Human papillomavirus infection and lung adenocarcinoma: special benefit is observed in patients treated with immune checkpoint inhibitors.

BACKGROUND: Human papilloma virus (HPV) has been associated with the development and modulation of response in a series of neoplasms. In the case of lung adenocarcinoma, its role in etiology and pathogenesis is still controversial. Considering that this infection brings foreign epitopes, it could be of prognostic significance in patients with lung adenocarcinoma treated with immunotherapy. METHODS: In a retrospective cohort study we evaluated the presence of HPV genomic material in lung adenocarcinoma primary lesions with the INNO-LiPA platform. Viral replication was also evaluated by detecting the presence of oncoprotein E6/E7 messenger RNA (mRNA) by quantitative RT-PCR. To confirm possible hypotheses regarding viral oncogenesis, vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF1) were evaluated with stromal fibrosis and immunoscore. RESULTS: A total of 133 patients were included in the analysis, of whom 34 tested positive for HPV, reaching an estimated prevalence of 25.6% [95% confidence interval (CI) 18.2% to 32.9%]. E6/7 mRNA was identified in 28 out of the 34 previously positive cases (82.3%). In immune checkpoint inhibitor (ICI)-treated patients, the median overall survival reached 22.3 months [95% CI 19.4 months- not reached (NR)] for HPV-negative and was not reached in HPV-positive (HPV+) ones (95% CI 27.7-NR; P = 0.008). With regard to progression-free survival, HPV- patients reached a median of 9.2 months (95% CI 7.9-11.2 months) compared to 14.3 months (95% CI 13.8-16.4 months) when HPV was positive (P = 0.001). The overall response rate for HPV+ patients yielded 82.4% compared to 47.1% in negative ones. No differences regarding programmed death-ligand 1, VEGF, HIF1, stromal fibrosis, or immunoscore were identified. CONCLUSIONS: In patients with HPV+ lung adenocarcinoma, a significant benefit in overall response and survival outcomes is observed.

Clinicopathological and genomic correlates of programmed cell death ligand 1 (PD-L1) expression in nonsquamous non-small-cell lung cancer.

BACKGROUND: Programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) is the primary clinically-available biomarker of response to immunotherapy in non-small-cell lung cancer (NSCLC), but factors associated with PD-L1 expression are not well understood. MATERIALS AND METHODS: Consecutive nonsquamous NSCLCs with successful PD-L1 assessment and targeted next-generation sequencing were included in this retrospective study. Clinicopathological characteristics, gene mutations, and copy number changes in gene and chromosomal arms were compared among three PD-L1 expression groups: negative (TPS < 1%), low (TPS 1%-49%), and high (TPS ≥ 50%). A Q-value <0.25 was considered significant after multiple comparisons correction. RESULTS: A total of 909 nonsquamous NSCLCs were included. High PD-L1 expression compared with low and negative PD-L1 expression was associated with increased tobacco exposure (median pack-years: 25 versus 20 versus 20, respectively; P = 0.01), advanced stage at diagnosis (76% versus 67% versus 61% with advanced stage of disease, respectively; P < 0.001), and higher tumor mutational burden (TMB) (median 12.2 versus 10.6 versus 10.6 mutations/megabase, respectively; P < 0.001). Negative PD-L1 expression when compared with high PD-L1 expression was associated with: mutations in STK11 (19% versus 5%; Q < 0.001), EGFR (22% versus 11%; Q < 0.001), CTNNB1 (4.3% versus 0.4%; Q = 0.04), APC (5% versus 1%; Q = 0.17), and SMARCA4 (9% versus 4%; Q = 0.20); copy number loss of CD274 (PD-L1, 28% versus 6%; Q < 0.001), PDCD1LG2 (PD-L2, 28% versus 6%; Q < 0.001), and JAK2 genes (27% versus 7%; Q < 0.001), loss of chromosomal arm 9p (23% versus 10%; Q = 0.04), and gain of 1q (46% versus 21%; Q < 0.001). High PD-L1 expression compared with negative PD-L1 expression was associated with copy number gain of CD274 (11% versus 3%; Q = 0.01) and PDCD1LG2 (11% versus 3%; Q = 0.01). NSCLCs with CD274 loss, compared with those without loss, had a lower response rate (23% versus 9%; P = 0.006) and shorter progression-free survival (3.3 versus 2.0 months; P = 0.002) on immunotherapy. CONCLUSIONS: PD-L1 expression is associated with specific genomic alterations and clinicopathologic characteristics in nonsquamous NSCLC.

