An insight into clinicians' practices in breaking bad news of oral cancer diagnosis.

Communication is an integral component of effective healthcare delivery to patients, and this includes breaking bad news (BBN). However, clinicians in dentistry are rarely exposed to diseases that can negatively and seriously affect an individual's view of their future and pose a mortality risk, except for oral cancer. The aim of this study was to assess clinician practices in BBN of oral cancer diagnosis in Malaysia. An exploratory sequential mixed-methods study design was used. A qualitative study was conducted among 12 clinicians to gather relevant information regarding their practices in BBN of oral cancer diagnosis using a descriptive-interpretive approach. The themes that emerged were preparation for BBN, BBN setting, communication, emotional aspects, and summarizing the session. These themes were used to develop a questionnaire with 34 items. In the quantitative study, this questionnaire was sent to 87 clinicians who had experienced BBN of oral cancer diagnosis in the past 5 years; the response rate was 100%. An arbitrary cut-off score between the third and fourth quartiles was set to distinguish 'good' and 'poor' practice in BBN among the clinicians. The data analysis was performed using IBM SPSS Statistics version 23.0. Overall, at least two-thirds of the clinicians had good practices in BBN of oral cancer diagnosis. The clinicians' designation (oral and maxillofacial surgery consultant/specialist vs dental officer) and BBN experiences were factors associated with their practices in BBN of oral cancer diagnosis.

Evaluation of antiandrogen therapy in unresectable hepatocellular carcinoma: results of a European Organization for Research and Treatment of Cancer multicentric double-blind trial.

PURPOSE: The aim of the study was to evaluate the efficacy of antiandrogen therapy on overall survival and response in unresectable hepatocellular carcinoma (HCC). PATIENTS AND METHODS: A total of 244 patients with unresectable HCC were included in this multicentric double-blind trial. According to a two-by-two factorial design, patients were randomly assigned to receive one of the following treatments: pure antiandrogen plus placebo (A+P group, 60 patients); luteinizing hormone-releasing hormone (LHRH) agonist plus placebo (LHRH+P group, 62 patients); pure antiandrogen plus LHRH agonist (A+LHRH group, 62 patients); or placebo plus placebo (P+P group, 60 patients). Pure antiandrogen consisted of Anandron (Roussel-Uclaf Laboratory, Romainville, France) administered orally (300 mg daily for 1 month, then 150 mg daily). LHRH consisted of goseriline acetate (3.6 mg) or triptoreline (3.75 mg) administered monthly by subcutaneous injection. Treatment was given until death. Response was evaluated every 8 weeks according to World Health Organization (WHO) criteria. RESULTS: Six patients were considered ineligible. One patient had a complete response (A+P arm) and three had a partial response (two in the LHRH+P arm and one in the A+LHRH arm). An overall log-rank test did not demonstrate any significant difference in survival among the four arms. Taking the factorial design into account, comparison of survival showed no significant difference between Anandron-containing regimens and others, or between LHRH-containing regimens and others. No serious side effects occurred for any regimen. CONCLUSION: This controlled study shows clearly the lack of efficacy of androgen treatment in unresectable HCC.

Ifosfamide in advanced adenocarcinoma of the oesophagus or oesophageal-gastric junction area. Rotterdam Esophageal Tumor Study Group.

25 previously untreated patients with inoperable or metastatic adenocarcinoma of the oesophagus or oesophageal-gastric junction area were treated with ifosfamide 6 g/m2 over 48 hours, combined with mesna 6 g/m2. 1 complete response and 1 partial response were seen among 23 patients evaluable, with a response duration of 29+ months and 7 months, respectively. Toxicity was not severe: grade 3 infection in 2 patients, grade 3 leucopenia in 3 patients and grade 3 nausea in 4 patients. No life-threatening episodes or central nervous system toxicity were encountered. Ifosfamide has limited activity in adenocarcinoma of the oesophageal-gastric junction area.

Disease monitoring by the tumour markers cyfra 21.1 and TPA in patients with non-small cell lung cancer.

We evaluated the use of two tumour markers Cyfra 21.1 and tissue polypeptide antigen (TPA) for disease monitoring. Assessment of response to WHO criteria was compared to response assessment according to changes in the tumour marker levels. The criteria defined for marker response were a 65% decrease for a partial response and a 40% increase for progressive disease. When response evaluations with a positive lead time were included, 72% of 115 evaluations for Cyfra 21.1 and 59% of 107 evaluations for TPA yielded the same result. Most discordant evaluations were caused by those evaluations whereby the patient achieved a partial response according to the WHO criteria and had normalisation of the marker. Less cases with a positive lead time, more negative lead times, and more patients with progressive disease without an increase of the marker were seen with TPA compared to Cyfra 21.1. In conclusion, Cyfra 21.1 follows the changes in the tumour load better than TPA. Rising levels of both markers nearly always indicate disease progression, and such knowledge easily obtained may prevent the continuation of ineffective treatment.

