Long-term anorectal, urinary and sexual dysfunction causing distress after radiotherapy for anal cancer: a Danish multicentre cross-sectional questionnaire study.

AIM: The objective of primary radiotherapy for anal cancer is to remove cancer while maintaining anorectal function. However, little is known about anorectal function among long-term survivors without colostomy. Using a cross-sectional questionnaire study, we examined symptoms and distress related to the dysfunction of pelvic organs after radiotherapy for anal cancer. METHOD: A questionnaire regarding anorectal, urinary and sexual symptoms was sent to anal cancer patients without recurrence or colostomy, diagnosed during 1996-2003, and treated with curative intent (chemo)radiotherapy at three Danish centres. For each symptom we assessed frequency and severity and the level of symptom-induced distress (no, little, moderate or great distress). RESULTS: Of 94 eligible patients, 84 (89%) returned the completed questionnaire at a median of 33 months after radiotherapy. Incontinence for solid stools, liquid stools and gas occurred at least monthly in 31%, 54% and 79% of patients, respectively. Overall 40% of patients reported great distress from incontinence for solid or liquid stools at least monthly. Faecal urgency occurring at least monthly was experienced by 87% of patients and caused great distress in 43%. Stress, urge or another type of urinary incontinence occurred at least monthly in 45% and caused great distress in 21%. Urinary urgency occurred at least monthly in 48% but only caused great distress in 14%. Sexual desire was severely decreased in 58% and only 24% were satisfied with their sexual function. CONCLUSION: Distressing long-term anorectal and sexual dysfunction was common after radiotherapy for anal cancer, and morbidity due to urinary dysfunction was moderate.

First-line treatment of advanced ovarian cancer with paclitaxel/carboplatin with or without epirubicin (TEC versus TC)--a gynecologic cancer intergroup study of the NSGO, EORTC GCG and NCIC CTG.

BACKGROUND: The addition of anthracyclines to platinum-based chemotherapy may provide benefit in survival in ovarian cancer patients. We evaluated the effect on survival of adding epirubicin to standard carboplatin and paclitaxel. PATIENTS AND METHODS: We carried out a prospectively randomized phase III study comparing carboplatin plus paclitaxel (TC; area under the curve 5 and 175 mg/m(2)) with the same combination and epirubicin (TEC; 75 mg/m(2) i.v.). Between March 1999 and August 2001, 887 patients with epithelial ovarian, tubal or peritoneal cancer International Federation of Gynecology and Obstetrics stages IIB-IV were randomized to receive either TC (442 patients) or TEC (445 patients). RESULTS: Median time to progression was 16.4 months in the TEC arm and 16.0 months in the TC arm (hazard ratio 0.99; 95% confidence interval [CI]: 0.9-1.2). Median overall survival time was 42.4 months for the TEC arm and 40.2 for the TC arm (hazard ratio 0.96; 95% CI: 0.8-1.1). Grade 3/4 hematologic toxic effects and most grade 3/4 non-hematologic toxic effects were more frequent in the TEC arm. Accordingly, a quality-of-life analysis showed inferiority of TEC versus TC. CONCLUSION: The addition of epirubicin to standard carboplatin and paclitaxel treatment did not improve survival in patients with advanced ovarian, tubal or peritoneal cancer.

First-line treatment of ovarian cancer FIGO stages IIb-IV with paclitaxel/epirubicin/carboplatin versus paclitaxel/carboplatin.

