Bleomycin, vincristine, cisplatin/bleomycin, etoposide, cisplatin chemotherapy: an alternating, dose intense regimen producing promising results in untreated patients with intermediate or poor prognosis malignant germ-cell tumours.

Patients with poor and intermediate prognosis metastatic germ-cell tumours (MGCTs) are at a significant risk of relapse after standard platinum-based chemotherapy. Novel treatment regimens are required to improve survival. Dose intense, alternating combinations of drugs with known activity in germ-cell tumours represents one approach. In all, 43 patients with IGCCCG intermediate/poor prognosis MGCT were treated with a dose intense regimen alternating bleomycin, vincristine, cisplatin (BOP) with bleomycin, etoposide, cisplatin (BEP) to a maximum of three cycles. Data were collected on the maintenance of dose intensity, toxicity, response, progression-free (PFS) and overall survival (OS). The complete response rate was 58%; a further 7% of patients being rendered disease free by resection of viable residual tumour. With a median follow-up of more than 4 years in surviving patients, 3-year OS and PFS rates of 81% (95% CI: 66-91%) and 72% (95% CI: 56-83%) are seen, respectively. Bleomycin, vincristine, cisplatin (BOP)/bleomycin, etoposide, cisplatin (BEP) was well tolerated, with 86% of patients completing all planned courses. Toxicity was predominantly haematological with common toxicity criteria grade III neutropenia in 90% of patients. Cisplatin neuropathy and bleomycin-induced pulmonary toxicity represented the most significant nonhaematological toxicity. Bleomycin, vincristine, cisplatin (BOP)/bleomycin, etoposide, cisplatin (BEP) represents a practicable, well-tolerated, dose intense chemotherapy regimen with significant activity in intermediate and poor prognosis MGCT.

Is optimal first-line chemotherapy deliverable in all newly diagnosed ovarian cancers? A population-based study.

NICE guidance recommends the use of paclitaxel and a platinum therapy for all cases of ovarian cancer. We report our experience of treating 133 patients with ovarian cancer over a 3-year period. Where indicated, 91% received chemotherapy. A taxane/platinum combination was found to be appropriate in 63% of patients only.

A phase II study of mitomycin C, cisplatin and continuous infusion 5-fluorouracil (MCF) in the treatment of patients with carcinoma of unknown primary site.

Carcinoma of unknown primary site remains a common clinical diagnosis, accounting for between 5 and 10% of all cancer patients. Numerous combination chemotherapy regimens have been used in the management of carcinoma of unknown primary site, resulting in response rates of 0-48%. We present the results of a single centre phase II study of the use of the combination of mitomycin C (7 mg m(-2) on day 1 of cycles 1, 3 and 5) cisplatin (60 mg m(-2) on day 1) and continuous infusion 5-fluorouracil (300 mg m(-2) daily), MCF, delivered as a 21-day cycle, in patients with carcinoma of unknown primary site. Thirty-one patients with a diagnosis of carcinoma of unknown primary site were treated in Aberdeen Royal Infirmary between 1997 and 2001 with MCF. In total, 136 cycles of MCF were delivered (median of 5 cycles per patient). Toxicity was acceptable, with 19% grade 3 or 4 neutropenia, 16% grade 3 or 4 thrombocytopenia and 13% grade 3 or 4 nausea and vomiting. No cases of neutropenic sepsis were seen and there were no treatment-related deaths, however, six patients developed thrombotic complications. The overall response rate was 27% (CR 3%; PR 23%). Median time to progression was 3.4 months (95% CI 1.1-5.6 months) and median overall survival was 7.7 months (95% CI 5.7-9.8 months). Survival at 1 year was 28%, and at 2 years, 10%. MCF is a tolerable regimen with comparable toxicity, response rates and survival data to most platinum-based combination chemotherapy regimens in use for this devastating disease.

Freehand core biopsy in breast cancer: an accurate predictor of tumour grade following neoadjuvant chemotherapy?

