Role of Hematological Markers in Recurrent/Metastatic Head and Neck Squamous Cell Carcinoma Treated With Pembrolizumab.

BACKGROUND/AIM: The predictive role of hematological markers in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) treated with pembrolizumab remains unclear. PATIENTS AND METHODS: We conducted a multicenter retrospective cohort study to investigate the predictive impact of the pre-treatment hematological markers neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), CRP-albumin-lymphocyte (CALLY) index, and the modified Glasgow prognostic score (mGPS) on overall survival (OS) and progression-free survival (PFS) in patients with R/M SCCHN treated with pembrolizumab. From December 2019 to February 2022, 119 and 28 patients were treated with pembrolizumab alone and pembrolizumab plus chemotherapy, respectively. The optimal cut-off point of dichotomized hematological markers was calculated using the area under the receiver operating characteristic curve. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) were estimated using Cox proportional hazard models with adjustment for potential confounders. RESULTS: In the pembrolizumab monotherapy group, patients with higher NLR, PLR, and mGPS and a lower CALLY index showed significantly shorter OS after adjustment for potential confounders. In addition, all hematological markers examined in this study tended to be associated with clinical response, such as overall response rate or disease control rate (DCR); in particular, a lower CALLY index and higher mGPS were significantly associated with poor DCR. In the pembrolizumab with chemotherapy group, these hematological markers had a similar association with OS but not with clinical response. CONCLUSION: Pre-treatment NLR, PLR, CALLY index, and mGPS might be predictive markers of survival in patients with R/M SCCHN treated with pembrolizumab.

Effects of Pembrolizumab in Recurrent/Metastatic Squamous Cell Head and Neck Carcinoma: A Multicenter Retrospective Study.

BACKGROUND/AIM: Pembrolizumab exhibits anticancer efficacy in platinum-sensitive or platinum-unfit patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). However, no large-scale retrospective real-world data are available. This retrospective study aimed to examine the efficacy and safety of pembrolizumab in multiple facilities. PATIENTS AND METHODS: Data of 167 patients with R/M SCCHN treated with pembrolizumab between December 2019 and February 2022 were analyzed. The endpoint was overall survival (OS), progression-free survival (PFS), and immune-related adverse events (irAEs). OS and PFS were analyzed comparatively with and without irAEs, and complete response (CR) or partial response (PR), and stable disease (SD) or progressive disease (PD) were compared. RESULTS: One hundred thirty-five patients received pembrolizumab alone, whereas the others received pembrolizumab with chemotherapy. For the pembrolizumab only group, the median OS and PFS were 22.7 and 5.1 months, respectively. There were significant differences in OS and PFS between CR or PR and SD or PD (p<0.01, p<0.01, respectively). For pembrolizumab with chemotherapy, the OS was not reached and median PFS was 7.0 months. There was a significant difference in PFS between CR or PR and SD or PD (p<0.01). There was a significant difference in PFS between patients with and without irAEs (p=0.02). CONCLUSION: The real-world therapeutic effect of pembrolizumab for R/M SCCHN was comparable to that observed in the KEYNOTE048 trial. In addition, irAEs and best overall response were considered as prognostic factors.

Nivolumab for Platinum-refractory and -sensitive Recurrent and Metastatic Head and Neck Squamous Cell Carcinoma.

BACKGROUND/AIM: Nivolumab has antitumor efficacy in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) who relapse within 6 months after platinum-based therapy; however, the efficacy of nivolumab for platinum-sensitive R/M HNSCC has not been shown. Therefore, this study compared the efficacy and safety of nivolumab for platinum-refractory and platinum-sensitive R/M HNSCC. PATIENTS AND METHODS: This was a retrospective study of patients who received nivolumab for R/M HNSCC who had been previously treated with platinum-based anticancer drugs. Patients were divided into a platinum-sensitive and a platinum-refractory group, and progression-free survival (PFS), overall survival (OS), the overall response rate (ORR) [complete response (CR) + partial response (PR)], the disease control rate (DCR) (CR + PR + stable disease), and the incidence of immune-related adverse events (irAEs) were compared between the two groups. RESULTS: We included 88 patients with squamous cell carcinoma: 60 with platinum-refractory disease and 28 with platinum-sensitive disease. The median PFS in the platinum-refractory and platinum-sensitive groups were 2.7 months and 5.3 months, respectively (p=0.03), and the median OS were 8.8 months and 17.1 months, respectively (p=0.06). There were no significant differences in the ORR, DCR, or incidence of irAEs between the two groups (p>0.99, p=0.11, and p>0.99, respectively). CONCLUSION: Nivolumab is a safe and effective treatment for platinum-sensitive R/M HNSCC.