The objective of this study was to compare the safety and efficacy of carboplatin plus epirubicin and paclitaxel (TEC) to carboplatin and paclitaxel (TC), in the treatment of epithelial ovarian, peritoneal, or tubal carcinoma. Between March 1999 and August 2001, 887 patients were randomized to receive six to nine cycles of paclitaxel (175 mg/m2, 3 h intravenously) followed by carboplatin (AUC 5, Calvert formula) with or without epirubicin (75 mg/m2 intravenously prior to paclitaxel), on a 3-weekly schedule. The primary endpoint was progression-free survival. Demographic information: Residual disease <1 cm was reported on 41% of patients. At the end of treatment, 65% in the TEC and 55% in the TC arm had achieved a clinical complete response, and 18 and 25% a clinical partial response resulting in an overall response rate of 83% in the TEC and 80% in the TC arm, whereas 7 and 9% had progressive disease, respectively. The three-drug combination produced a markedly higher myelotoxicity, resulting in a higher frequency of febrile neutropenia (12.5% of the TEC and 1.5% of the TC patients) and a higher number of dose reductions and treatment delays. Cycle prolongation above seven days was seen in 7 and 5% of cycles in the TEC and TC arm, respectively. Stomatitis > or = grade 3 was also higher with TEC (4% TEC and 0.5% TC). Reductions in left ventricular ejection fraction of more than 15% after six courses were slightly more common with the TEC regimen (3% versus 1.5%), but the difference was not statistically significant (P = 0.2). In conclusion, treatment with the TEC combination produced a higher rate of complete responses than treatment with the TC combination. Toxicity was manageable. Long-term survival data are awaited.

Patients with ovarian cancer have elevated (51)Cr-EDTA plasma clearance early post-operatively.

Plasma clearance of (51)Cr-EDTA (Clp(EDTA)) is widely used to determine glomerular filtration rate prior to carboplatin based chemotherapy. We have observed that many patients with ovarian cancer have elevated Clp in the early post-operative phase compared to later phases. The purpose of this study was to examine whether this observation reflects a systematic difference. We retrospectively analysed data from 53 patients who had undergone surgery for ovarian cancer. Twenty-six patients had Clp(EDTA) measured early after the operation (mean, 8 days (range, 3-16 days)) (early group), and 27 patients had Clp(EDTA) measured late post-operatively (mean, 32 days (range, 19-48 days)) (late group). Clp(EDTA) values was measured before the first, third and fifth course of chemotherapy. Additionally, age, height, weight, cancer stage, ascites and tumour histology were noted. Mean Clp(EDTA) in the early group was significantly higher than in the late group (104+/-4.4 vs 89+/-3.5 ml.min(-1) per 1.73 m(2); P =0.005). Clp(EDTA) declined significantly in the early group from the first measurement after the operation until measurement before the third course of chemotherapy but remained constant in the late group. Clp(EDTA) was not correlated to ascites, cancer stage or tumour histology. It is concluded that patients with ovarian cancer have significantly higher Clp(EDTA) in the early post-operative phase than similar patients with Clp(EDTA) measured late post-operatively.

Phase II study of vinorelbine in the treatment of platinum-resistant ovarian carcinoma.

OBJECTIVE: The purpose of this phase II study was to evaluate on an intent-to-treat basis the activity and toxicity of single-agent vinorelbine (VRL) as second-line chemotherapy of patients with platinum-resistant ovarian cancer. Platinum-resistant disease was defined as disease refractory to or relapsing within 12 months after finishing platinum-containing chemotherapy. METHODS: VRL (30 mg/m(2)) was administered intravenously as a bolus injection days 1 and 8 every 21 days. Initially, four courses of VRL were given. Patients with responding or stable disease received four more courses of VRL to a maximum of eight courses. RESULTS: Twenty-eight of 33 eligible patients were considered evaluable for response. The overall response rate was 21% (7/33) (95% CI: 7--35). Median time to progression was 3.1 months and median survival was 10.1 months. Toxicity was generally mild. Leukopenia was the dose-limiting toxicity. CALGB grade III/IV infection was observed in 15/0% of patients. The most important nonhematologic toxicities were nausea and constipation. Grade III/IV nausea was observed in 6/0% and grade III/IV constipation in 3/3% of patients. Peripheral neurotoxicity was only a minor problem with no grade III/IV toxicity. No patients stopped treatment because of toxicity and no toxic death was reported. CONCLUSION: VRL was generally well tolerated, but the activity in platinum-resistant ovarian cancer was only modest, although fully comparable to other second-line treatments. Further studies are required to define the role of VRL in combination chemotherapy for ovarian cancer.

Invasive oxygen measurements and pimonidazole labeling in human cervix carcinoma.

