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.

Long-term results of a randomised phase III trial of weekly versus three-weekly paclitaxel/platinum induction therapy followed by standard or extended three-weekly paclitaxel/platinum in European patients with advanced epithelial ovarian cancer.

BACKGROUND: Weekly paclitaxel/carboplatin might improve survival in platinum-resistant epithelial ovarian cancer (EOC). We compared efficacy of first-line weekly to three-weekly paclitaxel/cis- or carboplatin (PCw and PC3w) induction therapy, followed by either three or six PC3w cycles. PATIENTS AND METHODS: In this multicentre, randomised phase III trial with 2×2 design, patients with FIGO stage IIb-IV EOC were randomised to six cycles PCw (paclitaxel 90mg/m(2), cisplatin 70mg/m(2) or carboplatin AUC 4) or three cycles PC3w (paclitaxel 175mg/m(2), cisplatin 75mg/m(2) or carboplatin AUC 6), followed by either three or six cycles PC3w. Primary endpoints were progression free survival (PFS) and overall survival (OS). Secondary endpoints were response rate (RR) and toxicity. RESULTS: Of 267 eligible patients, 133 received PCw and 134 PC3w. The first 105 patients received cisplatin, after protocol amendment the subsequent 162 patients received carboplatin. Weekly cisplatin was less well tolerated than weekly carboplatin. All PC3w cycles were well tolerated. At the end of all treatments, RR was 90.8% with no differences between the treatment arms. After a follow-up of median 10.3years (range 7.1-14.8), median PFS was 18.5 (95% confidence interval (CI) 15.9-21.0) months for PCw and 16.4 (95% CI 13.5-19.2) months for PC3w (p=0.78). Median OS was 44.8 (95% CI 33.1-56.5) months for PCw and 41.1 (95% CI 34.4-47.7) months for PC3w (p=0.98). CONCLUSIONS: There was no benefit in terms of OS, PFS or RR for a weekly regimen nor for extended chemotherapy as first-line treatment for EOC in European patients.

Prognostic factors for survival in patients with advanced oesophageal cancer treated with cisplatin-based combination chemotherapy.

The objective of this study was to identify prognostic factors for survival in patients with advanced oesophageal cancer, who are treated with cisplatin-based combination chemotherapy. We analysed the baseline characteristics of 350 patients who were treated in six consecutive prospective trials with one of the following regimens: cisplatin/etoposide, cisplatin/etoposide/5-fluorouracil, cisplatin/paclitaxel (weekly) and cisplatin/paclitaxel (biweekly). Predictive factors in univariate analyses were further evaluated using multivariate analysis (Cox regression). The median survival of all patients was 9 months. The 1, 2 and 5-year survival rates were 33, 12 and 4%, respectively. The main prognostic factors were found to be WHO performance status (0 or 1 vs 2), lactate dehydrogenase (normal vs elevated), extent of disease (limited disease defined as locoregional irresectable disease or lymph node metastases confined to either the supraclavicular or celiac region vs extensively disseminated disease) in addition to the type of treatment (weekly or biweekly cisplatin/paclitaxel regimen vs 4-weekly cisplatin/etoposide with or without 5-fluorouracil). Although weight loss, liver metastases and alkaline phosphatase were significant prognostic factors in univariate analyses, these factors lost their significance in multivariate analyses. The median survival for patients without any risk factors was 12 months, compared to only 4 months in patients with WHO 2 plus elevated LDH and extensive disease. The performance status, extent of disease, LDH and the addition of paclitaxel to cisplatin are independent prognostic factors in patients with advanced oesophageal cancer, who are treated with cisplatin-based combination chemotherapy.

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.

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.

Phase II study of the combination cisplatin, etoposide, 5-fluorouracil and folinic acid in patients with advanced squamous cell carcinoma of the esophagus.

