Dr Nirmal Kumar Gupta
Christie Hospital - Manchester
The role of chemotherapy in head and neck cancer remains uncertain inspite of several clinical trials world-wide. Two metaanalysis in recent years show possible benefit when single agent were used and the drug has been administered synchronously with radiotherapy. A large trial under the auspices of UKCCR in the United Kingdom has accumulated over 750 patients and may show conclusively in the next few years whether chemotherapy is of any benefit in head and neck cancer.
This presentation is a 15 year follow up of a randomised clinical trial when
Methotrexate was administered 100 mg/m 2 iv on day 0 (24 hours before commencement of radiotherapy) and day 14 of a 3 week course of radiotherapy.
There were no drug related deaths. There has been no increase of late morbidity.
The overall primary control rate is higher in the Methotrexate group but there is little benefit in survival. However, a significant improvement was seen in oropharyngeal cancer, both in local control and survival.
The addition of Methotrexate to radiation had no influence on subsequent
development of metastases in neck nodes.
This treatment is relatively inexpensive and easy to administer as an outpatient provided facilities are available to monitor the serum Methotrexate concentration.
Z. Lajtman, D. Nosso, S. Bačić, V. Borčić, T. Znaor
The aim of our study was to evaluate the use of laryngeal (laryngotracheal) mucosa for reconstruction of the pharyngeal (pharyngoesphageal) defect that results from resection of advanced piriform sinus carcinoma. Thirteen patients with T3 and T4 piriform sinus carcinoma who were treated surgically between January 1995 and January 1999, were studied. All patients underwent surgical resection of the tumor (partial pharyngectomy and total laryngectomy) and immediate reconstruction with laryngeal (laryngotrachcal) mucosa. Depending on the extent of tumor spread into the adjacent neck lymph nodes unilateral or bilateral cervical lymph node dissection was performed. Six patients had unilateral radical neck dissection and remaining 7 patients had bilateral modified neck dissection. There was no flap loss. Eleven patients without complications started oral intake of food 14 days after surgery. Two patients had pharyngocutaneous fistula and they started oral feeding after 23 and 38 days.
All of the patients underwent radical postoperative radiotherapy received a dose of between 6000 and 6600 cGy administered over six weeks in 30 fractions. Three patients received two courses of preoperative chemotherapy and five of them received three courses of postoperative chemotherapy with cisplatinum and 5-fluorouracil.
Postoperative follow - up ranged from 6 to 48 months (average 32 months). Three patients died in the first year after surgery (two had distant metastases and one had local recurrence), two patients in the second year (one had a distant metastases and one had lymph node metastases) and three patients in the third year (two had a distant metastases and one developed a cancer of the posterior pharyngeal wall).
The facts as less trauma, low incidence of complications and fast reconvalescence using our operation, we consider very important because the outcome in these patients remains poor, regardless of therapy. That is why we advocate the use of laryngeal (laryngotracheal) mucosa as a method of choice in pharyngeal (pharyngoesphageal) reconstruction after resection of advanced piriform sinus carcinoma.
Virag M, Aljinović N,
Uglešić V, Milenović A, Lukšić I
Department of Maxillofacial Surgery, University Hospital Dubrava, Zagreb, Croatia
The treatment of recurrent or advanced cancer involving the tongue is always demanding and very often disappointing, but reports on larger series of patients addressing the surgical salvage and its final outcome are very few. The objective of this study was to determinate curative potential of total glossectomy.
The study is a retrospective chart and database review and includes 48 patients who had total glossectomy in the period 1976-97. All of the patients were treated by composite resection, 33 as initial treatment, 15 following a recurrence. In four cases surgery was performed as emergency treatment and in four after emergency external carotid ligation. All patients except four (two had a simultaneous second primary in the hypopharynx) had no laryngectomy but almost all had cricopharyngeal myotomy. All patients had either a recurrent or T4 oral cavity tumor. All except one patient had a pectoralis major flap for reconstruction. Survival for all patients was calculated and analysed.
