a case series.

AIMS: Foreign materials used in ocular surface surgery may lead to local complications such as discomfort, scarring, or infection. Plasma-derived products such as fibrin glue may produce possible hypersensitivity reactions whereas the risk of viral transmission remains. We describe a simple method of achieving conjunctival autograft adherence during pterygium surgery avoiding potential complications associated with the use of fibrin glue or sutures. METHODS: After pterygium excision and fashioning of the autologous conjunctival graft, the recipient bed is encouraged to achieve natural haemostasis and relative dessication before graft placement. Excessive haemorrhage in the graft bed is tamponaded. Graft adherence and positioning is examined 20 min after surgery. RESULTS: A total of 15 eyes of 12 patients (mean (SD) age 73.7 (11.2) years), 8 females underwent SGF autologous conjunctival graft post-pterygium excision. Mean graft area was 24(1.5)mm(2). Mean follow-up time was 9.2 (2.2) months. Cosmesis was excellent in all cases and visual acuity improved in one patient. There were no intra- or post-operative complications requiring further treatment. CONCLUSION: This simple technique for pterygium surgery may prevent potential adverse reactions encountered with the use of foreign materials and in this small series provided safe and comparable results to current methods.

Induction chemotherapy followed by concurrent chemoradiation for advanced head and neck cancer: improved disease control and survival.

PURPOSE: To determine tumor response rate, patterns of failure, toxicity, and survival in advanced squamous head and neck cancer after a combined treatment program that consists of induction chemotherapy, organ-sparing surgery, and concurrent chemoradiation. Long-term outcome data are presented. PATIENTS AND METHODS: Between July 1991 and March 1993, 93 patients received three cycles of induction chemotherapy that consisted of cisplatin, fluorouracil (5-FU), l-leucovorin, and alpha-interferon2b (PFLl-alpha) followed by optional limited surgery and six to eight cycles of 5-FU, hydroxyurea, and concurrent radiation (FHX) to a total radiation dose of 65 to 75 Gy. RESULTS: Ninety-three patients were entered onto this study and 97% had stage IV disease, with 66 patients who were N2 or N3. Sixty-one patients (66%) achieved a clinical complete remission (CR) after induction therapy. Thirty-four patients underwent surgery. Seventy-nine patients proceeded to FHX. With a median follow-up time of 43 months for surviving patients, 20 patients have had disease progression (13 local, two distant, five both), and there have been 35 deaths (18 from disease, six treatment-related, two from a second primary, and nine for other medical reasons). At 5 years, progression-free survival is 68%, and overall survival is 62%. Surgery was organ-preserving, as only a single laryngectomy and no glossectomies were performed in primary management. Acute toxicity related to PFLl-alpha consisted of severe or life-threatening mucositis in 57% and leucopenia in 65% of patients. During FHX, 81% of patients had grade 3 or 4 mucositis. CONCLUSION: PFLl-alpha is a highly active regimen that induced clinical CR in two thirds of patients. When followed by limited surgery and FHX, resultant local and distant disease control, organ preservation, and overall 5-year survival are very promising in high-risk stage IV patients. Based on these local control and survival data, further evaluation of this treatment sequence, induction chemotherapy followed by concurrent chemoradiation, is warranted. Identification of similarly active but less toxic regimens is a high priority.

Phase II study of induction and adjuvant chemotherapy for squamous cell carcinoma of the head and neck. A long-term analysis for the Illinois Cancer Center.

BACKGROUND: In 1982, the Illinois Cancer Center initiated a Phase II trial in which the following treatment was administered: Induction chemotherapy (cisplatin and infusional 5-fluorouracil [5-FU]) was administered before definitive local therapy. Definitive local therapy, consisting of surgery, radiation, or both, was followed by three cycles of the same chemotherapy program. METHODS: Eligible patients had Stage III or IV squamous cell carcinoma of the head and neck with no distant metastases. Three cycles of induction chemotherapy were given. Cisplatin, 100 mg/m2, was infused over 60 minutes on Day 1; thereafter, 5-FU (1000 mg/m2/day) was given continuously for 5 days. Cycles were repeated at 3-week intervals. Local therapy was individualized, according to tumor stage and site. Patients who responded were to receive an additional three cycles of chemotherapy after surgery or radiation. RESULTS: Eighty-one patients were entered into the trial, and 71 were considered both eligible and evaluable. After induction chemotherapy, 59 patients (83%) responded, 23 of whom experienced complete response. Sixty-nine patients completed definitive local treatment, but only 22 proceeded to the planned adjuvant cycles of treatment. Median follow-up of surviving patients was 12 years. At last follow-up, 13 patients were alive and free of malignancy, 9 of whom never had disease recurrence or a second primary tumor. These 13 patients had an acceptable quality of life, were ambulating, and were fully capable of caring for themselves. Overall, nine patients had second primary malignancies. Thirty-four percent of patients were alive at 5 years, and 21% were alive at 10 years. Of 58 deaths, 44 resulted from progressive disease and 8 resulted from second primary cancers. Four patients died of unrelated causes, and two suffered lethal acute toxicity from the chemotherapy program. Late toxicity was moderate. Among 23 patients surviving at least 6 years, there were 3 cases of hypothyroidism, presumed to be secondary to radiation. Xerostomia was modest, consistent with usual radiation effects. Of the 13 patients who were alive and free of malignancy at last follow-up, none had clinical manifestations of serious late end organ toxicity. CONCLUSIONS: During long term follow-up after multimodal treatment of locally advanced squamous cell carcinoma, no obvious benefit was observed from the chemotherapy component of the treatment regimens rendered. Only 21% of patients achieved 10-year survival with the following causes of failure, in descending order of frequency: disease recurrence, second malignancies, other medical problems, and treatment-related deaths. The results of this trial are consistent with the results of other induction chemotherapy trials, indicating the need for innovative treatment strategies. These data do not support the continued use of induction chemotherapy with the cisplatin and infusional 5-FU program.