Comparison of Dosage of Nivolumab in Efficacy and Safety for Recurrent Metastatic Squamous Cell Carcinoma.

BACKGROUND/AIM: There are no real-world comparative data of nivolumab doses of 3 mg/kg and 240 mg/body for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). We investigated the efficacy and safety of nivolumab in treating recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) at different doses using real-world data. PATIENTS AND METHODS: R/M SCCHN patients who received nivolumab were divided into the 3 mg/kg and 240 mg/body groups and retrospectively examined for efficacy and safety. RESULTS: A total of 199 patients (3 mg/kg and 240 mg/body, 88 and 111 patients, respectively) were included. The 3 mg/kg vs. 240 mg/body groups had similar overall response rates (15% vs. 25, p=0.15), disease control rates (46% vs. 57%, p=0.15), overall survival (9.5 months vs. 10.9 months), and progression-free survival (3.7 months vs. 3.8 months, p=0.95). The incidence of immune-related adverse events was also similar in both groups. CONCLUSION: In R/M SCCHN patients, nivolumab showed similar efficacy and safety at doses of 3 mg/kg and 240 mg/body.

Investigation of the Efficacy and Safety of Nivolumab in Recurrent and Metastatic Nasopharyngeal Carcinoma.

BACKGROUND/AIM: Nivolumab, an anti-PD-1 inhibitor, has demonstrated efficacy in patients with several types of recurrent and metastatic (R/M) squamous cell carcinoma of the head and neck. We evaluated patients with R/M-NPC receiving nivolumab. PATIENTS AND METHODS: Twelve patients with R/M-NPC were enrolled at 4 institutions. The primary endpoint was overall survival, and secondary endpoints were i) progression-free survival (PFS), ii) overall response rate (ORR), iii) disease control rate (DCR), and iv) treatment-related toxicity. RESULTS: The 1-year survival rate was 75.8%, the median PFS was 2.8 months, and the 1-year PFS rate was 33.3%. The best therapeutic response was complete response in 2, stable disease in 3 and progressive disease in 7 patients. The ORR of all patients was 16.7% and the DCR was 41.7%. CONCLUSION: Nivolumab is a useful and relatively safe second-line systemic therapy in patients with R/M-NPC, and even patients who do not respond to nivolumab may survive for a long time.

Salvage Chemotherapy After Nivolumab for Recurrent or Metastatic Head and Neck Carcinoma.

BACKGROUND/AIM: The treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) has remained challenging. The effect of salvage chemotherapy (SCT) after nivolumab has been identified recently in other cancer types. The aim of this study was to examine the efficacy of SCT after nivolumab treatment in patients with R/M HNSCC. PATIENTS AND METHODS: A retrospective study was conducted at four institutions in Japan. Fifty-six patients were enrolled in the study. RESULTS: The overall survival (OS) in SCT patients was significantly longer than that in best supportive care (BSC) patients. In the SCT patients, the median OS, median progression-free survival (PFS) and objective response rate (ORR) were 7.3 months, 2.3 months and 36%, respectively. Prognostic factor for OS and ORR was performance score (PS) and previous radiation, respectively. CONCLUSION: SCT after nivolumab is associated with better clinical outcomes in patients with R/M HNSCC compared to those receiving BSC.

Ca2+-dependent contractility of isolated and demembranated macronuclei in the hypotrichous ciliate Euplotes aediculatus.