The 5-year disease free survival rate calculated by Kaplan-Meier method was 39%. However, since a significant number of patients died of tumor unrelated reasons (8), treatment complications (4) or were lost to follow up (3), the direct method gives a more realistic insight into the results. Fourteen patients had recurrent disease: 11 local, 1 regional and 2 distant. Nineteen patients had no evidence of disease when last seen, but only 5 out of 33 patients treated before 1996 (15%) were alive and without evidence of disease 2 years or more after last treatment. Ten patients never regained the ability to swallow. The functional results concerning swallowing, aspiration and speech were unpredictable.
The results of this study show that the long term survival is low due to various reasons, but the surgical salvage of patients with advanced cancer involving the tongue is warranted since at this stage of disease no better options are available. At least, it offers substantial palliation.
B. Cucevic, N. Rakušić, University Clinic for Pulmonary Diseases, Jordanovac, Zagreb
Pleural talk powder application (poudrage) is a procedure consisting of insufflation of 2-5 ml of sterile talk powder into the pleural cavity, with aim to achieve pleural obliteration (pleurodesis), thus blocking the formation of pleural fluid, what can be useful in repeated occurrence of malignant pleural effusions.
In this study we analysed results of pleural poudrage in 72 patients with malignant pleural effusions, hospitalised in our Clinic from Jan 1996 to Dec 1998. In all the patients talk poudrage was performed in topical anaesthesia during the medical thoracoscopy, by the rigid thoracoscopic instrument. Evacuation of all amount of pleural fluid was followed by the insufflation of 5 ml of sterile talk powder into the pleural cavity. After that, pleural drainage was observed for 5 days.
The procedure was successful in 70 (97%) of patients, meaning there were no recurrence of pleural effusion at least one month after the procedure. Serious complications were observed in 6.9% of patients (5 empyema, 1 pneumonitis and 1 death immediately after the procedure). Pain and elevated body temperature occurred in marked percentage of patients (38% and 60% respectively), but both symptoms was treated successfully by analgesics and antipyretics.
We conclude, pleural poudrage is safe, successful and inexpensive method in treatment of malignant pleural effusions.
Andrej Kogler, MD, PhD
Department of Neurosurgery, Sestre milosrdnice University Hospital, Zagreb
From 1988 through 1998, there were 82 children with the diagnosis of infratentorial tumor, and 75 of them where operated on. The age ranged from 5 months to 15 years, and there were 45 males and 37 females. Computed tomography (CT) and magnetic resonance imaging (MRI) were performed as the main diagnostic modalities. All operated tumors were submitted to histopathologic and immunohistochemical analysis. There were 32 ependymomas (including anaplastic ependymomas), 28 medulloblastomas, 13 pilocytic astrocytomas, and 2 brainstem gliomas. There were seven children with inoperable brainstem glioma.
Fedor Šantek, Lijerka Markulin-Grgić
Completed data forms including the long-term follow-up data from 32 patients with ependimoma were analysed in this study. The patients were treated at the Clinic of Oncology and Radiotehrapy in Rebro University Hospital, Zagreb School of Medicine, Croatia in the period from 1972-91. The criterion for entering the analysis was the pathologicaly confirmed report of ependymoma of various malignancy grade, completed course of radiotherapy and data-completed follow-up. According to the WHO classification (Kleihues P. at all, 1992.) the tumours have been graded as I in 19/32 (59%) of all our patients, as II in 9/32 (27%) and as grade III in 4/32 (13%) of the patients.
Median survival in all the patients was 60 months, median event-free survival 57 months and 5 and 10 years survival 50% and 25% respectively (min 8, max. 324 months).
Significant survival differences in this cohort of ependymoma patients were observed according to the following factors:
Dr Robert Hunter
Christie Hospital, Manchester, UK
The successful management of advanced cancer of the cervix by radical radiotherapy remains a major challenge to the radiation oncologist. In spite of many decades of clinical investigation including the use of different x-ray volumes, different fractionation and overall time, different intra cavitary techniques and different balances between x-ray therapy and ICT there is no consensus that one particular approach is optimal. Even with modern imaging and sophisticated treatment planning patients are effectively treated by standard techniques minimally tailored to the individual. Associated with relatively poor survival for stages 2B and 3B, radiation oncologist have accepted significant levels of morbidity (5-10%) and have failed to develop strategies to avoid them.