PURPOSE: This study was designed to compare tumor hypoxia assessed by invasive O2 sensitive electrodes and pimonidazole labeling in primary human cervix carcinomas. METHODS AND MATERIALS: Twenty-eight patients with primary cervix carcinomas (FIGO Stage Ib-IVa) were investigated. Both invasive pO2 measurements and pimonidazole labeling were obtained in all patients. Before treatment, patients were given pimonidazole as a single injection (0.5 g/m2 i.v.). Ten to 24 h later, oxygenation measurements were done by Eppendorf histography, and after this procedure biopsies were taken for pimonidazole-binding analysis. Tumor oxygen partial pressure (pO2) was evaluated as the median tumor pO2 and the fraction of pO2 values < or = 10 mmHg (HF10). Biopsies were formalin fixed and paraffin embedded, and hypoxia was detected by immunohistochemistry using monoclonal antibodies directed against reductively activated pimonidazole. Pimonidazole binding was evaluated by a semiquantitative scoring system. RESULTS: Both Eppendorf measurements and pimonidazole binding showed large intra-and intertumor variability. A comparison between pimonidazole binding expressed as the fraction of fields at the highest score and HF10 showed a trend for the most well-oxygenated tumors having a low fraction of fields; however, the correlation did not reach statistical significance (p = 0.43, r = 0.165; Spearman's rank correlation test). CONCLUSION: Hypoxia measured in human uterine cervix carcinomas is heterogeneously expressed both within and between tumors when assessed by either invasive pO2 measurements or pimonidazole binding. Despite a trend that tumors with high pO2 values expressed less pimonidazole binding, no correlation was seen between the two assays in this preliminary report.

Granisetron compared with prednisolone plus metopimazine as anti-emetic prophylaxis during multiple cycles of moderately emetogenic chemotherapy.

This randomized, double-blind, double-dummy parallel study compared the anti-emetic efficacy and tolerability of the serotonin antagonist granisetron with prednisolone plus the dopamine D2 antagonist metopimazine during nine cycles of moderately emetogenic chemotherapy. Chemotherapy naive women with stage I or II breast cancer scheduled to intravenous cyclophosphamide, fluorouracil and methotrexate or cyclophosphamide, epirubicin and fluorouracil every 3 weeks were included. Patients received a single intravenous dose of granisetron 3 mg or a 3-day oral treatment with prednisolone 25 mg once a day plus metopimazine 30 mg four times a day. A total of 223 women were enrolled and 218 patients (97.8%) were evaluable for efficacy. Granisetron (n = 109) was superior to prednisolone plus metopimazine (n = 109) in the prophylaxis of acute nausea and vomiting during the first cycle of chemotherapy (P < 0.001) and prednisolone plus metopimazine was superior on days 2-5 (P = 0.002). Overall, granisetron was superior on days 1-5 (P = 0.009). The median number of cycles completed with granisetron was five (95% confidence interval 4-6) compared with two (95% confidence interval 2-2) for prednisolone plus metopimazine (P = 0.0019). Constipation and rash were reported more frequently with granisetron (P < 0.001 and P = 0.043 respectively) and palpitations more frequently with prednisolone plus metopimazine (P = 0.015). In conclusion, the number of cycles completed with granisetron was significantly higher than the number completed with prednisolone plus metopimazine, but the anti-emetic efficacy of both treatments declined during multiple cycles of moderately emetogenic chemotherapy.

[Chemotherapy and radiotherapy as part of curative management of esophageal cancer]. / Kemoterapi og strålebehandling som led i kurativ behandling af cancer esophagi.

Chemotherapy and irradiation it combination or alone have been employed in the treatment of oesophageal carcinomas for many years. However, their place in curative treatment is not definitively clarified. Several non-randomized studies indicate an effect from combined chemotherapy and irradiation possibly followed by surgery. Randomized studies published during the last few years confirm an increased curability in patients who have received combined treatment. New multicentre trials show that a more aggressive attitude is indicated in selected groups of patients with oesophageal carcinoma. Due to the variable spectrum of the disease and complexity of the treatment the treatment should be given in centres which master the different modalities.

Immunohistochemical evaluation of estrogen and progesterone receptors in paraffin-embedded, formalin-fixed endometrial tissues: comparison with enzyme immunoassay and immunohistochemical analysis of frozen tissue.