The hypotrichous ciliated protozoan Euplotes aediculatus possesses a characteristic C-shaped somatic nucleus (macronucleus) within the cytoplasm, which shows dynamic shape change during the cell cycle. It is shown that isolated macronuclei possess Ca(2+)-dependent contractility. Macronuclei were isolated, stuck fast on the glass surface, and subjected to different concentrations of Ca(2+) in a Ca(2+)-EGTA buffer. The nuclei became expanded at [Ca(2+)]<10(-7)M, and they contracted on subsequent addition of higher concentrations of Ca(2+). Cycles of expansion and contraction of the nucleus could be repeated many times by alternate addition of EGTA and Ca(2+), indicating that the size of isolated nuclei can be regulated by [Ca(2+)] alone. The nuclear contraction was observed in all phases of the cell cycle, but contractility was less evident around replication bands in the S phase. In addition to the hypotrichous ciliate Euplotes, similar Ca(2+)-dependent nuclear contractility was found to exist in other cell types, including protozoans of different taxa (a heliozoon Actinophrys sol and a peniculine ciliate Paramecium bursaria), and also mammalian culture cells (HeLa cells). Our findings suggest a possibility that Ca(2+)-dependent nuclear contractility may be shared among diverse eukaryotic organisms.

Dose-escalated cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) chemotherapy for patients with diffuse lymphoma: Cancer and Leukemia Group B studies 8852 and 8854.

BACKGROUND: To address the feasibility and outcome of moderate dose intensification with granulocyte-colony stimulating factor (G-CSF) for patients with aggressive non-Hodgkin lymphoma (NHL), the Cancer and Leukemia Group B (CALGB) conducted two studies evaluating dose-escalated cyclophosphamide and etoposide in the cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide (CHOPE) regimen. METHODS: Eligibility criteria included histologically documented, diffuse small cleaved, diffuse mixed, diffuse large cell, or immunoblastic lymphoma, Stage III--IV or bulky Stage II disease, and an ECOG performance status of 0--1. CALGB 8852, a group-wide study, accrued 227 patients: 120 patients in the pilot study to determine the maximum tolerated dose (MTD) without G-CSF and 107 in the pilot study of dose-escalated CHOPE with G-CSF. CALGB 8854, a limited-institution, Phase I study, enrolled 38 patients and determined the MTD of CHOPE with G-CSF to be used in CALGB 8852. The MTD in both studies was defined as the dose at which 50% of patients had 1) Grade 4 neutropenia or thrombocytopenia lasting 7 days or more, or 2) Grade 3--4 hemorrhage or nonhematologic toxicity (excluding alopecia, nausea, and emesis), or 3) were prevented from receiving 100% of drug on Day 22. RESULTS: The MTD of CHOPE without G-CSF was cyclophosphamide 1000 mg/m(2) on Day 1 and etoposide 100 mg/m(2) on Days 1--3 with doxorubicin 50 mg/m(2) on Day 1, vincristine 1.4 mg/m(2) (maximum, 2 mg) on Day 1, and prednisone 100 mg on Days 1--5. With the addition of G-CSF at 200 microg/m(2) on Days 5--19, the MTD was cyclophosphamide 1500 mg/m(2) and etoposide 160 mg/m(2) on Days 1-3 with standard doses of doxorubicin, vincristine, and prednisone. Increasing the dose of G-CSF from 200 microg/m(2) to 400 microg/m(2) did not allow for further dose escalation. The primary toxicity in all cohorts was neutropenia. Four toxic deaths occurred on CALGB 8852. The 5-year failure free survival (FFS) and overall survival (OS) rates for eligible patients on CALGB 8852 were 31% (95% confidence interval [95%CI], 23--39) and 48% (95%CI, 40--57), respectively. The 5-year FFS and OS rates for eligible patients on CALGB 8854 were 34% (95%CI, 17--52) and 51% (95%CI, 33--70), respectively. CONCLUSIONS: Moderate dose escalation with G-CSF is feasible. However, response and survival rates of patients who receive dose-escalated CHOPE, even with the addition of G-CSF, appear similar to the rates reported with standard-dose CHOP.

Cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) for advanced-stage Hodgkin's disease: CALGB 8856.