Core biopsy is an increasingly used technique in the pre-operative diagnosis of breast carcinoma, as it provides useful prognostic information with respect to tumour type and grade. Neoadjuvant chemotherapy is being used in the treatment of large and locally advanced breast cancers but little is known regarding the correlation between tumour histology on pre-treatment core biopsy and that in residual tumour following primary chemotherapy and surgery. This study aimed to evaluate the accuracy of core biopsy in predicting these features in patients treated with primary chemotherapy. One hundred and thirty-three patients with carcinoma of the breast diagnosed on clinical, radiological and cytological examination underwent core biopsy, followed by primary chemotherapy (with cyclophosphamide, vincristine, doxorubicin and prednisolone) and surgery. The false-negative rate for pre-treatment core biopsy was 14%, with 91% agreement between the grade demonstrated on core biopsy and that in the residual tumour following completion of chemotherapy. Tumour type in the residual post-chemotherapy tumour was predicted by core biopsy in 84%. This study suggests that pre-treatment core biopsy histology accurately predicts residual tumour histology following primary chemotherapy and surgery in patients with breast cancer.

What is achieved by mammographic surveillance after breast conservation treatment for breast cancer?

BACKGROUND: After breast conservation surgery for breast cancer, patients are followed up by regular clinical examination and mammography, at intervals which vary according to local practice. However, the optimum interval remains unclear with current guidelines suggesting mammography should be carried out every 1 to 2 years. This study has investigated this aspect and, in particular, whether mammography or clinical examination or both allowed an early detection of recurrence of the disease in the conserved breast. METHODS: A total of 695 patients who had undergone breast conservation surgery were identified from a database of prospectively recorded data during the period 1990 to 1995. Clinical examination and annual mammography were performed in accordance with local protocol. The results of clinical examination, mammography, and local recurrence rates were evaluated. RESULTS: A total of 2,181 mammograms were undertaken in the 695 patients studied. Local recurrence of disease in the conserved breast occurred in 21 patients (3%), at a mean follow-up of 3.5 years. The first identification of tumor recurrence was by clinical examination in 11 patients with local recurrence, and by the surveillance mammography in the other 10 patients with local recurrence. Overall, mammography detected the local recurrence in 13 of 20 (65%) patients who underwent this examination. In the other patients, the recurrence was detected on clinical examination only. In addition, in 52 patients, mammography was falsely positive, giving a false positive rate of 2.3%. Contralateral cancers in the opposite breast were detected in 2 patients. CONCLUSIONS: The detection of local disease after breast conservation surgery requires both clinical examination and mammography. In the context of our follow-up policy, in 52% of patients with local recurrence, this was first identified by clinical examination. Disease recurrence was identified in the other 48% of patients by mammographic surveillance. Overall, mammography will identify or confirm local recurrence in two thirds of women. However, in a small number of cases (2.3% in our series) mammography will give false positive results. New imaging modalities to assist in the diagnosis of local recurrence of disease after breast conservation surgery are required.

Primary pulmonary osteosarcoma: case report and molecular analysis.

BACKGROUND: Primary pulmonary osteosarcoma is an extremely rare malignancy. To date, only 12 cases have been reported, with a high mortality rate. The authors report on a newly diagnosed patient and describe investigations that were performed using immunohistochemistry and comparative genomic hybridization (CGH). METHODS: The clinical course of a woman age 37 years is presented. Along with routine histologic examination, immunohistochemistry was used to demonstrate differentiation-associated proteins, oncoproteins, and other markers; CGH analysis for genomic alterations; and histochemistry to demonstrate alkaline phosphatase activity. RESULTS: Immunohistochemical analysis showed varying expression patterns using antibodies against a panel of tumor markers. Most notable was high overexpression of BCL-2 and cyclin D. CGH analysis showed that this neoplasm contained a much higher level of genetic aberrations compared with skeletal osteosarcoma. CONCLUSIONS: This tumor exhibited features common to skeletal osteosarcomas but also had some unique features. Genome analysis suggests that this tumor has several genetic aberrations in common with extraskeletal osteosarcoma. The novel regions of instability identified within the tumor genome may contribute toward the unique tumor phenotype and relative chemoresistance.

Positron emission tomography using [(18)F]-fluorodeoxy-D-glucose to predict the pathologic response of breast cancer to primary chemotherapy.