Correlation between changes in the tumour markers CA-M26 and CA-M29 and standard response evaluation in patients with metastatic breast cancer.

In this study we correlated response evaluated by standard WHO criteria to strict defined criteria of tumour marker response in 63 patients with metastatic breast cancer. Pretreatment sensitivity at first evaluation was 71% and 85% for CA-M26 and CA-M29, respectively. Of the 156 evaluations for CA-M26 and 178 for CA-M29 in 26 and 30 patients with evaluable lesions 72% and 67% were concordant with the results of the clinical evaluations. When the discordant evaluations due to lead time were included the concordances were 87% for CA-M26 and 83% for CA-M29. Of the 70 evaluations for CA-M26 and 92 for CA-M29 in 19 and 24 patients with non-evaluable lesions 59% and 72% were concordant with the results of the clinical evaluations. Most importantly, progressive disease according to the changes in the marker level nearly always predicted disease progression. Such knowledge obtained in a simple way may prevent continuation of ineffective treatment in patients with metastatic breast cancer.

No evidence of known types of human papillomavirus in squamous cell cancer of the oesophagus in a low-risk area. Rotterdam Oesophageal Tumour Study Group.

Controversial results regarding the presence and role of human papillomavirus in the development of oesophageal squamous cell carcinoma have been published. We used multiple broad-spectrum polymerase chain reactions to identify HPV DNA in oesophageal carcinomas from a low-incidence area. Paraffin embedded- and snap-frozen specimens from oesophageal cancer tissues of 63 patients were examined with a PCR technique with several primer pairs, capable of detecting most known HPV types. In none of the oesophagus cancer tissues could HPV DNA be detected. The role of HPV in this type of carcinoma in a low incidence area remains unclear.

A phase I study of local treatment of liver metastases with recombinant tumour necrosis factor.

15 patients with therapy-resistant liver metastases were treated in a phase I study with recombinant tumour necrosis factor (rTNF). rTNF was injected into a liver metastasis by ultrasound guidance, using a 50 micrograms escalating dose schedule (3 patients/dosage) ranging from 100 to 350 micrograms per injection. Influenza-like symptoms such as fever, chills, nausea and vomiting were the main clinical side-effects. 2 patients experienced transient hypotension, probably due to concomitant use of morphine. Other toxicities, as reported after systemic use of rTNF, such as decrease in leucocytes and platelet counts, renal or liver toxicity were not observed. No difference was seen in subpopulations of lymphocytes (CD3+, CD4+, CD8+, CD16+ and CD19+) prior to and after rTNF injection. In 8 patients stable disease occurred in rTNF-treated metastases. The maximal dose used by this route of administration is 350 micrograms per injection. Based on these observations we conclude that the toxicity of rTNF injected into liver metastases by sonographic control is transient and mild. The results suggest that intratumoral administration of rTNF might play a role in local tumour control.

Randomised phase II trial of carboplatin and iproplatin in advanced urothelial cancer.

47 patients with advanced urothelial cancer and no prior chemotherapy were randomly assigned to therapy with either carboplatin or iproplatin. Both platinum analogues were administered intravenously every 28 days at doses of 400 mg/m2 carboplatin and 300 mg/m2 iproplatin. None of 14 evaluable patients treated with carboplatin responded. Therefore, this arm was closed and from then on all eligible patients were registered on the iproplatin arm. 5 of 29 evaluable patients treated with iproplatin achieved a partial response (17%) for a median duration of 27 weeks (range 22-37). Iproplatin did not induce renal function disturbance. Gastrointestinal toxicity was mild to moderate. Bone marrow toxicity predominantly consisted of thrombocytopenia and required platelet transfusions in 13% of patients. 2 patients developed hypersensitivity reactions. It is concluded that the bone marrow toxicity and the chance of hypersensitivity render iproplatin an unattractive alternative to cisplatin.

Prognostic significance of tissue polypeptide-specific antigen (TPS) in patients with advanced non-small cell lung cancer.