Radionecrosis versus progresión de la enfermedad en metástasis cerebrales: valor del 18F-DOPA PET/TC/RM / Radionecrosis versus disease progression in brain metastasis. Value of 18F-DOPA PET/CT/MRI

La utilización del 18F-DOPA PET/TC junto a la superposición con imágenes de resonancia magnética y el empleo de métodos de análisis visual y semicuantitativo permitió diferenciar entre las alteraciones posradiocirugía vs. sospecha de progresión de la enfermedad en un paciente con metástasis cerebrales de melanoma, permitiendo tomar una conducta quirúrgica correcta precozmente (AU)

The use of 18F-DOPA PET/CT with magnetic resonance imaging fusion and the use of visual methods and quantitative analysis helps to differentiate between changes post-radiosurgery vs. suspicion of disease progression in a patient with brain metastases from melanoma, thus facilitating taking early surgical action (AU)

Radionecrosis versus disease progression in brain metastasis. Value of (18)F-DOPA PET/CT/MRI. / Radionecrosis versus progresión de la enfermedad en metástasis cerebrales: valor del (18)F-DOPA PET/TC/RM.

The use of (18)F-DOPA PET/CT with magnetic resonance imaging fusion and the use of visual methods and quantitative analysis helps to differentiate between changes post-radiosurgery vs. suspicion of disease progression in a patient with brain metastases from melanoma, thus facilitating taking early surgical action.

A randomised phase II study of oxaliplatin alone versus oxaliplatin combined with 5-fluorouracil and folinic acid (Mayo Clinic regimen) in previously untreated metastatic colorectal cancer patients.

The aim of this study was to examine the efficacy and safety of both oxaliplatin as a single agent and oxaliplatin in combination with dailyx5 bolus 5-fluorouracil and folinic acid (5-FU/FA, Mayo clinic regimen) in the first-line treatment of metastatic colorectal cancer (CRC) patients. 73 advanced CRC patients were randomised to receive either oxaliplatin 85 mg/m(2) every 2 weeks (35 patients), or the same treatment combined with 5-FU 425 mg/m(2)/day and FA 20 mg/m(2)/dayx5 days every 4 weeks (38 patients). Treatment was continued until disease progression or unacceptable toxicity. All patients had documented inoperable disease and no previous chemotherapy for advanced disease. Based on the investigators' assessment of best response, objective response rate was 9% (95% confidence interval (CI) 2-24%) in the oxaliplatin arm, and 45% (95% CI 27-64%) in the oxaliplatin+5-FU/FA arm. Median progression-free survival (PFS) was 2 months (95% CI 1.7-2.4 months) in the oxaliplatin arm and 3.9 months (95% CI 2.9-5 months) in the oxaliplatin+5-FU/FA arm. Severe neutropenia was seen in 23% of patients in the oxaliplatin+5-FU/FA arm, and none in the oxaliplatin arm. There were two treatment-related deaths, both in the oxaliplatin+5-FU/FA arm. In the oxaliplatin+5-FU/FA arm, severe diarrhoea, vomiting and stomatitis were seen in 34, 14 and 14% of the patients, respectively. In conclusion, oxaliplatin at a dose of 85 mg/m(2) given every 2 weeks was well tolerated and has limited activity in metastatic CRC, while the combination of this treatment with the full-dose Mayo clinic regimen (5-FU bolus 425 mg/m(2)/day+FA 20 mg/m(2)/dayx5 days every 4 weeks), although active, was unfeasible due to a high level of myelosuppression and gastrointestinal toxicity. Alternative lower dosing or other regimens are to be explored to ascertain the value of bolus 5-FU/FA combined with oxaliplatin.

Intensive concomitant chemoradiotherapy in locally advanced unresectable squamous cell carcinoma of the head and neck: a phase II study of radiotherapy with cisplatin and 7-week continuous infusional fluorouracil.