PURPOSE: To determine whether [(18)F]-fluorodeoxy-D-glucose ([(18)F]-FDG) positron emission tomography (PET) can predict the pathologic response of primary and metastatic breast cancer to chemotherapy. PATIENTS AND METHODS: Thirty patients with noninflammatory, large (> 3 cm), or locally advanced breast cancers received eight doses of primary chemotherapy. Dynamic PET imaging was performed immediately before the first, second, and fifth doses and after the last dose of treatment. Primary tumors and involved axillary lymph nodes were identified, and the [(18)F]-FDG uptake values were calculated (expressed as semiquantitative dose uptake ratio [DUR] and influx constant [K]). Pathologic response was determined after chemotherapy by evaluation of surgical resection specimens. RESULTS: Thirty-one primary breast lesions were identified. The mean pretreatment DUR values of the eight lesions that achieved a complete microscopic pathologic response were significantly (P =.037) higher than those from less responsive lesions. The mean reduction in DUR after the first pulse of chemotherapy was significantly greater in lesions that achieved a partial (P =.013), complete macroscopic (P =.003), or complete microscopic (P =.001) pathologic response. PET after a single pulse of chemotherapy was able to predict complete pathologic response with a sensitivity of 90% and a specificity of 74%. Eleven patients had pathologic evidence of lymph node metastases. Mean pretreatment DUR values in the metastatic lesions that responded did not differ significantly from those that failed to respond (P =.076). However, mean pretreatment K values were significantly higher in ultimately responsive cancers (P =.037). The mean change in DUR and K after the first pulse of chemotherapy was significantly greater in responding lesions (DUR, P =.038; K, P =.012). CONCLUSION: [(18)F]-FDG PET imaging of primary and metastatic breast cancer after a single pulse of chemotherapy may be of value in the prediction of pathologic treatment response.

Current and potential chemotherapeutic agents used for induction chemotherapy in the treatment of breast cancer.

A substantial proportion of breast cancers are large (<3 cm) or locally advanced (T3, T4, TXN2) at the time of initial presentation. The therapeutic goals that must be achieved in patients with such cancers are to obtain adequate local disease control so that surgery can be performed and to abolish occult distant metastases therefore improving survival. Over the past three decades conventional adjuvant chemotherapy regimens have been employed pre-operatively (neo-adjuvant or primary chemotherapy) to achieve these goals. Studies have now shown that the survival of patients who receive neo-adjuvant chemotherapy is comparable to that of those who receive the same chemotherapy regimen following surgery. It is also apparent that although clinical tumour response rates to neo-adjuvant chemotherapy may be high there is considerable scope for improvement in the corresponding pathological tumour response. Furthermore, data from major studies that have comprehensively evaluated the use of pre-operative chemotherapy now indicates that the pathological response of breast cancers following treatment is of far greater prognostic importance than the clinical response. Recent interests has focoused, therefore, on the implementation of more prolonged or dose intensive chemotherapy regimens with the aims of improving pathological response to treatment and ultimately overall survival. Newer antineoplastic agents are also becoming available that may be used alone or in combination with conventional therapies in order that tumor response may be improved. This review describes current and potential therapeutic agents that may be used for the induction therapy of breast cancer.

Psychological, clinical and pathological effects of relaxation training and guided imagery during primary chemotherapy.

The diagnosis and treatment of breast cancer are stressful, and stress may be associated with a poorer response to chemotherapy. There is a need, therefore, to develop and evaluate interventions that might enhance quality of life and, possibly, improve treatment response. The effects of relaxation combined with guided imagery (visualizing host defences destroying tumour cells) on quality of life and response to primary chemotherapy, to date, have not been adequately evaluated. Ninety-six women with newly diagnosed large or locally advanced breast cancer (T2 > 4 cm, T3, T4, or TxN2 and M0) took part in a prospective, randomized controlled trial. Patients were randomized following diagnosis to a control condition (standard care) or to the experimental condition (standard care plus relaxation training and imagery). Psychometric tests to evaluate mood and quality of life were carried out before each of the six cycles of chemotherapy and 3 weeks after cycle 6: tests of personality and coping strategy were carried out prior to cycles one and six. Clinical response to chemotherapy was evaluated after six cycles of chemotherapy using standard UICC criteria and pathological response was assessed from the tissue removed at surgery. As hypothesized, patients in the experimental group were more relaxed and easy going during the study (Mood Rating Scale). Quality of life was better in the experimental group (Global Self-assessment and Rotterdam Symptom Checklist). The intervention also reduced emotional suppression (Courtauld Emotional Control Scale). The incidence of clinically significant mood disturbance was very low and the incidence in the two groups was similar. Finally, although the groups did not differ for clinical or pathological response to chemotherapy, imagery ratings were correlated with clinical response. These simple, inexpensive and beneficial interventions should be offered to patients wishing to improve quality of life during primary chemotherapy.