Since the mid 1980’s the Christie Hospital and the Paterson Institute have been exploring different methods of assessing the individual patient and her cancer. Initial prospective studies utilising clonogenic assays have identified the invitro measurement of SF2 (Surviving fraction at 2 Gy) as the most significant prognostic factor in patients with stages with 1B, 2 and 3 carcinoma. This important prognostic factor is particularly valuable in patients under the age of 50 with a tumour diameter greater than 4 cm and advanced stage. The SF2 measurement is independently the most significant prognostic factor in our patients. This work has then been extended to normal tissues including lymphocytes and fibroblasts and it has demonstrated a correlation between normal tissue sensitivity and late radiation reactions.
This research laboratory based assessment process is only possibly in 70% of patients, takes 4 weeks and is technically sophisticated. In an attempt to avoid these problems different techniques investigating DNA integrity including the micronucleus assay and electrophoretic DNA separation techniques are being explored.
Complementing these studies the importance of apoptosis in the primary tumour and its vascular density have been linked to outcome by the team. In an attempt to capture as full information as possible new patients with locally advanced carcinoma of the cervix for radical treatment are having dynamic MR scanning to assess vascularity, tumour Po2 (ependorph histograph), SF2 of tumour and normal tissues as well as histological assessment of tumour vascularity oxygenation and apoptosis.
The challenge is to develop a small group of biological parameters that accurately reflect the likelihood of cure of the patient with minimal risk of significant normal tissue injury. They are likely to require a measure off the number of clonogens; their radiation sensitivity, the tumour environment Po2 and other intrinsic biological parameters that properly reflect the chance of success.
V. Kukura, S. Ciglar,
M. Podobnik, Ž. Duić, G. Zovko
Department of Obstetrics and Gynaecology, “Merkur” University Hospital, Zagreb, Croatia
The problem of puncture ovarian cysts is relapse on follow up examinations. The purpose of the study is treatment of cysts with concentrated alcohol. Alcohol is a sclerosing agent and preservative. On contact, it causes the epithelial cells lining a cyst to became nonviable.
For this procedure the ovarian cyst must be unilocular, sonolucent, with smooth inner wall of the capsule, without septa and without neovascularisation on transvaginal colour Doppler. Serum CA 125 levels were lower than 35 U/ml. This offer the possibility of more conservative management of ovarian cysts that have a low risk of malignancy. Under the control of 5 MHz transvaginal probe we calculated cyst fluid volume and punctured capsule by 18 gauge needle. The cyst was evacuated by syringe as completely as possible. Cyst fluid was immediately sent for cytological examination. If the cytological finding was negative, approximately 50% of the quantity of aspired fluid was replaced with 96% alcohol. Alcohol remained in situ for 5 minutes and then it was completely evacuated. Patients were monitored for 24 hours and first follow-up examination was 3 months after the procedure.
During the period of 10 years, from 1989-1998, we punctured 296 patients with the age range from 20 to 60 years. For the local anaesthesia we injected 2% Xylocain into posterior fornix. The cysts fluid volumes were between 40 and 140 ml. In our study 176 patients were punctured without replacement with 96% alcohol. After three months there were 40 relapses in the group of patients without replacement with alcohol, i.e. 22.70%. In the group of 120 patients with alcohol sclerosis, relapse appeared in 6 cases (5.00%) where the volumes of cysts were above 100 ml. Five of the patients had very intensive pelvic pain but we treated them conservatively with analgesics. No menstrual disturbance was noticed in any patient.
Technique of puncture is simple and easy performed. Method of treating with 96% alcohol showed good results. Cyst volume higher than 100 ml is better to be treated surgically, by laparoscopy or laparotomy.
Dr David Deakin
Christie Hospital, Manchester, England, United Kingdom
The rarity of soft tissue sarcoma (STS) and the multiplicity of presenting sites leads to difficulty in diagnosis, assessment and the formulation of a treatment strategy. A case can be made for patients with STS to be referred to a specialist team at an early stage.
Surgery remains the main stage of treatment for localised disease. Increasingly limb sparing operations such as compartmental resections are performed. If the excision is inadequate, further surgery should be performed if possible; otherwise radiotherapy should be offered. In a series of 47 consecutive patients treated with radiotherapy at the Christie Hospital for incomplete tumour resections 15 patients developed local recurrence. In 11 patients this was combined with distant metastases.