PURPOSE: To evaluate an intensive concomitant chemoradiotherapy protocol of conventional radiotherapy with intermittent cisplatin (CDDP) and continuous-infusion fluorouracil (5-FU) in unresectable, locally advanced squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Fifty-seven patients with unresectable stage IV MO disease (International Union Against Cancer [UICC]/American Joint Committee on Cancer [AJCC], 1987) received radiotherapy 70 Gy followed by CDDP 80 mg/m2 and 5-FU 300 mg/m2/d. Response was assessed 2 months after treatment completion. RESULTS: Thirty patients (52%) received the full treatment schedule; 53 (93%) received full-dose radiotherapy, while 48 (84%) were given at least 75% of the planned chemotherapy doses. Severe mucositis (World Health Organization [WHO]) grade 3 to 4 was the limiting toxicity and was seen in 79% of patients. The median time for mucositis resolution was 8 weeks. Other toxicities were generally manageable, but there were four treatment related deaths (7%). Fifty patients were assessable for activity, with an overall response rate of 70% (95% confidence interval [CI], 58% to 82%). Complete response (CR) and partial response (PR) rates were 42% and 28%, respectively. CONCLUSION: This simultaneous combined-modality regimen was feasible at the cost of severe mucosal toxicity, which required hospitalization with nutritional, parenteral, and hydroelectrolytic support. The high response rate achieved (70%) did not translate into improved survival, probably due to patient eligibility. The likelihood of cure of this high-tumoral-volume patient population remains low (approximately 10%), despite the association of two therapeutic modalities at full standard therapeutic intensity.

Phase I and pharmacology study of flavone acetic acid administered two or three times weekly without alkalinization.

Flavone acetic acid (FAA, NSC 347512) is a synthetic flavonoid compound with a unique form of preclinical antitumor activity, but its mechanism of action is still not known. In an attempt to exploit the remarkable preclinical activity of this compound in such a way as to allow its use as a clinically useful agent, we performed a phase I and pharmacology study with frequent administration and no hyperhydration or alkalinization. Sixteen patients (9 men, 7 women) were given FAA as 6-h i.v. infusions 2 or 3 times a week (10 and 6 patients, respectively), at doses ranging from 2.5 to 8.1 g/m2. A total of 130 doses were administered during this study. Sedation, arterial hypotension, vomiting and diarrhea were the predominant toxicities observed at the highest dose (8.1 g/m2. One patient developed severe but reversible multiple organ failure. No treatment-related deaths occurred. Pharmacokinetics was linear for the doses studied, with peak plasma levels ranging from 39 to 449 micrograms/ml and a mean terminal half-life of 3.1 h. No drug accumulation was observed with this frequent-administration schedule. No objective response was observed. Three FAA infusions per week at 8.1 g/m2 could be recommended as an optimal and tolerable schedule.

5-Fluorouracil and interferon-alpha in chemotherapy refractory bladder carcinoma: an effective regimen.

Seventy-seven patients with metastatic transitional cell carcinoma of the bladder who were unable to receive primary Cisplatin-based therapy or failed primary chemotherapy received one of three sequential 5-Fluorouracil-based salvage regimens: a) 5-Fluorouracil (1000 mg/m2 B.S.A. x 5 days) and Mitomycin-C (14 mg/m2 B.S.A. 6 week intervals), b) 5-Fluorouracil (750 mg/m2 B.S.A. x 5 days) and a-Interferon (5 miu/m2 B.S.A. daily x 5 then 3 times a week (TIW), c) 5-Fluorouracil (500 mg/m2 B.S.A. x 5 days), a-Interferon (5 miu/m2 B.S.A. x 5 days then TIW) and 13-Cis Retinoic Acid in escalating doses daily. Only 1 (6%) of the patients with regimen A responded, whereas 9 (30%) of the patients with regimen B and 8 (27%) in regimen C responded. Although all responses were partial remissions, responses were seen in patients with advanced and initially refractory transitional cell carcinomas. This data reveals that a-Interferon and 5-Fluorouracil is an effective combination in the treatment of metastatic transitional cell carcinoma and worthy of further study.

Phase I and pharmacokinetic study of brequinar (DUP 785; NSC 368390) in cancer patients.