Psychological factors can predict the response to primary chemotherapy in patients with locally advanced breast cancer.

This study evaluated the possible value of psychological variables in predicting clinical and pathological response to primary chemotherapy. 96 women with newly diagnosed large, or locally advanced, breast cancer (T2 > 4 cm, T3, T4, N2 and M0) participated in a prospective, randomised trial to evaluate the effects of relaxation training with guided imagery and L-arginine on response to primary chemotherapy. Before the first of six cycles of primary chemotherapy, women were assessed using the Hospital Anxiety and Depression Scale (HADS) and the Eysenck Personality Questionnaire (EPQ). The primary outcomes were clinical response (evaluated using standard International Union Against Cancer (UICC) criteria) and pathological response (graded by means of a previously published 5-point scale) following primary chemotherapy. Stepwise linear regressions were used to estimate the predictive value of age, menopausal status, clinical nodal status, tumour size at diagnosis, oestrogen receptor status, dietary supplementation (L-arginine versus placebo), personality (EPQ-L scores), mood (HADS scores) and a psychological intervention. HADS depression score was a significant independent predictor of pathological response to chemotherapy. HADS anxiety score was a significant independent predictor of clinical response. Because the original tumour size before chemotherapy (also a significant predictor of clinical and pathological responses) was taken into account in the analyses, the results cannot be explained in terms of psychobiological factors related to tumour size. This study supports the importance of psychological factors as independent predictors of response to primary chemotherapy in patients with breast cancer. If they can be replicated, these findings have major implications for the management of women with breast cancer. Psychological factors need to be assessed and evaluated in future trials of chemotherapy.

Acute phase proteins in patients with large and locally advanced breast cancer treated with neo-adjuvant chemotherapy: response and survival.

Seventy-seven patients with locally advanced breast cancer were treated with multimodality therapy comprising of six pulses of neo-adjuvant chemotherapy (doxorubicin, cyclophosphamide, vincristine and prednisolone) at 21-day intervals, followed by surgery (breast conservation or mastectomy) with appropriate axillary surgery, radiotherapy and adjuvant tamoxifen. The serum concentrations of acute phase proteins, C-reactive protein (CRP), á-1-anti-trypsin, albumin and transferrin were measured in serum taken prior to commencement of treatment. Patients were followed up for a median of 31 months and their clinical and histological responses and overall survival recorded. Univariate analyses revealed that tumour stage (p=0.01), clinical lymph node status (p=0. 02) and pre-treatment levels of serum albumin (p=0.002) and á-1-anti-trypsin (p=0.06) predicted overall survival. Using the Cox proportional hazards model reduced pre-treatment levels of serum albumin (p<0.00001), progressive lymph node involvement with tumour (p<0.005), and advancing tumour stage (p<0.01) were independent prognostic indicators for a poorer survival in patients with locally advanced breast cancer receiving neo-adjuvant chemotherapy.

Treatment of large and locally advanced breast cancers using neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant (primary) chemotherapy is being used increasingly in the treatment of patients with large and locally advanced breast cancer with the aim of reducing the size of the primary tumor and eliminating micrometastatic disease. Response rates to, compliance with, and survival of patients following neoadjuvant chemotherapy have been variable. We report the results of a consecutive series of 77 patients with breast cancer who received neoadjuvant chemotherapy. METHODS: Seventy-seven patients with locally advanced breast cancers were treated with multimodality therapy comprising up to six cycles of chemotherapy (cyclophosphamide, vincristine, doxorubicin, and prednisolone), radiotherapy, and then surgery. The median follow-up was 54 months. Clinical response rates to therapy and overall survival have been documented. In addition, prognostic factors for survival were identified using the Cox proportional hazards model. RESULTS: The overall objective response rate of the primary tumor to chemotherapy alone was 87% (25% complete and 62% partial responses, UICC criteria). Following radiotherapy the response rate was 90% (52% complete and 38% partial responses). The overall 5-year survival for all patients was 0.48. However, the probability of survival at 5 years was 0.74 in those with a complete response, and 0.36 if there was a partial clinical response, but no patients who had either stasis of disease or progression survived for 5 years. Independent predictors of better survival that were identified were a complete histopathological response after chemotherapy and radiotherapy, a complete clinical response to chemotherapy, and five or six cycles of chemotherapy versus four or less. CONCLUSIONS: Neoadjuvant chemotherapy in patients with large and locally advanced breast cancers can result in satisfactory local control and overall survival rates, especially in patients with a complete clinical or histopathological response after treatment.