A meta-analysis of the value of adjuvant chemotherapy for localised STS shows a benefit of 6%, 10% and 10% for local relapse free survival, distant relapse free survival and overall recurrence free survival respectively at 10 years. For overall survival a 4% benefit of 10 years was not statistically significant. Adjuvant chemotherapy for STS should only be performed in the context of a controlled clinical trial.
Chemotherapy for metastatic disease is disappointing and again randomised clinical trial evidence is required wherever possible.
Orlić, University of Zagreb, Scholl of Medicine, Department
of Orthopaedic Surgery
Limb sparing is a great challenge in contemporary oncology, because the reconstructions of skeleton are performed in the patients with the most aggressive bone sarcomas. Between 25.120 operative procedures performed during the 14 years period, there was the large group of 1011 patients with bone tumors and tumors like lesions. The true incidence of tumors between all operative procedures is 4.02%.
From 1987 to 1997 at the Department of Orthopaedic Surgery, School of Medicine, University of Zagreb, special modular uncemented mega - endoprosthesis were implanted in 43 patients following “en bloc” resection. Since 1987 the number of operation is slowly increasing except during the war in 1992 and 1993. Indications for the “en bloc” resection and reconstruction with a special mega - endoprosthesis were: active and aggressive benign or all types of malignant bone tumors, tumors like lesions, massive destruction of the proximal femur after severe war injuries or instability of standard hip endoprosthesis. There were 27 bone sarcomas. Osteosarcoma was resected in 12 patients, Ewing sarcoma and chondrosarcoma in 6, fibrosarcoma, synovisarcoma and periosteal osteosarcoma in 1 patient. Among the treated patients, 21 (49%) were females and 22 (51%) males with different incidence of age groupsd. Salvage surgery of the hip joint was performed in 22 (51%) and that of the knee joint in 21 (48%) patients. “En bloc” resection and salvage surgery of the knee joint for the destruction of the distal femoral region and that of the proximal tibia were done in 14 and 7 patients respectively.
The treatment results were analysed with special attention paid to the incidence of revision surgery to be performed after salvage procedures. Out of 43 patients reoperation was done in 14 (32.6%). By means of rebiopsy, local recurrence of malignant bone tumor was established in 6 patients. Reoperation for technical complications was done in three patients, infection was registered in three patients, and luxation of endoprothesis in two. Out of 43 controlled patients with modular mega - endoprosthesis, 5 died from malignant tumor.
The treatment results obtained in our patients with bone sarcoma when the modular uncemented mega - endoprosthesis was performed, point out a good results. The annual incidence of osteosarcoma in the Republic of Croatia is 0.103 cases per 100 000 inhabitants; of Ewing sarcoma incidence is 0.055; and of chondrosarcoma 0.046 cases.
Dr Roger James
Christie Hospital Manchester
A number of new trials have enabled us to increase response rate in colorectal cancer up to 50%.
A new trial launched in the United Kingdom in September, will compare two drugs Oxaliplatin and Irinotecan.
With regard to rectal cancer, three new trials in Europe are assessing the importance of pre and post operative radiotherapy.
In addition advances in surgery have altered recurrence rates for rectal cancer.
F. Šantek, L. Markulin-Grgić, N. Šarić
Fluorouracil (FU) is one of the most frequently used chemotherapeutic agents, not only for colorectal carcinoma, then also for others carcinomas.
It is a pyrimidine antimetabolite but the way of its activity is not completely known.
It can be used either as a “bolus” intravenous injection or as continuos infusion. There is some doubt about diversity of its mechanism of action dependently on the dose schedule used.
FU can be also successfully combined with other agents, such as leucovorin, methotrexate, or some new active agents (Oxaliplatin etc.).
Beside that, when the 5-FU is given via the hepatic artery, patients tolerate two to three times the intravenous dose, and the responses in colorectal metastases to the liver are doubled.
Therefore is not surprising that there is a lot of currently protocols for its use, and some of them will be briefly presented in this review.
Dr Alan Stewart
Christie Hospital Manchester
Conservative surgery followed by radical radiotherapy to the breast has now been widely accepted as optimal treatment for many patients with early breast cancer. Numerous trials in carefully selected women and with prolonged follow-up have demonstrated local control rates identical to mastectomy with better cosmetic results and improved quality of life.