Pharmacodynamics of fluorouracil-based induction chemotherapy in advanced head and neck cancer.

PURPOSE AND METHODS: To optimize the biochemical modulation of fluorouracil (5-FU), we administered the pure I-stereoisomer of leucovorin (LV) as a 132-hour continuous intravenous infusion (CIV) with cisplatin 100 mg/m2, 5-FU 640 mg/m2/d as a 120-hour CIV, and interferon alfa-2b (IFN) at 2 MU/m2/d for 6 days for three cycles (I-PFL-IFN). Pharmacologic parameters included morning (AM) and afternoon (PM) plasma concentrations of 5-FU, LV and its active metabolite 5-methyl tetrahydrofolate (MTHF), and dihydropyrimidine dehydrogenase (DPD) activity in peripheral mononuclear cells. RESULTS: Eighty-nine patients were treated (86 stage IV). Neutropenia and mucositis were the most common toxicities. Sixty-six percent achieved a complete remission (CR). There was a trend for higher PM versus AM 5-FU concentrations (median, 1.64 v 1.51 mumoles/L; P = .08), but not for LV plus MTHF (P = .66). The mean +/- SD DPD activity was 0.21 +/- 0.14 nmol/min/mg and did not correlate with plasma concentrations of 5-FU or LV plus MTHF or clinical toxicities. Higher PM 5-FU concentrations correlated with worse leukopenia (P = .04) and severity of mucositis (P = .04). PM 5-FU concentration was higher in women than in men (P = .07), with no apparent difference in severity of toxicities. The maximum 5-FU concentration was higher in CR than non-CR patients (median, 2.01 v 1.54 mumoles/L; P = .02) and higher in women than men who achieved a CR (median, 2.77 v 1.91 mumoles/L; P = .03). No correlation of CR with dose-intensity was found. CONCLUSION: L-PFL-IFN is active in stage IV head and neck cancer. 5-FU concentration is a significant predictor of toxicity. In women, optimization of response outcome requires a higher 5-FU concentration. Individualized 5-FU dosing to obtain higher 5-FU plasma concentrations may be indicated.

Chemotherapy of squamous cell carcinoma of head and neck: the future is now.

In 1996, there is an established role for chemotherapy in head and neck cancer. Patients with recurrent disease will be offered combination chemotherapy. In this setting, investigations of new drugs or combinations and the pursuit of concomitant chemo-reirradiation are of interest. In patients with locoregionally advanced disease, induction chemotherapy can be used with the goal of larynx preservation. In addition, a role for chemotherapy in nasopharyngeal cancer appears to be emerging with increased survival as therapeutic goal. The combination of cisplatin and 5-FU does not need to be tested further, however, a more definitive evaluation of a biochemically modulated PF regimen might be of interest. Furthermore, induction chemotherapy represents an ideal investigational tool in which to further evaluate the activity of several new drugs in head and neck cancer patients. Finally, concomitant chemoradiotherapy has resulted in increased survival in several randomized clinical studies. Given the poor outcome of standard radiotherapy in patients with unresectable disease, we favor the administration of concomitant chemoradiotherapy in this group of patients as a standard therapy. In our opinion, the use of radiation therapy alone in this group of patients should be restricted to patients with poor performance status or other high medical risks that render the administration of chemotherapy unadvisable. Finally, given the high incidence of second malignancies and general medical complications in cured head and neck cancer patients, studies of chemoprevention and good preventive medical care by a medical oncologist should be made available to all patients.

Phase II study of all-trans-retinoic acid and alpha-interferon in patients with advanced non-small cell lung cancer.

Between April 1993 and June 1994, 29 patients (pts) with unresectable, locally advanced, or metastatic non-small cell lung cancer were treated with a combination of p.o. trans-retinoic acid (TRA), 150 mg/m2/day, in three divided doses and s.c. IFN-alpha, 3 x 10(6) units/day. The age range was 41-80 years (median, 63 years). The Eastern Cooperative Oncology Group performance status was 0-1 (24 pts) and 2 (5 pts). Pts had advanced disease, refractory to conventional therapy (5 stage IIIB and 24 stage IV). Twenty-one pts had adenocarcinoma, six had squamous cell carcinoma, and two had large cell carcinoma. Only 3 pts completed 8 weeks of treatment, requiring neither interruption nor dose modification. Fatigue occurred in 88% of pts. A syndrome complex consisting of dry oral and nasal mucosa, recurrent sinus infections, and epistaxis occurred in 64% of pts. Grade II/III dermatitis was seen in 52%. Severe scrotal dermatitis was seen in 7 pts (47% of 15 males). Hypertriglyceridemia was moderate/severe in 11 pts, and 3 pts required gemfibrozil for levels up to 1660 mg/dl. Hematological toxicity was not encountered, and none of the pts had leukocytosis. One pt died with complications of myocardial infarction while on TRA/IFN-alpha. Twenty-five pts had more than 2 weeks of treatment and are evaluable for response; two pts died early with complications of cancer, and two pts declined to continue after only 3 and 5 days of treatment. Final assessment of response was by accepted clinical and radiological criteria at 8 weeks. There have been four objective responses: complete response, 2 (18+ and 17 months) and partial response, 2 (7 and 14 months). Responses were observed in all histologies. Combined differentiation treatment with TRA/IFN-alpha has modest but objective activity in non-small cell lung cancer. Toxicity is considerable. Additional studies to elucidate the biological basis of TRA/IFN-alpha and to define prognostic parameters predicting response are needed.