Potentiation of the response to chemotherapy in patients with breast cancer by dietary supplementation with L-arginine: results of a randomised controlled trial.

Patients with large primary breast cancers are being treated with neo-adjuvant chemotherapy. Studies in animals have shown that responses to chemotherapy can be increased by dietary manipulation of tumour cell metabolism. Also dietary supplementation with the amino acid L-arginine, resulted in an increase in tumour metabolic activity expression of the nuclear activation antigen, Ki67, in patients with breast cancer. Therefore, we have carried out a randomised, double blind, placebo controlled trial to determine if L-arginine supplementation is beneficial in patients with breast cancer, undergoing neo-adjuvant chemotherapy. 96 patients were randomised to receive L-arginine (30 g/day) for three days (n = 48) or placebo (n = 48) prior to undergoing chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisolone), 6 pulses at 21-day intervals. Clinical and pathological responses were assessed in both groups of patients following completion of chemotherapy. The clinical response rate was 77% (23% complete and 54% partial responses) in the L-arginine treated group, compared with 71% (15% complete and 56% partial) in the placebo group of patients (p = ns). However, in patients with tumours less than 6 cm in initial diameter, there was a significant increase in the better histopathological responses in the L-arginine group, when compared with the placebo group of patients (88% vs 52%, p = 0.04). This may have important implications for clinical practice.

Referral patterns within Scotland to specialist oncology centres for patients with testicular germ cell tumours. The Scottish Radiological Society and the Scottish Standing Committee of the Royal College of Radiologists.

Details of 1123 patients registered in Scotland between 1983 and 1990 for testicular cancer under the Scottish Cancer Registration Scheme were obtained and compared with registrations within the five Scottish oncology centres. Some registration discrepancies were identified. Twenty-eight cancer registrations (2.5%) were coded to the wrong site, 29 patients seen at oncology centres had no cancer registration and 14 cancer registrations had the wrong histology. Five hundred and twenty-seven patients with testicular non-seminomatous germ cell tumours (NSGCT) and 567 with testicular seminoma were identified. Referral rates to specialist oncology centres for testicular germ cell tumours were measured by period and health board area of residence. For the whole study period 92% of NSGCT and 93% of seminoma patients were referred to specialist centres for treatment. Referral rates for different health board areas of residence were not significantly different. This study shows that within Scotland the majority of patients with testicular NSGCT and seminoma are referred to specialist centres, and suggests referral rates of around 92% are underestimates. Access is not related to area of residence.

A Scottish national audit of current patterns of management for patients with testicular non-seminomatous germ-cell tumours. The Scottish Radiological Society and the Scottish Committee of the Royal College of Radiologists.

A detailed casenote review was performed on all 65 patients registered with testicular non-seminomatous germ cell tumours (NSGCT) during 1989 under the Scottish Cancer Registration Scheme. Details of management at presentation and 2 years following diagnosis were recorded and analysed. In a small number of patients an unacceptable delay in diagnosis was noted. Variation was found in the frequency and type of investigations performed on patients placed on surveillance, types of chemotherapy regimens used and numbers of patients entered into trials. Three per cent of patients had a biopsy of the contralateral testis and 27% of patients defaulted from clinic attendance. Considerable variation in the management of testicular NSGCT in Scotland has been identified. The introduction of management guidelines should result in a more consistent approach to the care of these patients. Support, both financial and psychological, may reduce the unacceptable rate of default.

A Scottish national mortality study assessing cause of death, quality of and variation in management of patients with testicular non-seminomatous germ-cell tumours. The Scottish Radiological Society and the Scottish Standing Committee of the Royal College of Radiologists.