In this study, we evaluated the prognostic value of the tumour marker, tissue polypeptide-specific antigen (TPS), in 203 patients with non-small cell lung cancer (NSCLC), and related this to several other known prognostic factors. TPS was significantly correlated with lactate dehydrogenase (LDH), gamma-glutamyltranspeptidase and alkaline phosphatase, and the median level of TPS in patients with stage 4 disease was significantly higher as compared to stage 3A and 3B disease. In the univariate analysis, performance status, stage of disease, LDH, alkaline phosphatase, a histology of undifferentiated large cell carcinoma and TPS all had a statistically significant association with survival. Multivariate analysis showed that stage of disease, performance status, histology and TPS were the most important prognostic factors. TPS has prognostic significance for survival in patients with advanced NSCLC, independent from performance status and stage of disease.

Results of a randomised phase II study of cisplatin plus 5-fluorouracil versus cisplatin plus 5-fluorouracil with alpha-interferon in metastatic pancreatic cancer: an EORTC gastrointestinal tract cancer group trial.

A randomised phase II study of 5-fluorouracil (5-FU) plus cisplatin (CDDP) with or without alpha-interferon 2b was performed in patients with pancreatic cancer with measurable metastatic disease outside the pancreas. The treatment in arm A consisted of cisplatin (100 mg/m(2)) on day 1, followed by a continuous infusion of 5-FU 1000 mg/m(2) for 4 days and in arm B the same treatment was given plus alpha-interferon 2b in a dose of 3 million Units/day subcutaneously (s.c.) from day 1 for 5 days. 36 patients were entered in the trial, 18 in each arm. In arm B only 15 patients were eligible. No responses were observed in the 5-FU/CDDP arm and only 2 partial responses were achieved in the interferon-arm, lasting 27 and 32 weeks, respectively. Both treatment arms showed considerable toxicity. It has to be concluded that both treatment regimens have little activity and cannot be recommended.

High-dose 5-fluorouracil plus low dose methotrexate plus or minus low-dose PALA in advanced colorectal cancer: a randomised phase II-III trial of the EORTC Gastrointestinal Group.

The aim of this study was to investigate whether N-(phosphonacetyl)-L-aspartic acid (PALA) can enhance the activity of low-dose methotrexate (LD-MTX) modulated infusional 5-fluorouracil (5-FU) in patients with advanced colorectal cancer. 198 patients were randomised either to (i) 5-FU 60 mg/kg as a continuous infusion over 48 h, to be given weekly four times and thereafter every 2 weeks, with methotrexate 40 mg/m(2) administered just before 5-FU (control regimen) or to (ii) PALA 250 mg/m(2) as a 15 min infusion administered 24 h before 5-FU and methotrexate which was given as described in the control regimen. The response rate was 13% in the patients randomised to the control arm and 7% in the patients randomised to the experimental arm. If stabilisation of the disease was also considered as a positive response, these figures become 54 and 46%, respectively. All these differences did not reach statistical significance. The median durations of progression-free survival (PFS) in the two treatment groups were not significantly different. The median duration of survival was 13.1 months in the control arm and 11.9 months in the experimental arm (P=0.31). No benefit was obtained by adding PALA to LD-MTX+infusional FU. Taking into account data from US trials, the modulating effect of PALA, although 'promising' in phase II, could not be substantiated in randomised studies.

What is the optimal dose and duration of treatment with etoposide? I. Maximum tolerated duration of daily treatment with 50, 75, and 100 mg of oral etoposide.

Because etoposide is a cell-cycle phase-specific drug, its degree of cytotoxicity likely relies on duration of cell exposure to a specific concentration. We investigated the maximum tolerated duration of oral etoposide treatment at doses of 100, 75, and 50 mg/d in previously treated patients with biopsy-proven, advanced cancer. "Maximum tolerated" was defined as tumor progression or hematologic toxicity (World Health Organization [WHO] grade > or = 2). The maximum tolerated duration in 19 patients given 100 mg/d was > or = 21 days, since this was the predetermined cutoff point; 3 patients discontinued etoposide because of early tumor progression, and 6 others had developed leukopenia or thrombocytopenia (WHO grade > 2) by day 21. The maximum tolerated duration in 13 patients given 75 mg/d was a median of 11 weeks (range, 2 to 19); 6 patients developed tumor progression and 6 others leukopenia (WHO grade > or = 2) requiring discontinuation of treatment. Ten patients given 50 mg/d tolerated therapy for a median of 13 weeks (range, 3 to 26 weeks); treatment was halted in seven patients because of tumor progression, two because of leukopenia (WHO grade > or = 2), and one because of stomatitis. The data from this study and others suggest that above a certain minimal plasma level, etoposide induces concentration-dependent cumulative toxicity. What remains to be determined is the minimal plasma level per tumor type. It will also be interesting to see whether myelopoiesis, thrombocytopoiesis, and erythropoiesis have differential sensitivity to etoposide, since thrombocytopenia did not occur using daily etoposide doses of 50 and 75 mg, whereas at the same doses 10 of 23 patients required erythrocyte transfusion.