Brequinar (DUP 785, NSC 368390) is a 4-quinoline carboxylic acid derivative with broad spectrum antitumour activity in experimental models that acts as an antimetabolite by specific inhibition of de novo pyrimidine synthesis. We performed a phase I study of brequinar administered as a 10 min intravenous (i.v.) infusion for 5 consecutive days, every 4 weeks. 67 evaluable patients were entered in this study and a total of 130 courses were administered at doses ranging from 2 to 350 mg/m2. The dose-limiting toxicity was myelosuppression with predominant thrombocytopenia. Myelosuppression was dose-related and non-cumulative, with considerable interpatient variability depending on haematological risk factors. The maximum tolerated dose of brequinar was 210 mg/m2/day in poor risk patients whereas patients with good risk haematological profile tolerated higher doses (up to 350 mg/m2/day). Other non-limiting toxicities included nausea and vomiting, mucositis and skin reactions. Brequinar plasma pharmacokinetic profiles were biphasic with alpha half-life ranging from 0.1 to 0.7 h, and beta half-life ranging from 1.5 to 8.2 h. Increase in brequinar area under the plasma concentration versus time curves (AUC) was nonlinear. Day 5 brequinar pharmacokinetics obtained in 21 patients indicated a significant increase in AUC (47%) and half-life beta (133%) compared to day 1 pharmacokinetics in the same patient. Brequinar plasma AUC and the per cent change in platelet count at nadir were correlated (P < 0.001). Although no objective response was observed in this study, one minor response was noted in cervical lymph nodes of a Hodgkin's disease patient.

Pharmacokinetics and metabolism of 4'-iodo-4'-deoxy-doxorubicin in humans.

PURPOSE: 4'-iodo-4'-deoxydoxorubicin is a new anthracycline that currently is under clinical evaluation. To improve the management of future trials, we have determined its pharmacokinetics and metabolism during a phase I/II study and have tried to relate the parameters obtained to the hematologic toxicity of the drug in terms of the survival of blood cells. PATIENTS AND METHODS: The pharmacologic study included 19 patients who were entered at dose levels that ranged between 6 and 90 mg/m2; nine patients were treated at 80 mg/m2, which is close to the maximum recommended dose level. Blood sampling was performed from the end of the bolus infusion to 48 hours after treatment. Drug and metabolites were extracted and analyzed by high-performance liquid chromatography (HPLC), and the data were processed by nonlinear fitting to multicompartment models. RESULTS: Plasma concentrations were best fitted to a three-compartment model with half-lives of 5.2 minutes, 0.79 hours, and 10.3 hours. The total body clearance and volume of distribution at steady state were high (350 L/h/m2 and 2,065 L/m2). The drug was metabolized extensively to a 13-dihydroderivative, 4'-iodo-4'-deoxy-doxorubicinol; the mean area under the curve (AUC) ratio metabolite/parent drug was the highest observed ever for an anthracycline (12.1 +/- 7.4); the metabolite was cleared from the plasma with an elimination half-life of 15.3 hours. The AUCs of the parent compound and its metabolite were related linearly to the dose administered, and showed no saturation phenomenon. Urinary excretion was studied in nine patients and showed a cumulative elimination of less than 6% of the dose administered, two thirds of which were eliminated in the first 12 hours after injection. Ninety-three percent to 100% of the elimination of fluorescent compounds occurred in the form of the metabolite. Drug concentration in five tumor samples showed a rapid uptake of the drug from plasma and a preferential uptake of the parent drug compared with the metabolite. Blood cell counts after 4'-iodo-4'-deoxydoxorubicin treatment showed significant correlations among the surviving fractions of both granulocytes and platelets and the AUCs of the parent drug and its metabolite; the most significant correlations were obtained for the granulocytes and the metabolite. Significant correlations between AUCs and blood-cell survivals were maintained, even if only the nine patients treated at the dose of 80 mg/m2 were taken into account for the computation. CONCLUSIONS: Our results especially show that myelosuppression that is induced by 4'-iodo-4'-deoxydoxorubicin can be well predicted by the measure of the AUC of the drug and its metabolite. This could be used for the further development of the drug toward high-dosage schedules.