Monoclonal antibody (MoAb) 1D5 with specificity to the estrogen receptor (ER), MoAb 1A6, and a polyclonal antibody (PoAb) (the latter two with specificity to the progesterone receptor [PgR]) were used to stain microwave-pretreated sections of formalin-fixed, paraffin-embedded normal and malignant endometrial tissues (n = 60). The tissues were previously evaluated for ER and PgR by enzyme immunoassay (EIA) (n = 44) and immunohistochemical analysis of frozen tissue (ICAfroz, n = 59). With results of EIA as a reference, the ER-1D5 method yielded a better agreement on receptor status, i.e., positive versus negative (74 vs. 51%) and a higher sensitivity (71 vs. 45%) but a similar high specificity (100%) than the ER-ICA method. Compared with results of PgR-EIA, the immunohistochemical assays for PgR gave similar results as to agreement (86-95%) and sensitivity (95-97%). Quantitative agreement on the fraction of cells stained for ER and PgR by immunohistochemical analysis in frozen and formalin-fixed tissue was obtained in approximately 60% of the cases. The results of semiquantitation were correlated with the results of both ICA and EIA. The MoAbs 1D5 and 1A6, as well as the anti-PgR PoAb, thus seem to be valid for evaluation of ER and PgR status in formalin-fixed endometrial tissue. Differences in the specificity of the Abs and in the sensitivity of the methods used to demonstrate ER and PgR might explain some of the discordant findings.

Oral treosulfan as second-line treatment in platinum-resistant ovarian cancer: a phase II study. The Danish Ovarian Cancer Study Group.

OBJECTIVE: To evaluate the effect of oral treosulfan in patients with platinum-resistant ovarian cancer. METHODS: A phase II trial of oral treosulfan 500 mg per day in 30 females with platinum resistant ovarian cancer. All patients had measurable or evaluable disease. RESULTS: The treatment was well tolerated. One patient (3%) achieved a partial response lasting 12+ months. Seven patients had stable disease for 5.3 months (median) range 4.4-7.5 months. Median time to progression was 11.5 weeks (95% C.L. 11-12 weeks). Median survival was 31 weeks (95% C.L. 30-35 weeks). CONCLUSION: Oral treosulfan in the present schedule is not recommended in platinum resistant ovarian cancer.

Treatment outcome following radiotherapy in elderly patients with bladder cancer.

BACKGROUND AND PURPOSE: The optimal treatment of elderly patients with bladder cancer is not established. This study aimed to evaluate prognostic variables for survival and morbidity, which may be important for treatment strategy. MATERIAL AND METHODS: The medical records of 94 patients aged > or = 75 years receiving curatively intended radiotherapy for bladder cancer were reviewed retrospectively. RESULTS: Median age was 78 years (range 75-93 years). Fifty patients had T1-2 tumors, and 42 patients had T3-4 tumors. The total planned dose was 57.6-62.6 Gy in 24-30 fractions in 6 weeks. In 76 patients, a 2 week rest period was planned after 16 fractions (split course). Half of the patients were hospitalized during or after the treatment because of gastrointestinal or urogenital side effects. Median survival was 13.9 months (range 0.6-150.0 + months), 29% survived for 2 years and 7% survived for 5 years. Patients aged > 78 years survived for a shorter period than patients aged 75-78 years (13.4 versus 16.1 months). Univariate survival analysis revealed that low stage (T1-2), good performance status (PS < or = 1), split course treatment, no treatment interruption due to side effects, and no hospitalization during treatment were associated with long survival. In multivariate analyses, T-stage, split course treatment, and performance status were independent prognostic factors. CONCLUSION: The results confirm that curative intended radiotherapy is feasible in elderly patients, but patients with stage T3-4 and PS > 1 have a short survival. These patients should be offered palliative treatment.

Dose-effect study of carboplatin in ovarian cancer: a Danish Ovarian Cancer Group study.