A phase I study of daily oral teniposide for 20 days.

In this phase I study, teniposide was administered orally for 20 consecutive days to patients with refractory cancers. All patients but one were pretreated. When given for 20 consecutive days, the maximum tolerated dose of teniposide was 100 mg/d. Myelosuppression was the dose-limiting toxicity, and occurred between days 17 and 31. In all patients blood counts had sufficiently recovered by day 35 to begin another 20-day course. Gastrointestinal toxicity persisted in 6 of 15 patients despite antiemetics. Total alopecia was observed in 10 of 13 patients at risk. We recommend teniposide 100 mg/d for 20 consecutive days for evaluation of antitumor efficacy in phase II studies.

A phase I dose finding study of a biweekly schedule of a fixed dose of cisplatin with increasing doses of paclitaxel in patients with advanced esophageal cancer.

We performed a phase I study of a fixed dose of cisplatin combined with increasing doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) given in a biweekly schedule to determine the maximum tolerated dose in patients with advanced esophageal cancer. The starting dose was cisplatin 60 mg/m2 and paclitaxel 100 mg/m2, given by intravenous infusion every 2 weeks. Patients were re-treated when the granulocyte counts were greater than 0.75 x 10(9)L and the platelet counts were greater than 75 x 10(9)/L. The paclitaxel dose has been escalated to 160 mg/m2 and the maximum tolerated dose has not yet been reached. At the higher dose levels, more grade 3 and 4 granulocytopenia was observed, but no patient had to be hospitalized because of febrile neutropenia. Nonhematologic toxicity was mild at all dose levels. Increasing the dose of paclitaxel from 100 mg/m2 to 160 mg/m2 leads to an approximately 50% increase in the dose intensity, as calculated in milligrams per square meter per week (mg/m2/wk) over six cycles. Of the 31 patients evaluable for response, 17 (55%) achieved either a partial or a complete response. In conclusion, biweekly administration of cisplatin and paclitaxel, with re-treatment at a granulocyte level greater than 0.75 x 10(9)/L, is feasible and well tolerated, and has a promising response rate in patients with advanced esophageal cancer. Further accrual is ongoing to determine the maximum tolerated dose of this schedule.

What is the optimal dose and duration of treatment with etoposide? II. Comparative pharmacokinetic study of three schedules: 1 x 100 mg, 2 x 50 mg, and 4 x 25 mg of oral etoposide daily for 21 days.

The large interpatient and intrapatient pharmacokinetic variability of oral etoposide is well known. We investigated whether dose fractionation would result in less variability. Fifteen patients (five in each etoposide schedule) were given either 100 mg once daily, 50 mg twice daily, or 25 mg four times daily for 21 days. On days 1, 8, and 15 blood samples were collected during 24 hours to measure plasma etoposide levels. Hematologic toxicity was determined by weekly leukocyte and platelet counts and expressed as the relative decrease in these parameters. Once-daily administration of etoposide 100 mg correlated with a significantly higher peak concentration than was observed with the other two schedules. The mean area under the concentration versus time curve (AUC) and mean time with a plasma etoposide concentration above 1 microgram/mL were similar with the three schedules. Peak plasma concentrations, AUCs, and times with plasma concentration above 1 micrograms/mL correlated significantly with the relative decrease in leukocyte but not platelet counts. Large interpatient and intrapatient variability of pharmacokinetic parameters was observed with all three schedules. These data do not support fractionating a daily 100-mg etoposide dose. Moreover, it does not appear useful to adjust oral etoposide doses based on pharmacokinetic data obtained once during a prolonged treatment period. Finally, adjusting oral etoposide doses based on hematologic toxicity seems advisable to decrease the interpatient variability of etoposide's pharmacokinetics.

Absolute bioavailability and pharmacokinetics of oral teniposide.