Neoadjuvant chemotherapy consisting of cisplatin and continuous infusions of bleomycin and 5-fluorouracil for advanced head and neck cancer. The need for a new stratification for stage IV (M0) disease.

A Phase II study of cisplatin (100 mg/m2 on day 1) and bleomycin (15 mg intravenous push day 1) followed by 5 days of continuous intravenous infusions of 5-fluorouracil (5-FU) (650 mg/m2/d) and bleomycin (16 mg/m2/d) repeated at 21-day intervals was performed in 54 previously untreated patients with nonmetastatic (M0), locoregionally advanced head and neck squamous cell carcinoma (SCC). The aim of this study was to increase the complete response rate to chemotherapy and to identify prognostic factors that may influence local control and disease-free survival. From April 1986 until August 1988, 5 patients with Stage III and 49 with Stage IV (International Union Against Cancer-American Joint Committee on Cancer 1986 [UICC-AJCC]) disease received this regimen. Thirty (61%) patients with Stage IV disease had bulky nodal disease (9 N2c and 21 N3) and 29 (53%) had T4 primary lesions. The response rate was 59% (95% confidence interval, 47% to 71%) and the complete response rate to chemotherapy was 13% (95% confidence interval, 0% to 26%). The response rate was greatly influenced by tumoral volume and performance status (PS). The complete response rate to chemotherapy was 40% for patients with Stage III disease (2 of 5 patients) versus 10% for patients with Stage IV disease (5 of 49 patients; P = 0.02). The response rate for patients with Stage III disease was 100% (5 of 5 patients) versus 55% for patients with Stage IV disease (27 of 49 patients; P = 0.14). For patients with Stage IV bulky nodal disease (N2c-N3), the response rate was 43% (13 of 30 patients) and the complete response rate to chemotherapy was 3% (1 of 30 patients) versus 68% (13 of 19 patients; P = 0.13) and 21% (4 of 19 patients; P = 0.07), respectively, for patients with Stage IV less than N2b disease. The local control rate after definitive therapy was 100% for patients with Stage III disease, 70% (17 of 24 patients) for patients with Stage IV less than N2b disease, and 17% (5 of 30 patients) for patients with bulky nodal disease (P = 0.0005). As of February 1991, with a median follow-up time of 38 months (range, 30 to 53 months), 4 of 5 patients with Stage III disease and 7 of 19 patients with Stage IV less than N2b disease were alive with no evidence of disease (37%) versus 0 of 30 patients with bulky nodal disease (P = 0.001).(ABSTRACT TRUNCATED AT 400 WORDS)

Perianal ulcer in disseminated histoplasmosis.

A 65-year-old man with stage I testicular seminoma, treated with surgery and radiation, had fever of unknown origin, adrenal insufficiency, and an isolated perianal ulcer. Tissue diagnosis of disseminated histoplasmosis was established by biopsy of the perianal ulcer, an unusual cutaneous manifestation of the disease. Treatment with amphotericin B resulted in rapid clinical improvement and complete healing of the perianal ulcer.

Recurrent and/or metastatic head and neck squamous cell carcinoma: a clinical, univariate and multivariate analysis of response and survival with cisplatin-based chemotherapy.