Successful treatment of advanced-stage Hodgkin's disease (HD) may critically depend on dose intensity. Because mechlorethamine, Oncovin, procarbazine, and prednisone (MOPP), and Adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) are not suitable for major dose escalation, we evaluated the activity and toxicity of combined cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide (CHOPE) in advanced HD, here used at conventional dose intensity, as a preparatory study prior to using this regimen at higher dose intensity. Ninety-two patients were treated with CHOPE (cyclophosphamide, 750 mg/m2, day 1; doxorubicin, 50 mg/m2, day 1; vincristine, 1.4 mg/m2, days 1 and 8; prednisone, 100 mg/day, days 1-5; and etoposide, 80 mg/m2, days 1, 2, and 3) every 21 days. All had advanced HD with no prior chemotherapy with 46% stage IV, 63% with B symptoms, and 57% with bulky disease (> 5 cm). Radiation and growth factor support were not permitted. Full-dose vincristine (not capped at maximum 2 mg/dose) was used in the first 33 patients. An initial cohort of 41 patients was treated with four cycles of CHOPE to evaluate safety and efficacy followed by four cycles of ABVD. A second cohort of 51 patients was treated with 6-8 cycles of CHOPE alone. Toxicity was generally acceptable and primarily hematologic, with neutrophils < 500 in 63% of cohort I and 90% of cohort II, and platelets < 25,000 in 7% of cohort I and 8% of cohort II. The long-term neurotoxicity of full-dose, high-intensity vincristine was acceptable and largely reversible. In cohort I, 92% of patients achieved a complete response (CR) or partial response (PR) with four cycles of CHOPE and 85% were in CR after four additional cycles of ABVD. In cohort II, 77% achieved a CR with 6-8 cycles of CHOPE alone. FFS was 76% in cohort I and 59% in cohort II, with a median follow-up of 8.2 and 5.7 years, respectively. CHOPE, at conventional dose intensity as used here, is an effective first-line regimen for the treatment of advanced-stage HD and may warrant evaluation using higher doses of cyclophosphamide and etoposide with granulocyte colony stimulating factor (G-CSF) support.

A phase III, randomized, double-blind, placebo-controlled study of peldesine (BCX-34) cream as topical therapy for cutaneous T-cell lymphoma.

BACKGROUND: The purine nucleoside phosphorylase inhibitor peldesine is a new agent being evaluated as a T-cell inhibitor. OBJECTIVE: We attempted to determine the efficacy of peldesine (BCX-34) in a 1% dermal cream formulation as a treatment for cutaneous T-cell lymphoma (CTCL). METHODS: Ninety patients with patch and plaque phase CTCL, histologically confirmed by a referee dermatopathologist, were enrolled in a randomized, double-blind, placebo-controlled study. BCX-34 dermal cream 1% or the vehicle cream (as a placebo control) was applied twice daily to the entire skin surface for up to 24 weeks. Efficacy of the topical therapy was assessed in terms of complete or partial (> or = 50%) clearing of patches and plaques. RESULTS: Of the 89 patients able to be examined, 43 received BCX-34 and 46 received the placebo vehicle cream. One patient withdrew early and was not analyzed. The two groups were well balanced for potential prognostic factors. A total of 28% (12/43) of the patients treated with BCX-34 showed a response, but 24% (11/46) of patients who received vehicle also responded (P =.677). CONCLUSION: Although BCX-34 dermal cream 1% was not significantly better than the control as therapy for patch and plaque-phase CTCL, this appears to be the first published placebo-controlled trial evaluating treatment for CTCL. Whether the vehicle cream has more than a placebo therapeutic effect is unclear. The relatively high (24%) placebo response rate should be kept in mind in assessing other treatments for early-stage CTCL.

Inhibitors of the enzyme purine nucleoside phosphorylase as potential therapy for psoriasis.

Purine nucleoside phosphorylase (PNP) is one of the enzymes comprising the purine salvage pathway , and is responsible for the catalysis of the reversible phosphorolytic cleavage of purine ribonucleosides and 2'-deoxyribonucleosides. The pivotal role of PNP in T-cell proliferation has been demonstrated in patients with inherited PNP deficiency, where T-cell levels may be 1-3% of normal. This observation helped establish the critical role of PNP in T-cells and provided a rationale for developing inhibitors of PNP. Inhibitors of PNP may be useful for treating a variety of T-cell related autoimmune diseases including psoriasis, rheumatoid arthritis and Crohn s disease and T-cell cancers. In this manuscript, the x-ray crystal structure of the PNP enzyme is described. Results of a structure-based drug design program aimed at designing small-molecule inhibitors of PNP are also described. Of the many classes of compounds synthesized, studied and reviewed, only one, the 3-pyridinylmethyl-9-deazaguanine (BCX-34, 39) analog has been used in clinical trials. Both topical and oral formulations of BCX-34 were studied in psoriatic patients and the results of these clinical trials are described.