The objective of this study was to determine the toxicity and the efficacy of the combination of cisplatin, etoposide, 5-fluorouracil (5-FU) and folinic acid in the treatment of patients with advanced squamous cell carcinoma of the esophagus. Patients received cisplatin 80 mg/m(2) i.v. on day 1, etoposide 125 mg/m(2) i.v. on day 1 and etoposide 200 mg/m(2) p.o. on days 3 and 5, 5-FU 375 mg/m(2)/day continuously i.v. combined with folinic acid 30 mg p.o. 6 times per day on days 1--4. Courses were repeated every 4 weeks until progression or up to a maximum of 6 courses. Patients were evaluated for response after every two courses. Sixty-nine patients received a total of 291 courses (median 4, range 1--6). The hematological toxicity consisted of leukocytopenia grade 3 or 4 in 17 and 16% of patients, respectively. Leukocytopenic fever was seen in 19% of patients. Thrombocytopenia grade 3 or 4 was seen in 13 and 7% of patients, respectively. Non-hematological toxicity consisted of nausea/vomiting grade 3 in 32%, diarrhea grade 3 in 6% and mucositis grade 3 or 4 in 23% of patients. The overall response rate was 34% (complete response 4%, partial response 30%) and the median time to progression was 7 months in 13 patients who received no additional treatment. The median survival for all patients was 9.5 months with a 1-year survival rate of 36%. Ten patients with initially locally unresectable disease (N=2) or celiac or supraclavicular lymph node metastases (N=8) who received additional treatment (esophageal resection in seven patients and radiotherapy in three patients) after they had responded to chemotherapy had a 3-year survival of 50%. We conclude that the combination cisplatin and etoposide combined with 5-FU and folinic acid is a safe and active regimen for patients with advanced squamous cell carcinoma of the esophagus. Mucositis is the most prevalent toxicity.

Phase I study of a biweekly schedule of a fixed dose of cisplatin with increasing doses of paclitaxel in patients with advanced oesophageal cancer.

We performed this dose-finding study with a fixed dose of cisplatin and increasing doses of paclitaxel given every 2 weeks to determine the maximum tolerable dose of this schedule. Sixty-four patients with advanced oesophageal cancer were treated with a cisplatin dose of 60 mg m(-2) and increasing doses of paclitaxel from 100 mg m(-2) up to 200 mg m(-2) both administered over 3 h for a maximum of six cycles in patients with stable disease or eight cycles in responding patients. Patients were retreated when the granulocytes were > 0.75 x 10(9) l(-1) and the platelets > 75 x 10(9) l(-1). The dose of paclitaxel could be increased to 200 mg m(-2) without encountering dose limiting haematological toxicity. At the dose levels 190 mg m(-2) and 200 mg m(-2) of paclitaxel cumulative sensory neurotoxicity became the dose-limiting toxicity. The dose intensity of paclitaxel calculated over six cycles rose from 50 mg m(-2) per week to 85 mg m(-2) per week. Only three episodes of granulocytopenic fever were encountered out of a total of 362 cycles of treatment. Of the 59 patients evaluable for response, 31 (52%) had a partial or complete response. In a biweekly schedule with a fixed dose of 60 mg m(-2) cisplatin it is possible to increase the dose of paclitaxel to 180 mg m(-2). At higher dose levels, neurotoxicity becomes the dose-limiting toxicity. The observed response rate warrants further investigation of this schedule.

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.

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.

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.

Cisplatin and etoposide in oesophageal cancer: a phase II study. Rotterdam Oesophageal Tumour Study Group.

In the search for effective chemotherapy regimens which can be used in multimodality treatment programmes for patients with cancer of the oesophagus, we conducted a phase II trial to determine the activity and toxicity of the combination of cisplatin and etoposide in patients with advanced squamous cell carcinoma of the oesophagus. Seventy-three consecutive patients with unresectable or metastatic squamous cell carcinoma of the thoracic oesophagus were treated with cisplatin 80 mg m-2 by 4 h infusion on day 1, etoposide 100 mg (fixed dose) by 2 h infusion on day 1 and 2, and etoposide 200 mg m-2 orally on day 3 and 5. Courses were repeated every 4 weeks, for a maximum of six courses. The oral dosages of etoposide were modified individually until a significant degree of myelosuppression was reached. Of 65 evaluable patients, five complete responses (CRs) and 26 partial responses (PRs) were seen, for an overall response rate of 48% (95% confidence interval 35-60%). Median time to progression was 7 months (range 3-72 + months). There were two toxic deaths (neutropenic sepsis). The response rate equals that of other cisplatin-based regimens. Its toxicity profile allows addition of a third active drug such as 5-fluorouracil.