A detailed casenote review was performed on 55 patients registered with testicular non-seminomatous germ cell tumours (NSGCT) between 1983 and 1988 under the Scottish Cancer Registration Scheme and who had died by 1992. Details of all aspects of clinical management relating to their NSGCT and death details were extracted and summarised. An assessment was made on whether the patients' management had been optimal. An analysis of 5 year survival rates by the five Scottish oncology centres demonstrated significant differences between centres (range 70.4-94.2; chi 2 = 14.46, d.f. = 4, P = 0.006). Some patients in all centres were assessed as having received suboptimal treatment, but two centres performed less well than the other three. There is a suggestion that the number of patients treated suboptimally decreases with increasing number of patients seen, but this does not reach statistical significance.

Comparison of granisetron alone and granisetron plus dexamethasone in the prophylaxis of cytotoxic-induced emesis.

Two hundred and seventy-eight adult chemonaive patients, receiving moderately emetogenic chemotherapy were randomly allocated to receive either intravenous (i.v.) granisetron 3 mg plus i.v. dexamethasone 8 mg or i.v. granisetron 3 mg plus i.v. placebo dexamethasone prior to chemotherapy. Eight-two per cent of all patients recruited were female, and 91% of all patients consumed less than 10 units of alcohol per week, suggesting a study population with an increased risk of nausea and vomiting. In the first 24 h 85% of patients who received granisetron plus dexamethasone were complete responders compared with 75.9% of the patients receiving granisetron alone (P = 0.053). There were statistically significant improvements in complete response over 7 days (P = 0.029) and in the numbers of patients receiving rescue antiemetic (P = 0.0004). Toxicity was minimal with no significant differences between treatment groups. These results confirm the antiemetic activity of granisetron and show that it has an additive effect in combination with dexamethasone.

Dietary supplementation with L-arginine in patients with breast cancer (> 4 cm) receiving multimodality treatment: report of a feasibility study.

L-Arginine has been shown, in human breast cancers, to increase protein synthesis and the number of cells in the growth phase of the cell cycle. L-Arginine, therefore, may potentiate the response of breast cancers to cell cycle-specific cytotoxic agents. This phase II pilot study assessed the clinical, radiological and pathological responses in 44 patients with breast cancers > 4 cm in diameter (46 tumours: T2, n = 6; T3, n = 22; T4, n = 19), who received oral L-arginine 30 g day-1 for 3 days prior to each cycle of CHOP chemotherapy, followed after 4-6 cycles by radiotherapy. Following this treatment, 95% of patients had a clinical response: complete response in 30% and partial response in 65%. Imaging, ultrasound and mammography revealed response rates of 91% and 76% respectively. Surgery was performed in 43 patients. Histological examination revealed that in 18% of cases there was no residual evidence of tumour. Furthermore, if residual tumour was identified, the degree of destruction was graded as 'severe' in 36% and 'moderate' in 30% of cases. Further studies are now required to evaluate the potential beneficial use of nutritional pharmacology in combination with existing treatment regimens.

Cutaneous malignant melanoma, Scotland, 1979-89. The Scottish Melanoma Group.

The Scottish Melanoma Group (SMG) was established in 1979 to assess mortality from and incidence, features, pathological data, and management of cutaneous malignant melanoma in Scotland. Incidence during the first five years and five-year survival have already been reported. We now have data about incidence and mortality over eleven years in relation to anatomical site and pathological types. From 1979 to 1989, 1354 male and 2459 female patients with primary cutaneous malignant melanomas were first diagnosed in Scottish residents. The incidence rate per 100,000 population per year has increased from 3.4 in 1979 to 7.1 in 1989 for men, and from 6.6 to 10.4 for women. The overall increase over eleven years is 82% (7.4% per year). The greatest rates of increase are seen in lesions of the superficial spreading histogenetic type, arising on the female leg and the male trunk. Following public education programmes started in 1985, the proportion of all melanomas less than 1.5 mm thick has shown a sustained and significant increase. Mortality data for 1661 patients for whom a minimum of five-year follow-up is available shows five-year survival of 71.6% overall (77.6% for women, 58.7% for men). The survival advantage for women persists when appropriate statistical adjustment is made for thickness, ulceration, and histogenetic type. These data are useful in designing public education programmes aimed at both primary and secondary prevention of melanoma and in auditing changes in trends that might result from such education.