Little attention has been paid however to determine the optimal dose and fractionation to be used for these patients. Surveys of “routine practice” both in the UK and North America have shown wide ranges of dose/fractionation in use. In addition radiobiological advice has been to use fraction sizes of less than 2 Gy with extended overall time to achieve good results. There are no large randomised phase III trials reported to address this question.
The Christie Hospital has used a tumour dose of 40 Gy in 15 fractions (fraction size 2.67 Gy) for many years to treat early breast cancer. We have analyzed results from a large cohort of patients treated over a 4 year period with long term follow-up. The probability of recurrence in the breast at 5 years is 6.7%, which compares favorably with series reporting higher overall doses. Further results from this analysis and details of cosmesis will be discussed.
We are now participating in a large multicentre prospective study to compare the 2 most commonly used dose/fractionation schedules in the UK to provide further information on optimal treatment for early breast cancer.
Stjepan Gamulin and Jasminka
Jakić Razumović from departments of Pathophysiolpgy and Pathology Clinical
Hospital Centre and University School of Medicine Zagreb
We have studied the correlation of two methods (immunohistology and ELISA in cytosol) of cathepsin D (CD) determination in breast cancer tissue. CD expression in tumor cells and tumor tissue macrophages was determined by standard immunohistochemistry using an anti-cathepsin D mouse monoclonal antibody in tumor tissue specimens derived from 56 patients. CD concentrations were measured by an ELISA method in cytosol prepared from the same tumors. CD positivity was correlated with tumor size, hystologycal grade and cytosol estrogen and progesterone receptor concentrations. There was no statistically significant correlation between examined parameters and either CD positivity by immunohistochemistry or cytosol CD concentration. The correlation between CD expression in tumor cells by imunohistochemistry and cytosol CD concentration was not found either. However, there was a significant association between abundance of CD positive macrophages and cytosol CD concentration. CD positive macrophages were abundant in most of cytosol CD positive specimens.
These results suggest that breast cancer cytosol CD concentration is the cumulative result of CD content in both carcinoma cells and stromal macrophages.
We have also analysed the relationship of the immunohistochemical expression of c-erbB-2 oncoprotein and various established prognostic factors such as tumor size, axillary node status, oestrogen and progesterone receptor status, DNA ploidy, proliferation index, cathepsin D expression and histological grade in 93 ductal invasive breast carcinoma specimens. The expression of c-erbB-2 shown by immunohistochemical intense membrane staining was found in 49 (52.7%) of tumors. Cathepsin D positive cytoplasmic granular staining and positive stromal macrophages were found in 60 (64.5%) and 72 (77.4%) tumors respectively. Univariate analysis showed that overall survival correlated significantly with axillary lymph node involvement and expression of oestrogen and progesterone receptors status separately for each of the receptors and for their coexpression and only marginally for c-erbB-2 overexpression. In multivariate analysis only axillary lymph node metastases and coexpression of oestrogen and progesterone receptors were found to be independent and significant prognostic factors.
However when the patients were stratified according to c-erbB-2 expression it was shown that the patients with c-erbB-2 overexpression and grade II tumors, tumor size grater than 2 cm in diameter, high content of aneuploid cells and the presence of cathepisin D positive stromal macrophages had shorter long term survival than the c-erbB-2 negative patients. These results pointed out that C-erbB-2 overexpression divides grade II tumor patients into prognostically two different groups.
Podolski P, Mrsić M, Budišić
Z, Grgić M, Jakić J, Markulin-Grgić L.
Clinical Hospital Centre Rebro, Zagreb
HER 2 receptor overexpression is observed in 25-30% of breast cancers and predicts worse prognosis in patients with positive lymph nodes and metastatic disease. Since HER 2 plays a role in breast cancer pathogenesis and more aggressive behaviour, it has been proposed as a target for therapeutic antibody.
Preclinical studies demonstrated that highly specific murine monoclonal antibodies generated to bind to the extracellular domain of HER 2, should have a role in the treatment of the metastatic breast cancer (MBC), not only as monotherapy but also in the combination with chemotherapy.
Based on this data, the recombinant humanised anti-HER 2 antibody trastuzumab (HerceptinŇ ) was evaluated in human clinical trials, as a new treatment option for the women with MBC who have tumours that overexpress HER 2.