PURPOSE: To elucidate the effect of a doubled carboplatin dose-intensity in epithelial ovarian cancer in combination with a fixed dose of cyclophosphamide. PATIENTS AND METHODS: A total of 222 patients with epithelial ovarian cancer stages II to IV were included in the study. Following surgery, patients were randomly assigned to receive carboplatin at an area under the concentration-versus-time curve (AUC) of 4 (AUC4) or carboplatin at an AUC of 8 (AUC8) and cyclophosphamide 500 mg/m2 given every 4 weeks for six courses. The AUC was calculated according to Calvert's formula. In 123 patients, the carboplatin AUC was also measured based on a single-sample method and the results were compared with the calculated AUC. The end points of the trial were complete pathologic remission (CPR) and crude survival. RESULTS: Approximately 50% of patients in both arms underwent second-look surgery. The frequency of CPR was 32% and 30%, respectively. The survival curves showed no significant difference (P = .84). The dose-intensity of cyclophosphamide was almost identical in the two arms, whereas that of carboplatin was different. In the AUC8 arm, the dose-intensity was 1.86 times that of the AUC4 arm. The results also demonstrated good agreement between the calculated and the measured AUC in most patients. Bone marrow toxicity was significantly higher in the AUC8 arm. CONCLUSION: A doubling of the carboplatin dose-intensity did not result in any significant improvement of pathologic remission or survival. Calvert's formula can be used to give a fairly accurate estimate of the carboplatin AUC. Bone marrow toxicity increased with higher dose-intensity, and a further increase of dose is only feasible with growth-factor or stem-cell support.

A phase 2 study with epirubicin as second-line treatment of patients with advanced epithelial ovarian cancer.

Thirty-six patients with advanced epithelial ovarian cancer received epirubicin as second-line therapy after primary treatment with carboplatin and cyclophosphamide. Thirty-four patients were evaluatable for response, 36 for toxicity. There were 9 responses (response rate 26.4%, 95% CI = 12.9-44.4), 2 complete and 7 partial. Median duration of response was 149 days (range 42-183); 4 patients with partial remission are still on study. Toxicity consisted of fatal cardiac failure and paravenous injection (1 patient), fatal leukopenia and sepsis (1 patient), and severe loss of appetite, nausea and vomiting, fatigue, and general malaise in 3 patients. Platelet nadir grade 4 (WHO) was observed in 2 patients while leukocyte nadir grade 4 was seen in 3 patients. The present study showed a high response rate from standard-dose epirubicin. Toxicity was acceptable in most patients, but 2 patients died from treatment complications which gives a treatment-related mortality rate of 6%. Response was primarily seen in patients with minor tumor load and in good general condition.

Antiemetic treatment with two different doses of methylprednisolone in breast cancer patients: a double-blind randomized cross-over study with evaluation of efficacy parameters.

This randomized double-blind cross-over study followed a previous one which showed an antiemetic efficacy from methylprednisolone (MP) 250 mg superior to placebo. The present study compared MP 40 mg with 250 mg in breast cancer patients treated with non-cisplatin chemotherapy. Preference after course II was the determining parameter. Participation in two courses was compulsory for evaluation, participation in four courses was optional. Interim analyses were performed after each 12 patients to a maximum of 60 patients. As there was no significant difference in preference in 60 patients the study was closed. Patients treated with the CEF regimen, patients who requested rescue antiemetics and patients completing four study courses had a better effect from high-dose MP reflected in preference and other parameters. Global assessments, measurement of emetic volumes and the visual analog scale for nausea gave a fair coherence with patients' preference. The numbers of emetic episodes and observer registered nausea were of no value. The stability of preference and other parameters after course II and IV, respectively, was low. The present study did not prove superiority from high-dose MP. This hypothesis must be tested in patients more severely bothered by emesis after chemotherapy. These results show the complexity of evaluation of antiemetic effect and demonstrate the dependency of a given result on the parameter used.

Lack of effect from mitomycin c plus 5-fluorouracil in platin-resistant ovarian cancer: a phase II study.

Sixteen patients with advanced ovarian cancer were included in a phase II study with mitomycin c (MMC) plus 5-fluorouracil (5-FU). All patients had previously received platin-based combination therapy, but were resistant to this treatment. A MMC 10 mg m-2 intravenous (iv) bolus was given on day 1 every 6 weeks, and 5-FU 1000 mg m-2 was given iv on days 1-3 every 3 weeks, as a continuous infusion over 72 h. Fifteen patients were evaluable for response. There were no responders, neither partial nor complete. The median survival was 6 months. The toxicity was primarily bone marrow suppression. The treatment was generally well tolerated. No patients had grade 4 toxicity and only five had grade 3 hematologic toxicity. In conclusion, we find the present regimen to be ineffective in the treatment of platin-resistant ovarian cancer.