One hundred two patients with recurrent and/or metastatic head and neck squamous cell cancer were entered into four consecutive phase II trials, all cisplatinum (C-DDP, 100 mg/m2/cycle)-based. The two combinations tried were C-DDP, bleomycin, and fluorouracil (CFB) on 54 patients, and cisplatinum and vindesin in 36 patients (CV). The CFB combination was given with C-DDP by continuous infusion over 96 hours (23 patients) or on day 1 (31 patients). The CV regimen was also given in two different schedules, with VDS at 3 mg/m2/g weekly (12 patients) or by a 96-hour continuous infusion (0.6 to 1.0 mg/m2/d) in 24 patients. The following variables: sex, age, performance status, previous therapy, local recurrence, length of disease-free interval (DFI), distant metastases, weight loss, primary site, histological differentiation, type of chemotherapy, previous chemotherapy, evaluable/measurable disease, erythrosedimentation rate, and their relation with response to chemotherapy (WHO) and survival were submitted to both univariate and multivariate analysis (Cox). Overall response rate (RR:CR + PR) was 25 (28%) of 90. In the CFB protocols, RR was 12 (22%) of 54 vs. 13 (38%) of 36 (P = 0.15, NS) in the CV combination group. For the four different combinations the RR was CFB C-DDPci 7 (30%) of 23, CFB C-DDP 1 hour 5 (16%) of 31, CV VDS weekly 2 (17%) of 12, CV VDSci 11 (45%) of 24. The patient populations were very different, with the latest combination consisting of metastatic patients exclusively. Univariate analysis of multiple variables showed age less than 60 years, PS:0 or 1, no previous therapy, absence of local relapse, metastatic disease, long DFI, and that measurable disease was significant for the probability of response. Median survival was 7 months for the 90 evaluated patients, 5 months for nonresponders, and 9 months for responders (P = 0.01). In the univariate analysis, significant factors for survival were PS:0 or 1, a weight loss below 10%, long DFI, response to chemotherapy, erythrosedimentation rate (ESR) of less than 30 mm/1st hr, presence of bone metastasis, and the number of metastases. Multivariate analysis shows PS, the absence of local relapse, and disease-free interval as significant prognostic factors for response. Multivariate analysis factors of significance for survival were PS, weight loss, and response to chemotherapy. The analysis of the clinical pattern showed an evolution in RR from 3 (8%) of 36 on previously irradiated local recurrent disease to 8 (73%) of 11 in previously untreated patients with metastatic disease at presentation.(ABSTRACT TRUNCATED AT 400 WORDS)

Computed tomographic density of metastatic lymph nodes as a treatment-related prognostic factor in advanced head and neck cancer.

Pretherapeutic identification of patients likely to benefit from neoadjuvant chemotherapy for head and neck epidermoid cancer is of interest. We retrospectively analyzed the pretherapeutic computed tomographic (CT) scans of lymph nodes of 70 patients with head and neck cancer. All 70 patients were clinically classified as having stage IV disease. The purpose of our analysis was to compare the prognostic value of CT node density with that of the following factors: age, T and N categories, Eastern Cooperative Oncology Group performance status, tumor site, histopathologic type of disease [squamous cell carcinoma (SCC) or undifferentiated carcinoma of nasopharyngeal type (UNCT)], and type of local-regional treatment. A simple two-grade nodal density grading system was devised. The density of normal adjacent muscle was chosen as the density standard. A node was classified grade 1 if less than 33% of the node consisted of hypodense zones. A node was classified grade 2 if more than 33% of the node consisted of hypodense zones. Patients with grade 1 nodes had a complete response rate of 68% (21/31) compared with 8% (3/39) for those with grade 2 nodes (P less than .0001). The only other factor associated with complete node response was UCNT (P less than .03). However, node density remained the significant prognostic factor after adjustment for histopathologic type. Follow-up ranged from 16 to 44 months, with a median of 29 months. Patients with grade 1 nodes had a median survival time of 32 months versus 13 months for those with grade 2 nodes (P less than .01). A prospective study should validate the prognostic value of CT node density and its possible use in determining optimal multimodal therapy for advanced head and neck cancers.

Phase II study of cisplatin and continuous-infusion 5-fluorouracil and bleomycin for recurrent and metastatic head and neck squamous-cell carcinoma.

5-Fluorouracil (5-FU) and bleomycin (BLM) are active agents in head and neck squamous-cell cancer (H-N-scc). Less toxicity and an enhanced activity have been reported when these agents are administered by continuous infusion (CI), with or without a bolus of cisplatin (CDDP), another active agent. Thirty-three patients with recurrent and/or metastatic head and neck squamous cell carcinoma were treated with a combination regimen including CDDP (100 mg/m2) on day 1 plus BLM (15-mg bolus followed by 16 mg/m2/day by CI) and 5-FU (650 mg/m2/day by CI) on days 1-5 every 3 weeks. Thirty-one patients were evaluable for toxicity and response. The response rate (RR) was 15% (5 of 31), with one complete response (CR) and four partial responses (PRs), at a confidence interval of 95% (0-34%). Four of the five responders had not received previous radiotherapeutic treatment. Toxicity was deemed acceptable; nausea and vomiting and stomatitis were moderate. Only one patient had irreversible renal toxicity, after two cycles of chemotherapy. No symptomatic lung toxicity was observed. Good antitumour activity was noted for previously untreated disease (3 of 4; 75% RR). This combination of drugs proved to be inactive, however, in previously irradiated recurrent and/or metastatic H-N-scc (1 of 25; 4% RR). These results underscore the need to be extremely attentive to different patient populations when selecting therapeutic schedules and when analyzing reported results.