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.

5-fluorouracil and folinic acid in advanced adenocarcinoma of the esophagus or esophago-gastric junction area. Rotterdam Esophageal Tumor Study Group.

BACKGROUND: The results of chemotherapy against gastric cancer or esophageal squamous cell carcinomas cannot be generalized to adenocarcinomas of the esophagus. Therefore the combination of 5-fluorouracil and folinic acid was studied in esophageal adenocarcinoma. PATIENTS AND METHODS: After a loading dose of 4 x 90 mg folinic acid orally, a continuous infusion of 5-fluorouracil 500 mg/sqm/day for 5 days with concommitant folinic acid 6 x 60 mg/day orally, was administered to 29 consecutive patients with metastatic adenocarcinoma of the esophagus or esophagogastric junction area. RESULTS: This schedule was tolerated well with mild mucositis and diarrhea. In one patient reversible cardiotoxicity was seen. Five patients obtained a partial remission (19%; 95% confidence interval (CI): 6%-38%), and 8 patients stable disease. One early death. CONCLUSIONS: This combination has modest activity against adenocarcinoma of the esophagus; its toxicity profile permits incorporation in combination protocols.

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.

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.

Phase II study of carboplatin and etoposide as a first line regimen in patients with metastatic breast cancer.

BACKGROUND: The data available on the role of carboplatin and etoposide in breast cancer, especially in patients with no or minimal prior therapy are limited. PATIENTS AND METHODS: We performed a phase II study with carboplatin and etoposide as first line treatment in 34 patients with metastatic breast cancer. The treatment regimens was carboplatin 300 mg/m2 day 1, and etoposide 100 mg/m2 days 1, 3 and 5 every four weeks. RESULTS: Of 33 evaluable patients, 2 achieved complete responses (6%) lasting 4 and 5 months, 7 patients (21%) achieved partial responses with a median duration of 6+ (range 5-8) months, 15 patients had stable disease, and 9 progressed during treatment. The major toxicity was myelosuppression WHO grades 3 or 4 leukocytopenia or thrombocytopenia were seen in 15 and 10 patients, respectively. One formally ineligible patient with an impaired renal function died 14 days after the start of treatment because of a septicaemia in the presence of a grade 4 leukocytopenia. Besides this patient no other patient presented with granulocytopenic fever. CONCLUSION: In view of the observed response rate of 27% (95% confidence interval 11%-43%) we think that carboplatin and etoposide given in this dose and schedule has probably no clear advantage over the more commonly used regimens.

Evaluation of a new tumour marker in patients with non-small-cell lung cancer: Cyfra 21.1.

The Cyfra 21.1 assay is a newly developed test which measures in serum a fragment of cytokeratin 19. We evaluated this marker in 212 patients with non-small-cell lung cancer (NSCLC), predominantly stage 3a-b and 4, and compared it with three other markers: carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and tissue polypeptide antigen (TPA). Sensitivities for Cyfra 21.1, TPA, CEA and SCC (using cut-off levels corresponding to a 95% specificity for benign lung diseases) were 40%, 40%, 42% and 19% respectively. The sensitivity of CEA was significantly higher in patients with adenocarcinomas compared with the other three markers, while the sensitivity of Cyfra 21.1 and TPA was significantly higher in patients with squamous cell carcinomas. The value of Cyfra 21.1 for monitoring disease during chemotherapy could be evaluated in 23 patients with squamous cell carcinomas. When the cases of lead time were included a concordance between clinical evaluations according to WHO response criteria and evaluations according to changes in the marker levels of 74% was found. The criteria defined for marker response were a 65% decrease in the marker level for a partial response and a 40% increase for progressive disease. In particular, increasing levels of this marker indicated usually disease progression. In conclusion, Cyfra 21.1 is a useful serum marker for patients with NSCLC, especially for disease monitoring of patients with squamous cell carcinoma during and after chemotherapy.

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.