Pharmacokinetics and pharmacodynamics of peldesine (BCX-34), a purine nucleoside phosphorylase inhibitor, following single and multiple oral doses in healthy volunteers.

The pharmacokinetic parameters of peldesine (BCX-34) were investigated after single and multiple oral doses in two groups of healthy adult volunteers. The pharmacodynamic elevation of endogenous inosine and 2'-deoxyguanosine was simultaneously monitored. The first group of 8 subjects received an intravenous dose (18 mg/m2) and five oral doses (30, 63, 108, 144, and 192 mg/m2) of drug. A second group of 12 subjects received 160 mg/m2 in four and in six divided doses orally. Serial blood samples and total urine outputs were collected during dosing and for at least 24 hours after the last dose was administered. One set of samples was analyzed using high-pressure liquid chromatography/ultraviolet (LC/UV) methods, validated for intact drug in human plasma and urine samples. Another set of samples was analyzed for the biomarkers, inosine and 2'-deoxyguanosine, using high-pressure LC with either mass spectrometry (MS) or electrochemical detection (EC) methods. The pharmacokinetic parameters of inosine and 2'-deoxyguanosine were calculated using noncompartmental methods and correlated against the pharmacokinetic parameters of BCX-34. For the single-dose study, the results exhibited linear pharmacokinetics over the dose range from 30 to 144 mg/m2. The calculated terminal half-life was 3.5 +/- 1.0 h, and the absolute bioavailability of the oral formulation was approximately 51%. Analysis of urine in the first 24 hours of collection accounted for approximately 82% of the absorbed intact drug. Evaluation of the multiple-dose pharmacokinetics indicated that steady-state blood concentrations were achieved by 24 hours when the drug was administered four or six times a day. A drug dose-related elevation of plasma 2'-deoxyguanosine was observed. This phenomenon was not seen with plasma inosine levels. However, analysis of urine samples showed an increase in inosine output with an increase in the drug dose. The calculated terminal half-life of inosine and 2'-deoxyguanosine was 15.3 +/- 1.8 h and 1.3 +/- 0.1 h, respectively.

Phase 2 trial of moderately high dose single agent mitoxantrone in platinum and paclitaxel-refractory ovarian cancer.

In the human clonogenic assay, mitoxantrone possesses among the steepest dose-response curves of any cytotoxic agent against ovarian cancer. To test the potential clinical relevance of this observation, we conducted a phase 2 trial of moderately high dose single agent mitoxantrone (28 mg/m2 delivered every 3-4 weeks) along with granulocyte-macrophage colony stimulating factor (250 micrograms/m2/day beginning 24 h after mitoxantrone and continuing until neutrophil recovery) in 34 patients with clinically defined platinum and paclitaxel-refractory ovarian cancer. The major toxicity of treatment was severe neutropenia which was almost universal. However, there were no treatment-related infectious deaths. Significant cardiac toxicity was not observed. Five of 33 evaluable patients demonstrated objective evidence of a response to treatment (1 patient achieving a partial response of measurable tumor masses, 4 patients achieving a > or = 50% reduction in CA-125 antigen level), with a median duration of response of 3 months (range 2-5 months). We conclude that moderately high dose mitoxantrone has definite, although very limited, single agent activity in platinum and paclitaxel-refractory ovarian cancer. Unfortunately, as this regimen produces severe hematologic toxicity and response durations are short, it cannot be recommended for routine clinical use. The role of an even higher dose mitoxantrone schedule employed as a component of a high dose chemotherapy program with bone marrow or peripheral progenitor cell protection in the treatment of ovarian cancer remains to be defined.

A phase I study of paclitaxel, doxorubicin, and cisplatin in patients with previously untreated epithelial ovarian cancer.