A phase II study of cisplatin and continuous infusion of vindesine in metastatic head and neck squamous cell cancer.

The chemotherapeutic treatment of recurrent and/or metastatic squamous cell carcinoma (SCC) of the head and neck (H & N) has a very dismal prognosis, with survival usually not exceeding 1 year. Reported objective response rates vary between 3% and 70%. This difference appears largely attributable to the heterogeneity of the patient populations included in most published Phase II studies in H & N cancer. They usually include together initially metastatic, recurrent, and post primary treatment metastatic disease patients. These patients respond differently to chemotherapy. Because of this situation, we decided to study a more homogeneous patient population consisting of metastatic patients only. Cisplatin (CDDP) and vindesine (VDS) are active agents in H & N SCC. As VDS has a cycle-specific activity, the therapeutic index may be increased if it is administered in a continuous infusion (CI) schedule. Thirty-three patients with metastatic H & N (69% biopsy proven) were treated with a combination regimen including CDDP (100 mg/m2) day 1 and VDS 0.6 to 1 mg/m2 for 96 hours of CI. Thirty-one patients were evaluable for response: five had a complete response (CR; 16%) and 11 had a partial response (PR; 36%) with an overall rate response of 52% (95% confidence limit: 33% to 70%). Median duration of CR was 6.4 months (3 to 19 months) and 4.4 months for PR (3 to 6 months). A decrease in the leukocytes was the main toxicity encountered with this regimen. This combination regimen containing CDDP and CI VDS was well tolerated and active in H & N SCC. The incorporation of an active vinca-alkaloid in neoadjuvant regimens should be considered.

Specificity of the phase I trial for cytotoxic drugs in oncology.

The phase I trial in oncology follows a very different methodology than in other areas of medicine. Its main objective is the identification of the maximal tolerated dose with short and middle range toxicity limits. In general the therapeutic index of anticancer drugs is narrow and the efficacy of drugs is closely associated with their toxic range: specially hematologic. This toxicity has to be well defined within its nature, its gravity, its dose relationship and its reversibility. It is usually correlated with pharmacokinetic. The cytotoxic agents have as their main target DNA and therefore the long term toxicity is poorly defined and seldom wellknown. The oncology phase I trial is always done in advanced cancer patients and in the great majority of cases after several therapeutic tentative having failed. It is never done in healthy volunteers. Patients have to be informed of the nature of the trial with the possibility of a therapeutic response as an associated objective.

96-hour continuous infusion of cis-platinum, 5-fluorouracil and bleomycin in recurrent or metastatic head and neck squamous cell carcinoma, unexpected anemia.

Cis-platinum, 5-fluorouracil and bleomycin are active agents in head and neck SCC. When given by continuous infusion (C.I.) lower toxicity and increased activity have been reported. A 4-day trial of triple C.I. including these reagents was conducted for recurrent and/or metastatic head and neck SCC. Cis-platinum 25 mg/m2/day, 5-FU 650 mg/m2/day and bleomycin 10 mg/m2/day were given for 4 days every 4 weeks. Twenty-nine patients were entered, 27 were evaluable for toxicity and 3 for response. The response rate was 30% (one CR and seven PR). Patient compliance was poor (one central and one peripheral i.v. line) and toxicity was acceptable except for the unexpected anemia; 48% of patients required red cell transfusion. One patient died of bleomycin-induced lung toxicity and minor renal toxicity related to parenteral hydration was observed in the first 16 patients. In conclusion, this combination is moderately active in recurrent and/or metastatic head and neck SCC. Patient compliance was poor and cumulative anemia was an unexpected toxic event. Further trials with this triple C.I. chemotherapy are not recommended for the alcoholic, undernourished, very advanced cancer patient population.