The absolute bioavailability and pharmacokinetics of orally administered teniposide were investigated in 25 patients. All patients received 50 to 60 mg/m2 teniposide intravenously on day 1, before oral administration. Six patients received 60 mg/m2 as a single oral dose on day 8; 5 patients received 60 mg/m2 and 120 mg/m2 as a single oral dose on days 8 and 15, respectively; 5 patients received 120 mg/m2 and 240 mg/m2 as a single oral dose on days 8 and 15, respectively; 6 patients received 60 mg/m2 as a single oral dose on 5 consecutive days from days 8 to 12; and 3 patients received 50 mg/m2 three times a day at 6-hour intervals on day 8. The mean absolute bioavailability was 41.6% +/- 14.2% with a large interindividual variability (range, 19.7% to 71.4%) and a low intraindividual variability (range, 2.8% to 13.9%). At a dose of 240 mg/m2, the bioavailability was decreased, whereas administration of multiple doses on 1 day or 5 consecutive days increased the overall bioavailability. In conclusion, teniposide can be administered orally with a bioavailability comparable with that of etoposide. The schedule dependency of both drugs warrants investigations of oral administration for 21 or more days. A formulation of teniposide capsules of 50 mg or less would be most helpful to facilitate oral administration.

Adjuvant chemotherapy after resection of adenocarcinoma of the periampullary region and the head of the pancreas. A non-randomized pilot study.

From 1980 till 1984 16 patients were entered into a non-randomized pilot study, to investigate the feasibility of five courses of adjuvant 5-fluorouracil, Adriamycin and mitomycin C (FAM) after a curative resection of pancreatic or periampullary cancer. The survival of this group of patients was compared with that of 36 patients who underwent a curative resection alone between 1977 and 1984. Four patients received less than 20%, 4 patients 50%-60% and 7 patients greater than or equal to 80% of the calculated dose of adjuvant chemotherapy. The chemotherapy was badly tolerated. Only 1 patient resumed some of his normal activity during chemotherapy. The 3-year actuarial survival after curative resection with and without FAM was similar, i.e. 24% and 28% respectively. These data suggest that adjuvant FAM after a Whipple's operation or total pancreatectomy is not feasible because of additive postoperative and chemotherapy-induced morbidity.

Evaluation of CA19-9 serum levels for monitoring disease activity during chemotherapy of pancreatic adenocarcinoma.

Between 1987 and 1990 21 patients with proven adenocarcinoma of the pancreas were treated with chemotherapy in four different phase II studies. For 14 patients, serial measurements of CA19-9 serum levels and clinical evaluations of response by computed tomography scan and/or ultrasound were available. Clinical stable disease and progressive disease were accompanied by stable or exponentially rising serum levels of CA19-9. One patient with clinical partial remission showed a 90% decline of CA19-9. However, a 75% decline of CA19-9 was also observed in a patient with rapidly progressive disease. These data seem to indicate that the CA19-9 serum level may be used as an easy and sensitive tool to evaluate progressive disease during chemotherapy.

Neoadjuvant treatment in oesophageal cancer: the needs for future trials. The Rotterdam Esophageal Tumor Study Group.

In view of the poor survival after surgery alone for oesophageal cancer, combination with chemotherapy seems rational. A concept of upfront chemotherapy is discussed and seems especially useful for these tumours. The published randomized trials, studying the effect of neoadjuvant chemotherapy do, however, not (yet) show an improved overall survival, apart from one study with a significant median survival benefit at an interim evaluation. The responding patients have in all trials a far better survival than the non-responders. The numbers of patients are small and results of other ongoing and future trials should be awaited. New trials testing high-dose chemotherapy with bone marrow support should be initiated.

Early detection and treatment of oesophageal and gastric cancer. The Rotterdam Oesophageal Tumour Study Group.

Early oesophageal and gastric cancer are unique forms of oesophageal and gastric carcinoma with an excellent prognosis. Remarkable changes have taken place in the epidemiology of upper gastrointestinal malignancies. In particular, the incidence of adenocarcinoma of the distal oesophagus and the gastric cardia has risen over the past two decades. In the United States and Europe, early detection is dependent on a low threshold for upper gastrointestinal endoscopy with biopsy, because specific symptoms and physical findings are rarely present in patients with early oesophageal and gastric cancer. In addition to histology, the detection of possible markers of malignancy, such as aneuploidy (detected by flow cytometry) and the presence of oncogenes and tumour-suppressor genes, in biopsy material may be of value in the diagnosis of early cancers. For patients with early oesophageal or gastric cancer, surgery offers the best hope of cure. If patients are at high risk for surgery, an endoscopic resection may be an alternative option. This review discusses the definitions, the changes in epidemiology, the current options for diagnosis and treatment, and the value of screening programs for patients with early oesophageal or gastric cancer.