OBJECTIVE: Although doxorubicin is not currently popular as a primary agent in ovarian cancer, overviews of previous studies suggest that the inclusion of doxorubicin may have improved outcome. The purpose of this phase I study was to determine the maximal dose of doxorubicin that could be added to standard doses of paclitaxel and cisplatin with G-CSF support. METHODS: Women with FIGO stage III or IV epithelial ovarian cancer were primarily treated with escalating doses of doxorubicin in combination with paclitaxel (135 mg/m2 over 24 h) and cisplatin (75 mg/m2) every 3 weeks. Doxorubicin was started at 30 mg/m2 and escalated by 10 mg/m2 per treatment level. All patients received G-CSF support. RESULTS: Eleven patients were treated at two dose levels. Dose limiting toxicity (DLT) was reached at the 40 mg/m2 dose of doxorubicin. All patients experienced grade 4 neutropenia although none required hospitalization. DLT included renal toxicity and prolonged thrombocytopenia. Despite vigorous antiemetic regimens 60% of patients experienced severe nausea and vomiting. Nine patients were assessable for response. Eight patients have had a complete clinical response (89%). Of the five patients undergoing second-look laparotomy two were negative. CONCLUSIONS: The maximum tolerated dose of doxorubicin in this three-drug regimen is 30 mg/m2 with standard doses of paclitaxel and cisplatin. Hematologic toxicity is manageable using G-CSF. Doxorubicin appears to increase the renal toxicity of cisplatin which may be exaggerated by marked nausea and vomiting. This is an active but toxic regimen and alternative sequences and strategies should be evaluated.

Randomized trial of cisplatin versus cisplatin plus mitolactol versus cisplatin plus ifosfamide in advanced squamous carcinoma of the cervix: a Gynecologic Oncology Group study.

PURPOSE: Cisplatin, mitolactol (dibromodulcitol), and ifosfamide have been the most active single agents in squamous carcinoma of the cervix identified so far by the Gynecologic Oncology Group (GOG). Combinations of cisplatin plus ifosfamide and cisplatin plus mitolactol are prospectively compared with cisplatin alone. PATIENTS AND METHODS: Patients were randomized to receive cisplatin 50 mg/m2 or the same dose of cisplatin plus mitolactol (C + M) 180 mg/m2 orally on days 2 to 6, or cisplatin plus ifosfamide (CIFX) 5 g/m2 given as a 24-hour infusion plus mesna 6 g/m2 during and for 12 hours after the ifosfamide infusion, every 3 weeks for up to six courses. Of 454 patients entered, 438 were eligible and analyzed for response and survival. RESULTS: CIFX had a higher response rate (31.1% v 17.8%, p = .004) and longer progression-free survival (PFS) time (P = .003) compared with cisplatin alone. The median times to progression or death were 4.6 and 3.2 months, respectively. C + M showed no significant improvement in these parameters compared with cisplatin alone. Survival was associated with initial performance score (PS; 0 was more favorable; P < .001) and with age (younger was unfavorable, P = .025). There was no significant difference in overall survival between cisplatin and either of the combinations. Leukopenia, renal toxicity, peripheral neurotoxicity, and CNS toxicity were more frequent with CIFX (P < .05). CONCLUSION: CIFX improved the response rate and PFS duration in advanced cervix cancer compared with cisplatin alone, but at the cost of greater toxicity and with no improvement in survival.

Chemotherapy for stage IVB or recurrent cancer of the uterine cervix.

Numerous drugs and drug combinations have been evaluated, largely in phase II trials, for the treatment of carcinoma of the uterine cervix. There clearly is a need for effective chemotherapy for this disease, but the results to date have unfortunately not met that need. Cisplatin is active but overrated. Drug combinations have not shown a consistent advantage and require careful study, with the initial focus on maximizing the complete response rate in women with no or minimal prior chemotherapy and with adequate sample size to have confidence about the results. The patient populations under treatment need to be carefully defined with respect to potential prognostic factors for response and survival, so that results will be more reproducible. The few large, randomized trials completed so far have failed to show a survival benefit with combination chemotherapy; in fact, there does not appear to have been a comparison of chemotherapy with best supportive care. Systemic therapy of cervical cancer remains experimental.