Tropisetron (Navoban) in the prevention of chemotherapy-induced nausea and vomiting--the Nordic experience.

An open, noncomparative, Nordic multicenter study was carried out during 1991-1992 to evaluate the 5-HT3 receptor antagonist tropisetron (Navoban) as an antiemetic agent for various types of cancer chemotherapy. A total of 630 patients were recruited from 15 centers in Sweden, Denmark, and Finland. Gynecological cancers (60%), breast cancer (15%), and lung cancer (10%) were the main diagnoses. Prior experience of chemotherapy was documented in 338 patients (54%). In 260 patients (41%), cisplatin was part of the cytostatic regimen. Carboplatin (23%), doxorubicin (27%), and epidoxorubicin (24%) were also frequently included. In all, 23 cytostatic agents were used in various combinations. The mean number of courses studied was 4.6 (range 1-19). Altogether, 394 of 619 evaluable patients (64%) were completely protected from acute nausea and vomiting during the first course of chemotherapy. Delayed nausea and vomiting were completely prevented in 45%-73% (days 2-6) in the complete series. Treatment efficacy remained stable (60%-79%) during ten consecutive courses of chemotherapy. With noncisplatin regimens, complete protection from acute nausea and vomiting was achieved in 72% compared with 52% for cisplatin regimens (P < 0.0001). Patients without prior experience of chemotherapy had higher control rates of acute nausea and vomiting (72%) compared to patients treated before (57%) during the first course, but not later on. There were no differences in delayed nausea and vomiting.(ABSTRACT TRUNCATED AT 250 WORDS)

On-demand antiemetic treatment with the serotonine antagonist tropisetron in cisplatin-treated cancer patients.

Fourteen cancer patients treated with cisplatin received repeated infusions of tropisetron on-demand in conjunction with emesis. In subsequent chemotherapy courses, prophylactic tropisetron was given in a dose identical to the cumulated dose in study course 1. Tropisetron in study course 1 abolished emesis after 7.5 min (5 mg). Duration of effect was more than 7 h in 50% of the patients. No relationship between dose and duration of effect was seen. After study course 2, eight of 10 patients preferred prophylactic tropisetron. Two patients with hypertension had a severe increase in blood pressure probably related to tropisetron. It is concluded that tropisetron has an instant and lasting effect on nausea and vomiting when given on-demand. The majority of patients, however, prefer prophylactic treatment. Hypertension may be a side effect from tropisetron and caution should be displayed in hypertensive patients.

Double-blind randomized cross-over trial comparing methylprednisolone with placebo in chemotherapy-induced nausea and vomiting: a study with special reference to efficacy parameters.

Sixty-one patients with breast cancer who received chemotherapy participated in a double-blind randomized cross-over study with methylprednisolone (MP) 250 mg as a single i.v. injection before chemotherapy and placebo as antiemetic treatment. The determining efficacy parameter was preference. Other parameters used were a visual analogue scale for nausea, a categorical four-point nausea intensity scale recorded by a nurse observer, emetic amounts, emetic episodes, acceptance of nausea and vomiting, and global assessments for nausea and vomiting. MP showed a significant antiemetic effect compared with placebo which was most pronounced for moderately emetogenic chemotherapy. The visual analogue scale, emetic amounts, acceptance and global assessments were easy to handle and showed coherence with preference, whereas nausea intensity and emetic episodes were resource demanding to record and showed no coherence with preference. It is concluded that for a precise evaluation of nausea and vomiting the visual analogue scale and emetic amounts are most reliable; for ambulatory patients global assessments seem to be sufficient.

[Treatment of cervix cancer in Denmark]. / Behandlingen af cancer cervicis uteri i Danmark.

The current status of cervical cancer treatment in Denmark is discussed. Diagnostic aspects and problems of classification are presented briefly supplemented with a comment on new prognostic parameters based on a semiquantitative score system and flow cytometry. Surgery is the treatment of election for the early stages whereas radiotherapy is the treatment of choice in advanced stages. Chemotherapy should only be employed in the framework of clinical trials. It is concluded that centralised treatment should be maintained.