A phase I clinical trials determined that trastuzumab is safe and has a dose-dependent pharmacokinetics. A phase II studies, evaluating trastuzumab in refractory MBC, reported excellent tolerability and response rate up to 20%. Results of a multinational, randomised phase III clinical trial combining trastuzumab and front-line chemotherapy for MBC, demonstrated that trastuzumab prolonged time to progression, overall response rate and overall survival duration.
In the beginning of 1999, at our Centre, we have started introducing HerceptinŇ in our treatment regimens for women with relapsed MBC. To date, 17 patients have received HerceptinŇ as monotherapy, or in combination with non-antracycline chemotherapy.
All of them had been heavily pretreated before for metastatic disease, with two or more chemotherapeutic regimens. A majority of the patients had a high disease burden, 12 (71%) with dominant visceral metastatic disease. HER 2 overexpression was determined by immunohistochemistry, in all the patients.
Three women received HerceptinŇ alone, eleven HerceptinŇ , and TaxolŇ , and three HerceptinŇ and some of other non-antracyclines (cisplatin, gemcitabine). In all the patients, HerceptinŇ was administered as an i.v. 4 mg/kg loading dose followed by i.v. 2 mg/kg per week. Cisplatin 75 mg/m2 and gemcitabine 800 mg/m2 were given every 3 weeks, and Taxol Ň 90 mg/m2 on weekly schedule.
There were confirmed 6 partial responses (5 in HerceptinŇ + TaxolŇ group and 1 in HerceptinŇ alone), 3 stable diseases and 2 diseases progressions. Six patients in HerceptinŇ + TaxolŇ group haven’t completed therapy yet. Grade 3-4 neutropenia was observed in 2 patients. Other G 3 toxicities that have been noted are peripheral neuropathy in 3, diarrhoea in 4 and oncholysis in 1 patient. Serial heart ultrasound showed no significant decline in LVEF.
According to our preliminary experience HerceptinŇ therapy showed promising results and acceptable toxicity in women with heavily pretreated MBC.
Tanja Čufer, MD,PhD
The theoretical prediction that breast cancer is a systemic disease
and that patients may benefit from addition of systemic therapy to local
treatment, has now been confirmed by three decades of clinical investigations.
A long-term follow up of individual trials and the International Overview
(1,2,3) based on meta-analyses, clearly showed the potential of both, hormonal
therapies with tamoxifen and/or ovarian ablation and chemotherapy (the
most well represented polychemotherapy was CMF: cyclophosphamide, methotrexate
and 5-fluorouracil) to prolong disease-free and overall survival in nearly
all groups of patients. The benefits being equally shared among premenopausal
and postmenopausal patients, with node-negative and node-positive disease.
However, there is still a lot of uncertainty regarding the most appropriate
treatment for each individual patient. Although the seminal trials and
meta-analysis (1,2,4) confirmed that five years of tamoxifen is better
than one or two years, the optimal duration of tamoxifen therapy has not
been defined yet. In an attempt to increase the efficacy of adjuvant therapy
anthracyclines, which are considered to be the most effective drugs for
metastatic disease, were introduced into adjuvant therapy. Despite some
encouraging results the role of anthracyclines in adjuvant setting remains
controversial. They seem to be more effective than CMF, if used in proper
dose (5). In addition to the proper dose used the results can be further
improved by different scheduling of the drugs, such as the sequential application
of different drugs which allows for high-dose density of each individual
drug. There are some new promising data showing that the sequential use
of non-cross resistant drugs, such as anthracyclines and taxoids (6), may
improve the results of adjuvant treatment. The role of combined chemohormonal
therapy in the adjuvant therapy of breast cancer has been an continuing
issue of debate, however the results of same individual studies (7,8,9)
as well as International Overview already showed that in both pre and postmenopausal
patients with positive hormonal receptors, sequential treatment with chemotherapy
and tamoxifen is better than tamoxifen or chemotherapy alone. There are
also some new promising strategies such as high-dose chemotherapy with
stem cell support and inclusion of biologics and vaccines into adjuvant
therapy, the value of which remains to be confirmed. Future possibilities
opened by inclusion of biologics into adjuvant therapy are discussed.
SANYKO - LEDERLE-WYEHT
ALFA MEDI TRADE